−Removed: We are a biopharmaceutical company focused on discovering and developing novel small molecule therapeutics that selectively degrade disease-causing proteins by harnessing the body’s own natural protein degradation system.
−Removed: Our proprietary targeted protein degradation, or TPD, platform, which we refer to as Pegasus, allows us to discover highly selective small molecule protein degraders with activity against disease-causing proteins throughout the body.
−Removed: We believe that our small molecule protein degraders have unique advantages over existing therapies and allow us to address a large portion of the human genome that was previously intractable with traditional modalities.
−Removed: We focus on biological pathways that have been clinically validated but where key biological nodes/proteins have not been drugged or are inadequately drugged.
−Removed: To date, we have utilized our Pegasus platform to design novel protein degraders focused in the areas of immunology-inflammation and oncology, and we continue to apply our platform’s capabilities to additional therapeutic areas.
−Removed: We have a mission to drug all target classes in human cells using TPD.
−Removed: Our current clinical stage programs are IRAK4, STAT3, and MDM2, which each address high impact targets within biologically-proven pathways, providing the opportunity to treat a broad range of immuno-inflammatory diseases, hematologic malignancies, and/or solid tumors.
−Removed: Our programs exemplify our focus on addressing high impact targets that have been elusive to conventional modalities and that drive the pathogenesis of multiple serious diseases with significant unmet medical needs.
−Removed: Our disclosed preclinical programs target STAT6 and TYK2, two proteins in well-validated pathways where we believe our degrader technology has the potential to offer unique advantages as compared to competing therapies.
−Removed: Both programs are currently in IND-enabling studies.
−Removed: With respect to our IRAK4 program, we are collaborating with Sanofi S.A, or Sanofi, on the development of drug candidates targeting IRAK4 outside the oncology and immuno-oncology fields.
−Removed: We are developing KT-474, a highly active and selective, orally bioavailable IRAK4 degrader, for the treatment of interleukin-1 receptor/toll-like receptor or IL-1R/TLR-driven immunology-inflammation conditions and diseases with high unmet medical need, including hidradenitis suppurativa, or HS, an inflammatory skin disease, as well as atopic dermatitis, or AD, and potentially other indications.
−Removed: We have completed our Phase 1 trial of KT-474, which included cohorts of healthy volunteers, as well as patients with HS and AD.
−Removed: Phase 2 clinical trials of KT-474, conducted by Sanofi, are initially investigating its potential in HS and AD.
−Removed: The clinical trials for both indications have been initiated, and patient dosing is ongoing.
−Removed: With respect to our clinical oncology programs, we are evaluating KT-333, a STAT3 degrader, in a Phase 1 clinical trial in patients with relapsed/refractory liquid and solid tumors, including aggressive lymphomas.
−Removed: Patient enrollment and dosing are ongoing in the Phase 1a portion of the trial, and we expect to present additional clinical data in 2024.
−Removed: In September 2023, we announced that the FDA, granted KT-333 Fast Track Designation for the treatment of relapsed/refractory peripheral T cell lymphoma, an indication for which we have previously received Orphan Drug Designation.
−Removed: Our Phase 1 clinical trial of KT-253, our MDM2 degrader, was initiated in March 2023.
−Removed: The study is evaluating the safety, tolerability, pharmacokinetics/pharmacodynamics, and clinical activity of ascending doses of KT-253 in adult patients with relapsed or refractory high grade myeloid malignancies, acute lymphocytic leukemia, or ALL, lymphomas, and solid tumors.
−Removed: Patient enrollment and dosing are ongoing in the Phase 1a portion of the trial, and we provided initial safety, proof-of-mechanism and proof-of-concept data in November of 2023.
−Removed: We expect to present additional clinical data in 2024.
−Removed: In June 2023, KT-253 was granted orphan drug designation by the FDA for the treatment of acute myeloid leukemia.
−Removed: In November 2023, we announced the decision to discontinue the development of our KT-413 (IRAKIMiD) program, despite reaching expected degradation levels and a lack of dose-limiting toxicities, in order to focus resources to support our growing immunology pipeline.
−Removed: Our mission is to discover, develop and commercialize novel and transformative therapies that improve the lives of patients with serious diseases.
−Removed: We have a unique target selection strategy that is focused on undrugged/inadequately drugged targets where targeted protein degradation (TPD) is the only or best unlocking drug modality.
−Removed: Our first in class programs target proteins that have strong genetics and clinical pathway validation and serve areas with large clinical and commercial opportunities.
−Removed: TPD is a disease-agnostic technology, and we are currently advancing this modality across several disease areas, with a primary focus in immunology as well as selected key therapeutic targets in oncology.
−Removed: Our goal is to leverage our leading capabilities in TPD and to become a fully integrated biopharmaceutical company with a pipeline of novel degrader medicines.
−Removed: We intend to achieve this goal by pursuing the following strategic objectives:
−Removed: • Advance our existing clinical pipeline .
−Removed: We have advanced four programs into human clinic testing, including our current ongoing clinical stage programs which target IRAK4, STAT3 and MDM2.
−Removed: We believe these programs have the potential to treat multiple immuno-inflammatory and/or oncology indications.
−Removed: Our clinical pipeline is consistent with our target selection strategy that focuses on undrugged or inadequately drugged targets in validated pathways.
−Removed: • Build a broad and diverse pipeline of novel protein degraders .
−Removed: Guided by our drug development principles, innovative platform capabilities, and the learnings from our clinical-stage programs, we continue to identify therapeutic targets that have disruptive therapeutic potential and are well-suited for a TPD approach.
−Removed: Our two most advanced pre-clinical programs, STAT6 and TYK2, reflect our increased pipeline focus on immunology.
−Removed: These programs target significant and well-validated opportunities in which we believe our technology has the potential to deliver biologic-like activity with the convenience of an oral pill.
−Removed: • Expand and protect our proprietary know-how and intellectual property .
−Removed: We have developed a broad patent estate protecting our intellectual property, which we intend to expand to further protect the drug candidates we develop and our platform.
−Removed: Our intellectual property includes proprietary know-how as well as a broad series of patents.
−Removed: • Pursue synergistic collaboration opportunities .
−Removed: To further our goal of delivering transformative therapies to the broadest patient populations, we intend to become a fully integrated biopharmaceutical company.
−Removed: In addition to our ongoing collaboration with Sanofi, we expect to leverage additional strategic partnerships that can contribute complementary capabilities in discovery, development and commercialization in disease areas both within and outside of our core areas of therapeutic focus.
−Removed: • Build our organizational capabilities .
−Removed: We continue to build capabilities across our organization, including expertise in key therapeutic areas and functions.
−Removed: We view these capabilities as a strategic advantage, and as critical to our objective to become a fully-integrated biotechnology company.
−Removed: Background of Targeted Protein Degradation
−Removed: Proteins are responsible for the structure, function and regulation of tissues and organs.
−Removed: Cells in the body continuously synthesize and degrade proteins, maintaining an equilibrium called protein homeostasis.
−Removed: Most diseases are the result of aberrant protein behavior driven by activation, mutation, or downregulation of the protein itself, or by the gene responsible for the transcription and translation of that particular protein.
−Removed: With a deepened molecular understanding of various diseases and the characterization of the full human genome, research efforts have increasingly focused on the development of medicines to address malfunctioning proteins responsible for oncologic, auto-immune, cardio-metabolic, neurodegenerative, and rare genetic diseases.
−Removed: The ‘druggable’ genome challenge
−Removed: Several therapeutic modalities have been developed over the years to address aberrant protein activity.
−Removed: These have included small molecule inhibitors of protein function, therapeutic antibodies, oligo-based therapeutics such as RNA interference therapeutics, antisense oligonucleotides, or ASO, and other genetic therapies.
−Removed: Some of these modalities have had a tremendous impact on the treatment of diseases and quality of life of patients, and several others, while earlier stage, offer potential.
−Removed: However, these traditional modalities face specific challenges that limit their therapeutic impact and reach.
−Removed: Some of the limitations of existing modalities include the following:
−Removed: • Traditional small molecule therapeutics are unable to block the function of proteins without a catalytic or substrate binding site and cannot block proteins with dual function, as such are not effective against transcription factors, scaffolding and adaptor proteins, many of which play a key role in certain diseases.
−Removed: • Therapeutic antibodies are generally too large to penetrate cells and are therefore typically limited to protein targets that are extracellular, or outside of the cell, whereas most proteins are inside the cell.
−Removed: They also have to be dosed parenterally and can be costly and complex to develop and manufacture.
−Removed: • Oligo-based therapeutics are capable of drugging proteins elusive to small molecules in some cases but have significant drug delivery challenges with dosing and in achieving systemic distribution, greatly limiting the breadth of diseases they are able to address effectively.
−Removed: These therapeutics can also be costly and complex to develop and manufacture.
−Removed: As a result of these limitations, we believe that only 20% of the full human genome has been effectively drugged to date.
−Removed: New therapeutic modalities which can overcome some of these challenges are necessary to expand the drugged proteome/genome and provide new efficacious medicines to patients in need.
−Removed: We believe that TPD is such a modality.
−Removed: Targeted Protein Degradation
−Removed: One of the methods that cells use to control the balance between the synthesis of new proteins and the degradation and disposal of damaged and/or misfolded proteins, is ubiquitin-proteasome system, or UPS.
−Removed: The discovery of ubiquitin-mediated protein degradation provided important insights into specific processes like cellular division and DNA repair and led to the discovery of UPS’ critical roles in various cellular pathways, including the cell cycle, signaling pathways, the regulation of gene expression, and responses to oxidative stress.
−Removed: The discovery of the UPS also revealed a new modality to harness this cellular process for the treatment of diseases.
−Removed: As shown below in figure 1, the UPS comprises a series of finely orchestrated enzymatic sequences that ultimately lead to protein polyubiquitination and degradation by the proteasome in cells.
−Removed: Protein ubiquitination is a cellular process involving an enzymatic cascade consisting of ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin-protein ligases (E3).
−Removed: In humans, there are two classes of ubiquitin activating E1 enzymes, more than 30 E2 enzymes, and approximately 600 E3 ligases.
−Removed: The E3/E2/ubiquitin ligase complex (shown in blue) binds to a substrate protein (shown in orange) to mediate the transfer of ubiquitin, which leads to degradation of the target protein through the proteasome.
−Removed: Targeted protein degradation is a new modality that co-opts this innate cellular process.
−Removed: The core of the TPD modality consists of a small molecule that we refer to as a heterobifunctional degrader.
−Removed: The role of this heterobifunctional degrader molecule is to mediate a “new” interaction through the formation of a ternary complex between a disease-causing protein and an E3 ligase.
−Removed: The E3 liaise tags the protein target for degradation by attaching a series of ubiquitin, and the proteasome recognizes the tagged protein and degrades it into small peptides .
−Removed: Forming an efficient ternary complex, as shown in step 2 in the figure below, is a critical step in TPD, and its formation, function, and effect on cellular and in vivo systems is vital to the success of the degradation and its impact on disease.
−Removed: In addition, the degrader molecule needs to be able to effect degradation in a variety of different cell types and contexts and have the right pharmaceutical properties to be therapeutically dosed to patients.
−Removed: As shown in step 3 and step 4 in the figure below, after the degrader facilitates the ubiquitination of the target protein, and as the protein is degraded by the proteasome, the molecule separates from the protein, and is able to form another ternary complex to conduct the degradation process again.
−Removed: This iterative mechanism is catalytic, which results in increased potency even at lower concentrations, another key differentiator from other modalities such as small molecule inhibitors and therapeutic antibodies.
−Removed: Due to the unique advantages of TPD, this transformative modality is capable of targeting proteins traditionally undrugged by small molecules.
−Removed: Specifically, TPD can target proteins without a catalytic function such as scaffolding proteins and transcription factors, with small molecule-like drug properties that can potentially be dosed orally and distributed systemically unlike oligo-based therapeutics such as RNAi’s.
−Removed: TPD molecules also are amenable to existing small molecule manufacturing principles which are less costly than other therapeutic modalities.
−Removed: Because of the catalytic nature of the degradation process, we believe the modality has the potential to be therapeutically effective with smaller amounts of drug substance and less frequent dosing than traditional therapeutics.
−Removed: The use of small molecules to affect protein homeostasis has been clinically and commercially validated by multiple drugs over the past two decades.
−Removed: Drugs such as bortezomib and fulvestrant have been understood to inhibit the proteasome and target the estrogen receptor for proteasome-dependent degradation, respectively.
−Removed: More recently, immunomodulatory imide drugs such as lenalidomide and pomalidomide have been understood on a post-hoc basis to direct the degradation of a series of transcription factors via the UPS.
−Removed: These immunomodulatory drugs have validated the concept of using the UPS to degrade proteins and elicit a pharmacological and therapeutic effect in disease settings.
−Removed: However, unlike earlier approaches in this field, TPD takes this proven concept further to prospectively target the degradation of a wider range of proteins through the rational design of heterobifunctional degraders which coordinate the discreet binding of target proteins and E3 ligases to drive the desired protein degradation.
−Removed: An important factor for the efficiency of a degrader is the specificity and affinity to the targeted E3 ligase.
−Removed: The various E3 ligases have different distribution and cellular localization profiles that are important factors when considering which E3 ligase to use for a particular disease protein target.
−Removed: There are approximately 600 E3 ligases that occur in nature, but to date only a handful of these E3 ligases have been evaluated for therapeutic purposes, leaving a substantial portion of the genome available for targeting.
−Removed: Our Pegasus TM Platform
−Removed: Our proprietary drug discovery platform, called Pegasus, enables us to rationally design targeted protein degraders that have the potential to drug all target classes in the cell.
−Removed: Our approach is rooted in an understanding of the relationship between E3 ubiquitin ligases and target proteins, which allows us to identify the properties that make a target both ligandable and degradable, and determine how multiple factors impact potency, selectivity, pharmacokinetics (PK) and pharmacodynamics (PD).
−Removed: We have built extensive capabilities and knowledge that contributes to the development of our preclinical and clinical pipeline.
−Removed: Our proprietary chemistry expertise enables the design and optimization of both E3 ligase and target protein binders, with artificial intelligence (AI) enabled insights, allowing for the opportunity to design of targeted protein degraders with optimal pharmaceutical properties.
−Removed: Additionally, we utilize our E3 ligase Whole-Body Atlas includes the expression profiles of approximately 600 unique E3 ligases.
−Removed: Using this Atlas, we are able to match target proteins with appropriate E3 ubiquitin ligases based on expression, distribution, intracellular localization and biology, a process that is enabled with our machine learning-based algorithms.
−Removed: We continue to utilize our Quantitative System Pharmacology Model, which measures and predicts a diverse set of parameters that impact target protein levels, based on an understanding of PK/PD, both in vitro and in vivo, and across healthy and diseased tissues and cell types.
−Removed: We have also focused on identifying novel tissue restricted or selective E3 ligases, beyond traditional cereblon/IMiD interactions, that enable the design of molecules that target both undrugged and un-ligandable proteins through small molecule interactions.
−Removed: Our Therapeutic Pipeline
−Removed: Our pipeline includes immunology and oncology programs in various stages of clinical and preclinical development.
−Removed: Our immunology programs include IRAK4, STAT6 and TYK2.
−Removed: Our oncology pipeline includes STAT3 and MDM2.
−Removed: We also have multiple programs in earlier stages of development, not depicted here, and are exploring targets in therapeutic areas outside of oncology and immunology.
−Removed: The following table summarizes our publicly-disclosed clinical and near-term clinical stage pipeline.
−Removed: 1 KT-474 (SAR444656) partnered with Sanofi, with Kymera option to participate in the development and commercialization, and 50/50 profit split, in the United States.
−Removed: Double digit tiered royalties in ROW;
−Removed: 2 Current indications:
−Removed: Other diseases shown, where IL-1R/TLR pathway has been implicated in pathogenesis, are additional potential opportunities;
−Removed: 3 Assessment of STAT3 I/I opportunity is ongoing.
−Removed: Our Immunology programs:
−Removed: IRAK4, STAT6 and TYK2
−Removed: We are developing KT-474, a highly active and selective, orally bioavailable IRAK4 degrader, for the treatment of IL-1R/TLR-driven immunology-inflammation conditions and diseases with high unmet medical need.
−Removed: The initial indications being pursued include HS and AD.
−Removed: We have chosen to pursue IRAK4 degradation due to the well-validated role of the IL-1R/TLR pathway in immunology and inflammation and the potential advantage that drugging a single node of multiple different mediators of inflammation has over other approaches focused on targeting one of many cytokines that stimulate the IRAK4 node.
−Removed: IRAK4 is a critical node in the IL-1R/TLR signaling pathway, which is dependent on both IRAK4’s kinase activity and scaffolding function.
−Removed: We have observed through our in vitro and in vivo studies that KT-474 induces IRAK4 degradation, impacting both the kinase and the scaffolding functions, and therefore can efficiently and selectively block IL-1R/TLR-mediated inflammation in a way we believe to be superior to IRAK4 kinase inhibitors.
−Removed: We therefore believe KT-474 has the potential to improve outcomes over current treatment options as well as other drugs currently in development.
−Removed: We are collaborating with Sanofi on the development of drug candidates targeting IRAK4 outside of oncology and immuno-oncology fields.
−Removed: Sanofi recently advanced KT-474 into two Phase 2 clinical trials in patients with HS and AD, and the first patients were dosed in each trial in the fourth quarter of 2023.
−Removed: See the section entitled “Business— Collaborations—Collaboration Agreement with Sanofi" appearing elsewhere in this Annual Report for more information.
−Removed: We are developing degraders that target STAT6, an essential transcription factor specific to the IL-4/IL-13 signaling pathway and the central driver of Type 2 inflammation in allergic diseases.
−Removed: STAT6 is a genetically validated target and we believe the pathway has been clinically validated by approved IL-4/IL-13-targeting biologics, such as dupilumab.
−Removed: In preclinical studies, KT-621, our first-in-class oral STAT6 degrader, demonstrated full inhibition of the IL-4/IL-13 pathway in all relevant human cell contexts evaluated with strong picomolar potency similar or superior to pathway biologics such as dupilumab.
−Removed: KT-621 also demonstrated strong activity in multiple preclinical efficacy studies.
−Removed: In addition, at low oral doses, KT-621 demonstrated nearly full in vivo STAT6 degradation and was well-tolerated in multiple preclinical toxicity studies.
−Removed: KT-621 has been developed as a once daily oral small molecule degrader which we believe has the potential to have broad activity across multiple diseases, which may include atopic dermatitis, asthma, chronic obstructive pulmonary disorder, eosinophilic esophagitis and chronic rhinosinusitis with nasal polyps, among others.
−Removed: We expect to initiate a Phase 1 clinical trial in the second half of 2024.
−Removed: We are developing degraders that target TYK2, a member of the Janus Kinase or JAK family required for Type I interferon or IFN, interleulin-12, or IL-12 and interleulin-23, or IL-23 signaling.
−Removed: TYK2 is a genetically- and clinically-validated target in autoimmune and inflammatory diseases.
−Removed: TYK2 has a well-established scaffolding function that plays a key role in cytokine receptor surface expression and activation.
−Removed: In preclinical studies, KT-294, our first-in-class oral TYK2 degrader, demonstrated picomolar to nanomolar potencies across all relevant human cell contexts evaluated, representing what we believe is the only approach to TYK2 targeting that has the potential to recapitulate the human loss-of-function biology of nearly full pathway inhibition of Type I IFN, IL-12 and IL-23, while also sparing interleukin-10, or IL-10.
−Removed: Degradation of TYK2 has the potential to overcome the challenges of small molecule inhibitors, which have limitations due to lack of selectivity, limited target engagement, and/or lack of potent activity against Type I IFN.
−Removed: KT-294 has been developed as a once daily oral small molecule degrader with a potential biologics-like activity profile, which we believe has the potential to address conditions such as inflammatory bowel disease, psoriasis, psoriatic arthritis and lupus, among others.
−Removed: We expect to initiate a Phase 1 clinical trial in the first half of 2025.
−Removed: Our Oncology programs:
−Removed: STAT3 and MDM2
−Removed: We are developing our selective STAT3 degraders for the treatment of hematological malignancies and solid tumors.
−Removed: We are also exploring the potential for STAT3 degradation in autoimmune diseases.
−Removed: STAT3 is a transcription factor activated through a variety of different cytokine and growth factor receptors via JAKs as well as through oncogenic fusion proteins and mutations in STAT3 itself.
−Removed: We believe the diverse functions of STAT3 in tumor biology, evasion of immune surveillance by tumor cells, and inflammation and fibrosis provide opportunities to address a wide variety of high unmet need disease
−Removed: indications through the targeting of a single genetically and clinically validated pathway.
−Removed: While the JAK-STAT pathway has been partially addressed with several clinically successful JAK-targeting agents, we believe there are currently no drugs that specifically affect STAT3 broadly across all the relevant cell types.
−Removed: Small molecule STAT3 dimerization inhibitors targeting the SH2 domain have been in development, but significant challenges remain:
−Removed: first, homology of SH2 domains among all STAT family members impacts the ability to achieve specificity for STAT3, and second, inability to block dimerization independent transcriptional activities of STAT3.
−Removed: For these reasons, we believe that STAT3 degraders may provide a transformative solution to the development of targeted and selective drugs to address multiple STAT3 dependent pathologies.
−Removed: We are currently evaluating our STAT3 degrader, KT-333, in a Phase 1 clinical trial in patients with relapsed/refractory liquid and solid tumors, including aggressive lymphomas.
−Removed: Patient enrollment and dosing are ongoing in the Phase 1a dose escalation portion of the trial, and we expect to provide additional clinical data in 2024.
−Removed: We are developing degraders that target MDM2 for the treatment of solid tumors and hematological malignancies.
−Removed: MDM2 is the crucial regulator of the most common tumor suppressor, p53, which remains intact (or wild type) in close to 50% of cancers.
−Removed: Unlike small molecule inhibitors, our MDM2 degrader, KT-253, has been shown preclinically to have the ability to overcome the MDM2 feedback loop and rapidly induce apoptosis, even with brief exposures.
−Removed: We initiated a Phase 1 clinical trial of KT-253 in May 2023, which is designed to evaluate the safety, tolerability, PK/PD and clinical activity in adult patients with liquid and solid tumors.
−Removed: Patient enrollment and dosing are ongoing in the Phase 1a dose escalation portion of the trial, and we expect to provide additional clinical data in 2024.
−Removed: Our Approach to Target Selection
−Removed: To realize on the promise of TPD, we have taken a unique and differentiated approach to target selection, which has several key tenets that guide our research and development efforts, as seen in Figure 3.
−Removed: We focus on undrugged or inadequately drugged targets, such as transcription factors and scaffolding proteins, within pathways with clear clinical validation and validation through human genetics/causal biology.
−Removed: We identify targets where TPD is the best or the only solution, with a strong degrader rationale and line of sight to demonstrating superiority of our modality over existing drugs within these pathways.
−Removed: Additionally, we focus on areas of significant patient need and large commercial opportunities.
−Removed: Clinical Immunology:
−Removed: We are developing KT-474, a highly active and selective, orally bioavailable IRAK4 degrader, for the treatment of IL-1R/TLR-driven immuno-inflammatory conditions and diseases with high unmet medical need, including HS, AD and others.
−Removed: We have chosen to pursue IRAK4 degradation due to the well-validated role of the IL-1R/TLR pathway in immunology and inflammation and the potential advantage that drugging a single node of multiple different mediators of inflammation has over other approaches focused on targeting one of many cytokines that stimulate the IRAK4 node.
−Removed: IRAK4 is a critical node in the IL-1R/TLR signaling pathway, which is dependent on both IRAK4’s kinase activity and scaffolding function.
−Removed: We have observed through our in vitro and in vivo studies that KT-474 induces IRAK4 degradation, impacting both the kinase and the scaffolding functions, and therefore can selectively block IL-1R/TLR-mediated inflammation in a way we believe to be superior to IRAK4 kinase inhibitors.
−Removed: We therefore believe KT-474 has the potential to improve outcomes over current treatment options as well as other drugs currently in development.
−Removed: The KT-474 Phase 1 trial, which included healthy volunteers and HS and AD patients, was completed in October 2022.
+Added: We are a clinical-stage biopharmaceutical company dedicated to reinventing the treatment of human disease through the development of innovative, highly differentiated medicines that address significant health problems and that meaningfully improve patients’ lives.
+Added: We are committed to advancing novel technologies to address targets that have known disease-causing biology, but which have not been drugged, or have been inadequately drugged, often based on limitations of existing technologies.
+Added: Our approach is intended to discover and develop a new generation of medicines in a disease-agnostic manner.
+Added: We are a leader in targeted protein degradation, or TPD, a next-generation small molecule therapeutic modality that engages the body’s natural cellular recycling system to selectively eliminate disease-causing proteins.
+Added: Our objective is to develop molecules that are both potent and highly selective, creating the potential for our medicines to uniquely address diseases that are poorly served by current treatment options.
+Added: To date, we have progressed five programs into clinical development and expect to advance at least one new molecular entity into clinical testing annually.
+Added: We intend to leverage our drug development expertise to become a fully integrated biopharmaceutical company with an industry-leading pipeline of novel medicines.
+Added: Our current focus is primarily directed at high-value targets in immunology.
+Added: We believe there are more than 160 million patients in the United States, Europe and Japan that are diagnosed with some of the most prevalent immune-inflammatory diseases that our programs are designed to address, nearly half of whom remain untreated.
+Added: Of those treated, most patients are treated with therapies that do not treat the underlying diseases but mostly their symptoms.
+Added: As a result, only a small percentage of patients, which we believe to be approximately 3% of the diagnosed population with severe inflammatory diseases, are currently treated with systemic advanced therapies, mostly injectable biologics.
+Added: While generally efficacious, biologics have drawbacks.
+Added: Biologics tend to be more expensive to manufacture, and the cost is typically passed on to patients and payors.
+Added: Patient access to therapy can also be a challenge, as biologics are more complex to prescribe and reimburse than small molecule medicines.
+Added: Additionally, biologics are administered as injections, a less preferred route of administration for patients as compared to oral medications, which offer greater flexibility for patients.
+Added: We believe we have the potential to deliver a compelling value proposition to a significant underserved patient population:
+Added: small molecule medicines with biologics-like activity through the convenience of oral administration of a pill.
+Added: Our publicly disclosed immunology programs target STAT6, TYK2 and IRAK4, each of which addresses targets within validated pathways, providing the opportunity to treat a broad range of diseases.
+Added: We are developing KT-621 as part of our STAT6 program, which is currently being evaluated in a Phase 1 clinical trial in healthy volunteers.
+Added: Our lead molecule in our TYK2 program is KT-295, which we anticipate will enter the clinic in the second quarter of 2025.
+Added: We are collaborating with Sanofi S.A., or Sanofi, on the development of drug candidates targeting IRAK4, including KT-474/SAR444656, outside of oncology and immuno-oncology fields.
+Added: Sanofi has initiated two Phase 2b clinical trials of KT-474 in patients with hidradenitis suppurativa (HS) and in patients with atopic dermatitis (AD).
+Added: Our pipeline focuses on addressing high impact targets that have been elusive to conventional modalities and that drive the pathogenesis of multiple serious diseases with significant unmet medical needs.
+Added: In addition to our immunology focus, we also have research initiatives in other therapeutic areas.
+Added: Additionally, we believe many of our key discovery and development capabilities have broad applicability, creating an opportunity for us to develop impactful therapeutics leveraging small-molecule modalities in addition to TPD.
+Added: We intend to achieve our mission to discover and develop novel and transformative medicines that improve the lives of patients with serious diseases by pursuing several key strategic objectives:
+Added: • We plan to advance our existing clinical and preclinical programs through critical inflection points that we believe will de-risk our molecules and approach.
+Added: • Guided by our drug development principles, we intend to expand our therapeutic pipeline by continuing to identify high-value targets that have disruptive therapeutic potential and that are well-suited for our approaches.
+Added: • We will continue to invest in our capabilities to identify novel molecules that address elusive targets and optimize them to highly specific drug candidates in a disease agonistic manner.
+Added: • We have developed a broad patent estate and expect to expand and protect our proprietary know-how and intellectual property.
+Added: • To advance our goal of becoming a fully integrated biopharmaceutical company, we intend to build our organizational capabilities, including expertise in key therapeutic areas, development and eventually commercial functions.
+Added: • We also will continue to consider synergistic collaboration opportunities that further our goal of delivering transformative therapies to the broadest patient populations.
+Added: Drug Discovery Approach and Capabilities
+Added: Our approach to target selection and our proprietary drug discovery capabilities enable us to rationally design innovative medicines that ultimately have the potential to address disease causing proteins of all classes.
+Added: We place significant emphasis on target selection, which is focused on potentially first-in-class or best-in-class opportunities.
+Added: We are focused on deploying our technology against diseases in areas of significant patient need that are not yet meaningfully addressed by traditional medicines, and where we believe TPD is the only or best way to elucidate the desired biology or clinical outcome.
+Added: This approach includes addressing undrugged proteins in nodes of pathways with clinical validation and supported by strong human genetics, many of which are difficult to drug transcription factors or scaffolding proteins.
+Added: After identifying a protein of interest, we use our toolbox of integrated capabilities to help accelerate the discovery and development of small molecule medicines, enabling us to study molecular structures and gain a better understanding of the biological mechanisms of proteins.
+Added: Critical components of our capabilities include the following:
+Added: • A comprehensive hit identification strategy using high-content as well as fit-for-purpose technologies such as DNA encoded libraries and fragment based as well as X-ray based screenings;
+Added: • Machine learning and artificial intelligence in virtual screening, hit validation and optimization technologies;
+Added: • Lead optimization expertise that includes X-ray crystallography, cryogenic electron microscopy, and pharmacokinetic/pharmacodynamic-centric enabled lead optimization;
+Added: • Proprietary global quantitative proteomics techniques;
+Added: • Translational biology focused on patient disease samples.
+Added: Our TPD approach is rooted in a deep understanding of the relationship between E3 ubiquitin ligases and target proteins, which allows us to identify the properties that make a target both ligandable and degradable and to determine how multiple factors impact potency, selectivity, pharmacokinetics (PK) and pharmacodynamics (PD).
+Added: We have built extensive capabilities and knowledge that contribute to the development of our preclinical and clinical pipeline.
+Added: We have generated predictive models that reflect our deep knowledge and understanding of the interplay between targets and drug properties, driving optimization of drug disposition and in vitro and in vivo PK/PD relationships of our compounds across different tissue and cell types.
+Added: Due to its unique advantages, TPD is capable of targeting proteins traditionally undrugged by small molecules.
+Added: Specifically, TPD can target proteins without a catalytic function such as scaffolding proteins and transcription factors, with small molecule-like drug properties that can potentially be dosed orally and distributed systemically, unlike other modalities.
+Added: Because of the catalytic nature of the degradation process, we believe the TPD modality has the potential to be therapeutically effective with smaller amounts of drug substance and less frequent dosing than traditional therapeutics.
+Added: TPD molecules have been shown to be amenable to existing small molecule manufacturing principles which can be less costly than other therapeutic modalities.
+Added: The following table summarizes our disclosed clinical and near-term clinical stage pipeline.
+Added: Our Disclosed Immunology Programs
+Added: STAT6 Program
+Added: We are developing oral medicines that target STAT6, an essential transcription factor specific to the IL-4/IL-13 signaling pathway and the central driver of Type 2 inflammation in allergic and atopic diseases.
+Added: STAT6 is a genetically validated target, and the IL-4/13 pathway has been clinically validated by approved biologics, including dupilumab, an injectable monoclonal antibody designed to treat T Helper 2 (TH2) diseases.
+Added: Background on Pathway and Target
+Added: STAT6 is the essential and specific transcription factor required for IL-4 and IL-13 cytokine-signaling and a central driver of TH2-driven inflammation in atopic and allergic diseases.
+Added: The pathogenic role of STAT6 is supported by human genetics showing that gain of function mutations of STAT6 cause severe early onset allergic diseases in humans.
+Added: Additionally, STAT6 knockout in mice is protective in multiple allergic disease models, and those mice develop normally and are viable and fertile.
+Added: Published research also has demonstrated that a partial loss-of-function variant in STAT6, found in a study of individuals in Iceland, resulted in dampened IL-4 signaling and protection from TH2-driven asthma.
+Added: Development Opportunities
+Added: We estimate that more than 130 million people in the US, Europe and Japan suffer from diseases predominately driven by TH2 inflammation.
+Added: There are existing therapeutics that have validated key pathways across many of these diseases, including atopic dermatitis, asthma, chronic obstructive pulmonary disease, chronic rhinosinusitis with nasal polyps, eosinophilic esophagitis, prurigo nodularis, bullous pemphigoid and others.
+Added: Many of the existing treatments include injectable biologics, some of which have demonstrated strong efficacy, but which can be inconvenient for patients, difficult to reimburse and are costly to manufacture.
+Added: Small molecule inhibitors have also been developed to treat certain TH2-mediated diseases, but often insufficiently block these signaling pathways, limiting their efficacy, and in certain cases may carry various safety risks.
+Added: Based on its preclinical profile, we believe KT-621 has the potential to provide comparable clinical activity to biologics with the convenience of oral dosing and, as a result, the potential to access a broader patient population.
+Added: We believe KT-621 has potential utility in many dermatology and respiratory indications including, but not limited to, atopic dermatitis (AD), asthma, chronic obstructive pulmonary disease (COPD), chronic rhinosinusitis with nasal polyps (CRSwNP), eosinophilic esophagitis (EoE), chronic spontaneous urticaria (CSU) and prurigo nodularis (PN), among others.
+Added: We expect to focus our development strategy in these areas, which have been validated with existing treatments, such as dupilumab, that act to inhibit TH2 cell differentiation.
+Added: We are initially targeting AD, asthma and COPD.
+Added: Atopic Dermatitis
+Added: Atopic dermatitis (AD) is a chronic, pruritic inflammatory skin disease that occurs most frequently in children but also affects adults.
+Added: In the major global markets, the diagnosed prevalence of AD is estimated at 42 million patients, with approximately 60% falling into the moderate-to-severe category.
+Added: AD follows a chronic relapsing course over months to years, with dry skin and severe pruritus as the primary symptoms, sometimes accompanied by skin thickening from chronic scratching and fissuring.
+Added: AD is treated symptomatically with topical therapies, including emollients, corticosteroids, and phosphodiesterase inhibitors.
+Added: The leading FDA-approved systemic treatment is the IL-4Ra targeting antibody dupilumab, which is considered a safe and effective treatment for AD.
+Added: Nonetheless, penetration of existing therapies, including dupilumab, remains low, leaving a significant percentage of patients who are currently underserved.
+Added: Asthma is a chronic lung disease affecting people of all ages.
+Added: It is caused by inflammation and muscle tightening around the airways, which makes it harder to breathe.
+Added: Symptoms can include coughing, wheezing, shortness of breath and chest tightness.
+Added: These symptoms can be mild or severe and can come and go over time.
+Added: In major global markets, it is estimated that approximately 55 million people worldwide are diagnosed with asthma, with approximately 50% falling into the moderate or severe category.
+Added: Asthma is a leading chronic disease in children, affecting about 5 million children under the age of 18.
+Added: Treatments include inhaled corticosteroids, bronchodilator medications and biologics, such as dupilumab, for moderate to severe disease.
+Added: Chronic Obstructive Pulmonary Disease
+Added: COPD is a progressive, chronic lung disease that makes it difficult to breathe.
+Added: COPD damages the lungs and narrows the airways, making it difficult to move air in and out of the lungs.
+Added: Smoking and air pollution are the most common causes of COPD, but it also affects nonsmokers.
+Added: COPD develops gradually over many years, and symptoms are often initially mistaken for a smoker's cough or asthma.
+Added: Diagnosis often occurs in patients over 60 years old, when symptoms worsen.
+Added: Symptoms include coughing, shortness of breath, especially during mild activity, fatigue and frequent respiratory infections, significantly impacting quality of life.
+Added: COPD is the third leading cause of death worldwide.
+Added: It is estimated that approximately 34 million people worldwide are diagnosed with COPD, with up to 50% having uncontrolled disease.
+Added: Treatments for COPD include inhaled steroids to reduce inflammation in the airways as well as bronchodilator inhalers to relax airways and improve airflow.
+Added: Dupilumab is the only known biologic approved for the treatment of COPD.
+Added: KT-621 Preclinical Development
+Added: Our lead molecule in our STAT6 program is KT-621, an investigational, potentially first-in-class oral STAT6 degrader being developed for the treatment of immuno-inflammatory diseases.
+Added: We have conducted comprehensive preclinical studies in multiple models to assess KT-621’s selectivity, potency, degradation levels, efficacy and tolerability.
+Added: Preclinical Selectivity
+Added: We evaluated KT-621’s selectivity by measuring degradation of different proteins at concentrations as high as 100 times the DC90 of KT-621, which is the degradation concentration at which 90% of the target protein is degraded.
+Added: In preclinical testing, STAT6 was the only protein that KT-621 degraded out of the approximately 10,000 proteins that were detected by mass spectrometry, as shown in Figure 2.
+Added: Additionally, no other STAT proteins were degraded.
+Added: Preclinical Potency
+Added: We evaluated KT-621 potency using TH2 functional assays to assess its impact on IL-4/IL-13 signaling.
+Added: We measured IL-4 and IL-13 induced Thymus and activation-regulated chemokine (TARC), release assays in human Peripheral Blood Mononuclear Cells (PBMCs), IL-4/IL-13 induced CD23 expression assays in human CD19 B cells and IL-13 induced periostin release assays in human bronchial and esophageal smooth muscle cells.
+Added: In these models, KT-621 fully blocked the IL-4/IL-13 pathway in human TH2 functional assays, with IC50’s lower than dupilumab, as shown in Figure 3.
+Added: Preclinical Degradation Levels
+Added: In in vivo studies, KT-621 robustly degraded STAT6 across multiple preclinical species, including mouse, rat, dog and non-human primates (NHPs).
+Added: In dogs, we tested doses ranging from 0.2 to 12.8 milligrams per kilogram (mpk), with doses between approximately 1 and 3 mpk leading to maximal STAT6 degradation near depletion, as shown in Figure 4.
+Added: Additionally, KT-621, dosed at 10 mpk for 14 days, degraded STAT6 across key disease-relevant tissues, including blood, spleen, skin and lung in NHPs, as shown in Figure 4.
+Added: Preclinical Efficacy
+Added: To understand its efficacy potential, we assessed KT-621 in a one-month lung inflammation model induced by intranasal house dust mite administration, which we believe is the most relevant preclinical model of TH2 inflammation.
+Added: KT-621 was dosed in IL4/IL4Rα humanized mice once daily orally for 31 days at the same three dose levels, 2, 8 and 32 mpk, leading to 72%, 85% and 91% degradation in the spleen, respectively.
+Added: As illustrated in Figure 5, the dominant TH2 inflammation was demonstrated by the greatly elevated IgE in the serum and TARC, two well-established TH2 biomarkers.
+Added: KT-621 showed robust inhibition at all three dose levels.
+Added: In preclinical testing, KT-621 blocked TH2 inflammation in vivo equally or better than an IL-4Rα saturating dose of dupilumab in the intranasal HDM asthma model for all these TH2 measures.
+Added: KT-621 reduced disease severity in the lung in the HDM asthma model, with amelioration of lung remodeling seen after low daily oral doses of KT-621 comparable to dupilumab.
+Added: Preclinical Tolerability
+Added: We observed no adverse events in any of our preclinical safety studies of KT-621, including at doses that led to concentrations 30 to 40-fold above the predicted efficacious human exposures.
+Added: KT-621 Clinical Development
+Added: In the fourth quarter of 2024, we initiated a Phase 1 clinical trial to test and assess single- and multiple-ascending doses of KT-621 in healthy adult volunteers.
+Added: The Phase 1 trial is designed to evaluate KT-621’s safety, tolerability, PK and PD effects in an estimated 120 subjects.
+Added: We expect to disclose the Phase 1 trial results of the single- and multiple- ascending study in the second quarter of 2025.
+Added: In addition, we plan to initiate a Phase 1b trial in AD patients in the second quarter of 2025, and Phase 2b trials in AD and asthma patients in late 2025 and early 2026, respectively.
+Added: We are developing highly potent and selective degraders of TYK2, required for Type I interferon, or IFN, IL-12 and IL-23 signaling with both genetic and clinical validation in autoimmune and inflammatory diseases.
+Added: Background on Pathway and Target
+Added: TYK2, a member of the Janus kinase (JAK) family of kinases, binds the IL-12, IL-23 and Type I IFN receptors to recruit and phosphorylate STAT transcription factors.
+Added: Additionally, TYK2 has a well-established scaffolding function that plays a key role in cytokine receptor surface expression and activation.
+Added: A loss of function variant is protective in autoimmune diseases and deucravacitnib, an allosteric inhibitor of TYK2, as well as multiple biological agents targeting IL-12, IL-23 and IFN-α have been approved for the treatment of multiple autoimmune diseases, making TYK2 a highly validated target.
+Added: Degradation of TYK2, which can fully recapitulate the human knockout biology by completely removing the protein, has the potential to overcome the challenges of small molecule inhibitors, which have limitations due to lack of selectivity, limited target engagement, and/or lack of potent activity against Type I IFN, driven by inability to block the scaffolding function.
+Added: TYK2 degraders have the potential to achieve full pathway inhibition of Type I IFN, IL-12 and IL-23 while sparing IL-10 in a once daily oral pill with a potential biologics-like activity profile.
+Added: Development Opportunities
+Added: We estimate that more than 20 million people in the US, Europe and Japan are diagnosed with Type I IFN and IL-12/IL-23 mediated diseases.
+Added: There are numerous indication opportunities across multiple immunological therapeutic areas including dermatology, gastroenterology, rheumatology, and central nervous system.
+Added: The potential for TYK2 to be effective across multiple indications is supported by pathway biologics and TYK2 small molecule inhibitors.
+Added: We believe that TYK2 degradation differentiates from inhibition and has the potential to demonstrate full pathway inhibition comparable to biologics, but with the benefit of a daily, oral profile.
+Added: As a result, we believe oral TYK2 degraders have the potential to be the first oral therapy to deliver biologic-like activity in diseases such as irritable bowel disease and psoriasis, among others.
+Added: KT-295 Preclinical Development
+Added: Our lead molecule in our TYK2 program is KT-295, an investigational, first-in-class oral TYK2 degrader being developed for the treatment of autoimmune and inflammatory diseases.
+Added: We have conducted comprehensive preclinical studies in multiple models to assess KT-295’s selectivity, potency, degradation levels and tolerability.
+Added: Preclinical Selectivity
+Added: We evaluated KT-295 selectivity by measuring degradation of different proteins at concentrations as high as 100 times the DC90 of KT-295.
+Added: Based on our proteomics data, KT-295 is a highly selective picomolar TYK2 degrader.
+Added: In particular, KT-295 is completely selective over the JAK family members, as shown in Figure 6.
+Added: Preclinical Potency
+Added: KT-295 achieved picomolar degradation in human PBMC and keratinocytes and low nanomolar (nM) inhibition of our functional assays across a range of cell types as shown in Figure 7.
+Added: In preclinical in vitro cell assays, KT-295 potently inhibited STAT phosphorylation and downstream cytokine release in IL-23, IL-12 and type I IFN pathways.
+Added: KT-295 demonstrated that we spare the IL-10 and IL-22 pathways completely.
+Added: Preclinical Degradation Levels
+Added: KT-295 achieved dose dependent degradation of TYK2 in vivo with low oral doses.
+Added: Specifically, in non-human primates, upon repeat daily low oral doses, KT-295 can degrade TYK2 in a dose responsive manner and reach full degradation of TYK2, providing a path to full target engagement.
+Added: Preclinical Tolerability
+Added: The tolerability of TYK2 degradation is supported by complete deficiency in humans where these individuals are generally healthy with some increased risk of mycobacteria and viral infections that are relatively mild, curable and tend not to recur.
+Added: In completed preclinical studies, KT-295 was generally well tolerated with no adverse events related to KT-295 at any evaluated doses or concentrations.
+Added: KT-295 IND-enabling studies are ongoing to support its advancement into Phase 1 testing.
+Added: KT-295 Clinical Development
+Added: We intend to advance KT-295 into Phase 1 clinical testing in the second quarter of 2025.
+Added: IRAK4 Program
We are collaborating with Sanofi on the development of drug candidates targeting IRAK4 outside of oncology and immuno-oncology fields.
+Added: KT-474/SAR444656 is a highly active and selective oral IRAK4 degrader for the treatment of IL-1R/TLR-driven immuno-inflammatory conditions and diseases with high unmet medical need.
Sanofi has advanced KT-474 into Phase 2 clinical trials in patients with HS and AD, both which were initiated in the fourth quarter of 2023.
See the section entitled “Business—Collaborations—Collaboration Agreement with Sanofi” appearing elsewhere in this Annual Report for more information.
−Removed: Biology and Mechanism of Action
+Added: Background on Pathway and Target
IRAK4 is a key component of the myddosome, a multiprotein complex involved in innate immunity that mediates signaling through TLRs and IL-1Rs.
The IRAK4 protein is ubiquitously expressed across multiple different tissue types, including skin, lymphoid tissue, bone marrow, gastrointestinal tract and lung.
+Added: IL-1 family cytokines, including IL-1a, IL-1ß, IL-18, IL-36, and IL-33, have been implicated in a variety of different immunology-inflammation conditions and diseases.
+Added: As both TLRs and IL-1Rs are involved in the production and response to all of these IL-1 family cytokines, IRAK4 targeting with a single small molecule degrader could impact multiple different cytokines and chemokines, having the potential to achieve a
+Added: broad, generally well-tolerated, anti-inflammatory effect, and providing a novel therapeutic approach to the treatment of IL-1R/TLR-driven diseases.
The function of IRAK4 is dependent both on its kinase activity and on its scaffolding function, which are required for the assembly of the myddosome complex following TLR or IL-1R engagement and MYD88 activation.
While the kinase function is primarily responsible for the phosphorylation events in the IRAK4-JNK axis, the scaffolding function is primarily responsible for the NF-KB activation and downstream gene traction of several key pro-inflammatory cytokines and chemokines.
−Removed: We believe IRAK4 degradation is superior to IRAK4 kinase inhibition as our preclinical data suggests that it is critical to block both the kinase activity and scaffolding functions of the IRAK4 protein, which requires removal, as opposed to just inhibition, of the protein.
−Removed: IL-1 family cytokines, including IL-1a, IL-1ß, IL-18, IL-36, and IL-33, have been implicated in a variety of different immunology-inflammation conditions and diseases.
−Removed: As both TLRs and IL-1Rs are involved in the production and response to all of these IL-1 family cytokines, IRAK4 targeting with a single small molecule degrader could impact multiple different cytokines and chemokines and thereby provide a transformative approach to the treatment of IL-1R/TLR-driven diseases.
+Added: There is genetic de-risking of chronic IRAK4 suppression, as adult humans who lack IRAK4 due to null mutations are healthy.
+Added: Clinical validation for targeting this pathway comes from IRAK4 small molecule inhibitors and from antibodies targeting individual IL-1 family cytokines that all signal through the IRAK4 protein in diseases that include AD, HS, rheumatoid arthritis, generalized pustular psoriasis, and others.
+Added: Therefore, we believe that removing IRAK4 will be able to have the combined activity of all the known anti-IL-1 family biologics, achieving our best-in-pathway objective.
+Added: We believe IRAK4 degradation is superior to IRAK4 kinase inhibition.
+Added: Our preclinical data suggests that it is critical to block both the kinase activity and scaffolding functions of the IRAK4 protein, which requires removal, as opposed to just inhibition, of the protein.
Development Opportunities
2 unchanged sentences
These present opportunities where we believe a highly efficient and selective IRAK4 degrader would provide significant advantages over both currently approved treatment options and those in clinical development.
−Removed: We are initially prioritizing HS and AD, autoimmune dermatologic conditions where there is clinical proof of concept for targeting cytokines impacted by the IL-1R/TLR pathway but for which there continues to be a high level of unmet need.
−Removed: There are many other diseases where the IL-1R/TLR pathway has been implicated in pathogenesis and could be additional potential opportunities targeting respiratory, GI and rheumatology.
+Added: There are many diseases where the IL-1R/TLR pathway has been implicated in pathogenesis and there could be additional potential opportunities targeting respiratory, gastrointestinal and rheumatology conditions.
+Added: We and our collaborator, Sanofi, are initially prioritizing HS and AD, autoimmune dermatologic conditions where there is clinical proof-of-concept for targeting cytokines impacted by the IL-1R/TLR pathway but for which there continues to be a high level of unmet need.
Hidradenitis Suppurativa
−Removed: HS is a chronic, destructive, painful and debilitating inflammatory skin disease affecting up to 1% of both the U.S.
+Added: Hidradenitis suppurativa (HS) is a chronic, destructive, painful and debilitating inflammatory skin disease affecting up to 1% of both the U.S.
and global population.
−Removed: Patients with HS have numerous painful, draining nodules and abscesses, usually within skin folds, that are characterized by inflammation and bacterial colonization.
+Added: Patients with HS have numerous painful, draining nodules and abscesses, usually within skin folds, which are characterized by inflammation and bacterial colonization.
Currently HS is treated symptomatically with corticosteroids, antibiotics and surgery.
−Removed: The only FDA-approved treatment for HS is the anti-TNF antibody adalimumab, which provides some benefit to approximately 50% of patients with moderate-to-severe disease but is not curative.
−Removed: Thus, there remains a high unmet need for better therapies for the treatment of HS.
−Removed: Bacterial activation of TLRs, as well as the production of IL-1a, IL-1ß, and IL-36 by keratinocytes and inflammatory cells leading to inflammation characterized by high levels of TNF-a, IL-6, and IL-17, are central to the pathogenesis of HS.
−Removed: Monoclonal antibodies targeting individual cytokines such as IL-1a (bermekimab), IL-1a/ß receptor (anakinra), and IL-17 (secukinumab and bimekizumab) have shown preliminary clinical activity in HS and provide clinical validation for targeting the IL-1R/TLR pathway in HS.
−Removed: As such, an IRAK4 degrader which acts on multiple cytokines as well as TLRs has the potential to offer a significant advantage over the single-cytokine-targeting agents currently being developed.
+Added: There are currently limited, effective FDA-approved treatment options for HS, which include biologics and are often limited to patients with moderate to severe disease.
+Added: We believe there remains a high unmet need for better therapies for the treatment of HS.
Atopic Dermatitis
−Removed: AD is a chronic, pruritic inflammatory skin disease that occurs most frequently in children but also affects adults.
−Removed: In the major global markets, the diagnosed prevalence of AD is estimated over 60 million patients, with approximately 40%, or 24 million, falling into the moderate-to-severe category.
−Removed: AD follows a chronic relapsing course over month to years, with dry skin and severe pruritus as the primary symptoms, sometimes accompanied by skin thickening from chronic scratching and fissuring.
+Added: Atopic dermatitis (AD) is a chronic, pruritic inflammatory skin disease that occurs most frequently in children but also affects adults.
+Added: In the major global markets, the diagnosed prevalence of AD is estimated at 42 million patients, with approximately 60% falling into the moderate-to-severe category.
+Added: AD follows a chronic relapsing course over months to years, with dry skin and severe pruritus as the primary symptoms, sometimes accompanied by skin thickening from chronic scratching and fissuring.
AD is treated symptomatically with topical therapies, including emollients, corticosteroids, and phosphodiesterase inhibitors.
−Removed: The leading FDA-approved systemic treatment is the IL-4Ra targeting antibody dupilumab, though only approximately 40% of moderate-to-severe disease patients met the primary endpoint in its Phase 3 trials, leaving a significant percentage of patients who are currently underserved.
−Removed: Furthermore, there is evidence that IL-18 and IL-1 are both involved in the generation of inflammation in both AD and other autoimmune and inflammatory diseases, including eosinophilic asthma and chronic rhinosinusitis.
−Removed: Single-cytokine-targeting monoclonal antibodies against IL-18 (GSK1070806) and IL-1a (bermekimab)have shown preliminary clinical activity in AD while a monoclonal antibody against IL-1a/b (lutikizumab) has shown preliminary clinical activity in HS.
−Removed: Thus, we believe the ability of an IRAK4 degrader to impact the production of both IL-18 and IL-1, through complete TLR signaling blockade, and the cellular response to both cytokines, through complete IL-1R signaling blockade, provides a compelling mechanistic rationale for development in AD and HS and other autoimmune and inflammatory diseases.
−Removed: Clinical Studies and Data
−Removed: In December 2021, we completed dose escalation in the Single Ascending Dose, or SAD and Multiple Ascending Dose, or MAD portions of the KT-474 Phase 1 trial in healthy volunteers.
−Removed: The trial evaluated safety, tolerability and pharmacokinetics in 105 healthy volunteers.
−Removed: The SAD portion consisted of single doses ranging from 25 to 1600 mg.
−Removed: The MAD portion consisted of escalating doses ranging from 50 mg to 200 mg that were administered for 14 consecutive days.
−Removed: Highlights of the healthy volunteer portion of the trial included robust (>95%) and sustained IRAK4 degradation with single and multiple daily doses (Figure 5) and broad inhibition of ex vivo TLR-mediated cytokine induction (Figure 6).
+Added: The leading FDA-approved systemic treatment is the IL-4Ra targeting antibody dupilumab, which is considered a safe and effective treatment for AD.
+Added: Nonetheless, penetration of existing therapies, including dupilumab, remains low, leaving a significant percentage of patients who are currently underserved.
+Added: KT-474 Preclinical Development
+Added: We have demonstrated KT-474’s high activity, selectivity and therapeutic potential in both in vitro and in vivo studies.
+Added: Preclinical data show that orally administered KT-474 safely and selectively suppressed IRAK4 expression in rodents and non-rodents, inhibited inflammation, including neutrophil infiltration, in murine models mechanistically relevant to the pathogenesis of HS and AD and potentially other diseases, and demonstrated a therapeutic advantage of IRAK4 degradation over IRAK4 kinase inhibition.
+Added: KT-474 Clinical Development
+Added: The KT-474 Phase 1 program three-part trial was designed to evaluate single and multiple ascending doses of KT-474 to assess safety, tolerability and pharmacokinetics in healthy adult volunteers and then in HS and AD patients.
+Added: The single ascending dose, or SAD, and multiple ascending dose, or MAD, portions of the KT-474 Phase 1 trial evaluated safety, tolerability and pharmacokinetics in 105 healthy volunteers.
+Added: The SAD (Part A) consisted of single doses ranging from 25 to 1600 mg.
+Added: The MAD (Part B) consisted of escalating doses ranging from 50 mg to 200 mg that were administered for 14 consecutive days.
+Added: KT-474 demonstrated >95% and sustained IRAK4 degradation with single and multiple daily doses and broad inhibition of ex vivo TLR-mediated cytokine induction.
KT-474 was generally well-tolerated across all dose groups.
−Removed: Following the healthy volunteer portion of the trial, we completed a single dose, food-effect cohort to establish the dose for the patient cohort, or Part C, of the KT-474 Phase 1 trial, which included HS and AD patients and which was completed in October 2022.
−Removed: The HS and AD patient cohort was an open label study in 21 patients with HS and AD.
−Removed: The patients were administered a 75 mg daily dose taken with food, which we estimated would be equivalent exposure to 100 mg fasted, one of the doses in our SAD/MAD trial.
+Added: The Phase 1 trial included a patient cohort (Part C) which was an open label study in a total of 21 HS and AD patients.
+Added: The patients were administered a 75 mg daily dose taken with food, which we estimated would be equivalent exposure to 100 mg fasted.
The patient cohort dose of 75 mg was administered for 28 consecutive days.
−Removed: The KT-474 plasma PK at the 75 mg once daily, or QD dose (in the fed state) in patients was comparable to healthy volunteers in the MAD portion of the Phase 1 clinical trial who received 100 mg once daily in the fasted state, the MAD cohort which we refer to as MAD3.
−Removed: Additionally, mean Cmax (6-hour post dose concentration) and Ctrough (pre-dose concentration) levels at steady state in Part C were in line with MAD3 levels at Day 14, and the mean half-life of 44 hours was within the range observed in MAD (34-59 hours).
−Removed: Additionally, KT-474 concentrations in plasma led to a comparable level of IRAK4
−Removed: degradation in healthy volunteers and HS/AD patients.
−Removed: Specifically, at concentrations above 3 ng/mL degradation was generally above 80% in both populations.
−Removed: Additionally, IRAK4 levels in PBMC in patients with evaluable samples were near the lower limit of quantification at Day 28.
−Removed: KT-474 demonstrated high skin exposure in the skin of evaluable HS and AD patients, as shown below in Figure 7.
−Removed: Additionally, baseline IRAK4 levels in skin lesions of evaluable HS and AD patients were approximately twice the levels of healthy volunteers.
−Removed: By Day 28 of dosing, the mean IRAK4 level in skin lesions of AD and HS patients was reduced to approximately the same level as healthy subjects, as shown below in Figure 8.
−Removed: KT-474 was generally well-tolerated.
−Removed: There were no serious adverse events, no drug-related infections, and no adverse events observed leading to dose interruption or discontinuation.
−Removed: A modest, non-adverse QTc prolongation, consistent with that observed by Day 7 in the MAD portion of the healthy volunteer study, was also observed in the patient cohort but spontaneously resolved back to baseline with continued dosing during the 28-day dosing period.
−Removed: To determine whether KT-474 had a systemic anti-inflammatory effect in HS and AD patients, plasma levels of IL-6, CRP, SAA and IL-1b were measured at baseline and at various times during and after the 28-day treatment period.
−Removed: In patients whose baseline levels were greater than the upper limit of normal, the evaluable patients showed suppression of all 4 analytes, with mean maximum reductions through Day 42 ranging from 41 to 63%.
−Removed: The patient cohort also evaluated how systemic IRAK4 degradation in blood and skin would affect the expression of proinflammatory genes known to be relevant to either AD or HS.
−Removed: In AD, affected genes included the Th2 cytokine IL-5, the inflammasome NLRP3, as well as CXCL1 and IL-2RB.
−Removed: Genes affected in HS included IL-1 family cytokines IL-1 and IL-36A, mediators of Th1 inflammation such as IFN-g and GZMB, the Th17 cytokine IL-17A, and drivers of innate immunity such as IL-8 and CSF3.
−Removed: The downregulation was substantial with many genes inhibited more than 90% in both diseases.
−Removed: log2(fold change):
−Removed: -1 = 50% decrease, -2 = 75% decrease, -3 = 87.5% decrease.
−Removed: Part C included exploratory clinical endpoints used for HS and AD.
−Removed: The endpoints were chosen to assess the effect of KT-474 treatment on the burden of skin disease as well as on symptoms such as pain and pruritus that impact quality of life for HS and AD patients.
−Removed: In AD patients, as shown in Figure 10, there was a mean 37% reduction in skin lesions as measured using the Eczema Area and Severity Index (EASI) score, with reductions in individual patients of up to 76%.
+Added: Baseline IRAK4 levels in skin lesions of evaluable HS and AD patients were approximately twice the levels of healthy volunteers.
+Added: By Day 28 of dosing, the mean IRAK4 level in skin lesions of AD and HS patients was reduced to approximately the same level as healthy volunteers.
+Added: In addition, promising clinical activity was observed in HS and AD patients including a reduction of signs and symptoms of HS and AD.
+Added: The Phase 1 data was published in Nature Medicine in November 2023.
+Added: In the KT-474 Phase 1 trial, the proportion of HiSCR50 responders was 50% in those with moderate-to-severe disease.
+Added: Hidradenitis Suppurativa Clinical Response (HiSCR) is a validated clinical tool that has been used to assess efficacy in HS patients.
+Added: HiSCR50 response is defined as a 50% or greater reduction in inflammatory lesions and no increase in abscesses or draining fistulas.
+Added: Symptoms of pain were significantly impacted by KT-474 with an average reduction in patients with moderate to severe disease of 55%, with a maximum reduction occurring between days 28 and 42.
+Added: Figure 9 highlights the initial clinical impact of KT-474 in HS patients in the third part of the Phase 1 trial.
+Added: In addition, there was a mean 37% reduction in skin lesions as measured using the EASI score with reductions in individual AD patients of up to 76%.
Maximum reduction was seen by day 28 and was maintained at day 42.
−Removed: As shown in Figure 11, mean peak pruritus in AD patients over the past week or past 24 hours was reduced by 52% and 63%, respectively, with maximum reductions occurring by Day 42.
−Removed: Peak pruritus responders, defined as ≥4 Unit reduction in peak pruritus over the past week or past 24 hours, were seen in 57% and 71% of AD patients, respectively, with responses sustained after Day 28.
−Removed: The Validated Investigator’s Global Assessment, or vIG, of disease severity improved in 2 of 7 AD patients and remained stable in the others out to Day 42.
−Removed: In HS patients, the efficacy analyses were performed in all patients, which included two patients with very severe disease.
−Removed: In addition, efficacy analyses were also performed in a subset of HS patients that only had moderate to severe disease, which was the target population for this study.
−Removed: The AN count was reduced by up to an average of 46% in all HS patients and by an average of 51% in the moderate to severe subset, with reductions in individual patients of up to 100% and with maximum reduction occurring by Day 42.
−Removed: The proportion of patients achieving an AN count of 0, 1 or 2 at Day 28 was 42% in all HS patients and 50% in those with moderate to severe disease.
−Removed: HiSCR50 response is defined as a 50% or greater reduction in AN count and no increase in abscesses or draining fistulas.
−Removed: As shown in Figure 12, at Day 42, the proportion of HiSCR50 responders was 42% in all HS patients and 50% in those with moderate to severe disease.
−Removed: HiSCR75 response, defined as 75% or greater reduction in AN count, was seen in 25% of all HS patients and 30% of those with moderate to severe disease.
−Removed: Symptoms of pain and pruritus were also measured.
−Removed: As shown in Figure 13, there was a 49 to 55% mean reduction in the Pain Numerical Rating Scale, or NRS, in all HS patients and in those HS patients with moderate to severe disease, respectively, with maximum reduction occurring between Days 28 and 42.
−Removed: Pain NRS30 response is defined as at least a 30% reduction and at least one unit reduction from baseline in Pain NRS.
−Removed: As also shown in Figure 13, the Pain NRS responder rate was 50% in all HS patients and 60% in those HS patients with moderate to severe disease, sustained after Day 28.
−Removed: There also was a mean reduction in peak pruritus of 62% in all HS patients and 68% in those HS patients with moderate to severe disease, with maximum reduction by Day 42 in all HS patients and by Day 28 in those with moderate to severe disease.
−Removed: Additionally, the Physician’s Global Assessment of disease severity improved in 5 HS patients, including clearing of disease in 1 patient with moderate disease at baseline, and remained stable in the other evaluable patients out to Day 42.
−Removed: Clinical Development Plan
−Removed: In the fourth quarter of 2023, the first patients were dosed in the Phase 2 clinical trials of KT-474 in HS and AD.
−Removed: The Phase 2 clinical trial in HS, or ZEN, is a double blind, placebo-controlled, 2-arm randomized trial consisting of a KT-474 oral tablet, or placebo, once-daily.
−Removed: The primary outcome measure is percent change from baseline in total abscess and inflammatory nodule (AN) count.
−Removed: Select secondary outcome measure include proportion of patients achieving HiSCR50, AN Count ≤2;
−Removed: absolute change from baseline in HIS4;
−Removed: proportion of patients with improvement in Hurley Stage, AN50;
−Removed: change from baseline in reported daily worst pain HS-Skin Pain-NRS;
−Removed: and proportion of participants achieving at least 30% reduction and at least 1 unit reduction in daily worst pain using HS-Skin Pain-NRS.
−Removed: The Phase 2 clinical trial in AD, or ADVANTA, is a double blind, placebo-controlled, 3-arm randomized trial consisting of a KT-474 dose 1 oral tablet, a KT-474 dose 2 oral tablet, or placebo, once-daily.
−Removed: The primary outcome measure is percent change from baseline in EASI.
−Removed: Select secondary outcome measure include proportion of participants with vIGA-AD of 0 or 1 and a reduction from baseline of ≥2 points;
−Removed: proportion of participants achieving EASI-50 EASI-75 EASI-90;
−Removed: proportion of participants with reduction of weekly average of daily PP-NRS by ≥4 points from baseline;
−Removed: percent change from baseline in weekly average of daily PP-NRS;
−Removed: and absolute change from baseline in weekly average of daily PP-NRS.
−Removed: Topline data from the two ongoing trials is expected in the first half of 2025.
−Removed: Additionally, Kymera and Sanofi are evaluating opportunities to expand in indications beyond HS and AD.
−Removed: Preclinical Immunology:
−Removed: STAT6 and TYK2
−Removed: We are developing degraders that target STAT6, an essential transcription factor specific to the IL-4/IL-13 signaling pathway and the central driver of Type 2 inflammation in allergic diseases.
−Removed: STAT6 is a genetically validated target and the pathway has been clinically validated by approved IL-4/IL-13-targeting biologics, including dupilumab.
−Removed: Biology and Mechanism of Action
−Removed: STAT6 is the specific transcription factor required for IL-4 and 13 cytokine signaling.
−Removed: There are two types of IL-4 receptors, type I consisting of IL-4 receptor alpha and gamma C, and type II with IL-4 receptor alpha and IL-13 receptor alpha 1.
−Removed: IL-4 signals through both type I and II receptors and IL-13 signals through type II only.
−Removed: Upon IL-4 or IL-13 binding to the receptor, the downstream activated JAK kinases phosphorylate and activate STAT6, leading to allergic TH2 inflammation.
−Removed: STAT6 regulated cytokines are clinically validated targets for allergic diseases as demonstrated by the clinical efficacies of the biologics targeting IL-4 and IL-13 signaling.
−Removed: Unlike JAK inhibitors, which are activated by multiple cytokine pathways, STAT6 is specifically activated by IL-4 and 13 cytokines, which supports STAT6 as a means to selectively block IL-4 and 13 signaling.
−Removed: The pathogenic role of STAT6 is also supported by human genetics showing that gain of function mutations of STAT6 cause severe early onset allergic diseases in human.
−Removed: Additionally, STAT6 knockout in mice is protective in multiple allergic disease models, and those mice develop normally and are viable and fertile.
−Removed: Development Opportunities
−Removed: We estimate that more than 150 million people in the US, Europe and Japan suffer from TH2-driven diseases.
−Removed: There are existing pathway therapeutics that have validated many of these diseases, including atopic dermatitis, prurigo nodularis, Asthma, COPD, chronic rhinosinusitis with nasal polyps, eosinophilic esophagitis and others.
−Removed: We believe that STAT6 degradation has the potential to demonstrate full pathway inhibition comparable to biologics, but with the benefit of a simple, daily, oral profile.
−Removed: The preference that many patients may have for an oral option could allow us to access many more patients worldwide than current injectable biologics, potentially transforming the treatment paradigm of TH2 diseases.
−Removed: Preclinical Studies and Data
−Removed: Our lead STAT6 degrader, KT-621, is an extremely potent degrader of STAT6.
−Removed: As shown in Figure 15, KT-621 demonstrated picomolar degradation potencies across all the disease relevant human primary cell types that were studied, making KT-621 one of the most potent heterobifunctional degraders we have designed and tested at Kymera.
−Removed: We demonstrated STAT6 degradation across hematopoietic cells which are involved in all TH2 diseases;
−Removed: epithelial cells, including keratinocytes and lung epithelial cells, which are involved in skin and respiratory indications;
−Removed: smooth muscle cells from the lung and esophagus, which are involved in respiratory and GI indications;
−Removed: and vascular endothelial cells which are involved in inflammatory cell infiltration in all TH2 diseases.
−Removed: We also demonstrated dose-dependent degradation across both Hematopoietic cells and tissue cells, as shown below in Figure 16.
−Removed: We use mass spectrometry to measure the degradation selectivity profile of all our programs, including STAT6.
−Removed: The following figure is a volcano plot that depicts the degradation selectivity of KT-621.
−Removed: As shown in the figure, at concentrations as high as 100 times the DC90 of KT-621, STAT6 is the only protein that KT-621 degraded out of the approximately 10,000 proteins that were detected by mass spectrometry.
−Removed: Specifically, no other STAT proteins were degraded, demonstrating the very high degradation selectivity of KT-621.
−Removed: We tested KT-621 for functional selectivity against all the other STAT proteins in cytokine assays, which are shown below in the tables and graphs.
−Removed: Consistent with the observed proteomics selectivity, KT-621 only inhibited STAT6 function, and did not impact any other STAT proteins, as shown in the flat dose response curves, further demonstrating the high functional selectivity of KT-621.
−Removed: KT-621 was also evaluated in TH2 functional assays to assess its impact on IL-4 and 13 signaling.
−Removed: Specifically, we measured IL-4 and 13 induced TARC release assays in human PBMC, IL-4 and 13 induced CD23 expression assays in human CD19 B cells (which is a B cell activation marker and correlates with IgE class switch) and IL-13 induced periostin release assays in human bronchial and esophageal smooth muscle cells.
−Removed: We chose TARC, IgE and periostin as PD biomarkers as they are all well-established biomarkers that are used in the clinic for TH2 diseases.
−Removed: We also compared the ability of KT-621 to
−Removed: block the pathways with dupilumab.
−Removed: As shown below in Figure 19, in our preclinical testing, KT-621 fully blocked the IL-4/IL-13 pathway in human TH2 functional assays with IC50’s lower than dupilumab.
−Removed: We also evaluated KT-621 by assessing levels of degradation in vivo.
−Removed: In our studies, KT-621 robustly degraded STAT6 across multiple preclinical species including mouse, rat, dog and non-human primates.
−Removed: Specifically, KT-621 was able to achieve dose-dependent deep degradation of STAT6 with low oral doses.
−Removed: In Figure 20, we depict KT-621’s in vivo degradation in dogs, illustrating dose-dependent degradation.
−Removed: We tested doses ranging from 0.2 to 12.8 mpk, with doses between approximately 1 and 3 mpk leading to maximal STAT6 degradation near depletion.
−Removed: Additionally, in our studies KT-621 demonstrated rapid degradation onset, notably within just a few hours following a single oral dose.
−Removed: These results, and other PK/PD studies we have completed, suggest the potential for low and developable efficacious doses of KT-621 in humans.
−Removed: We also evaluated the degradation of STAT6 in key disease relevant tissues in non-human primates.
−Removed: The following Figure 21 illustrates that KT-621, dosed at 10 mpk for 14 days, degraded STAT6 across key disease-relevant tissues, including blood, spleen, skin and lung.
−Removed: The above degradation represented dosing at the lowest dose level in our dose range finding safety study.
−Removed: In that study, we dosed as high as 300 mpk daily for 14 days and reached concentrations that were above 40-fold of our efficacious concentration.
−Removed: At all dose levels in our study, including the highest dose level, KT-621 was well tolerated with no adverse events or relevant findings.
−Removed: In preclinical models of the skin and lung, we assessed the in vivo activity of KT-621.
−Removed: First, we assessed KT-621 in a two-week atopic dermatitis model induced by topical application of low-calcemic vitamin D3 analog MC903.
−Removed: The model utilized IL-4/IL-4Rα humanized mice which allowed response to dupilumab and enabled us to compare preclinical activity.
−Removed: KT-621 was dosed once daily orally for 11 days at 2, 8, and 32 mpk.
−Removed: These doses led to ~70%, 80% and 90% degradation, respectively, in the spleen as illustrated in Figure 22.
−Removed: In this preclinical study, dupilumab was dosed 4 times subcutaneously, at 25 mpk twice weekly, a level expected to ensure constant IL-4Rα saturation with full IL-4/13 blockade.
−Removed: We estimated that dose to be equivalent to 300 mg every other week in humans, which is the highest approved dose regimen in humans.
−Removed: As illustrated in Figure 23, the prominent TH2 inflammation demonstrated by the elevated total serum IgE in the PO vehicle and the SubQ IgG4 control groups, compared to the no MC903 group.
−Removed: In contrast, KT-621 robustly and dose dependently inhibited IgE elevation to levels that were comparable to dupilumab, in this preclinical study.
−Removed: Of note, the KT-621 dose that led to 90% STAT6 degradation produced similar activity in this preclinical model to an IL-4Rα saturating dose of dupilumab, indicating full IL-4 and IL-13 blockade by KT-621 in vivo .
−Removed: * Significance to PO vehicle (MC903);
−Removed: # Significance to SC IgG4 25 mpk BIW
−Removed: We assessed KT-621 in a one-month lung inflammation model induced by intranasal house dust mite (HDM) administration, which we believe is considered to be the most relevant preclinical model of TH2 inflammation.
−Removed: Unlike ovalbumin, which is commonly used in mouse models but does not induce airway inflammation in humans, house dust mite is a real-world allergen that can induce asthma in humans.
−Removed: The intranasal HDM model has a dominant TH2 inflammation and was used for the preclinical development of dupilumab.
−Removed: Similar to the skin model previously described, we used the IL4/IL4Rα humanized mice.
−Removed: KT-621 was dosed once daily orally for 31 days at the same three dose levels, 2, 8 and 32 mpk, leading to 72, 85 and 91% degradation in the spleen, respectively, consistent with the previous skin model.
−Removed: Dupilumab was dosed 9 times subcutaneously twice weekly at 25 mpk, meant to ensure constant IL-4Rα saturation with full IL-4/IL-13 blockade, and similarly equivalent to that of the highest approved dose of 300 mg every other week in humans.
−Removed: As illustrated in Figure 24, the dominant TH2 inflammation was demonstrated by the greatly elevated IgE in the serum, TARC and periostin release in the bronchoalveolar lavage, and eosinophil recruitment to the lung.
−Removed: All are well-established TH2 biomarkers.
−Removed: KT-621 showed robust inhibition at all three dose levels.
−Removed: In this preclinical study, KT-621 blocked TH2 inflammation in vivo equally or better than an IL-4Rα saturating dose of dupilumab in the intranasal HDM asthma model for all these TH2 measures.
−Removed: *Significance to PO vehicle (HDM);
−Removed: # Significance to SC IgG4 Ctrl 25 mpk
−Removed: Clinical Development Plan
−Removed: Our lead STAT6 degrader, KT-621, is currently in IND enabling studies.
−Removed: We expect to begin a Phase 1 clinical trial in the second half of 2024, and to report the Phase 1 results in 2025.
−Removed: We are developing highly potent and selective degraders of TYK2, a member of the JAK family required for Type I interferon, or IFN, IL-12 and IL-23 signaling with both genetic and clinical validation in autoimmune and inflammatory diseases.
−Removed: Biology and Mechanism of Action
−Removed: As seen in Figure 25, TYK2, a member of the JAK family of kinases, binds the IL-12, IL-23 and Type I IFN receptors to recruit and phosphorylate signal transducer and activation of transcription (STAT) transcription factors.
−Removed: Additionally, TYK2 has a well-established scaffolding function that plays a key role in cytokine receptor surface expression and activation.
−Removed: A loss of function variant is protective in autoimmune diseases and an allosteric inhibitor (deucravacitnib) of TYK2 as well as multiple biological agents targeting IL-12, IL-23 and IFN-α have been approved for the treatment of multiple autoimmune diseases, making TYK2 a highly validated target.
−Removed: Degradation of TYK2, which can fully recapitulate the human knockout biology by completely removing the protein, has the potential to overcome the challenges of small molecule inhibitors, which have limitations due to lack of selectivity, limited target engagement, and/or lack of potent activity against Type I IFN.
−Removed: TYK2 degraders therefore have the potential to achieve full pathway inhibition of Type I IFN, IL-12 and IL-23 while sparing IL-10 in a once daily oral pill with a potential biologics-like activity profile.
−Removed: Development Opportunities
−Removed: We estimate that more than 20 million people in the US, Europe and Japan suffer from Type I IFN and IL-12/IL-23 mediated diseases.
−Removed: There are numerous indication opportunities across multiple immunological therapeutic areas including dermatology, gastroenterology, rheumatology, and CNS.
−Removed: The potential for TYK2 to be effective across multiple indications is supported by pathway biologics and TYK2 small molecule inhibitors.
−Removed: We believe that TYK2 degradation differentiates from inhibition and has the potential to demonstrate full pathway inhibition comparable to biologics, but with the benefit of a daily, oral profile.
−Removed: Preclinical Studies and Data
−Removed: We have developed a highly potent and selective TYK2 degrader, KT-294.
−Removed: In Figure 26, our proteomics data demonstrates KT-294, a highly selective picomolar TYK2 degrader, recapitulates TYK2 human deficiency biology and fully inhibits Type I IFN and IL-12/23 signaling and spares IL-10/IL-22.
−Removed: In particular, KT-294 is extremely selective over the JAK family members.
−Removed: In Figure 27, we achieved picomolar degradation in human PBMC and keratinocytes and low nM inhibition of our functional assays across a range of cell types.
−Removed: We have potent preclinical efficacy on the IL-23 and IL-12 signaling pathways in PBMCs and potent inhibition on the Type I IFN pathway in PBMCs and also in specific B-cell assays.
−Removed: We demonstrated that we spare the IL-10 and IL-22 pathways completely.
−Removed: IL-10 has essential roles in intestinal homeostasis such as epithelial repair and mucosal healing, which is important in diseases such as Inflammatory Bowel Disease, or IBD.
−Removed: In fact, loss of function mutations of IL-10 cause early onset refractory colitis in humans.
−Removed: In Figure 28, we show western blots demonstrating that when TYK2 is not present in a cell, we can induce pSTAT3 with IL-10, showing TYK2 is not necessary for IL-10 signaling.
−Removed: We also show the TYK2 small molecule inhibitor, deucravacitinib, can block that pathway signaling exclusively due to its ability to inhibit JAK1, and not through TYK2.
−Removed: In Figure 29, we have an assay where we induce phospho-STAT3 in monocytes with IL-10, in this context our degrader has no effect on pSTAT3 because it doesn’t inhibit the IL-10 pathway.
−Removed: However, in contrast, deucravacitinib potently inhibits the IL-10 signaling as shown with the decrease of the orange data points.
−Removed: Similarly in Figure 30, we have monocytes where we use IL-10 to suppress LPS induced TNF-α.
−Removed: KT-294 has no effect on IL-10 suppression of LPS induced TNF-α release, however deucravacitinib inhibits IL-10’s function of suppressing LPS induced TNF-α release and see an increase in TNF-α, which is demonstrated by the orange data points.
−Removed: Additionally, we compared KT-294 to TAK-279, an investigational TYK2 inhibitor that is selective over JAK, and as a result spares IL-10.
−Removed: In our experiment, we used a concentration of TAK-279 that was expected to fully occupy TYK2 and a concentration of KT-294 that was expected to fully degrade TYK2 to assess if there were any biological differences between the two compounds.
−Removed: The concentrations were determined based on the IC95 of the IFNα pSTAT2 assay which is the most difficult TYK2-related cytokine assay to inhibit.
−Removed: RNAseq data show KT-294 has superior inhibition of the IFN pathway signature genes, as illustrated in the 21 gene signature score in Figure 31.
−Removed: Differences in the innate immune pathway, as shown in Figure 32, were observed.
−Removed: We believe this is due to the fact KT-294 fully removes the protein, and all possible scaffolding functions, phenocopying human knockout.
−Removed: Based on clinical findings, TAK-279 does not achieve clinical exposures of more than about 77nM with 35mg repeat dosing, which is close to the TAK-279 Phase 3, 30 mg dose.
−Removed: At clinically relevant exposures, we believe it is likely that TAK-279 will not reach these levels of pathway inhibition shown by KT-294 in figure 31.
−Removed: KT-294 achieved dose dependent deep degradation of TYK2 in vivo with low oral doses.
−Removed: Specifically, in non-human primates, or NHP, upon repeat daily low oral doses, KT-294 can degrade TYK2 in a dose responsive manner and reach full degradation of TYK2, providing a path to pharmacological target engagement, as shown in figure 33.
−Removed: Clinical Development Plan
−Removed: We expect to initiate a Phase 1 clinical trial of our TYK2 degrader, KT-294, in the first half of 2025 and to report data in 2025.
−Removed: Clinical Oncology:
−Removed: STAT3 and MDM2
−Removed: We are developing our selective STAT3 degraders for the treatment of hematological malignancies and solid tumors.
−Removed: We are also exploring the potential for STAT3 degradation in autoimmune diseases.
−Removed: STAT3 is a transcription factor activated through a variety of different cytokine and growth factor receptors via JAKs, as well as through oncogenic fusion proteins and mutations in STAT3 itself.
−Removed: We believe the diverse functions of STAT3 in tumor biology, evasion of immune surveillance by tumor cells, and inflammation and fibrosis provide opportunities to address a wide variety of high unmet need disease indications through the targeting of a single genetically and clinically validated pathway.
−Removed: While the JAK-STAT pathway has been partially addressed with several clinically successful JAK-targeting agents, we believe there are currently no drugs that specifically affect STAT3 broadly across all the relevant cell types.
−Removed: Small molecule STAT3 dimerization inhibitors targeting the SH2 domain have been in development, but significant challenges remain.
−Removed: Homology of SH2 domains among all STAT family members impacts the ability to achieve specificity for STAT3, and an inability to block dimerization independent transcriptional activities of STAT3.
−Removed: For these reasons, we believe that STAT3 degraders may provide a transformative solution to the development of targeted and selective drugs to address multiple STAT3 dependent pathologies.
−Removed: We are currently evaluating our STAT3 degrader, KT-333, in a Phase 1 clinical trial in patients with relapsed/refractory liquid and solid tumors, including aggressive lymphomas.
−Removed: Patient enrollment and dosing are ongoing in the Phase 1a portion of the trial, and we expect to provide additional clinical data in 2024.
−Removed: Biology and Mechanism of Action
−Removed: STAT3 (signal transducer and activator of transcription 3) is a transcription factor and a member of the STAT protein family.
−Removed: In response to cytokines and growth factors, STAT3 is phosphorylated by receptor-associated serine/threonine kinases, and phosphorylated STAT3, or p-STAT3, then forms dimers that translocate into the nucleus, bind to DNA, and regulate transcription of a wide variety of genes involved in oncogenesis, inflammation and fibrosis.
−Removed: STAT3 is frequently mutated and activated in numerous cancers, including clinically aggressive hematologic malignancies with high unmet medical need.
−Removed: Mechanistically, aberrant activation of STAT3 has been directly linked to the promotion of cancer cell survival, proliferation, and metastasis.
−Removed: In addition, STAT3 regulates the crosstalk between tumor, stroma, and immune cells to promote an immunosuppressive tumor microenvironment.
−Removed: STAT3 activation by IL-6 and TGF-ß is also involved in the pathogenesis of autoimmunity and fibrosis.
−Removed: These various roles of STAT3 in disease pathogenesis make it an attractive target for drug development in cancer and autoimmune and fibrotic diseases.
−Removed: Small molecule inhibitors against JAK family kinases, such as JAK1, JAK2, JAK3, and TYK2, have been approved for the treatment of autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis and target the JAK2/STAT5 pathway.
−Removed: In oncology, JAK inhibitors have been approved for hematological malignancies with mutations leading to activation of the JAK2/STAT5 pathway, including primary myelofibrosis and polycythemia vera, and for acute graft
−Removed: versus host disease.
−Removed: JAK inhibitors block signaling of a number of cytokines and growth factors and reduce activation not only of STAT3 but also STAT1 and STAT5 in response to these stimuli.
−Removed: For modulating anti-tumor effects, this broad activity may have conflicting consequences.
−Removed: In particular, the inhibition of STAT1 activity dampens anti-tumor immune responses by cytolytic T cells and antigen presenting cells, thereby counteracting a productive immune response that could be achieved by inhibition of STAT3 alone.
−Removed: As a result, JAK inhibitors have not shown clinical activity in cancer beyond the myeloproliferative neoplasms.
−Removed: The broad activity of JAK inhibitors is also associated with class-specific adverse effects.
−Removed: By targeting STAT3 selectively, these immunosuppressive and safety liabilities associated with broader STAT1 and STAT5 inhibition through JAK inhibition may be avoided while also effectively addressing JAK-dependent and independent activation of STAT3.
−Removed: Monoclonal antibodies directed against pro-inflammatory cytokines such as IL-6 or their receptors IL-6R have also been approved for select autoimmune diseases.
−Removed: However, autoimmune and fibrotic diseases and certain cancers are often regulated by multiple cytokines.
−Removed: As such, targeting STAT3 has the potential to be more effective since it is involved in signaling by not just IL-6, but also by TGF-ß and cytokines such as IL-12, IL-2 and IL-15.
−Removed: Consequently, targeting STAT3 directly has the potential to block multiple signaling pathways that converge on STAT3 and reverse pathological processes that contribute to a tumor-permissive microenvironment.
−Removed: Development Opportunities
−Removed: The multiple effects of a STAT3 degrader on oncogenesis, tumor cell resistance to tyrosine kinase inhibitors and chemotherapy, and evasion of immune surveillance provide multiple development opportunities in hematologic malignancies and solid tumors.
−Removed: Hematologic Malignancies
−Removed: Oncogenic STAT3 mutations and/or STAT3 pathway activations are highly common in peripheral T-cell lymphoma, or PTCL and cutaneous T-cell lymphoma, or CTCL.
−Removed: Every year, approximately 8,000 patients are diagnosed with PTCL and approximately 6,000 patients are diagnosed with CTCL across major global markets.
−Removed: STAT3 mutations and pathway activations along with responsiveness of PTCL subsets and CTCL to immune checkpoint inhibitors point to a dependency on STAT3 in these indications and therefore the opportunity to develop a STAT3 degrader as a monotherapy.
−Removed: The standard of care for first-line treatment of PTCL is the combination of brentuximab vedotin, a CD30-directed antibody-drug conjugate, and chemotherapy.
−Removed: The majority of PTCL patients, including ALK-ALCL, PTCL-Not Otherwise Specified, AITL and NK/T lymphoma subtypes, eventually progress and die of their disease.
−Removed: For patients with refractory/relapsed disease, current treatment options are limited and approved therapies pralatrexate and romidepsin have shown limited efficacy.
−Removed: High prevalence of STAT3 mutations (approximately 13-38%) and STAT3 pathway activation (up to 90%) is found in these refractory/relapsed PTCL subsets with high unmet need.
−Removed: Given the documented effect of STAT3 downregulation on levels of programmed death-ligand 1, or PD-L1, we expect our STAT3 degrader to have a dual effect in these patients.
−Removed: In CTCL patients with advanced stage disease and the highest levels of STAT3 activation, there are no curative therapies and no standard of care.
−Removed: Antibody-drug conjugates, HDAC inhibitors, and immune checkpoint inhibitors have some activity and are used upfront or in refractory/relapsed patients, but there remains a high unmet need for an effective therapeutic with both tumor-intrinsic as well as immunomodulatory antitumor effects.
−Removed: STAT3 pathway activation is also present in virtually all patients with T- and NK-cell large granular lymphocytic leukemia, and up to 70% of patients have oncogenic STAT3 mutations.
−Removed: These findings are highly indicative of STAT3 dependency, which is further supported by the preliminary clinical activity of JAK inhibitors in these patients.
−Removed: STAT3 activation is also commonly observed in AML and in DLBCL even though STAT3 mutations are infrequent.
−Removed: PD-L1 overexpression in DLBCL has been linked to worse disease outcomes and responses to anti-PD-1/PD-L1 drugs have been reported in these patients.
−Removed: Given STAT3 has downstream impact on PD-1/PD-L1, we believe that a STAT3 degrader has the potential to achieve profound clinical effects both as a monotherapy and in combination with other active drugs.
−Removed: Cancers that are responsive to anti-PD-1/PD-L1 immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs), including non-small cell lung cancer, or NSCLC, head and neck squamous cell carcinoma, or HNSCC, breast cancer and colorectal cancer, are compelling development opportunities due to the established role of STAT3 in solid tumor resistance to ICIs and TKIs.
−Removed: Specifically, STAT3 degraders have the potential to improve responses upfront in combination with these modalities or overcome acquired resistance as add-on therapy in second line.
−Removed: Clinical Studies and Data
−Removed: In 2022, we initiated our Phase 1 clinical trial of KT-333 to evaluate the safety, tolerability, PK/PD and clinical activity of KT-333 dosed weekly on Days 1, 8 and 15 of 28-day cycles in adult patients with relapsed and/or refractory lymphomas, leukemias and solid tumors.
−Removed: Figure 35 below shows the details of the trial.
−Removed: In December 2023, we presented clinical data from the Phase 1 clinical trial of KT-333 in a poster session at the 2023 American Society of Hematology (ASH) Annual Meeting and Exposition.
−Removed: The poster provided an interim update with a data cut-off as of October 18, 2023.
−Removed: As of that date, twenty-nine patients, with median age of 65 years, had been treated across five dose levels (DL1-5) with a mean of eight doses, including five with cutaneous T-cell lymphoma (CTCL), two with large granular lymphocytic leukemia, or LGL-L, one each with peripheral T-cell lymphoma, or PTCL, B-cell and Hodgkins’s lymphoma, and nineteen with a variety of solid tumor malignancies.
−Removed: Overall, the data demonstrated early signs of antitumor activity at doses that were generally well-tolerated and associated with substantial STAT3 knockdown in blood and tumor.
−Removed: The following table highlights the demographics of the 29 patients that were treated across 5 dose levels as of the October 18, 2023, data cut-off.
−Removed: cholangiocarcinoma;
−Removed: colon adenocarcinoma;
−Removed: colorectal (4);
−Removed: head and neck (3);
−Removed: ovarian, pancreatic (2), peritoneal, rectal and renal;
−Removed: ⌂ = anaplastic T-cell lymphoma;
−Removed: Data cut-off:
−Removed: 18 October 2023.
−Removed: KT-333 was generally well tolerated with primarily Grade 1 and 2 adverse events which included constipation, fatigue, nausea and anemia.
−Removed: The only KT-333 related adverse events that were Grade 3 or higher were stomatitis, arthralgia, and decreased weight in one patient each.
−Removed: Two dose-limiting toxicities (DLTs), stomatitis and arthralgia, occurred in LGL-L patients at DL5 and no DLTs were observed in solid tumor/lymphoma patients.
−Removed: Based on these findings, the study protocol was revised to continue dose escalation in solid tumor and lymphoma patients separately from patients with leukemia, including LGL-L and T-cell prolymphocytic leukemia, or T-PLL patients.
−Removed: To demonstrate proof-of-mechanism, STAT3 degradation was evaluated in peripheral blood in cycles 1 and 2 using targeted mass spectrometry as shown in Figure 37.
−Removed: Mean maximum degradation of STAT3 in PBMCs post KT-333 infusion increased from 70% to 84% between dose levels 1 and 5 respectively.
−Removed: Percent change in STAT3 represents mean percent change of two STAT3 peptides from baseline.
−Removed: Up to 96% maximum knockdown of STAT3 protein was observed in PBMCs from patient in dose level 4.
−Removed: Recovery of STAT3 protein was observed between doses.
−Removed: As shown in Figure 38, pathway engagement in tumor was demonstrated through semiquantitative analysis of multiplex immunofluorescence data which showed a 69% decrease in STAT3 positive cells and 87% reduction in phospho STAT3 positive cells in a CTCL biopsy ~ 24 hours post KT-333 infusion compared to baseline.
−Removed: We observed clinical activity in 3 of 5 CTLC patients, including 2 partial responses and 1 stable disease.
−Removed: We also observed 1 partial response in Classic Hodgkin lymphoma, or cHL.
−Removed: Collectively, these results demonstrated single agent activity in liquid tumors that was supported by preclinical data.
−Removed: In solid tumors, where preclinically no strong single agent activity was observed, a pattern of more prolonged stable disease, or SD in Head & Neck tumors was observed with a total of 4 patients.
−Removed: The following tables highlight the response data as of the October 18, 2023, data cut-off.
−Removed: *Mucoepidermoid carcinoma of parotid gland (C7+), sinonasal adenocarcinoma (C5), cholangiocarcinoma (C3), renal cell cancer (C3+).
−Removed: * Received steroids during 1st week of C1 to treat symptoms arising from Sezary Syndrome;
−Removed: ¥ Discontinued d/t AE (Gr.
−Removed: 2 squamous cell carcinoma of skin);
−Removed: discontinued d/t PI discretion (stable disease at discontinuation);
−Removed: HNC1 = Mucoepidermoid carcinoma of parotid gland;
−Removed: HNC2 = Sinonasal adenocarcinoma.
−Removed: KT-333 resulted in substantial reduction of STAT3, pSTAT3 and SOCS3 in a CTCL patient tumor with concomitant induction of IFNγ-stimulated genes, suggestive of positive immunomodulatory response in the tumor microenvironment that both clinically and preclinically has been shown to enhance the activity of anti-PD-1 drugs, supporting potential expansion into combinations of KT-333 and anti-PD-1 agents.
−Removed: An interferon gamma signature predictive of sensitivity to anti-PD-1 therapy was induced in the tumor biopsy of a cutaneous T-cell lymphoma (CTCL) patient following treatment on the Phase 1 trial, indicating the potential of KT-333 to synergize with PD-1 antibody therapy.
−Removed: Clinical Development Plans
−Removed: The Phase 1a dose escalation portion of the trial is ongoing.
−Removed: We expect to provide additional clinical data in 2024.
−Removed: We are developing degraders that target MDM2 for the treatment of solid tumors and hematological malignancies.
−Removed: KT-253 targets MDM2, the crucial regulator of the most common tumor suppressor, p53.
−Removed: p53 remains intact (wild type) in close to 50% of cancers, meaning that it retains its ability to modulate cancer cell growth.
−Removed: While small molecule inhibitors (SMIs) have been developed to stabilize and upregulate p53 expression, they have been found to induce a feedback loop that increases MDM2 protein levels, which can repress p53 and limit their efficacy.
−Removed: In preclinical studies, KT-253 has shown the ability to overcome the MDM2 feedback loop and rapidly induce cancer cell death with brief exposures, providing the opportunity for an improved efficacy and safety profile.
−Removed: In May 2023, we began dosing in a Phase 1 clinical trial of KT-253.
−Removed: The study is designed to evaluate the safety, tolerability, PK/PD and clinical activity of KT-253 in adult patients with liquid and solid tumors.
−Removed: KT-253 has achieved clinical proof-of-mechanism in the Phase 1 trial and shown signs of anti-tumor activity in liquid and solid tumor types.
−Removed: Patient enrollment and dosing are ongoing in the Phase 1a portion of the trial, and we expect to provide additional clinical data in 2024.
−Removed: Biology and Mechanism of Action
−Removed: The murine double minute 2 (MDM2) oncoprotein is the major E3 ligase which controls the tumor suppressor p53.
−Removed: p53 is a transcription factor that regulates cellular responses to stress and guides cell fate decisions such as cell cycle arrest, DNA repair, senescence, and apoptosis and functional in close to 50% of cancers, both liquid and solid, and many p53 functional cell lines are dependent on MDM2 overexpression for p53 suppression and survival.
−Removed: Stabilization and upregulation of p53 by removal of MDM2 by degradation can cause cells to undergo cell death and/or cell cycle arrest.
−Removed: While MDM2 small molecule inhibitors have shown clinical activity in a variety of tumor types, the activity has been limited as a result of the inhibition of MDM2 leading to a feedback loop, as shown in Figure 43.
−Removed: This feedback loop results in upregulation of MDM2 protein expression, which in turn makes it more difficult for occupancy-driven small molecules to inhibit MDM2.
−Removed: As a result, small molecule inhibitors have had a more modest effect on p53 upregulation which often leads to cell cycle arrest rather than apoptosis, thereby limiting the efficacy of MDM2/p53 small molecule inhibitors.
−Removed: This feedback loop also necessitates more chronic exposure to drug to maintain modest MDM2 inhibition in tumors, potentially leading to toxic effects on normal cells that limits the safety and tolerability of these inhibitors.
−Removed: Degraders have the potential to overcome the MDM2 feedback loop by completely removing the protein in a catalytic manner.
−Removed: This enables the development of highly potent drugs that are able to induce strong p53 upregulation and an irreversible acute apoptotic response in tumor cells with just brief exposures, thereby maximizing efficacy and improving the safety profile by allowing time for the recovery of normal cells.
−Removed: Development Opportunities
−Removed: The large numbers of p53wt cell lines dependent on MDM2, as seen in Figure 44, gives a high-level view of the potential breadth of opportunities in oncology for a potent and well tolerated agent for this pathway.
−Removed: These tumor cell types include but are not limited to cancers which have amplification and over expression of MDM2.
−Removed: De-stabilization of p53 by MDM2 enables cells to survive by blocking both cell cycle arrest and apoptosis.
−Removed: While the opportunities are very diverse, we plan to focus our development efforts on tumors which are most susceptible to the acute apoptotic response elicited by our degraders, where we believe we will be able to achieve the greatest therapeutic index and efficacy.
−Removed: Our initial disease areas of interest are hematological malignancies and solid tumor indications where preclinically we see that MDM2 degradation leads to an acute apoptotic response predictive of clinical activity with intermittent dosing.
−Removed: For hematological malignances, KT-253 has potential monotherapy and combination opportunities in Acute Myeloid Leukemia (AML), and potential opportunities across Myelofibrosis, Myelodysplastic Syndrome (MDS), Acute Lymphocytic Leukemia (ALL) and TP53WT lymphomas.
−Removed: For solid tumors, KT-253 has monotherapy opportunities across a subset of adult and pediatric tumors, to be informed by emerging gene signature with potential for a tumor-agnostic development path.
−Removed: We are assembling a comprehensive preclinical and clinical dataset examining the factors impacting in vivo response to intermittent dosing with KT-253 across multiple different solid and liquid tumor types in order to derive patient selection biomarkers for the next stage of development after Phase 1a.
−Removed: Preclinical Studies and Data
−Removed: KT-253’s potent p53 stabilization, with brief exposures, drives apoptosis in cancer cells.
−Removed: In Figure 45, KT-253 demonstrated greater than 200-fold improvements in both in vitro cell growth inhibition and apoptosis than small molecule inhibitors.
−Removed: Unlike small molecule inhibitors, KT-253 removes the protein, which can overcome the p53-dependent feedback loop that upregulates MDM2 production.
−Removed: As seen in Figure 46, MDM2 levels are increased by the small molecule inhibitor (feedback loop), impairing p53 stabilization.
−Removed: In preclinical models, 4-hour target coverage by KT-253 was sufficient to induce apoptosis, as shown in Figure 47.
−Removed: These data support an intermittent dosing schedule of KT-253 can drive efficacy while increasing therapeutic index.
−Removed: KT-253 potently degrades MDM2 leading to pathway impact and antitumor activity superior to a small molecular inhibitor in preclinical models.
−Removed: Targeted proteomic analysis of RS4;11 (ALL) tumors demonstrated robust degradation of MDM2 one hour post dosing and associated pathway activation biomarkers including p53 and GDF15, as show in Figure 48.
−Removed: Figure 49 shows sustained tumor regressions in MV4;11 (AML) CDX models after a single 3 mg/kg KT-253 dose.
−Removed: Additionally, KT-253 demonstrated robust anti-tumor activity in MCC models.
−Removed: No efficacy was observed with the clinically relevant dosing regimen of the small molecule inhibitor (DS-3032).
−Removed: Clinical Studies and Data
−Removed: The Phase 1 trial, began dosing patients in May 2023, is evaluating the safety, tolerability, PK/PD, and clinical activity of KT-253 in patients with relapsed or refractory high grade myeloid malignancies, including AML, ALL, lymphoma and solid tumors.
−Removed: Patients in the Phase 1 dose escalation study will receive intravenous doses of KT-253 administered once every 3 weeks.
−Removed: The open-label study is intended to identify the recommended Phase 2 dose, and is comprised of two arms, with ascending doses of KT-253 in each arm.
−Removed: The first arm consists of patients with lymphomas and advanced solid tumors and the second arm consists of patients with high grade myeloid malignancies and ALL.
−Removed: As of the October 20, 2023, data cut-off date, a total of 9 patients with solid tumors had been enrolled onto dose levels 1-3 of Arm A and received a mean of 2.3 cycles with a range of 1 to 6 cycles.
−Removed: The data from Arm A of the ongoing Phase 1a trial demonstrated KT-253 clinical proof-of-mechanism and initial signs of clinical activity in the first 2 dose levels in patients.
−Removed: Clinical response results for all patients within a dose cohort were available for dose level 1.
−Removed: Based on exposures we did not expect this dose level to be clinically active, however, we observed that among the 3 solid tumor patients treated on dose level 1, there was 1 confirmed partial response after 4 cycles with treatment continuing after 6 cycles, 1 confirmed stable disease after 4 cycles with the patient subsequently discontinued from the study after 6 cycles for lack of response, and 1 patient with disease progression after cycle 1, as seen in Figure 51.
−Removed: The patient with the partial response had Merkel Cell Carcinoma, or MCC, metastatic to abdominal lymph nodes and skin who had previously been treated with chemotherapy as well as multiple different immune checkpoint inhibitors.
−Removed: There were no dose-limiting toxicities across dose levels 1-3.
−Removed: As of the data cut-off date, the most common drug-related adverse events.
−Removed: or AE’s, occurring in 2 or more patients included Grade 1/2 nausea and Grade 1 diarrhea.
−Removed: One patient at dose level 1 had a serious adverse event, or SAE, of Grade 3 hypotension during cycle 4 that was due to diminished oral intake deemed related to study drug.
−Removed: Treatment included IV fluids and the patient remains on study without dose reduction or recurrence of hypotension.
−Removed: As of the data cut-off date, there were no neutropenia or thrombocytopenia AEs even in patients who had received up to 6 cycles of therapy.
−Removed: Clinical Development Plan
−Removed: The KT-253 Phase 1a trial is an open label dose escalation study where adult patients with relapsed or refractory high grade myeloid malignancies, ALL, lymphomas and solid tumors receive IV doses of KT-253 once every 3 weeks.
−Removed: The study is intended to evaluate safety, tolerability, PK/PD and initial clinical activity and identify the recommended Phase 2 dose.
−Removed: It is comprised of two arms with ascending doses of KT-253 in each arm.
−Removed: Arm A is in patients with advanced solid tumors and lymphomas and Arm B is in patients with relapsed or refractory high grade myeloid malignancies, including AML, and ALL.
−Removed: The first patient was dosed in May 2023 and the first 2 dose levels in Arm A have been fully enrolled, with enrollment ongoing.
−Removed: Enrollment onto Arm B has also been initiated following demonstration of on-target pharmacology in the first 2 dose levels of Arm A.
−Removed: The Company expects to share additional clinical data in 2024.
+Added: The Eczema Area and Severity Index (EASI) is a validated tool that measures the severity of atopic dermatitis.
+Added: Peak pruritus was reduced by an average of 52% and 63%, respectively, with maximum reductions occurring by day 42.
+Added: Figure 10 highlights the initial clinical impact of KT-474 in AD patients in the third part of the Phase 1 study.
+Added: Clinical endpoints associated with improvement in skin lesions and symptoms addressing disease burden resulted in substantial responses in the majority of both HS and AD patients evaluated.
+Added: KT-474 was generally well-tolerated across all dose groups.
+Added: There were no serious adverse events, no drug-related infections, and no adverse events observed leading to dose interruption or discontinuation.
+Added: A modest, non-adverse QTc prolongation, consistent with that observed by Day 7 in the MAD healthy volunteer study, was also observed in the patient cohort but spontaneously resolved back to baseline with continued dosing during the 28-day dosing period.
+Added: In the fourth quarter of 2023, Sanofi initiated two Phase 2 clinical trials.
+Added: The Phase 2 randomized, double-blind, placebo-controlled, dose ranging trials are evaluating the safety and efficacy of KT-474 as a potential treatment of HS and AD.
+Added: In July 2024, Sanofi communicated to Kymera its decision to expand the ongoing Phase 2 trials in HS and AD following an interim review of safety and efficacy data by an independent data monitoring committee.
+Added: The expansion of the ongoing HS and AD KT-474 Phase 2 studies to larger dose-ranging Phase 2b studies is intended to accelerate overall development timelines and enable a subsequent transition into registrational Phase 3 trials.
+Added: The HS and AD Phase 2b trials are expected to be completed in the first half of 2026 and mid-2026, respectively.
+Added: Additionally, we and Sanofi are evaluating opportunities to expand in indications beyond HS and AD.
Collaboration Agreement with Sanofi (formerly Genzyme Corporation)
5 unchanged sentences
The Original Sanofi Agreement, as amended by the Amended Sanofi Agreement, is referred to herein as the Sanofi Agreement.
−Removed: Under the Sanofi Agreement, Kymera grants to Sanofi a worldwide exclusive license to develop, manufacture and commercialize certain lead compounds generated during the collaboration directed against IRAK4 and one additional undisclosed target in an undisclosed field of use.
+Added: Under the Sanofi Agreement, we granted to Sanofi a worldwide exclusive license to develop, manufacture and commercialize certain lead compounds generated during the collaboration directed against IRAK4 and one additional undisclosed target in an undisclosed field of use.
Such license is exercisable on a collaboration target-by-collaboration target basis only after a specified milestone.
5 unchanged sentences
In consideration for the exclusive licenses granted to Sanofi under the Sanofi Agreement, Sanofi paid to us an upfront payment of $150.0 million.
−Removed: In addition to the upfront payment, under the agreement we were eligible to receive certain development milestone payments of up to $1.48 billion in the aggregate, of which more than $1.0 billion relates to the IRAK4 program, upon the achievement of certain developmental or regulatory events.
−Removed: We will also be eligible to receive certain commercial milestone payments up to $700.0 million in the aggregate, of which $400.0 million relates to the IRAK4 program, which are payable upon the achievement of certain net sales thresholds.
−Removed: We will further be eligible to receive tiered royalties for each program on net sales ranging from the high single digits to high teens, subject to low-single digits upward adjustments in certain circumstances.
+Added: In addition to the upfront payment, under the agreement we were eligible to receive certain development milestone payments of up to $1.48 billion, and commercial milestone payments of up to $700.0 million, in the aggregate.
+Added: Of these milestones, we remain eligible to receive up to $1.0 billion in development milestones upon the achievement of certain developmental or regulatory events, and up to $400.0 million in commercial milestones which are payable upon the achievement of certain net sales thresholds, all of which are related to the IRAK4 program.
+Added: We will further be eligible to receive tiered royalties on net sales ranging from the high single digits to high teens, subject to low-single digits upward adjustments in certain circumstances.
The Sanofi Agreement, unless earlier terminated, will expire on a product-by-product basis on the date of expiration of all payment obligations under the Sanofi Agreement with respect to such product.
We or Sanofi may terminate the agreement upon the other party’s material breach or insolvency or for certain patent challenges.
−Removed: In addition, Sanofi may terminate the agreement for convenience or for a material safety event upon advance prior written notice, and we may terminate the agreement with respect to any collaboration candidate if, following Sanofi’s assumption of responsibility for the development,
−Removed: commercialization or manufacturing of collaboration candidates with respect to a particular target, Sanofi ceases to exploit any collaboration candidates directed to such target for a specified period.
+Added: In addition, Sanofi may terminate the agreement for convenience or for a material safety event upon advance prior written notice, and we may terminate the agreement with respect to any collaboration candidate if, following Sanofi’s assumption of responsibility for the development, commercialization or manufacturing of collaboration candidates with respect to a particular target, Sanofi ceases to exploit any collaboration candidates directed to such target for a specified period.
Additionally, in December 2022, Sanofi provided us with written notice of its intention to take KT-474 into Phase 2 clinical trials.
In the fourth quarter of 2023, the Company achieved two milestones of $40.0 million and $15.0 million relating to the dosing of the first patient in the Phase 2 clinical trial for the first and second indications, respectively.
−Removed: As of December 31, 2023, the Company had received the $40.0 million milestone with the $15.0 million included within the accounts receivable on the consolidated balance sheet.
+Added: As of December 31, 2024, the Company had received both the $40.0 million milestone and the $15.0 million milestone.
In September 2023, the Company and Sanofi mutually agreed to cease activities related to the undisclosed target and we are no longer eligible for the milestone and royalty payments associated with the second target.
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Companies developing small molecule protein degraders therapies for patients, include, but are not limited to, Arvinas, Inc., C4 Therapeutics, Inc., Nurix Therapeutics, Inc., and Foghorn Therapeutics, Inc.
−Removed: Further, several large pharmaceutical companies have disclosed preclinical investments in this field.
+Added: Further, several pharmaceutical companies have disclosed preclinical investments in this field.
Our competitors will also include companies that are or will be developing other targeted protein degradation methods as well as small molecule, antibody, or gene therapies for the same indications that we are targeting.
−Removed: In addition to competitors we face in developing small molecule protein degraders, we will also face competition in the indications we expect to pursue with our IRAK4, STAT6, TYK2, STAT3, and MDM2 programs.
−Removed: Many of these indications have approved standards of care which may include more traditional therapeutic modalities.
+Added: In addition to competitors we face in developing small molecule protein degraders, we will also face competition in the indications we expect to pursue with our IRAK4, STAT6 and TYK2 programs.
+Added: In particular, several pharmaceutical companies have announced partnerships around programs targeting STAT6, including Sanofi, Johnson & Johnson and Gilead Sciences, Inc.
+Added: More broadly, many of the indications targeted by our programs have approved standards of care which may include more traditional therapeutic modalities.
In order to compete effectively with these existing therapies, we will need to demonstrate that our protein degrader therapies are favorable to existing therapeutics.
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Our success depends in part on our ability to secure intellectual property protection for our product candidates and future products, as well as our platform protein degradation technologies and any other relevant inventions and improvements that are considered commercially important to our business.
−Removed: Our success also depends on our ability to defend and enforce our
−Removed: intellectual property rights, preserve the confidentiality of our proprietary information, and operate without infringing, misappropriating or otherwise violating the valid and enforceable patents and proprietary rights of third parties.
+Added: Our success also depends on our ability to defend and enforce our intellectual property rights, preserve the confidentiality of our proprietary information, and operate without infringing, misappropriating or otherwise violating the valid and enforceable patents and proprietary rights of third parties.
As with other biotechnology and pharmaceutical companies, our ability to secure and maintain intellectual property protection for our product candidates, future products, and other proprietary technologies will depend on our success in obtaining effective patent coverage and enforcing those patents if granted.
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Our intellectual property includes a portfolio of wholly owned patent families covering our platform E3 ligase ligand technology and our novel bifunctional degrader product candidates, including claims to compositions of matter, pharmaceutical compositions, methods of use, methods of treatment, and other related compounds and methods.
−Removed: Our intellectual property portfolio is in its very early stages, and, as of December 31, 2023, included 19 granted U.S.
+Added: Our intellectual property portfolio is in its early development stages, and, as of December 31, 2024, included 31 granted U.S.
patents, about 92 U.S.
−Removed: patent applications, about 25 international patent applications, five granted foreign patents, and about 449 foreign patent applications.
+Added: patent applications, about 31 international patent applications, 12 granted foreign patents, and about 543 foreign patent applications.
Our patent portfolio is generally organized into two categories:
2 unchanged sentences
Our platform E3 ligase ligand patent families are wholly owned and include four patent families directed to novel ligands for the cereblon E3 ubiquitin ligase, as well as methods of treatment and other related methods.
−Removed: As of December 31, 2023, our platform E3 ligase ligand patent families included three granted U.S.
−Removed: patents, five U.S.
+Added: As of December 31, 2024, our platform E3 ligase ligand patent families included five granted U.S.
+Added: patents, four U.S.
patent applications, and three patent applications in Europe.
2 unchanged sentences
Our protein degrader patent families are wholly owned and are directed to novel bifunctional degrader compounds that are useful in affecting ubiquitination of a target protein, as well as methods of treatment and other related methods.
−Removed: As of December 31, 2023, our protein degrader patent families included two granted U.S.
−Removed: patent, five U.S.
−Removed: patent applications and about 19 foreign patent applications filed in foreign jurisdictions, such as Australia, Canada, Europe, Israel, Japan, Mexico, New Zealand, and the Russian Federation.
+Added: As of December 31, 2024, our protein degrader patent families included three granted U.S.
+Added: patents, and about 26 patent applications in U.S., PCT, and foreign jurisdictions, such as Australia, Canada, Europe, Israel, Japan, Mexico, New Zealand, and the Russian Federation.
or foreign patents resulting from these applications, if granted and all appropriate maintenance fees paid, are expected to expire between 2038 and 2043, absent any patent term adjustments or extensions.
Target-Specific Degrader Patent Families
−Removed: Our target-specific degrader patent families are wholly owned and focus protection around degrader compounds that are designed to target specific proteins for degradation, as well as methods of treatment and other related methods.
+Added: Our target-specific degrader patent families focus protection around degrader compounds that are designed to target specific proteins for degradation, as well as methods of treatment and other related methods.
Such targets include, for example, IRAK (interleukin-1 receptor-associated kinases) and STAT (signal transducers and activators of transcription).
As of December 31, 2024, our target-specific degrader patent families included 23 granted U.S.
−Removed: patents, about 87 U.S.
−Removed: patent applications, about 22 international patent applications, three granted foreign patents, and about 423 patent applications filed in foreign jurisdictions, such as Australia, Brazil, Canada, China, Eurasia, Europe, Israel, India, Japan, Mexico, New Zealand, Singapore, South Africa, and Taiwan.
+Added: patents, seven granted foreign patents, and about 617 patent applications filed in U.S., PCT, and foreign jurisdictions, such as Australia, Brazil, Canada, China, Eurasia, Europe, Israel, India, Japan, Mexico, New Zealand, Singapore, South Africa, and Taiwan.
or foreign patents resulting from our target-specific degrader patent families, if granted and all appropriate maintenance fees paid, are expected to expire between 2038 and 2045, absent any patent term adjustments or extensions.
2 unchanged sentences
As of December 31, 2024, our IRAK-specific patent families included 17 granted U.S.
−Removed: patents, about 34 U.S.
−Removed: patent applications, about eight international patent applications, three granted foreign patents and about 293 patent applications filed in foreign jurisdictions,
−Removed: such as Australia, Argentina, Brazil, Canada, China, Europe, Eurasia, Gulf Cooperation Council, Israel, India, Japan, Mexico, New Zealand, Singapore, South Africa, and Taiwan.
+Added: patents, seven granted foreign patents, and about 367 patent applications filed in U.S., PCT, and foreign jurisdictions, such as Australia, Argentina, Brazil, Canada, China, Europe, Eurasia, Gulf Cooperation Council, Israel, India, Japan, Mexico, New Zealand, Singapore, South Africa, and Taiwan.
or foreign patents resulting from our IRAK-specific patent families, if granted and all appropriate maintenance fees paid, are expected to expire between 2038 and 2044, absent any patent term adjustments or extensions.
−Removed: With respect to the KT-474 product candidate, as of December 31, 2023, we own three granted U.S.
−Removed: patent, eight pending U.S.
−Removed: patent applications, five pending international patent applications, one granted foreign patent and about 128 patent applications filed in foreign jurisdictions, such as Australia, Brazil, Canada, China, Europe, Israel, India, Japan, South Korea, Mexico, New Zealand, Singapore, South Africa, and Taiwan, each with claims directed to compositions of matter covering KT-474 and/or methods of making or using KT-474.
+Added: With respect to the KT-474 product candidate, as of December 31, 2024, we own eight granted U.S.
+Added: patents, nine pending U.S.
+Added: patent applications, four pending international patent applications, three granted foreign patents and about 183 patent applications filed in foreign jurisdictions, such as Australia, Brazil, Canada, China, Europe, Israel, India, Japan, South Korea, Mexico, New Zealand, Singapore, South Africa, and Taiwan, each with claims directed to compositions of matter covering KT-474 and/or methods of making or using KT-474.
or foreign patents resulting from these patent families, if granted and all appropriate maintenance fees paid, are expected to expire between 2039 and 2044, absent any patent term adjustments or extensions.
STAT-Specific Patent Families
−Removed: Our STAT-specific patent families are wholly owned and focus on degrader compounds that are designed to specifically target signal transducers and activators of transcription (STAT) for degradation.
−Removed: As of December 31, 2023, our STAT-specific patent families included two granted U.S.
−Removed: patent, about 18 U.S.
−Removed: patent applications, three international patent applications, and about 49 patent applications filed in foreign jurisdictions, such as Australia, Canada, China, Eurasia, Europe, India, Israel, Japan, South Korea, Mexico, and Taiwan.
+Added: Our STAT-specific patent families focus on degrader compounds that are designed to specifically target signal transducers and activators of transcription (STAT) for degradation.
+Added: As of December 31, 2024, our STAT-specific patent families included three granted U.S.
+Added: patents and about 106 patent applications filed in U.S., PCT, and foreign jurisdictions, such as Australia, Canada, China, Eurasia, Europe, India, Israel, Japan, South Korea, Mexico, and Taiwan.
+Added: Two of the international patent applications directed to methods of treatment are co-owned with academic collaborators, and the remaining STAT-specific patent families are wholly owned.
or foreign patents resulting from our STAT-specific patent families, if granted and all appropriate maintenance fees paid, are expected to expire between 2040 and 2044, absent any patent term adjustments or extensions.
Other Target-Specific Patent Families
−Removed: As of December 31, 2023, we own one granted U.S.
−Removed: patent, about 31 U.S.
−Removed: patent applications, 10 international patent applications and about 81 patent applications filed in Australia, Argentina, Brazil, Canada, China, Europe, Gulf Cooperation Council, Israel, India, Japan, Mexico, New Zealand, Singapore, South Africa, and Taiwan which focus on degrader compounds designed to specifically target other proteins.
+Added: As of December 31, 2024, we own three granted U.S.
+Added: patents and about 132 patent applications filed in U.S., PCT, and foreign jurisdictions, such as Australia, Argentina, Brazil, Canada, China, Europe, Gulf Cooperation Council, Israel, India, Japan, Mexico, New Zealand, Singapore, South Africa, and Taiwan which focus on degrader compounds designed to specifically target other proteins.
or foreign patents resulting from these patent families, if granted and all appropriate maintenance fees paid, are expected to expire between 2040 and 2044, absent any patent term adjustments or extensions.
2 unchanged sentences
In certain cases, a patent term can be extended to recapture a portion of the term effectively lost as a result of the FDA regulatory review period.
+Added: With regard to a drug for which FDA approval is the first permitted marketing of the active ingredient, the Hatch-Waxman Act allows for extension of the term of one U.S.
+Added: patent that includes at least one claim covering the composition of matter of an FDA approved drug, an FDA-approved method of treatment using the drug, and/or a method of manufacturing the FDA-approved drug.
The Hatch-Waxman Act permits a patent term extension of up to five years beyond the expiration of the patent, though the total patent term, including any extension, must not exceed 14 years following FDA approval.
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When possible, we expect to apply for patent term extensions for patents covering our product candidates and their methods of use.
−Removed: We have and intend to file applications for trademark registrations in connection with our product candidates and other technologies in various jurisdictions, including the United States.
−Removed: We have applied to register both the KYMERA mark and the KYMERA THERAPEUTICS mark in the United States, Europe, and Canada.
−Removed: We also filed applications in the same jurisdictions for the mark IRAKIMiD, for pharmaceutical and medical preparations and therapeutics, as well as diagnostic reagents, for the treatment of oncology, autoimmune, immune-oncology and other related diseases.
−Removed: In addition, we filed applications for E3 HUMAN ATLAS and E3 LIGASE WHOLE BODY ATLAS in connection with pharmaceutical research and development and drug development and discovery services.
+Added: We have filed and intend to file applications for trademark registrations in connection with our product candidates and other technologies in various jurisdictions, including the United States and the European Union.
All of our European Union trademarks in existence as of December 31, 2020 were automatically cloned onto the United Kingdom register due to “Brexit.”
−Removed: Most recently, we filed an application for our K & Design mark in the United States, and we plan to file European Union, United Kingdom, and Canada applications based on our U.S.
−Removed: priority date in that application in due course.
+Added: As of December 31, 2024, our trademark portfolio includes registrations and allowed applications of the KYMERA mark and the KYMERA THERAPEUTICS mark in the United States, Europe, and Canada, all covering Class 5 pharmaceutical and medical preparations and therapeutics and Class 42 pharmaceutical research and development and drug development and discovery services, and registrations, allowed applications, and pending applications in Europe, the United States, and Canada respectively for our K & Design logo mark covering the same goods and services.
+Added: We also hold registrations of E3 HUMAN ATLAS and E3 LIGASE WHOLE BODY ATLAS in the European Union and the United Kingdom covering Class 42 pharmaceutical research and development and drug development and discovery services.
+Added: Trade Secrets
+Added: In addition to patents, we may rely on trade secrets and know-how to develop and maintain our competitive position.
+Added: Companies typically rely on trade secrets to protect aspects of their business that are not amenable to, or that they do not consider appropriate for, patent protection.
+Added: We protect trade secrets, if any, and know-how by establishing confidentiality agreements and invention assignment agreements with our employees, consultants, scientific advisors, contractors and partners.
+Added: These agreements provide that all confidential information developed or made known during the course of an individual or entity’s relationship with us must be kept confidential during and after the relationship.
+Added: These agreements also generally provide that all relevant inventions resulting from work performed for us or relating to our business and conceived or completed during the period of employment or assignment, as applicable, shall be our exclusive property.
+Added: In addition, we take other appropriate precautions, such as physical and technological security measures, to guard against misappropriation of our proprietary information by third parties.
Government Regulation
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Preclinical studies include laboratory evaluations of drug chemistry, formulation and stability, as well as in vitro and animal studies to assess safety and in some cases to establish the rationale for therapeutic use.
−Removed: The conduct of preclinical studies is subject to federal
−Removed: and state regulations and requirements, including GLP requirements for safety/toxicology studies.
+Added: The conduct of preclinical studies is subject to federal and state regulations and requirements, including GLP requirements for safety/toxicology studies.
The results of the preclinical studies, together with manufacturing information and analytical data must be submitted to the FDA as part of an IND.
−Removed: An IND is a request for authorization from the FDA to administer an investigational product to humans and must become effective before clinical trials may begin.
+Added: An IND is a request for authorization from the FDA to administer an investigational product to humans and must become effective
+Added: before clinical trials may begin.
Some long-term preclinical testing may continue after the IND is submitted.
18 unchanged sentences
These clinical trials are intended to establish the overall risk/benefit ratio of the investigational product and to provide an adequate basis for product approval and physician labeling.
−Removed: In March 2022, the FDA released a final guidance entitled “Expansion Cohorts:
−Removed: Use in First-In-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics,” which outlines how drug developers can utilize an adaptive trial design commonly referred to as a seamless trial design in early stages of oncology drug development (i.e., the first-in-human clinical trial) to compress the traditional three phases of trials into one continuous trial called an expansion cohort trial.
−Removed: Information to support the design of individual expansion cohorts are included in IND applications and assessed by FDA.
−Removed: Expansion cohort trials can potentially bring efficiency to drug development and reduce development costs and time.
Post-approval trials, sometimes referred to as Phase 4 clinical trials or post-marketing studies, may be conducted after initial marketing approval.
18 unchanged sentences
The FDA reviews an NDA to determine, among other things, whether the drug is safe and effective for the indications sought and whether the facility in which it is manufactured, processed, packaged or held meets standards designed to assure the product’s continued safety, quality and purity.
−Removed: Under the goals and polices agreed to by the FDA under the Prescription Drug User Fee Act, or PDUFA, the FDA targets ten months, from the filing date, in which to complete its initial review of a new molecular entity NDA and respond to the applicant, and six months from the filing date of a new molecular entity NDA for priority review.
−Removed: The FDA does not always meet its PDUFA goal dates for standard or priority NDAs, and the review process is often extended by FDA requests for additional information or clarification.
+Added: Under the goals and polices agreed to by the FDA under the Prescription Drug User Fee Act, or PDUFA, the FDA targets ten months, from the filing date, in which to complete its initial review of a new molecular entity NDA and respond to the applicant, and six months from the filing date of a new molecular entity NDA receiving priority review.
+Added: The FDA does not always meet its PDUFA goal dates for standard or priority review NDAs, and the review process is often extended by FDA requests for additional information or clarification.
Further, under PDUFA, as amended, each NDA must be accompanied by a user fee.
29 unchanged sentences
may be lost if the FDA later determines that the request for designation was materially defective or the manufacturer of the approved product is unable to assure sufficient quantities of the product to meet the needs of patients with the rare disease or condition.
−Removed: In September of 2022, KT-333, Kymera’s STAT3 degrader in development for relapsed and/or refractory lymphomas and solid tumors, was granted its second orphan drug designation by the U.S.
−Removed: Food and Drug Administration for the treatment of cutaneous T-cell lymphoma (CTCL), following its orphan drug designation for peripheral T-cell lymphoma (PTCL) in June of 2022.
−Removed: In June 2023, KT-253, Kymera’s MDM2 degrader in development for hematological malignancies and solid tumors, was granted orphan drug designation by the FDA for the treatment of acute myeloid leukemia.
−Removed: These designations provide incentives to encourage the development of medicines for rare diseases.
Expedited Development and Review Programs for Drugs
2 unchanged sentences
A new drug is eligible for Fast Track designation if it is intended to treat a serious or life-threatening disease or condition and demonstrates the potential to address unmet medical needs for such disease or condition.
−Removed: Fast Track designation provides increased opportunities for sponsor interactions with the FDA during preclinical and clinical development, in addition to the
−Removed: potential for rolling review once a marketing application is filed, meaning that the agency may review portions of the marketing application before the sponsor submits the complete application, as well as Priority Review, discussed below.
+Added: Fast Track designation provides increased opportunities for sponsor interactions with the FDA during preclinical and clinical development, in addition to the potential for rolling review once a marketing application is filed, meaning that the agency may review portions of the marketing application before the sponsor submits the complete application, as well as Priority Review, discussed below.
In addition, a new drug may be eligible for Breakthrough Therapy designation if it is intended to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.
25 unchanged sentences
Post-Approval Requirements for Drugs
−Removed: Drugs manufactured or distributed pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to recordkeeping, periodic reporting, product sampling and distribution, tracking and tracing, reporting of adverse experiences with the product, complying with promotion and advertising requirements, which include restrictions on promoting products for unapproved uses or patient populations (known as “off-label use”) and limitations on industry-sponsored scientific and educational activities.
+Added: Drugs manufactured or distributed pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to recordkeeping, periodic reporting, product sampling and
+Added: distribution, tracking and tracing, reporting of adverse experiences with the product, complying with promotion and advertising requirements, which include restrictions on promoting products for unapproved uses or patient populations (known as “off-label use”) and limitations on industry-sponsored scientific and educational activities.
Manufacturers and other parties involved in the drug supply chain for prescription drug products must also comply with product tracking and tracing requirements and for notifying the FDA of counterfeit, diverted, stolen and intentionally adulterated products or products that are otherwise unfit for distribution in the United States.
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or mandated modification of promotional materials and labeling and issuance of corrective information.
−Removed: Regulation of Companion Diagnostics
−Removed: Companion diagnostics identify patients who are most likely to benefit from a particular therapeutic product;
−Removed: identify patients likely to be at increased risk for serious side effects as a result of treatment with a particular therapeutic product;
−Removed: or monitor response to treatment with a particular therapeutic product for the purpose of adjusting treatment to achieve improved safety or effectiveness.
−Removed: Companion diagnostics are regulated as medical devices by the FDA.
−Removed: In the U.S., the FD&C Act, and its implementing regulations, and other federal and state statutes and regulations govern, among other things, medical device design and development, preclinical and clinical testing, premarket clearance or approval, registration and listing, manufacturing, labeling, storage, advertising and promotion, sales and distribution, export and import, and post-market surveillance.
−Removed: Unless an exemption or FDA exercise of enforcement discretion applies, diagnostic tests generally require marketing clearance or approval from the FDA prior to commercialization.
−Removed: The two primary types of FDA marketing authorization applicable to a medical device are clearance of a premarket notification, or 510(k), and approval of a premarket approval application, or PMA.
−Removed: To obtain 510(k) clearance for a medical device, or for certain modifications to devices that have received 510(k) clearance, a manufacturer must submit a premarket notification demonstrating that the proposed device is substantially equivalent to a previously cleared 510(k) device or to a preamendment device that was in commercial distribution before May 28, 1976, or a predicate device, for which the FDA has not yet called for the submission of a PMA.
−Removed: In making a determination that the device is substantially equivalent to a predicate device, the FDA compares the proposed device to the predicate device and assesses whether the subject device is comparable to the predicate device with respect to intended use, technology, design and other features which could affect safety and effectiveness.
−Removed: If the FDA determines that the subject device is substantially equivalent to the predicate device, the subject device may be cleared for marketing.
−Removed: The 510(k) premarket notification pathway generally takes from three to twelve months from the date the application is completed, but can take significantly longer.
−Removed: A PMA must be supported by valid scientific evidence, which typically requires extensive data, including technical, preclinical, clinical and manufacturing data, to demonstrate to the FDA’s satisfaction the safety and effectiveness of the device.
−Removed: For diagnostic tests, a PMA typically includes data regarding analytical and clinical validation studies.
−Removed: As part of its review of the PMA, the FDA will conduct a pre-approval inspection of the manufacturing facility or facilities to ensure compliance with the Quality System Regulation, or QSR, which requires manufacturers to follow design, testing, control, documentation and other quality assurance procedures.
−Removed: The FDA’s review of an initial PMA is required by statute to take between six months, although the process typically takes longer, and may require several years to complete.
−Removed: If the FDA evaluations of both the PMA and the manufacturing facilities are favorable, the FDA will either issue an approval letter or an approvable letter, which usually contains a number of conditions that must be met in order to secure the final approval of the PMA.
−Removed: If the FDA’s evaluation of the PMA or manufacturing facilities is not favorable, the FDA will deny the approval of the PMA or issue a not approvable letter.
−Removed: A not approvable letter will outline the deficiencies in the application and, where practical, will identify what is necessary to make the PMA approvable.
−Removed: Once granted, PMA approval may be withdrawn by the FDA if compliance with post-approval requirements, conditions of approval or other regulatory standards is not maintained, or problems are identified following initial marketing.
−Removed: On July 31, 2014, the FDA issued a final guidance document addressing the development and approval process for “In Vitro Companion Diagnostic Devices.” According to the guidance document, for novel therapeutic products that depend on the use of a diagnostic test and where the diagnostic device could be essential for the safe and effective use of the corresponding therapeutic product, the premarket application for the companion diagnostic device should be developed and approved or cleared contemporaneously with the therapeutic, although the FDA recognizes that there may be cases when contemporaneous development may not be possible.
−Removed: However, in cases where a drug cannot be used safely or effectively without the companion diagnostic, the FDA’s guidance indicates it will generally not approve the drug without the approval or clearance of the diagnostic device.
−Removed: The FDA also issued a draft guidance in July 2016 setting forth the principles for co-development of an in vitro companion diagnostic device with a therapeutic product.
−Removed: The draft guidance describes principles to guide the development and contemporaneous marketing authorization for the therapeutic product and its corresponding in vitro companion diagnostic.
−Removed: Once cleared or approved, the companion diagnostic device must adhere to post-marketing requirements including the requirements of the FDA’s QSR, adverse event reporting, recalls and corrections along with product marketing requirements and limitations.
−Removed: Like drug makers, companion diagnostic makers are subject to unannounced FDA inspections at any time during which the FDA will conduct an audit of the product(s) and our facilities for compliance with its authorities.
Other Regulatory Matters
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Other Healthcare Laws
−Removed: Healthcare providers, physicians, and third-party payors will play a primary role in the recommendation and prescription of any products for which we obtain marketing approval.
−Removed: Our business operations and any current or future arrangements with third-party payors, healthcare providers and physicians may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations that may constrain the business or financial arrangements and relationships through which we develop, market, sell and distribute any drugs for which we obtain marketing approval.
−Removed: In the United States, these laws include, without limitation, state and federal anti-kickback, false claims, physician transparency, pharmaceutical price reporting, and patient data privacy and security laws and regulations.
−Removed: If our operations are found to be in violation of any of such laws or any other governmental regulations that apply, we may be subject to penalties, including, without limitation, administrative, civil and criminal penalties, damages, fines, disgorgement, the curtailment or restructuring of operations, integrity oversight and reporting obligations, exclusion from participation in federal and state healthcare programs and responsible individuals may be subject to imprisonment.
−Removed: The scope and enforcement of each of these laws is uncertain and subject to rapid change in the current environment of healthcare reform, especially in light of the lack of applicable precedent and regulations.
−Removed: Federal and state enforcement bodies have recently increased their scrutiny of interactions between healthcare companies and healthcare providers, which has led to a number of investigations, prosecutions, convictions and settlements in the healthcare industry.
−Removed: It is possible that governmental authorities will conclude that our business practices do not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws and regulations.
−Removed: If our operations are found to be in violation of any of these laws or any other related governmental regulations that may apply to us, we may be subject to significant civil, criminal and administrative penalties, damages, fines, imprisonment, disgorgement, exclusion from government funded healthcare programs, such as Medicare and Medicaid, reputational harm, additional oversight and reporting obligations if we become subject to a corporate integrity agreement or similar settlement to resolve allegations of non-compliance with these laws and the curtailment or restructuring of our operations.
−Removed: If any of the physicians or other healthcare providers or entities with whom we expect to do business is found not to be in compliance with applicable laws, they may be subject to similar actions, penalties and sanctions.
+Added: Drug companies are subject to additional healthcare regulation and enforcement by the federal government and by authorities in the states and foreign jurisdictions in which they conduct their business.
+Added: These laws and regulations may limit our relationships with our partners, providers, and third-party payors.
+Added: Such laws include, without limitation, state and federal anti-kickback, fraud and abuse, false claims, and transparency laws and regulations related to drug pricing and payments and other transfers of value made to physicians and other healthcare providers.
+Added: They also include patient data privacy and security laws and regulations.
+Added: It is possible that governmental authorities will conclude that our business practices do not comply with current or future fraud and abuse laws or other healthcare laws and regulations.
+Added: If our operations or our partners’ operations are found to be in violation of any of such laws or any other governmental regulations that apply, by extension, we may be subject to penalties, including, without limitation, administrative, civil and criminal penalties, damages, fines, disgorgement, the curtailment or restructuring of operations, integrity oversight and reporting obligations, exclusion from participation in federal and state healthcare programs and responsible individuals may be subject to imprisonment.
+Added: These laws are broadly applicable, and the scope and enforcement of each of these laws is uncertain and subject to rapid change.
Ensuring business arrangements comply with applicable healthcare laws, as well as responding to possible investigations by government authorities, can be time- and resource-consuming and can divert a company’s attention from its business.
Insurance Coverage and Reimbursement
−Removed: In the United States and markets in other countries, patients who are prescribed treatments for their conditions and providers performing the prescribed services generally rely on third-party payors to reimburse all or part of the associated healthcare costs.
−Removed: Thus, even if a product candidate is approved, sales of the product will depend, in part, on the extent to which third-party payors, including government health programs in the United States such as Medicare and Medicaid, commercial health insurers and managed care organizations, provide coverage, and establish adequate reimbursement levels for, the product.
−Removed: In the United States, the principal decisions about reimbursement for new medicines are typically made by the Centers for Medicare & Medicaid Services, or CMS, an agency within the U.S.
+Added: In the United States and markets in other countries, providers and patients generally rely on third-party payors to reimburse associated healthcare costs.
+Added: Even if a product candidate is approved, sales of the product will depend, in part, on the extent to which third-party payors (like Medicare and Medicaid, commercial health insurers and managed care organizations, among others) provide coverage and establish adequate reimbursement levels for the product.
+Added: In the United States, principal decisions about reimbursement for new drugs are typically made by the Centers for Medicare & Medicaid Services, or CMS, an agency within the U.S.
Department of Health and Human Services.
−Removed: CMS decides whether and to what extent a new medicine will be covered and reimbursed under Medicare and private payors tend to follow CMS to a substantial degree.
−Removed: No uniform policy of coverage and reimbursement for drug products exists among third-party payors.
−Removed: Therefore, coverage and reimbursement for drug products can differ significantly from payor to payor.
−Removed: The process for determining whether a third-party payor will provide coverage for a product may be separate from the process for setting the price or reimbursement rate that the payor will pay for the product once coverage is approved.
−Removed: Third-party payors are increasingly challenging the prices charged, examining the medical necessity, reviewing the cost-effectiveness of medical products and services and imposing controls to manage costs.
−Removed: Third-party payors may limit coverage to specific products on an approved list, also known as a formulary, which might not include all of the approved products for a particular indication.
−Removed: In order to secure coverage and reimbursement for any product that might be approved for sale, a company may need to conduct expensive pharmacoeconomic studies in order to demonstrate the medical necessity and cost-effectiveness of the product, which will require additional expenditure above and beyond the costs required to obtain FDA or other comparable regulatory approvals.
−Removed: Additionally, companies may also need to provide discounts to purchasers, private health plans or government healthcare programs.
−Removed: Nonetheless, product candidates may not be considered medically necessary or cost effective.
+Added: CMS decides whether and to what extent a new medicine will be covered and reimbursed under Medicare.
+Added: Private payors tend to follow CMS.
+Added: No uniform policy of coverage and reimbursement for drug products exists among all third-party payors, and coverage and reimbursement can differ significantly from payor to payor for the same product.
+Added: The process for determining whether a third-party payor will provide coverage for a product may be separate from the process for setting the price or reimbursement rate that the payor will pay for the product.
+Added: Third-party payors increasingly challenge the prices charged, examine medical necessity, review the cost-effectiveness of medical products and services and impose controls to manage costs.
+Added: Third-party payors may limit coverage to products on an approved formulary, which might not include all of the approved products for a particular indication.
+Added: To secure coverage and reimbursement for any product that obtains approval, a company may need to conduct expensive pharmacoeconomic studies to demonstrate medical necessity and cost-effectiveness.
+Added: This requires additional expenditure above and beyond the costs required to obtain FDA or other regulatory approvals.
+Added: Companies may also need to provide discounts to purchasers, private health plans or government healthcare programs.
+Added: Products may not be considered medically necessary or cost effective.
A decision by a third-party payor not to cover a product could reduce physician utilization once the product is approved and have a material adverse effect on sales, our operations and financial condition.
−Removed: Additionally, a third-party payor’s decision to provide coverage for a product does not imply that an adequate reimbursement rate will be approved.
−Removed: Further, one payor’s determination to provide coverage for a product does not assure that other payors will also provide coverage and reimbursement for the product, and the level of coverage and reimbursement can differ significantly from payor to payor.
The containment of healthcare costs has become a priority of federal, state and foreign governments, and the prices of products have been a focus in this effort.
4 unchanged sentences
Current and future healthcare reform legislation
−Removed: In the United States and some foreign jurisdictions, there have been, and likely will continue to be, a number of legislative and regulatory changes and proposed changes regarding the healthcare system directed at broadening the availability of healthcare, improving the quality of healthcare, and containing or lowering the cost of healthcare.
−Removed: For example, in March 2010, the United States Congress enacted the Affordable Care Act, which, among other things, includes changes to the coverage and payment for products under government health care programs.
−Removed: The Affordable Care Act includes provisions of importance to our potential product candidates that:
−Removed: • created an annual, nondeductible fee on any entity that manufactures or imports specified branded prescription drugs and biologic products, apportioned among these entities according to their market share in certain government healthcare programs;
−Removed: • expanded eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to certain individuals with income at or below 133% of the federal poverty level, thereby potentially increasing a manufacturer’s Medicaid rebate liability;
−Removed: • expanded manufacturers’ rebate liability under the Medicaid Drug Rebate Program by increasing the minimum rebate for both branded and generic drugs and revising the definition of “average manufacturer price,” or AMP, for calculating and reporting Medicaid drug rebates on outpatient prescription drug prices;
−Removed: • addressed a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected;
−Removed: • expanded the types of entities eligible for the 340B drug discount program;
−Removed: • established the Medicare Part D coverage gap discount program by requiring manufacturers to provide point-of-sale-discounts off the negotiated price of applicable brand drugs to eligible beneficiaries during their coverage gap period as a condition for the manufacturers’ outpatient drugs to be covered under Medicare Part D;
−Removed: • created a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research.
−Removed: Since its enactment, there have been numerous judicial, administrative, executive, and legislative challenges to certain aspects of the Affordable Care Act, and we expect there will be additional challenges and amendments to the Affordable Care Act in the future.
−Removed: On June 17, 2021, the U.S.
−Removed: Supreme Court dismissed the most recent judicial challenge to the ACA brought by several states without specifically ruling on the constitutionality of the ACA.
−Removed: President Biden has issued multiple executive orders that have sought to address the issue of prescription drug costs.
−Removed: It is unclear how other healthcare reform measures of the Biden administrations or other efforts, if any, to challenge repeal or replace the ACA, will impact our business.
−Removed: Other legislative changes have been proposed and adopted in the United States since the Affordable Care Act was enacted.
−Removed: The Budget Control Act of 2011, among other things, included aggregate reductions of Medicare payments to providers of 2% per fiscal year, which went into effect in April 2013 and, due to subsequent legislative amendments to the statute, will remain in effect through 2032 unless additional Congressional action is taken.
−Removed: The American Taxpayer Relief Act of 2012 was signed into law, which, among other things, further reduced Medicare payments to several providers, including hospitals, imaging centers and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.
−Removed: Moreover, payment methodologies may be subject to changes in healthcare legislation and regulatory initiatives.
−Removed: For example, CMS may develop new payment and delivery models, including bundled payment models.
+Added: In the United States, there has always been and likely will continue to be proposed and finalized changes to reform the healthcare system, including attempts to broaden the availability of healthcare, improve the quality of healthcare, and contain or lower the cost of healthcare.
+Added: A significant example of such a healthcare reform measure is the Affordable Care Act, or ACA, enacted in March 2010.
+Added: The ACA, among other things, changed coverage and payment policies for products and services under government health care programs, including many provisions that affected how drug products are covered and reimbursed, included various reporting requirements for drug companies, and subjected drug companies to revisions in the calculation and payment of various rebate liability obligations owed to the government under various drug reimbursement programs.
+Added: It also expanded requirements for drug manufacturers to provide coverage in the form of discounts under the Medicare Part D program.
+Added: Since its enactment, there have been numerous judicial, administrative, executive, and legislative challenges to the ACA, and we expect there will be additional challenges and amendments to the ACA in the future.
+Added: This likely includes efforts to challenge, repeal or replace the ACA.
+Added: Other legislative healthcare reform measures have been enacted since the ACA and include, for example, legislative changes to how drug manufacturers calculate rebates owed under the Medicaid drug rebate program.
In addition, recently there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their commercial products, which has resulted in several Congressional inquiries and proposed and enacted state and federal legislation designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for pharmaceutical products.
1 unchanged sentence
Individual states in the United States have also increasingly passed legislation and implemented regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.
−Removed: The Inflation Reduction Act of 2022, or IRA includes several provisions that may impact our business t o varying degrees, including provisions that reduce the annual out-of-pocket spending cap for Medicare Part D beneficiaries from $7,050 to $2,000 starting in 2024, thereby eliminating the coverage gap;
−Removed: impose new manufacturer financial liability on many drugs reimbursed under Medicare Part D;
−Removed: allow the U.S.
−Removed: government to negotiate Medicare Part B and Part D pricing for certain high-cost drugs and biologics without generic or biosimilar competition;
−Removed: and require companies to pay rebates to Medicare for drug prices that increase faster than inflation.
+Added: Most recently, the Inflation Reduction Act of 2022, included several provisions that may impact our business to varying degrees.
+Added: This includes reducing the annual out-of-pocket spending cap for Medicare Part D beneficiaries from $7,050 to $2,000 starting in 2025;
+Added: imposing new manufacturer financial liability on many drugs reimbursed under Medicare Part D;
+Added: and allowing the U.S.
+Added: government to negotiate Medicare pricing for certain high-cost drugs and biologics without generic or biosimilar competition.
+Added: The IRA also requires drug companies to pay rebates to Medicare for drug prices that increase faster than inflation.
Further, under the IRA, orphan drugs are exempted from the Medicare drug price negotiation program, but only if they have one orphan designation and for which the only approved indication is for that disease or condition.
16 unchanged sentences
Political, economic and regulatory developments may further complicate pricing negotiations, and pricing negotiations may continue after reimbursement has been obtained.
−Removed: Reference pricing used by various European Union member states, and parallel trade, i.e., arbitrage between low-priced and high-priced member states, can further reduce prices.
+Added: Reference pricing used by various European Union member states, and parallel trade,
+Added: i.e., arbitrage between low-priced and high-priced member states, can further reduce prices.
There can be no assurance that any country that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any products, if approved in those countries.
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• Centralized procedure —If pursuing marketing authorization of a product candidate for a therapeutic indication under the centralized procedure, following the opinion of the European Medicines Agency’s Committee for Medicinal Products for Human Use, or CHMP, the European Commission issues a single marketing authorization valid across the EEA.
−Removed: The centralized procedure is compulsory for human medicines derived from biotechnology processes or advanced therapy medicinal products (i.e.
+Added: The centralized procedure is compulsory for human medicines derived from biotechnology
+Added: processes or advanced therapy medicinal products (i.e.
gene therapy, somatic cell therapy and tissue engineered products), products that contain a new active substance indicated for the treatment of certain diseases, such as HIV/AIDS, cancer, neurodegenerative disorders, diabetes, autoimmune diseases and other immune dysfunctions, viral diseases, and designated orphan medicinal products.
−Removed: For medicines that do not fall within these categories, an
−Removed: applicant has the option of submitting an application for a centralized marketing authorization to the European Medicines Agency, or EMA, as long as the medicine concerned contains a new active substance not yet authorized in the EU, is a significant therapeutic, scientific or technical innovation, or if its authorization would be in the interest of public health in the EU.
−Removed: Under the centralized procedure the maximum timeframe for the evaluation of an MAA by the EMA is 210 days, excluding clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the CHMP.
+Added: For medicines that do not fall within these categories, an applicant has the option of submitting an application for a centralized marketing authorization to the European Medicines Agency, or EMA, as long as the medicine concerned contains a new active substance not yet authorized in the EU, is a significant therapeutic, scientific or technical innovation, or if its authorization would be in the interest of public health in the EU.
+Added: Under the centralized procedure the maximum timeframe for the evaluation of a marketing authorization application, or MAA, by the EMA is 210 days, excluding clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the CHMP.
Clock stops may extend the timeframe of evaluation of an MAA considerably beyond 210 days.
6 unchanged sentences
Following this, additional marketing authorizations can be sought from other EU countries in a procedure whereby the countries concerned recognize the validity of the original, national marketing authorization.
−Removed: Now that the United Kingdom (which comprises Great Britain and Northern Ireland) has left the European Union, Great Britain is no longer covered by centralized marketing authorizations (under the Northern Ireland Protocol, centralized marketing authorizations currently continue to be recognized in Northern Ireland).
−Removed: On January 1, 2024, a new international recognition framework was put in place by the Medicines and Healthcare products Regulatory Agency, or MHRA, the UK medicine’s regulator, under which the MHRA may have regard to decisions on the approval of a marketing authorization made by the EMA and certain other regulators when considering whether to grant a Great Britain marketing authorization.
−Removed: The MHRA also has the power to have regard to marketing authorizations approved in EU Member States through decentralized or mutual recognition procedures with a view to more quickly granting a marketing authorization in the United Kingdom or Great Britain.
In the EU, innovative medicinal products for therapeutic indications that are authorized for marketing (i.e., reference products) qualify for eight years of data exclusivity and an additional two years of market exclusivity upon marketing authorization.
9 unchanged sentences
and (3) there exists no satisfactory method of diagnosis, prevention or treatment of such condition authorized for marketing in the EU or, if such a method exists, the product will be of significant benefit to those affected by that condition.
−Removed: Orphan medicinal products are eligible for financial incentives such as reduction of fees or fee waivers and are, upon grant of a marketing authorization,
−Removed: entitled to ten years of market exclusivity for the approved therapeutic indication.
+Added: Orphan medicinal products are eligible for financial incentives such as reduction of fees or fee waivers and are, upon grant of a marketing authorization, entitled to ten years of market exclusivity for the approved therapeutic indication.
During this ten-year orphan market exclusivity period, no MAA shall be accepted, and no marketing authorization shall be granted for a similar medicinal product for the same therapeutic indication.
1 unchanged sentence
An orphan product can also obtain an additional two years of market exclusivity in the EU where an agreed pediatric investigation plan for pediatric studies has been complied with.
−Removed: No extension to any supplementary protection certificate, or SPC, can be granted on the basis of pediatric studies for orphan indications.
+Added: No extension to any supplementary protection certificate, or
+Added: SPC, can be granted on the basis of pediatric studies for orphan indications.
The ten-year market exclusivity may be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria for orphan designation, for example, if the product is sufficiently profitable not to justify maintenance of market exclusivity.
−Removed: Additionally, a marketing authorization may be granted to a similar product for the same therapeutic indication at any time if (i) the second applicant can establish that its product, although similar, is safer, more effective or otherwise clinically superior;
+Added: Additionally, a marketing authorization may be granted to a similar product for the same therapeutic indication as an authorized orphan product at any time if (i) the second applicant can establish that its product, although similar to the authorized orphan product, is safer, more effective or otherwise clinically superior;
(ii) the marketing authorization holder for the authorized orphan product consents to a second orphan medicinal product application;
11 unchanged sentences
In April 2014, the EU adopted the Clinical Trials Regulation (EU) No 536/2014 (Clinical Trials Regulation) which replaced the Clinical Trials Directive 2001/20/EC on January 31, 2022.
−Removed: The Clinical Trials Regulation is directly applicable in all the EU Member States, meaning no national implementing legislation in each EU Member State is required.
−Removed: The transitory provision of the Clinical Trial Regulation provide that, by January 31, 2025, all ongoing clinical trials must have transitioned to the Regulation, The Clinical Trials Regulation aims to simplify and streamline the approval of clinical trials in the European Union.
+Added: The Clinical Trials Regulation aims to simplify and streamline the approval of clinical trials in the European Union.
The main characteristics of the regulation include:
5 unchanged sentences
Strict deadlines have been established for the assessment of clinical trial applications.
−Removed: The role of the relevant ethics committees in the assessment procedure will continue to be governed by the national law of the concerned EU Member State.
−Removed: However, overall related timelines will be defined by the Clinical Trials Regulation.
−Removed: The aforementioned EU rules are generally applicable in the European Economic Area, or EEA.
+Added: The role of the relevant ethics committees in the assessment procedure continues to be governed by the national law of the concerned EU Member State.
+Added: However, overall related timelines are defined by the Clinical Trials Regulation.
+Added: All of the aforementioned EU rules are generally applicable in the EEA.
Reform of the Regulatory Framework in the European Union
The European Commission introduced legislative proposals in April 2023 that, if implemented, will replace the current regulatory framework in the EU for all medicines (including those for rare diseases and for children).
−Removed: The European Commission has provided legislative proposals to the European Parliament and the European Council for their review and approval.
−Removed: In October 2023, the European Parliament published draft reports proposing amendments to the legislative proposals,
−Removed: which will be debated by the European Parliament.
+Added: The European Commission has provided legislative proposals to the European Parliament and the European Council for their review and approval, and, in April 2024, the European Parliament proposed amendments to the legislative proposals.
Once the European Commission’s legislative proposals are approved (with or without amendment), they will be adopted into EU law.
22 unchanged sentences
The UK formally left the EU on January 31, 2020.
−Removed: There was a transition period during which EU pharmaceutical laws continued to apply to the UK, which expired on December 31, 2020.
−Removed: However, the EU and the UK have concluded a trade and cooperation agreement, or TCA, which was provisionally applicable since January 1, 2021 and has been formally applicable since May 1, 2021.
−Removed: The TCA includes specific provisions concerning pharmaceuticals, which include the mutual recognition of GMP, inspections of manufacturing facilities for medicinal products and GMP documents issued, but does not provide wholesale mutual recognition of UK and EU pharmaceutical regulations.
−Removed: At present, Great Britain has implemented EU legislation on the marketing, promotion and sale of medicinal products through the Human Medicines Regulations 2012 (as amended) (under the Northern Ireland Protocol, the EU regulatory framework currently continues to apply in Northern Ireland).
−Removed: The regulatory regime in Great Britain therefore largely aligns with current EU regulations, however it is possible that these regimes will diverge in future now that Great Britain’s regulatory system is independent from the EU and the TCA does not provide for mutual recognition of UK and EU pharmaceutical legislation.
−Removed: However, notwithstanding that there is no wholesale recognition of EU pharmaceutical legislation under the TCA, under the new international recognition procedure in the UK
−Removed: mentioned above, the MHRA may take into account decisions on the approval of a marketing authorization from the EMEA (and certain other regulators) when considering an application for a Great Britain marketing authorization.
−Removed: On February 27, 2023, the UK government and the European Commission announced a political agreement in principle to replace the Northern Ireland Protocol with a new set of arrangements, known as the “Windsor Framework”.
−Removed: This new framework fundamentally changes the existing system under the Northern Ireland Protocol, including with respect to the regulation of medicinal products in the U.K.
−Removed: In principle, the MHRA will be responsible for approving all medicinal products destined for the U.K.
−Removed: market (i.e., Great Britain and Northern Ireland) and the EMA will no longer have any role in approving medicinal products destined for Northern Ireland.
−Removed: A single UK-wide marketing authorization will be granted by the MHRA for all medicinal products to be sold in the UK, enabling products to be sold in a single pack and under a single authorization throughout the UK.
−Removed: The Windsor Framework was approved by the EU-UK Joint Committee on March 24, 2023, so the UK government and the EU will enact legislative measures to bring it into law.
−Removed: On June 9, 2023, the MHRA announced that the medicines aspects of the Windsor Framework will apply from January 1, 2025.
+Added: As a result of the Northern Ireland Protocol, following Brexit, the EMA remained responsible for approving novel medicines for supply in Northern Ireland under the EU centralized procedure, and a separate authorization was required to supply the same medicine in Great Britain (England, Wales and Scotland).
+Added: A new framework named the Windsor Framework was approved by the EU-UK Joint Committee on March 24, 2023, and the medicines aspects of the Windsor Framework have applied since January 1, 2025.
+Added: This new framework fundamentally changes the previous system under the Northern Ireland Protocol, including with respect to the regulation of medicinal products in the U.K.
+Added: The MHRA is now responsible for approving all medicinal products destined for the U.K.
+Added: market (i.e., Great Britain and Northern Ireland) and the EMA no longer has any role in approving medicinal products destined for Northern Ireland under the EU centralized procedure.
+Added: A single UK-wide marketing authorization will be granted by the MHRA for all novel medicinal products to be sold in the U.K., enabling products to be sold in a single pack and under a single authorization throughout the U.K..
+Added: However, although a separate authorization is now required to market medicinal products in the U.K., under an international recognition procedure which was put in place by the MHRA on January 1, 2024, the MHRA may take into account decisions on the approval of a marketing authorization from the EMA (and certain other regulators) when considering an application for a U.K.
+Added: marketing authorization.
Employees and Human Capital
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Our corporate headquarters are located in Watertown, Massachusetts, where we lease and occupy approximately 100,624 square feet of office and laboratory space.
−Removed: The current term of our Watertown lease expires March 31, 2030, with an option to extend the term five additional years with 12 months’ notice with rent set at an agreed upon market rate.
−Removed: In December 2021, we entered into a lease for 100,624 square feet of office and laboratory space in Watertown, Massachusetts, which we are beginning to occupy in February 2024.
This lease has an initial term of 134 months, and we have two consecutive options to extend the term of the lease for five years each at then-market rates.
−Removed: We intend to sublease our current space to third parties after we have completed the move to our new facility.
+Added: Additionally, we lease 34,522 square feet of office and laboratory space in Watertown that we are not currently occupying.
+Added: The current term of this lease expires March 31, 2030, with an option to extend the term five additional years with 12 months’ notice with rent set at an agreed upon market rate.
+Added: We intend to sublease and are actively marketing the additional space to third parties.
Our new facility is expected to be sufficient to meet our current needs.
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We are the successor in interest to Kymera Therapeutics, LLC, a limited liability company formed under the laws of the State of Delaware on May 25, 2017, and the former holder of all of our outstanding shares of common stock.
−Removed: Our principal executive offices are located at 200 Arsenal Yards Blvd., Suite 230, Watertown, MA 02472 and our telephone number is (857) 285-5300.
+Added: Our principal executive offices are located at 500 North Beacon Street, 4th Floor, Watertown, MA 02472 and our telephone number is (857) 285-5300.
Our website address is www.kymeratx.com.
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Risks Related to Our Financial Position and Need for Additional Capital
−Removed: We are a biopharmaceutical company with a limited operating history and have not generated any revenue to date from drug sales, and may never become profitable.
−Removed: Biopharmaceutical drug development is a highly speculative undertaking and involves a substantial degree of risk.
+Added: We are a clinical stage company and that may make it difficult for our stockholders to evaluate the success of our business to date and to assess our future viability.
Since our formation in 2015 and our initial funding in 2016, our operations to date have been limited primarily to organizing and staffing our company, business planning, raising capital, researching and developing our drug discovery technology, developing our pipeline, building our intellectual property portfolio, undertaking preclinical studies and conducting Phase 1 clinical trials of our product candidates.
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We have not obtained regulatory approvals for any of our current product candidates.
−Removed: Typically, it takes many years to develop one new pharmaceutical drug from the time it is discovered to when it is available for treating patients.
−Removed: Consequently, any predictions we make about our future success or viability may not be as accurate as they could be if we had a longer operating history.
−Removed: In addition, as a business with a limited operating history, we may encounter unforeseen expenses, difficulties, complications, delays and other known and unknown factors, such as the pandemics or developments relating to macroeconomic conditions.
+Added: Any predictions we make about our future success or viability may not be as accurate as they could be if we had a longer operating history.
+Added: In addition, as a business with a limited operating history, we may encounter unforeseen expenses, difficulties, complications, delays and other known and unknown factors, such as developments relating to macroeconomic conditions.
We will need to transition from a company with a research and development focus to a company capable of supporting late-stage development and commercial activities.
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We have incurred significant operating losses since our inception and anticipate that we will incur continued losses for the foreseeable future.
−Removed: Since inception, we have focused substantially all of our efforts and financial resources on developing our proprietary targeted protein degradation drug discovery platform, or the Pegasus TM platform, and initial product candidates as well as supporting our collaborations and partnerships.
−Removed: To date, we have financed our operations primarily through the issuance and sale of our convertible preferred stock to outside investors and collaborators in private equity financings, upfront payments under our collaborations and our initial public offering (IPO), follow-on offerings, PIPE offering and at-the market sales program.
−Removed: From our inception through December 31, 2023, we raised an aggregate of approximately $1.07 billion of gross proceeds from such transactions and through our collaborations.
−Removed: In January 2024, we received approximately $316.2 million, before deducting underwriting discounts and commissions and estimated offering expenses, from a public offering of our common stock and pre-funded warrants to purchase shares of our common stock.
−Removed: In February 2024, we received $50 million before deduction sales commissions from sales of common stock under our sales agreement with Cowen and Company, LLC.
−Removed: As of December 31, 2023, our cash and cash equivalents and investments were $436.3 million.
+Added: Since inception, we have incurred significant operating losses.
+Added: To date, we have financed our operations primarily through the issuance and sale of our convertible preferred stock to outside investors, collaborators in private equity financings, upfront payments under our collaborations and sales of our common stock in our initial public offering (IPO) and multiple public and private offerings of common stock and our at-the market sales program.
+Added: As of December 31, 2024, our cash and cash equivalents and marketable securities were $850.9 million.
We have incurred net losses in each year since our inception, and we had an accumulated deficit of $754.6 million as of December 31, 2024.
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We expect to continue to incur significant expenses and increasing operating losses over the next several years and for the foreseeable future.
−Removed: Our prior losses, combined with expected future losses, have had and will continue to have an adverse effect on our stockholders’ deficit and working capital.
We expect our expenses to significantly increase in connection with our ongoing activities, as we:
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• advance research and development related activities to expand our product pipeline;
−Removed: • expand and improve the capabilities of our Pegasus TM platform;
+Added: • expand and improve the capabilities of our drug discovery platform;
• seek regulatory approval for our product candidates that successfully complete clinical development;
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The development of pharmaceutical drugs is capital-intensive.
−Removed: We are engaged in clinical development activities on various programs and are also currently advancing multiple development candidates through preclinical development across a number of potential indications.
We expect our expenses to increase substantially in connection with our ongoing activities, particularly as we continue the research and development of, advance the preclinical and clinical activities of, and seek marketing approval for, our current or future product candidates.
−Removed: In addition, if we obtain marketing approval for any of our current or future product candidates, we expect to incur significant commercialization expenses related to sales, marketing, product manufacturing and distribution to the extent that such sales, marketing, product manufacturing and distribution are not the responsibility of our collaborators.
+Added: In addition, if we obtain marketing approval for any of our current or future product candidates, we expect to incur significant commercialization expenses related to sales, marketing, product manufacturing and distribution to the extent that we exercise our opt-in rights with collaborators or that such sales, marketing, product manufacturing and distribution are not the responsibility of our collaborators.
We may also need to raise additional funds sooner if we choose to pursue additional indications and/or geographies for our current or future product candidates or otherwise expand more rapidly than we presently anticipate.
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If we are unable to raise capital when needed or on attractive terms, we would be forced to delay, scale back or discontinue the development and commercialization of one or more of our product candidates, and may be unable to expand our operations or otherwise capitalize on our business opportunities, as desired, which could materially affect our business, financial condition and results of operations.
−Removed: As of December 31, 2023, we had approximately $436.3 million of cash and cash equivalents and investments.
−Removed: In August 2020, we completed an IPO of our common stock by issuing 9,987,520 shares of our common stock, including the exercise in full by the underwriters of their option to purchase up to 1,302,720 additional shares of common stock, at a public offering price of $20.00 per share.
−Removed: The aggregate gross proceeds to us from the offering, before deducting underwriting discounts and commissions, and other estimated offering expenses payable by us, were approximately $199.8 million.
−Removed: Concurrent with the IPO, we announced the sale of 676,354 common shares at the public offering price per share in a private placement to Vertex.
−Removed: The aggregate gross proceeds to us from the concurrent private placement were approximately $13.5 million.
−Removed: The concurrent private placement also closed in August 2020.
−Removed: In July 2021, we completed a follow-on offering of our common stock and an additional private placement transaction with Vertex resulting, in the aggregate, in net proceeds of approximately, $243.1 million.
−Removed: In August 2022, we completed a PIPE offering of our common stock and pre-funded warrants resulting in gross proceeds of $150.0 million.
−Removed: In January 2024, we completed a follow-on offering of our common stock and pre-funded warrants resulting in gross proceeds of $316.2 million before deducting underwriting discounts and commissions and estimated offering expenses.
−Removed: In February 2024, we received $50 million before deduction sales commissions from sales of common stock under our sales agreement with Cowen and Company, LLC.
−Removed: We expect that the approximately $436.3 million of cash and cash equivalents and investments at December 31, 2023, together with the net proceeds from the first quarter of 2024 offerings and the $15 million milestone payment received in January of 2024 under our collaboration agreement with Sanofi, will be sufficient to fund our operations into the first half of 2027.
+Added: As of December 31, 2024, we had approximately $850.9 million of cash and cash equivalents and investments, which we expect will be sufficient to fund our operations into mid-2027.
We have based this estimate on assumptions that may prove to be wrong, and we could use our capital resources sooner than we currently expect.
−Removed: This estimate also assumes that we do not obtain any
−Removed: additional funding through collaborations or other strategic alliances.
+Added: This estimate also assumes that we do not obtain any additional funding through collaborations or other strategic alliances.
Our future capital requirements will depend on, and could increase significantly as a result of, many factors, including:
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Accordingly, we will need to continue to rely on additional funding to achieve our business objectives.
+Added: Raising additional capital may cause dilution to our stockholders, restrict our operations or require us to relinquish rights to our technologies or product candidates.
Any additional fundraising efforts may divert our management from their day-to-day activities, which may adversely affect our ability to develop and commercialize our current or future product candidates.
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We will continue to incur increased costs as a result of operating as a public company, and our management will be required to devote substantial time to new compliance initiatives.
−Removed: As a public company, we will continue to incur significant legal, accounting and other expenses that we did not incur as a private company.
−Removed: We are subject to the reporting requirements of the Securities Exchange Act of 1934, as amended, or the Exchange Act, which require, among other things, that we file with the Securities and Exchange Commission, or the SEC, annual, quarterly and current reports with respect to our business and financial condition.
−Removed: In addition, the Sarbanes-Oxley Act of 2002, as amended, or Sarbanes-Oxley Act, as well as rules subsequently adopted by the SEC and The Nasdaq Global Market to implement provisions of the Sarbanes-Oxley Act, impose significant requirements on public companies, including requiring establishment and maintenance of effective disclosure and financial controls and changes in corporate governance practices.
−Removed: Further, in July 2010, the Dodd-Frank Wall Street Reform and Consumer Protection Act, or the Dodd-Frank Act, was enacted.
−Removed: There are significant corporate governance and executive compensation related provisions in the Dodd-Frank Act that require the SEC to adopt additional rules and regulations in these areas, such as “say on pay” and proxy access.
−Removed: We were required to implement these requirements beginning in 2022 and incurred unexpected expenses in connection with such implementation.
+Added: As a public company, we will continue to incur significant legal, accounting and other expenses.
+Added: We are subject to the reporting requirements of the Securities Exchange Act of 1934, as amended, or the Exchange Act, the Sarbanes-Oxley Act of 2002, as amended, or Sarbanes-Oxley Act, and the Dodd-Frank Wall Street Reform and Consumer Protection Act, or the Dodd-Frank Act.
+Added: For example, the Exchange Act requires, among other things, that we file with the Securities and Exchange Commission, or the SEC, annual, quarterly and current reports with respect to our business and financial condition.
+Added: These reporting requirements continue to evolve, which has created uncertainty for public companies like us and accommodating these evolving standards may require increased legal and financial compliance costs and make some activities more time-consuming and costly.
Stockholder activism, the current political environment and the current high level of government intervention and regulatory reform may lead to substantial new regulations and disclosure obligations, which may lead to additional compliance costs and impact the manner in which we operate our business in ways we cannot currently anticipate.
−Removed: The rules and regulations applicable to public companies substantially increase our legal and financial compliance costs and make some activities more time-consuming and costly.
If these requirements divert the attention of our management and personnel from other business concerns, they could have a material adverse effect on our business, financial condition and results of operations.
−Removed: The increased costs will decrease our net income or increase our net loss and may require us to reduce costs in other areas of our business.
−Removed: For example, we expect these rules and regulations to make it more difficult and more expensive for us to obtain director and officer liability insurance and we may be required to incur substantial costs to maintain the same or similar coverage.
+Added: It may be more difficult and more expensive for us to obtain director and officer liability insurance in the future and we may be required to incur substantial costs to maintain the same or similar coverage.
We cannot predict or estimate the amount or timing of additional costs we may incur to respond to these requirements.
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For example, on March 10, 2023, Silicon Valley Bank, or SVB, was closed by the California Department of Financial Protection and Innovation, which appointed the Federal Deposit Insurance Corporation, or FDIC, as receiver.
−Removed: Since that date, SVB has announced they have been acquired by First Citizens Bank and have resumed mostly normal operations.
−Removed: Similarly, on March 12, 2023, Signature Bank and Silvergate Capital Corp.
−Removed: were each swept into receivership.
Since then, additional financial institutions have experienced similar failures and have been placed into receivership.
−Removed: In addition, if any of our customers, suppliers or other parties with whom we conduct business are unable to access funds pursuant to such instruments or lending arrangements with such a financial institution, such parties’ ability to pay their obligations to us or to enter into new commercial arrangements requiring additional payments to us could be adversely affected.
−Removed: In this regard, counterparties to SVB credit agreements and arrangements, and third parties such as beneficiaries of letters of credit (among others), may experience direct impacts from the closure of SVB and uncertainty remains over liquidity concerns in the broader financial services industry.
−Removed: Similar impacts have occurred in the past, such as during the 2008-2010 financial crisis.
−Removed: Inflation and rapid increases in interest rates have led to a decline in the trading value of previously issued government securities with interest rates below current market interest rates.
−Removed: Although the U.S.
−Removed: Department of Treasury, FDIC and Federal Reserve Board have announced a program to provide up to $25 billion of loans to financial institutions secured by certain of such government securities held by financial institutions to mitigate the risk of potential losses on the sale of such instruments, widespread demands for customer withdrawals or other liquidity needs of financial institutions for immediately liquidity may exceed the capacity of such program.
−Removed: Additionally, there is no guarantee that the U.S.
−Removed: Department of Treasury, FDIC and Federal Reserve Board will provide access to uninsured funds in the future in the event of the closure of other banks or financial institutions, or that they would do so in a timely fashion.
+Added: If other banks and financial institutions enter receivership or become insolvent in the future in response to financial conditions affecting the banking system and financial markets, then our ability to access our cash, cash equivalents and marketable securities may be threatened, which could have a material adverse effect on our business and financial condition.
Although we assess our banking and customer relationships as we believe necessary or appropriate, our access to funding sources and other credit arrangements in amounts adequate to finance or capitalize our current and projected future business operations could be significantly impaired by factors that affect us, the financial institutions with whom we have credit agreements or arrangements directly, or the financial services industry or economy in general.
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• Potential or actual cross-defaults in other credit agreements, credit arrangements or operating or financing agreements.
−Removed: In addition, investor concerns regarding the U.S.
−Removed: or international financial systems could result in less favorable commercial financing terms, including higher interest rates or costs and tighter financial and operating covenants, or systemic limitations on access to credit and liquidity sources, thereby making it more difficult for us to acquire financing on acceptable terms or at all.
Any decline in available funding or access to our cash and liquidity resources could, among other risks, adversely impact our ability to meet our operating expenses, financial obligations or fulfill our other obligations, result in breaches of our financial and/or contractual obligations or result in violations of federal or state wage and hour laws.
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Risks Related to Preclinical and Clinical Development
−Removed: We are very early in our development efforts and our IRAK4, STAT3 and MDM2 programs are in early clinical development.
−Removed: If we are unable to advance them through the clinic for safety or effective reasons or commercialize our product candidates or experience significant delays in doing so, our business will be materially harmed.
+Added: We are very early in our development efforts and our IRAK4 and STAT6 programs are in early clinical development.
+Added: If we are unable to advance them through the clinic for safety or efficacy reasons or commercialize our product candidates or experience significant delays in doing so, our business will be materially harmed.
Our ability to become profitable depends upon our ability to generate revenue.
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If we are unable to generate revenue, we will not become profitable and may be unable to continue operations without continued funding.
−Removed: Our approach to the discovery and development of product candidates based on our Pegasus platform is novel and unproven, which makes it difficult to predict the time, cost of development and likelihood of successfully developing any products.
−Removed: Our Pegasus TM platform utilizes a method known as targeted protein degradation, or TPD, to discover and develop product candidates.
+Added: Our approach to the discovery and development of product candidates is novel and unproven, which makes it difficult to predict the time, cost of development and likelihood of successfully developing any products.
+Added: We utilize a method known as targeted protein degradation, or TPD, to discover and develop product candidates.
Our future success depends on the successful development of this novel therapeutic approach.
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As such, there may be adverse effects from treatment with any of our current or future product candidates that we cannot predict at this time.
−Removed: As a result of these factors, it is more difficult for us to predict the time and cost of product candidate development, and we cannot predict whether the application of our Pegasus TM platform, or any similar or competitive platforms, will result in the development and marketing approval of any products.
−Removed: Any development problems we experience in the future related to our Pegasus TM platform or any of our research programs may cause significant delays or unanticipated costs or may prevent the development of a commercially viable product.
+Added: As a result of these factors, it is more difficult for us to predict the time and cost of product candidate development, and we cannot predict whether the application of our expertise in TPD will result in the development and marketing approval of any products.
+Added: Any development problems we experience in the future related to any of our research programs may cause significant delays or unanticipated costs or may prevent the development of a commercially viable product.
Any of these factors may prevent us from completing our preclinical studies and clinical trials or commercializing any product candidates we may develop on a timely or profitable basis, if at all.
We may not be successful in our efforts to identify or discover additional product candidates or we may expend our limited resources to pursue a particular product candidate or indication and fail to capitalize on product candidates or indications that may be more profitable or for which there is a greater likelihood of success.
−Removed: A key element of our strategy is to apply our Pegasus TM platform and product pipeline to address a broad array of targets and new therapeutic areas.
+Added: A key element of our strategy is to apply our expertise in TPD, and product pipeline to address a broad array of targets and new therapeutic areas.
The therapeutic discovery activities that we are conducting may not be successful in identifying product candidates that are useful in treating oncology, inflammation, immunology or genetic diseases.
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Because we have limited financial and management resources, we focus on a limited number of research programs and product candidates.
−Removed: We are currently focused on our immunology portfolio, consisting of IRAK4, STAT6 and TYK2 programs, which target key signaling pathways implicated in multiple inflammatory and autoimmune diseases, as well as our oncology portfolio, consisting of our STAT3 and MDM2 programs, which target numerous cancers.
+Added: We are currently focused on our immunology portfolio, consisting of our STAT6, TYK2 and IRAK4 programs, which target key signaling pathways implicated in multiple inflammatory and autoimmune diseases.
In some instances, we may decide to discontinue our investment in programs.
−Removed: For example, in November 2023, we announced the decision to discontinue the development of our KT-413 (IRAKIMID) program in order to focus resources to support our growing immunology pipeline.
+Added: For example, in November 2023, we announced the decision to discontinue the development of our KT-413 (IRAKIMID) and in October 2024, we announced the decision to discontinue the development of our KT-333 (STAT3) and KT-253 (MDM2) programs in order to focus resources to support our growing immunology pipeline.
As a result, we may forego or delay pursuit of opportunities with other current or future product candidates or for other indications that later prove to have greater commercial potential.
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Our business depends heavily on the successful development, regulatory approval and commercialization of our current or future product candidates.
−Removed: The preclinical studies and clinical trials of our current or future product candidates are, and the manufacturing and marketing of our current or future product candidates will be, subject to extensive and rigorous review and regulation by numerous government authorities in the U.S.
+Added: The preclinical studies and clinical trials of our current or future product candidates are, and the manufacturing and marketing of our current or future product candidates will be, subject to extensive and rigorous review and regulation by numerous government authorities, including in the U.S.
and in other countries where we intend to test or, if approved, market any of our current or future product candidates.
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Drug development is a long, expensive and uncertain process, and delay or failure can occur at any stage of any of our preclinical studies and clinical trials.
−Removed: This process can take many years and may include post-marketing studies and surveillance, which will require the expenditure of substantial resources.
+Added: For example, the preclinical and manufacturing data we submit to obtain authorization to proceed into human clinical trials may not be accepted initially or at all by a government authority, which could result in a clinical hold on a product candidate.
+Added: Clinical holds can delay clinical trial initiation and, even if successfully resolved, could occur at any time during clinical development as new data or information emerges.
+Added: The drug development process can take many years and may include post-marketing studies and surveillance, which will require the expenditure of substantial resources.
Of the large number of drugs in development in the U.S., only a small percentage will successfully complete the FDA regulatory approval process and will be commercialized, with similarly low rates of success for drugs in development in the European Union obtaining regulatory approval from the European Commission following scientific evaluation by the European Medicines Agency, or EMA.
Accordingly, even if we are able to obtain the requisite financing to continue to fund our development and preclinical studies and clinical trials, we cannot assure you that any of our current or future product candidates will be successfully developed or commercialized.
−Removed: For example, in December 2020, we submitted an IND application for KT-474 to initiate a first-in-human Phase 1 randomized, double-blind, placebo-controlled clinical trial in healthy volunteers and patients with HS or AD.
−Removed: The program was initially placed on partial clinical hold regarding the multiple ascending dose, or MAD) portion of the Phase 1 trial, pending FDA review of the interim data in healthy volunteers from the SAD portion of the trial.
−Removed: In June 2021, the FDA lifted the partial clinical hold on the MAD portion of the Phase 1 trial of KT-474 following review of interim SAD results, and the Phase 1 trial has since been completed.
We are not permitted to market our current or future product candidates in the U.S.
−Removed: until we receive approval of a New Drug Application, or an NDA, from the FDA, in the European Union, or EU, until we receive approval of a marketing authorization application, or an MAA, from the European Commission following scientific evaluation by the EMA, or in any other foreign countries until we receive the requisite approval from such countries.
+Added: until we receive approval of a New Drug Application, or an NDA, from the FDA, in the European Union, or EU, until we receive approval of a marketing authorization application, or an MAA, from the European Commission, or in any other foreign countries until we receive the requisite approval from such countries.
Obtaining approval of an NDA or MAA is a complex, lengthy, expensive and uncertain process, and the FDA or EMA may delay, limit or deny approval of any of our current or future product candidates for many reasons, including, among others:
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If we experience delays or difficulties in the initiation or enrollment of patients in clinical trials, our receipt of necessary regulatory approvals could be delayed or prevented.
−Removed: There may be delays in trial initiation, and we may not be able to locate and enroll a sufficient number of eligible patients to participate in these trials as required by the FDA or similar regulatory authorities outside the U.S.
+Added: There may be delays in trial initiation, including due to clinical holds or site activation delays, and we may not be able to locate and enroll a sufficient number of eligible patients to participate in these trials as required by the FDA or similar regulatory authorities outside the U.S.
Moreover, some of our competitors have ongoing clinical trials for current or future product candidates that treat the same patient populations as our current or future product candidates, and patients who would otherwise be eligible for our clinical trials may instead enroll in clinical trials of our competitors’ current or future product candidates.
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From time to time, we may publicly disclose preliminary or topline data from our preclinical studies and clinical trials, which is based on a preliminary analysis of then-available data, and the results and related findings and conclusions are subject to change following a more comprehensive review of the data related to the particular study or trial.
−Removed: For example, in December 2023, we announced positive interim results from our Phase 1 trial of KT-333 and in November 2023, we announced positive interim results from our Phase 1a trial of KT-253.
−Removed: However, there can be no assurance that the final topline data from either trial will be consistent with such results or otherwise viewed as positive.
+Added: There can be no assurance that the final topline data from our trials will be consistent with such results or otherwise viewed as positive.
We also make assumptions, estimations, calculations and conclusions as part of our analyses of data, and we may not have received or had the opportunity to fully and carefully evaluate all data.
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If we cannot replicate the positive results from our preclinical studies of our current or future product candidates in our future clinical trials, we may be unable to successfully develop, obtain regulatory approval for and commercialize our current or future product candidates.
−Removed: Positive results from our preclinical studies of our current or future product candidates, and any positive results we may obtain from our early clinical trials of our current or future product candidates, including the ongoing clinical trials of KT-474, KT-333 and KT-253 may not necessarily be predictive of the results from required later preclinical studies and clinical trials.
−Removed: Similarly, even if we are able to complete our planned preclinical studies or clinical trials of our current or future product
−Removed: candidates according to our current development timeline, the positive results from such preclinical studies and/or clinical trials of our current or future product candidates, including KT-474, KT-621, KT-294, KT-333 and KT-253, may not be replicated in subsequent preclinical studies or clinical trials.
+Added: Positive results from our preclinical studies of our current or future product candidates, and any positive results we may obtain from our early clinical trials of our current or future product candidates, including the ongoing clinical trials of KT-474 and KT-621, may not necessarily be predictive of the results from required later preclinical studies and clinical trials.
+Added: Similarly, even if we are able to complete our planned preclinical studies or clinical trials of our current or future product candidates according to our current development timeline, the positive results from such preclinical studies and/or clinical trials of our current or future product candidates, including KT-474, KT-621 and KT-295, may not be replicated in subsequent preclinical studies or clinical trials.
In particular, while we have conducted certain preclinical studies of KT-621 and KT-295, we do not know whether either of these product candidates will perform in our planned clinical trials as it has performed in these prior preclinical studies.
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If we fail to produce positive results in our planned preclinical studies or clinical trials of any of our current or future product candidates, the development timeline and regulatory approval and commercialization prospects for our current or future product candidates, and, correspondingly, our business and financial prospects, would be materially adversely affected.
−Removed: Additionally, our planned or future clinical trials may utilize an “open-label” trial design, such as the open-label patient portion of our Phase 1 clinical trials of KT-474, KT-333 and KT-253.
+Added: Additionally, our planned or future clinical trials may utilize an “open-label” trial design, such as the open-label patient portion of our completed Phase 1 clinical trial of KT-474.
An “open-label” clinical trial is one where both the patient and investigator know whether the patient is receiving the investigational product candidate or either an existing approved drug or placebo.
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In addition, open-label clinical trials may be subject to an “investigator bias” where those assessing and reviewing the physiological outcomes of the clinical trials are aware of which patients have received treatment and may interpret the information of the treated group more favorably given this knowledge.
−Removed: The results from an open-label trial, including our Phase 1 trials of KT-474, KT-333 and KT-253, may not be predictive of future clinical trial results with any of our product candidates for which we include an open-label clinical trial when studied in a controlled environment with a placebo or active control.
+Added: The results from an open-label trial, including our completed Phase 1 trial of KT-474, may not be predictive of future clinical trial results with any of our product candidates for which we include an open-label clinical trial when studied in a controlled environment with a placebo or active control.
The incidence and prevalence for target patient populations of our product candidates have not been established with precision.
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We are developing KT-474 for the treatment of a broad set of immunology-inflammation diseases, such as HS, an inflammatory skin disease, AD, and rheumatoid arthritis.
+Added: We are developing KT-621 for a broad set of immunology indications, with potential indications to include AD, asthma, COPD, CRSwNP, EoE, PN and others.
+Added: We are developing KT-295 for immunology indications, with such potential indications to include inflammatory bowel disease, or IBD, psoriasis, or PsO, psoriatic arthritis, or PsA, lupus and others.
The total addressable market opportunity for our product candidates will ultimately depend upon, among other things, their proven safety and efficacy, the diagnosis criteria included in the final label for each, whether our product candidates are approved for sale for these indications, acceptance by the medical community and patient access, product pricing and reimbursement.
−Removed: The number of patients for our product candidates in the United States and elsewhere may turn out to be lower than expected, patients may not be otherwise amenable to treatment with our products, or new patients may become increasingly difficult to identify or gain access to, all of which would adversely affect our results of operations and our business.
−Removed: A pandemic, epidemic, or outbreak of an infectious disease may materially and adversely affect our business and our financial results and could cause a disruption to the development of our product candidate.
+Added: The number of patients for our product candidates in the United States and elsewhere may turn out
+Added: to be lower than expected, patients may not be otherwise amenable to treatment with our products, or new patients may become increasingly difficult to identify or gain access to, all of which would adversely affect our results of operations and our business.
+Added: A pandemic, epidemic, or outbreak of an infectious disease may materially and adversely affect our business and our financial results and could cause a disruption to the development of our product candidates.
Public health crises such as pandemics or similar outbreaks could adversely impact our business.
−Removed: For example, in December 2019, a novel strain of a virus named SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), or coronavirus, which causes COVID-19, surfaced in Wuhan, China and has since spread worldwide, including to Eastern Massachusetts where our primary office and laboratory space is located.
−Removed: The pandemic and policies and regulations implemented by governments in response to the pandemic, most of which have been lifted, have had a significant impact, both direct and indirect, on businesses and commerce.
−Removed: The coronavirus pandemic has evolved considerably, and led to the
−Removed: implementation of various responses, including government-imposed quarantines, travel restrictions and other public health safety measures which now have been lifted.
−Removed: The extent to which any future pandemic impacts our operations or those of our third-party partners, including our preclinical studies or clinical trial operations, will also depend on future developments, which are highly uncertain and cannot be predicted with confidence, including the duration of the outbreak, new information that will emerge concerning the severity of disease and the actions to contain the disease or treat its impact, among others.
−Removed: For example, similar to other biopharmaceutical companies, we may experience delays in enrolling subjects in our clinical trials.
−Removed: Infectious diseases may also affect employees of third-party CROs located in affected geographies that we rely upon to carry out our clinical trials.
+Added: Infectious diseases may also affect research activities and employees of third-party CROs located in affected geographies that we rely upon to carry out our clinical trials.
In addition, the patient populations that our lead and other core product candidates target may be particularly susceptible to infectious diseases or its variants, which may make it more difficult for us to identify patients able to enroll in our clinical trials and may impact the ability of enrolled patients to complete any such trials.
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• the potential negative affect on the operations of our third-party manufacturers and the supply chain for our product candidates.;
−Removed: For example, in February 2020, one of our vendors for active pharmaceutical ingredient, or API, starting materials based in Wuhan, China ceased its operations for several weeks due to the COVID-19 pandemic, which caused a minor delay in the delivery of API starting materials to a separate vendor who manufactures API;
• interruptions in global shipping affecting the transport of clinical trial materials, such as patient samples, investigational drug product and conditioning drugs and other supplies used in our current and prospective clinical trials;
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Undesirable side effects caused by our current or future product candidates could cause us to interrupt, delay or halt preclinical studies or could cause us or regulatory authorities to interrupt, delay or halt clinical trials and could result in a more restrictive label or the delay or denial of regulatory approval by the FDA or other regulatory authorities.
−Removed: As is the case with many treatments for inflammatory and autoimmune diseases, cancer or other diseases, it is likely that there may be adverse side effects associated with the use of our product candidates.
+Added: As is the case with many treatments for inflammatory
+Added: and autoimmune diseases, cancer or other diseases, it is likely that there may be adverse side effects associated with the use of our product candidates.
Additionally, a potential risk in any protein degradation product is that healthy proteins or proteins not targeted for degradation will be degraded or that the degradation of the targeted protein in itself could cause adverse events, undesirable side effects, or unexpected characteristics.
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• our reputation may suffer.
−Removed: We believe that any of these events could prevent us from achieving or maintaining market acceptance of the affected product candidates and could substantially increase the costs of commercializing our current or future product candidates, if
−Removed: approved, and significantly impact our ability to successfully commercialize our current or future product candidates and generate revenues.
+Added: We believe that any of these events could prevent us from achieving or maintaining market acceptance of the affected product candidates and could substantially increase the costs of commercializing our current or future product candidates, if approved, and significantly impact our ability to successfully commercialize our current or future product candidates and generate revenues.
Manufacturing our current or future product candidates is complex and we may encounter difficulties in production.
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Legislative proposals are pending that, if enacted, could negatively impact U.S.
−Removed: funding for certain biotechnology providers having relationships with foreign adversaries or which pose a threat to national security.
+Added: companies and institutions that accept U.S.
+Added: funding for projects that utilize biotechnology equipment and services produced or provided by certain biotechnology providers having relationships with foreign adversaries and which pose a threat to national security.
+Added: This includes proposed legislation currently pending in the U.S.
+Added: Senate and House of Representatives.
The potential downstream adverse impacts on entities having only commercial relationships with any impacted biotechnology providers is unknown but may include supply chain disruptions or delays.
+Added: Though we do not currently receive U.S.
+Added: government funding, we are currently evaluating steps to mitigate any potential impact of any future stricter legislation towards foreign entities providing services to U.S.
+Added: based companies.
+Added: Depending on the terms of the final legislation enacted, these steps could result in additional costs and potential delays in development timelines resulting from related transition efforts.
If any CMO with whom we contract fails to perform its obligations, we may be forced to enter into an agreement with a different CMO, which we may not be able to do on reasonable terms, if at all.
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and by comparable authorities in other countries.
−Removed: Before we can commercialize any of our current and future product candidates, we must obtain marketing approval from the regulatory authorities in the relevant jurisdictions.
−Removed: We have not received approval to market any of our current product candidates from regulatory authorities in any jurisdiction, and
−Removed: it is possible that none of our current product candidates, nor any product candidates we may seek to develop in the future, will ever obtain regulatory approval.
+Added: Before we can commercialize any of our current and
+Added: future product candidates, we must obtain marketing approval from the regulatory authorities in the relevant jurisdictions.
+Added: We have not received approval to market any of our current product candidates from regulatory authorities in any jurisdiction, and it is possible that none of our current product candidates, nor any product candidates we may seek to develop in the future, will ever obtain regulatory approval.
As a company, we have only limited experience in filing and supporting the applications necessary to gain regulatory approvals and expect to rely on third-party CROs and/or regulatory consultants to assist us in this process.
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The FDA and comparable authorities in other countries have substantial discretion in the approval process and may refuse to accept any application or may decide that our data are insufficient for approval and require additional preclinical, clinical or other studies.
+Added: Supreme Court’s decision in July 2024 to overturn established case law giving deference to regulatory agencies’ interpretations of ambiguous statutory language has introduced uncertainty regarding the extent to which FDA’s regulations, policies and decisions may become subject to increasing legal challenges, delays or changes.
Our current or future product candidates could be delayed in receiving, or fail to receive, regulatory approval for many reasons, including the following:
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• the approval policies or regulations of the FDA or comparable foreign regulatory authorities may significantly change in a manner rendering our clinical data insufficient for approval.
+Added: With the change in presidential administrations in 2025, there is substantial uncertainty as to how, if at all, the new administration will seek to modify or revise the requirements and policies of the FDA and other regulatory agencies with jurisdiction over our product candidates.
+Added: The impending uncertainty could present new challenges or potential opportunities as we navigate the clinical development and approval process for our product candidates.
Even if we were to obtain approval, regulatory authorities may approve any of our current or future product candidates for fewer or more limited indications than we request, may not approve the price we intend to charge for our drugs, may grant approval contingent on the performance of costly post-marketing clinical trials, or may approve a product candidate with a label that does not include the labeling claims necessary or desirable for the successful commercialization of that product candidate.
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These designations, even if granted by the FDA, may not lead to a faster development, regulatory review or approval process, and such designations do not increase the likelihood that any of our product candidates will receive marketing approval in the United States.
−Removed: We may seek a Breakthrough Therapy Designation for one or more of our current or future product candidates.
A breakthrough therapy is defined as a drug that is intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition, and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.
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In addition, even if one or more of our current or future product candidates qualify as breakthrough therapies, the FDA may later decide that such product candidates no longer meet the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.
−Removed: We may seek Fast Track Designation for one or more of our current or future product candidates.
−Removed: In the third quarter of 2023, the U.S.
−Removed: Food and Drug Administration granted Fast Track designation to KT-333 for the treatment of both relapsed/refractory CTCL and relapsed/refractory PTCL.
If a drug is intended for the treatment of a serious or life-threatening condition and the drug demonstrates the potential to address unmet medical needs for this condition, the drug sponsor may apply for Fast Track Designation.
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Fast Track Designation alone does not guarantee qualification for the FDA’s priority review procedures.
−Removed: We may seek approval of KT-474, KT-621, KT-294, KT-333, KT-253 or any other future product candidate, where applicable, under the FDA’s accelerated approval pathway.
+Added: We or our collaborators may seek approval of KT-474, KT-621, KT-295, or any other future product candidate, where applicable, under the FDA’s accelerated approval pathway.
This pathway may not lead to a faster development or regulatory review or approval process and it does not increase the likelihood that our product candidates will receive marketing approval.
−Removed: We may seek accelerated approval of KT-474, KT-621, KT-294, KT-333, KT-253 or future product candidates.
+Added: We or our collaborators may seek accelerated approval of KT-474, KT-621, KT-295, or future product candidates.
A product may be eligible for accelerated approval if it treats a serious or life-threatening condition and generally provides a meaningful advantage over available therapies.
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In addition, receiving accelerated approval does not assure that the product’s accelerated approval will eventually be converted to a traditional approval.
−Removed: We have obtained orphan drug designation for some of our product candidates.
−Removed: We may also seek Orphan Drug Designation for certain of our other current or future product candidates, and we may be unsuccessful or may be unable to maintain the benefits associated with Orphan Drug Designation, including the potential for market exclusivity.
−Removed: The FDA has granted Orphan Drug Designation for KT-333 for the treatment of peripheral T cell lymphoma and cutaneous T cell lymphoma and for KT-253 for the treatment of acute myeloid leukemia.
−Removed: As part of our business strategy, we may also seek Orphan Drug Designation for certain indications of our other current or future product candidates, and we may be unsuccessful.
+Added: We may seek Orphan Drug Designation for certain of our current or future product candidates, and we may be unsuccessful or may be unable to maintain the benefits associated with Orphan Drug Designation, including the potential for market exclusivity.
+Added: As part of our business strategy, we may seek Orphan Drug Designation for certain indications of our other current or future product candidates, and we may be unsuccessful.
Regulatory authorities in some jurisdictions, including the U.S.
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In the U.S., Orphan Drug Designation entitles a party to financial incentives such as opportunities for grant funding towards clinical trial costs, tax advantages and user-fee waivers.
−Removed: Similarly, in the European Union, the European Commission, upon the recommendation of the EMA’s Committee for Orphan Medicinal Products, may grant orphan designation with respect products that are intended for the diagnosis, prevention or treatment of life-threatening or chronically debilitating conditions affecting not more than 5 in 10,000 persons in the European Union and for which no satisfactory method of diagnosis, prevention, or treatment has been authorized (or the product would be of significant benefit to those affected by the applicable condition).
−Removed: Additionally, designation may be granted for products intended for the diagnosis, prevention, or treatment of a life-threatening, seriously debilitating or serious and chronic condition when, without incentives, it is unlikely that sales of the product in the European Union would be sufficient to justify the necessary investment in developing the product.
+Added: The criteria for orphan designation in the European Union are similar in principle to the U.S.
+Added: - see the section of this Annual Report on Form 10-K titled “Government Regulation of Drugs Outside of the United States” for additional information.
In the European Union, orphan designation entitles a party to financial incentives such as reduction of fees or fee waivers.
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and ten years in the European Union.
−Removed: The exclusivity period in the European Union can be reduced to six years if at the end of the fifth year, it is established that a product no longer meets the criteria for Orphan Designation, including where it is shown that the product is sufficiently profitable so that market exclusivity is no longer justified.
−Removed: Orphan Drug exclusivity may be lost if the FDA or EMA determines that the request for designation was materially defective or if the manufacturer is unable to assure sufficient quantity of the drug to meet the needs of patients with the rare disease or condition.
Even if we obtain Orphan Drug exclusivity for a product, that exclusivity may not effectively protect the product from competition because competing drugs containing a different active ingredient can be approved for the same condition.
In addition, even after an orphan drug is approved, the FDA can subsequently approve the same drug for the same condition if the FDA concludes that the later drug is clinically superior in that it is shown to be safer, more effective or makes a major contribution to patient care.
−Removed: On August 3, 2017, the U.S.
−Removed: Congress passed the FDA Reauthorization Act of 2017, or FDARA.
−Removed: FDARA, among other things, codified the FDA’s pre-existing regulatory interpretation to require that a drug sponsor demonstrate the clinical superiority of an orphan drug that is otherwise the same as a previously approved drug for the same rare disease in order to receive orphan drug exclusivity.
−Removed: The new legislation reverses prior precedent holding that the Orphan Drug Act unambiguously requires that the FDA recognize the orphan exclusivity period regardless of a showing of clinical superiority.
−Removed: Moreover, in the Consolidated Appropriations Act of 2021, Congress did not further change this interpretation when it clarified that the interpretation codified in FDARA would apply in cases where the FDA issued an orphan designation before the enactment of FDARA but where product approval came after the enactment of FDARA.
−Removed: The FDA may further reevaluate the Orphan Drug Act and its regulations and policies.
−Removed: We do not know if, when or how the FDA may change the orphan drug regulations and policies in the future, and it is uncertain how any changes might affect our business.
−Removed: Depending on what changes the FDA may make to its Orphan Drug regulations and policies, our business could be adversely impacted.
Even if we receive regulatory approval for any of our current or future product candidates, we will be subject to ongoing obligations and continued regulatory review, which may result in significant additional expense.
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Inadequate funding for the FDA, the SEC and other government agencies, including from government shutdowns, or other disruptions to these agencies’ operations, could hinder their ability to hire and retain key leadership and other personnel, prevent new products and services from being developed or commercialized in a timely manner or otherwise prevent those agencies from performing normal business functions on which the operation of our business may rely, which could negatively impact our business.
+Added: Currently, federal agencies in the U.S.
+Added: are operating under a continuing resolution that is set to expire on March 14, 2025.
+Added: Without appropriation of additional funding to federal agencies, our business operations related to our product development activities for the U.S.
+Added: market could be impacted.
The ability of the FDA to review and approve new products can be affected by a variety of factors, including government budget and funding levels, the ability to hire and retain key personnel and accept the payment of user fees, and statutory, regulatory and policy changes.
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Our future growth may depend, in part, on our ability to penetrate foreign markets, where we would be subject to additional regulatory burdens and other risks and uncertainties that could materially adversely affect our business.
−Removed: We are not permitted to market or promote any of our current or future product candidates before we receive regulatory approval from the applicable regulatory authority in that foreign market, and we may never receive such regulatory approval for any of our current or future product candidates.
+Added: We are not permitted to market or promote any of our current or future product candidates before we receive regulatory approval from the applicable regulatory authority in that foreign market, and we may never receive such regulatory approval
+Added: for any of our current or future product candidates.
To obtain separate regulatory approval in many other countries we must comply with numerous and varying regulatory requirements of such countries regarding safety and efficacy and governing, among other things, clinical trials and commercial sales, pricing and distribution of our current or future product candidates, and we cannot predict success in these jurisdictions.
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• business interruptions resulting from geo-political actions, including war and terrorism.
−Removed: Foreign sales of our current or future product candidates could also be adversely affected by the imposition of governmental controls, political and economic instability, trade restrictions and changes in tariffs.
+Added: Foreign sales of our current or future product candidates could also be adversely affected by the imposition of governmental controls, political and economic instability, trade restrictions and changes in tariffs (including tariffs that have been or may in the future be imposed by the United States or other countries).
We may in the future conduct clinical trials for current or future product candidates outside the U.S., and the FDA and comparable foreign regulatory authorities may not accept data from such trials.
−Removed: We may in the future choose to conduct one or more clinical trials outside the U.S., including in Europe.
+Added: We may in the future choose to conduct one or more clinical trials outside the U.S., including in Europe and other geographies.
The acceptance of study data from clinical trials conducted outside the U.S.
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Many foreign regulatory authorities have similar approval requirements.
−Removed: In addition, such foreign trials would be subject to the applicable local laws of the foreign jurisdictions where the trials are conducted.
+Added: In addition, such foreign trials would be subject to the
+Added: applicable local laws of the foreign jurisdictions where the trials are conducted.
There can be no assurance that the FDA or any comparable foreign regulatory authority will accept data from trials conducted outside of the U.S.
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Even if we are able to commercialize any current or future product candidates, such drugs may become subject to unfavorable pricing regulations or third-party coverage and reimbursement policies, which would harm our business.
−Removed: Significant uncertainty exists as to the coverage and reimbursement status of any products for which we may obtain regulatory approval.
−Removed: and in other countries, sales of any products for which we may receive regulatory marketing approval for commercial sale will depend, in part, on the availability of coverage and reimbursement from third-party payors.
−Removed: Third-party payors include government healthcare programs (e.g., Medicare and Medicaid), managed care providers, private health insurers, health maintenance organizations and other organizations.
−Removed: These third-party payors decide which medications they will pay for and establish reimbursement levels.
−Removed: The availability of coverage and extent of reimbursement by governmental and other third-party payors is essential for most patients to be able to afford treatments such as targeted protein degradation therapies.
−Removed: In the United States and markets in other countries, patients generally rely on third-party payors to reimburse all or part of the costs associated with their treatment.
−Removed: Adequate coverage and reimbursement from governmental healthcare programs, such as Medicare and Medicaid, and commercial payors is critical to new product acceptance.
−Removed: Our ability to successfully commercialize our product candidates will depend in part on the extent to which coverage and adequate reimbursement for these products and related treatments will be available from government health administration authorities, private health insurers and other organizations.
−Removed: Even if coverage is provided, the approved reimbursement amount may not be high enough to allow us to establish or maintain pricing sufficient to realize a sufficient return on our investment.
−Removed: Government authorities and third-party payors, such as private health insurers and health maintenance organizations, decide which medications they will pay for and establish reimbursement levels.
−Removed: There is also significant uncertainty related to the insurance coverage and reimbursement of newly approved products and coverage may be more limited than the purposes for which the medicine is approved by the FDA or comparable foreign regulatory authorities.
−Removed: In the United States, the principal decisions about reimbursement for new medicines are typically made by the Centers for Medicare & Medicaid Services, or CMS, an agency within the U.S.
−Removed: Department of Health and Human Services, or HHS.
−Removed: CMS decides whether and to what extent our products will be covered and reimbursed under Medicare.
−Removed: Private payors tend to follow CMS to a substantial degree.
−Removed: Factors payors consider in determining reimbursement are based on whether the product is:
+Added: The regulations that govern marketing approvals, pricing, coverage and reimbursement for new drug products vary widely from country to country.
+Added: Current and future legislation may significantly change the approval requirements in ways that could involve additional costs and cause delays in obtaining approvals.
+Added: Some countries require approval of the sale price of a drug before it can be marketed.
+Added: In many countries, the pricing review period begins after marketing or product licensing approval is granted.
+Added: In some foreign markets, prescription pharmaceutical pricing remains subject to continuing governmental control even after initial approval is granted.
+Added: As a result, we might obtain marketing approval for a product in a particular country, but then be subject to price regulations that delay our commercial launch of the product, possibly for lengthy time periods, and negatively impact the revenues we are able to generate from the sale of the product in that country.
+Added: Adverse pricing limitations may hinder our ability to recoup our investment in one or more product candidates, even if our product candidates obtain marketing approval.
+Added: See the section of this Annual Report on Form 10-K entitled, “Business – Government Regulation – Other Healthcare Laws” and the section of this report entitled, “Business – Government Regulation – Current and Future Healthcare Reform Legislation” for more information.
+Added: Our ability to commercialize any product candidates successfully also will depend in part on the extent to which coverage and adequate reimbursement for these products and related treatments will be available from government health administration authorities, private health insurers and other organizations.
+Added: Government authorities and third-party payors, such as private health insurers and health maintenance organizations, decide which medications they will pay for and establish reimbursement
+Added: A primary trend in the U.S.
+Added: healthcare industry and elsewhere is cost containment.
+Added: Government authorities and third-party payors have attempted to control costs by limiting coverage and the amount of reimbursement for particular medications.
+Added: Increasingly, third-party payors are requiring that drug companies provide them with predetermined discounts from list prices and are challenging the prices charged for medical products.
+Added: Coverage and reimbursement may not be available for any product that we commercialize and, even if these are available, the level of reimbursement may not be satisfactory.
+Added: Reimbursement may affect the demand for, or the price of, any product candidate for which we obtain marketing approval.
+Added: Obtaining and maintaining adequate reimbursement for our products may be difficult.
+Added: We may be required to conduct expensive pharmacoeconomic studies to justify coverage and reimbursement or the level of reimbursement relative to other therapies.
+Added: If coverage and adequate reimbursement are not available or reimbursement is available only to limited levels, we may not be able to successfully commercialize any product candidate for which we obtain marketing approval.
+Added: Coverage and reimbursement by a third-party payor may depend upon a number of factors, including the third-party payor’s determination that use of a product is:
• a covered benefit under its health plan;
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• neither experimental nor investigational.
−Removed: Our ability to commercialize any current or future product candidates successfully also will depend in part on the extent to which coverage and reimbursement for these current or future product candidates and related treatments will be available from government authorities, private health insurers and other organizations.
−Removed: Moreover, a payor’s decision to provide coverage for a product does not imply that an adequate reimbursement rate will be approved.
−Removed: We cannot be sure that coverage will be available for any product candidate that we commercialize.
−Removed: If coverage is available, but reimbursement is available only to limited levels, we may not be able to successfully commercialize any product candidate for which we obtain marketing approval.
−Removed: In the U.S., no uniform policy exists for coverage and reimbursement for products among third-party payors.
−Removed: Therefore, decisions regarding the extent of coverage and amount of reimbursement to be provided can differ significantly from payor to payor.
−Removed: The process for determining whether a payor will provide coverage for a product may be separate from the process for setting the reimbursement rate a payor will pay for the product.
−Removed: One third-party payor’s decision to cover a particular product or service does not ensure that other payors will also provide coverage for the medical product or service.
−Removed: Third-party payors may limit coverage to specific products on an approved list or formulary, which may not include all FDA-approved products for a particular indication.
−Removed: Also, third-party payors may refuse to include a particular branded product on their formularies or otherwise restrict patient access to a branded drug when a less costly generic equivalent or other alternative is available.
+Added: There may be significant delays in obtaining coverage and reimbursement for newly approved drugs, and coverage may be more limited than the purposes for which the drug is approved by the FDA or similar regulatory authorities outside of the United States.
+Added: Moreover, eligibility for coverage and reimbursement does not imply that a drug will be paid for in all cases or at a rate that covers our costs, including research, development, manufacture, sale and distribution expenses.
+Added: Interim reimbursement levels for new drugs, if applicable, may also not be sufficient to cover our costs and may not be made permanent.
+Added: Reimbursement rates may vary according to the use of the drug and the clinical setting in which it is used, may be based on reimbursement levels already set for lower cost drugs and may be incorporated into existing payments for other services.
Net prices for drugs may be reduced by mandatory discounts or rebates required by government healthcare programs or private payors and by any future relaxation of laws that presently restrict imports of drugs from countries where they may be sold at lower prices than in the United States.
−Removed: Increasingly, third-party payors are requiring that drug companies provide them with predetermined discounts from list prices and are challenging the prices charged for medical products.
−Removed: We cannot be sure that reimbursement will be available for any product candidate that we commercialize and, if reimbursement is available, the level of reimbursement.
−Removed: In addition, many pharmaceutical manufacturers must calculate and report certain price reporting metrics to the government, such as average sales price, or ASP, and best price.
−Removed: Penalties may apply in some cases when such metrics are not submitted accurately and timely.
−Removed: Further, these prices for drugs may be reduced by mandatory discounts or rebates required by government healthcare programs.
−Removed: In order to secure coverage and reimbursement for any product that might be approved for sale, we may need to conduct expensive pharmacoeconomic studies in order to demonstrate the medical necessity and cost-effectiveness of our products, in addition to the costs required to obtain FDA or comparable regulatory approvals.
−Removed: Additionally, we may also need to provide discounts to purchasers, private health plans or government healthcare programs.
−Removed: Despite our best efforts, our product candidates may not be considered medically necessary or cost-effective.
−Removed: If third-party payors do not consider a product to be cost-effective compared to other available therapies, they may not cover an approved product as a benefit under their plans or, if they do, the level of payment may not be sufficient to allow us to sell our products at a profit.
−Removed: A decision by a third-party payor not to cover a product could reduce physician utilization once the product is approved and have a material adverse effect on sales, our operations and financial condition.
+Added: Third-party payors often rely upon Medicare coverage policy and payment limitations in setting their own reimbursement policies.
+Added: Our inability to promptly obtain coverage and adequate reimbursement rates from both government-funded and private payors for any approved products that we develop could have a material adverse effect on our operating results, our ability to raise capital needed to commercialize products and our overall financial condition.
+Added: There can be no assurance that our product candidates, even if they are approved for sale in the United States or in other countries, will be considered medically reasonable and necessary for a specific indication or cost-effective by third-party payors, or that coverage and an adequate level of reimbursement will be available or that third-party payors’ reimbursement policies will not adversely affect our ability to sell our product candidates profitably.
Finally, in some foreign countries, the proposed pricing for a product candidate must be approved before it may be lawfully marketed.
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Current and future healthcare legislative reform measures may have a material adverse effect on our business and results of operations.
−Removed: Changes in regulations, statutes or the interpretation of existing regulations could impact our business by requiring, for example:
−Removed: (i) changes to our manufacturing arrangements, (ii) additions or modifications to product labeling, (iii) the recall or discontinuation of our products or (iv) additional record-keeping requirements.
−Removed: If any such changes were to be imposed, they could adversely affect the operation of our business.
−Removed: In the United States and in some foreign jurisdictions, there have been, and likely will continue to be, a number of legislative and regulatory changes and proposed changes intended to broaden access to healthcare, improve the quality of healthcare, and contain or lower the cost of healthcare.
−Removed: For example, in March 2010, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act, or the ACA, was passed, which substantially changed the way healthcare is financed by both governmental and private insurers, and significantly impacted the U.S.
−Removed: pharmaceutical industry.
−Removed: The ACA, among other things, subjects biological products to potential competition by lower-cost biosimilars, expands the types of entities eligible for the 340B drug discount program, addresses a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected, increases rebates owed by manufacturers under the Medicaid Drug Rebate Program and extends the rebate program to individuals enrolled in Medicaid managed care organizations, establishes annual fees and taxes on manufacturers of certain branded prescription drugs, and creates a new Medicare Part D coverage gap discount program, in
−Removed: which manufacturers must agree to offer 50% (increased to 70% pursuant to the Bipartisan Budget Act of 2018, or BBA, effective as of January 2019) point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D;
−Removed: and provided incentives to programs that increase the federal government’s comparative effectiveness research.
−Removed: Since its enactment, there have been judicial, administrative, executive and Congressional legislative challenges to certain aspects of the ACA, and we expect there will be additional challenges and amendments to the ACA in the future.
−Removed: On June 17, 2021, the U.S.
−Removed: Supreme Court dismissed the most recent judicial challenge to the ACA brought by several states without specifically ruling on the constitutionality of the ACA.
−Removed: In addition, President Biden has issued multiple executive orders that have sought to address the issue of prescription drug costs.
−Removed: It is unclear how other healthcare reform measures of the Biden administration or other efforts, if any, to challenge, repeal or replace the ACA will impact our business.
−Removed: In addition, other legislative changes have been proposed and adopted in the United States since the ACA was enacted.
−Removed: • The Budget Control Act of 2011, among other things, created measures for spending reductions by Congress that included, along with subsequent legislation, aggregate reductions of Medicare payments to providers of up to 2% per fiscal year will remain in effect through 2032 unless additional Congressional action is taken.
−Removed: • The American Taxpayer Relief Act of 2012 among other things, further reduced Medicare payments to several providers, including hospitals, imaging centers and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.
−Removed: The BBA also amended the ACA, effective January 1, 2019, by increasing the point-of-sale discount that is owed by pharmaceutical manufacturers who participate in Medicare Part D and closing the coverage gap in most Medicare drug plans, commonly referred to as the “donut hole.”
−Removed: • The American Rescue Plan Act of 2021 eliminates the statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, effective January 1, 2024.
−Removed: • On May 30, 2018, the Right to Try Act, was signed into law.
−Removed: The law, among other things, provides a federal framework for certain patients to access certain investigational new drug products that have completed a Phase 1 clinical trial and that are undergoing investigation for FDA approval.
−Removed: Under certain circumstances, eligible patients can seek treatment without enrolling in clinical trials and without obtaining FDA permission under the FDA expanded access program.
−Removed: There is no obligation for a pharmaceutical manufacturer to make its drug products available to eligible patients as a result of the Right to Try Act.
−Removed: • The Inflation Reduction Act of 2022, or IRA, includes several provisions that may impact our business to varying degrees, including provisions that reduce the annual out-of-pocket spending cap for Medicare Part D beneficiaries from $7,050 to $2,000 starting in 2025, thereby effectively eliminating the coverage gap;
−Removed: impose new manufacturer financial liability on many drugs reimbursed under Medicare Part D;
−Removed: allow the U.S.
−Removed: government to negotiate Medicare Part B and Part D pricing for certain high-cost drugs and biologics without generic or biosimilar competition;
−Removed: and require companies to pay rebates to Medicare for drug prices that increase faster than inflation.
−Removed: Further, under the IRA, orphan drugs are exempted from the Medicare drug price negotiation program, but only if they have one orphan designation and for which the only approved indication is for that disease or condition.
−Removed: If a product receives multiple orphan designations or has multiple approved indications, it may not qualify for the orphan drug exemption.
−Removed: The implementation of the IRA is currently subject to ongoing litigation that challenges the constitutionality of the IRA’s Medicare drug price negotiation program.
−Removed: The effects of the IRA on our business and the healthcare industry in general is not yet known.
−Removed: Moreover, payment methodologies may be subject to changes in healthcare legislation and regulatory initiatives.
−Removed: For example, CMS may develop new payment and delivery models, such as bundled payment models.
−Removed: Recently, there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products.
−Removed: Such scrutiny has resulted in several recent U.S.
−Removed: Congressional inquiries and has further resulted in proposed and enacted federal and state legislation designed to, among other things, bring more transparency to drug pricing, reduce the cost of prescription drugs under Medicare, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drugs.
−Removed: Additionally, there has been increasing legislative and enforcement interest in the United States with respect to drug pricing practices.
−Removed: Specifically, there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in several U.S.
−Removed: Congressional inquiries and proposed and enacted federal
−Removed: and state legislation designed to, among other things, bring more transparency to drug pricing, reduce the cost of prescription drugs under Medicare, and review the relationship between pricing and manufacturer patient programs.
−Removed: On December 2, 2020, HHS published a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.
−Removed: The rule also creates a new safe harbor for price reductions reflected at the point-of-sale, as well as a safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers.
−Removed: Pursuant to court order, the removal and addition of the aforementioned safe harbors were delayed and the IRA further delayed implementation of this rule to January 1, 2032.
−Removed: Although a number of these and other proposed measures may require authorization through additional legislation to become effective, and the Biden administration may reverse or otherwise change these measures, both the Biden administration and Congress have indicated that they will continue to seek new legislative measures to control drug costs.
−Removed: At the state level, individual states are increasingly aggressive in passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.
−Removed: Legally mandated price controls on payment amounts by third-party payors or other restrictions could harm our business, financial condition, results of operations and prospects.
−Removed: In addition, regional health care authorities and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription drug and other health care programs.
−Removed: These measures could reduce the ultimate demand for our products, once approved, or put pressure on our product pricing, which could negatively affect our business, financial condition, results of operations and prospects.
−Removed: We expect that additional state and federal healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in reduced demand for our current or future product candidates or additional pricing pressures.
−Removed: We cannot predict the likelihood, nature or extent of government regulation that may arise from future legislation or administrative action in the United States.
−Removed: If we or any third parties we may engage are slow or unable to adapt to changes in existing requirements or the adoption of new requirements or policies, or if we or such third parties are not able to maintain regulatory compliance, our product candidates may lose any regulatory approval that may have been obtained and we may not achieve or sustain profitability.
+Added: In the United States and some foreign jurisdictions, there have been a number of legislative and regulatory changes and proposed changes regarding the healthcare system that could prevent or delay marketing approval of our product candidates, restrict or regulate post-approval activities and affect our ability to profitably sell any product candidates for which we obtain marketing approval.
+Added: The pharmaceutical industry has been a particular focus of these efforts and has been significantly affected by legislative initiatives.
+Added: Current laws, as well as other healthcare reform measures that may be adopted in the future, may result in more rigorous coverage criteria and in additional downward pressure on the price that we receive for any FDA approved product.
+Added: If reimbursement of our products is unavailable or limited in scope, our business could be materially harmed.
+Added: See the section of this report entitled, “Business – Government Regulation – Current & Future Healthcare Reform Legislation” for more information.
+Added: The continuing efforts of the government, insurance companies, managed care organizations and other payers of healthcare services to contain or reduce costs of healthcare may adversely affect:
+Added: • the demand for any of our product candidates, if approved;
+Added: • the ability to set a price that we believe is fair for any of our product candidates, if approved;
+Added: • our ability to generate revenues and achieve or maintain profitability;
+Added: • the level of taxes that we are required to pay; and
+Added: • the availability of capital.
+Added: We expect that these healthcare reforms, as well as other healthcare reform measures that may be adopted in the future, may result in additional reductions in Medicare and other healthcare funding, more rigorous coverage criteria, new payment methodologies and additional downward pressure on the price that we receive for any approved product and/or the level of reimbursement physicians receive for administering any approved product we might bring to market.
+Added: Reductions in reimbursement levels may negatively impact the prices we receive or the frequency with which our products are prescribed or administered.
+Added: Any reduction in reimbursement from Medicare or other government programs may result in a similar reduction in payments from private payors.
Our relationships with customers, health care providers, physicians, and third-party payors will be subject to applicable anti-kickback, fraud and abuse and other healthcare laws and regulations, which could expose us to criminal sanctions, civil penalties, exclusion from government healthcare programs, contractual damages, reputational harm and diminished future profits and earnings.
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These laws may impact, among other things, the business or financial arrangements and relationships through which we market, sell and distribute any current or future product candidates for which we obtain marketing approval.
−Removed: See the section of this report titled “Government Regulation -other Regulatory Matters – Other Healthcare Laws” for additional information.
+Added: See the section of this Annual Report on Form 10-K titled “Business - Government Regulation - Other Regulatory Matters - Other Healthcare Laws” for additional information.
The scope and enforcement of each of these laws is uncertain and subject to rapid change in the current environment of healthcare reform, especially in light of the lack of applicable precedent and regulations.
Federal and state enforcement bodies have recently increased their scrutiny of interactions between healthcare companies and healthcare providers, which has led to a number of investigations, prosecutions, convictions and settlements in the healthcare industry.
−Removed: Ensuring that our internal operations and future business arrangements with third parties comply with applicable healthcare laws and regulations will involve substantial costs.
+Added: Ensuring that our internal operations and future business arrangements with third parties comply with applicable healthcare laws and regulations will
+Added: involve substantial costs.
It is possible that governmental authorities will conclude that our business practices do not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws and regulations.
−Removed: If our operations are found to be in violation of any of these laws or any other governmental regulations that may
−Removed: apply to us, we may be subject to significant civil, criminal and administrative penalties, damages, fines, disgorgement, contractual damages, reputational harm, diminished profits and future earnings, imprisonment, exclusion from government funded healthcare programs, such as Medicare and Medicaid, and the curtailment or restructuring of our operations, as well as additional reporting obligations and oversight if we become subject to a corporate integrity agreement or similar settlement to resolve allegations of non-compliance with these laws.
+Added: If our operations are found to be in violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to significant civil, criminal and administrative penalties, damages, fines, disgorgement, contractual damages, reputational harm, diminished profits and future earnings, imprisonment, exclusion from government funded healthcare programs, such as Medicare and Medicaid, and the curtailment or restructuring of our operations, as well as additional reporting obligations and oversight if we become subject to a corporate integrity agreement or similar settlement to resolve allegations of non-compliance with these laws.
Further, defending against any such actions can be costly and time consuming, and may require significant financial and personnel resources.
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The provision of benefits or advantages to physicians to induce or encourage the prescription, recommendation, endorsement, purchase, supply, order or use of medicinal products is also prohibited in the EU.
−Removed: The provision of benefits or advantages to physicians is governed by the national anti-bribery laws of EU Member States, such as the U.K.
−Removed: Bribery Act 2010.
+Added: The provision of benefits or advantages to physicians is governed by the national anti-bribery laws of EU Member States and the Bribery Act 2010 in the U.K..
Infringement of these laws could result in substantial fines and imprisonment.
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Other activities subject to these laws include the improper use of information obtained in the course of clinical trials or creating fraudulent data in our preclinical studies or clinical trials, which could result in regulatory sanctions and cause serious harm to our reputation.
−Removed: We have adopted a code of conduct applicable to all of our employees, but it is not always possible to identify and deter misconduct by employees and other third parties, and the precautions we take to detect and prevent this activity may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a failure to comply with
−Removed: these laws or regulations.
+Added: We have adopted a code of conduct applicable to
+Added: all of our employees, but it is not always possible to identify and deter misconduct by employees and other third parties, and the precautions we take to detect and prevent this activity may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a failure to comply with these laws or regulations.
Additionally, we are subject to the risk that a person could allege such fraud or other misconduct, even if none occurred.
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Potential competitors also include academic institutions, government agencies and other public and private research organizations that conduct research, seek patent protection and establish collaborative arrangements for research, development, manufacturing and commercialization of new drugs.
−Removed: Competitors in our efforts to develop small molecule protein degraders therapies for patients, include, but are not limited to, Arvinas, Inc., C4 Therapeutics, Inc., Foghorn Therapeutics Inc.
−Removed: and Nurix Therapeutics, Inc., some of which have entered clinical development.
−Removed: Further, several large pharmaceutical companies have disclosed preclinical and clinical investments in this field.
+Added: Companies developing small molecule protein degraders therapies for patients, include, but are not limited to, Arvinas, Inc., C4 Therapeutics, Inc., Nurix Therapeutics, Inc., and Foghorn Therapeutics, Inc.
+Added: Further, several large pharmaceutical companies have disclosed preclinical investments in this field.
+Added: In particular, several pharmaceutical companies have announced partnerships around programs targeting STAT6, including Sanofi, Johnson & Johnson and Gilead Sciences, Inc.
Our competitors will also include companies that are or will be developing other targeted protein degradation methods as well as small molecule, antibody, or gene therapies for the same indications that we are targeting.
−Removed: In addition to the competitors we face in developing small molecule protein degraders, we will also face competition in the indications we expect to pursue with our IRAK4, STAT6, TYK2, STAT3 and MDM2 programs.
+Added: In addition to the competitors we face in developing small molecule protein degraders, we will also face competition in the indications we expect to pursue with our IRAK4, STAT6 and TYK2 programs.
Many of these indications already have approved standards of care which may include more traditional therapeutic modalities.
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Product liability lawsuits against us could cause us to incur substantial liabilities and could limit commercialization of any current or future product candidates that we may develop.
−Removed: We face an inherent risk of product liability exposure related to the testing of our current or future product candidates in human clinical trials and will face an even greater risk if we commercially sell any current or future product candidates that we may develop.
+Added: We face an inherent risk of product liability exposure related to the testing of our current or future product candidates in human clinical trials and will face an even greater risk if we commercially sell any current or future product candidates that we
If we cannot successfully defend ourselves against claims that our current or future product candidates caused injuries, we could incur substantial liabilities.
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• the inability to commercialize any current or future product candidates that we may develop.
−Removed: We do not yet maintain product liability insurance, and we anticipate that we will need to increase our insurance coverage when we begin clinical trials and if we successfully commercialize any product candidate.
+Added: We anticipate that we will need to increase our insurance coverage when we begin later stage clinical trials and if we successfully commercialize any product candidate.
Insurance coverage is increasingly expensive.
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If these third parties do not successfully carry out their contractual duties, comply with regulatory requirements or meet expected deadlines, we may not be able to obtain marketing approval for or commercialize our current and potential future product candidates and our business could be substantially harmed.
−Removed: We utilize and depend upon independent investigators and collaborators, such as medical institutions, CROs, contract manufacturing organizations and strategic partners to help conduct our preclinical studies.
+Added: We utilize and depend upon independent investigators and collaborators, such as medical institutions, CROs, contract laboratories, contract manufacturing organizations and strategic partners to help conduct or otherwise support our preclinical studies and clinical trials for our current product candidates, and we expect to rely on such third parties for our future product candidates.
We do not have the ability to independently conduct clinical trials.
−Removed: We rely on medical institutions, clinical investigators, contract laboratories, and other third parties, including collaboration partners, to conduct or otherwise support clinical trials for our current product candidates, and we expect to rely on such third parties for our future product candidates.
−Removed: We rely heavily on these parties for execution of clinical trials for our product candidates and control only certain aspects of their activities.
+Added: We rely heavily on external parties for execution of clinical trials for our product candidates and control only certain aspects of their activities.
Nevertheless, we are responsible for ensuring that each of our clinical trials is conducted in accordance with the applicable protocol, legal and regulatory requirements and scientific standards, and our reliance on CROs will not relieve us of our regulatory responsibilities.
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Failure to do so can result in fines, adverse publicity and civil and criminal sanctions.
−Removed: Although we designed the Phase 1 trials of KT-474, KT-333 and KT-253, and intend to design other clinical trials for our current or future product candidates, or be involved in the design when other parties sponsor the trials, we anticipate that third parties will conduct all of our clinical trials.
+Added: Although we designed the Phase 1 trials of KT-474 and KT-621 and intend to design other clinical trials for our current or future product candidates, or be involved in the design when other parties sponsor the trials, we anticipate that third parties will conduct all of our clinical trials.
As a result, many important aspects of our clinical development, including their conduct and timing will be outside of our direct control.
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These factors may materially adversely affect the willingness or ability of third parties to conduct our clinical trials and may subject us to unexpected cost increases that are beyond our control.
−Removed: If our CROs do not perform clinical trials in a satisfactory manner, breach their obligations to us or fail to comply with regulatory requirements, the development, marketing approval and commercialization of our current or future product candidates may be delayed, we may not be able to obtain marketing approval and commercialize our current or future product candidates, or our development programs may be materially and irreversibly harmed.
+Added: If our CROs do not perform clinical trials in a satisfactory manner, breach their obligations to us, fail to comply with regulatory requirements, or if they need to be replaced, any clinical trials such CROs are associated with may be extended, delayed or terminated, the development, marketing approval and commercialization of our current or future product candidates may be delayed, we may not be able to obtain marketing approval and commercialize our current or future product candidates, or our development programs may be materially and irreversibly harmed.
If we are unable to rely on clinical data collected by our CROs, we could be required to repeat, extend the duration of, or increase the size of clinical trials we conduct and this could significantly delay commercialization and require significantly greater expenditures.
If any of our relationships with these third-party CROs terminate, we may not be able to enter into arrangements with alternative CROs on commercially reasonable terms, or at all.
−Removed: If our CROs do not successfully carry out their contractual duties or obligations or meet expected deadlines, if they need to be replaced or if the quality or accuracy of the clinical data they obtain are compromised due to the failure to adhere to our clinical protocols, regulatory requirements or for other reasons, any clinical trials such CROs are associated with may be extended, delayed or terminated, and we may not be able to obtain marketing approval for or successfully commercialize our current or future product candidates.
+Added: If our CROs do not successfully
+Added: carry out their contractual duties or obligations or meet expected deadlines, if they need to be replaced or if the quality or accuracy of the clinical data they obtain are compromised due to the failure to adhere to our clinical protocols, regulatory requirements or for other reasons, any clinical trials such CROs are associated with may be extended, delayed or terminated, and we may not be able to obtain marketing approval for or successfully commercialize our current or future product candidates.
As a result, we believe that our financial results and the commercial prospects for our current or future product candidates in the subject indication would be harmed, our costs could increase and our ability to generate revenue could be delayed.
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The drug substance and drug product in our product candidates are supplied to us from a small number of suppliers, and in some cases sole source suppliers.
−Removed: Our ability to successfully develop our current or future product candidates, and to ultimately supply our commercial drugs in quantities sufficient to meet the market demand, depends in part on our ability to obtain the drug product and drug substance for these drugs in accordance with regulatory requirements and in sufficient quantities for commercialization and clinical testing.
−Removed: We do not currently have arrangements in place for a redundant or second-source supply of all drug product or drug substance in the event any of our current suppliers of such drug product and drug substance cease their operations for any reason.
+Added: We rely on and expect to continue to rely on our suppliers to develop our current or future product candidates, and to ultimately supply our commercial drugs in quantities sufficient to meet the market demand.
+Added: We do not currently have arrangements in place for a second-source supply of all drug product or drug substance.
Any delays in the delivery of our drug substance, drug product or starting materials could have an adverse effect and potentially harm our business.
For example, in February 2020, one of our vendors for API starting materials based in Wuhan, China ceased its operations for several weeks due to the COVID-19 pandemic, which caused a minor delay in the delivery of API starting materials to a separate vendor who manufactures API.
−Removed: Legislative proposals are pending that, if enacted, could negatively impact U.S.
−Removed: funding for certain biotechnology providers having relationships with foreign adversaries or which pose a threat to national security.
+Added: Regional or single-source dependencies may in some cases accentuate these risks.
+Added: For example, the pharmaceutical industry generally and in some instances we or our collaborators or other third parties on which we rely on depend on China-based suppliers or services providers for certain raw materials, products and services and other activities.
+Added: Our ability or the ability of our collaborators or such other third parties to continue to engage these China-based suppliers or service providers for certain preclinical research programs and clinical development programs could be restricted due to developments between the United States and China, including as a results of the escalation of tariffs or other trade restrictions or if the previously proposed federal legislation known as the BIOSECURE Act or a similar law were to be enacted.
+Added: Recently, there has been legislation proposed that, if enacted, could negatively impact U.S.
+Added: companies and institutions that accept U.S.
+Added: funding for projects that utilize biotechnology equipment and services produced or provided by certain biotechnology providers having relationships with foreign adversaries and which pose a threat to national security.
The potential downstream adverse impacts on entities having only commercial relationships with any impacted biotechnology providers is unknown but may include supply chain disruptions or delays.
−Removed: For all of our current or future product candidates, we intend to identify and qualify additional manufacturers to provide such API, drug product and drug substance prior to submission of an NDA to the FDA and/or an MAA to the EMA.
−Removed: We are not certain, however, that our single-source and dual source suppliers will be able to meet our demand for their products, either because of the nature of our agreements with those suppliers, our limited experience with those suppliers or our relative importance as a customer to those suppliers.
+Added: Though we do not currently receive U.S.
+Added: government funding, we are currently evaluating steps to mitigate any potential impact of any future stricter legislation towards foreign entities providing services to U.S.
+Added: based companies.
+Added: Depending on the terms of the final legislation enacted, these steps could result in additional costs and potential delays in development timelines resulting from related transition efforts For all of our current or future product candidates, we intend to identify and qualify additional manufacturers to provide such API, drug product and drug substance prior to submission of an NDA to the FDA and/or an MAA to the EMA.
+Added: We are not certain, however, that our single-source and dual source suppliers will be able to meet our demand for their products.
It may be difficult for us to assess their ability to timely meet our demand in the future based on past performance.
−Removed: While our suppliers have generally met our demand for their products on a timely basis in the past, they may subordinate our needs in the future to their other customers.
Establishing additional or replacement suppliers for the drug product and drug substance used in our current or future product candidates, if required, may not be accomplished quickly.
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We also cannot be certain that, following a strategic transaction, license, collaboration or other business development partnership, we will achieve the revenue or specific net income that justifies such transaction.
−Removed: Any delays in entering into new collaborations or strategic partnership agreements related to our current or future product candidates could
−Removed: delay the development and commercialization of our current or future product candidates in certain geographies or for certain indications, which would harm our business prospects, financial condition and results of operations.
+Added: Any delays in entering into new collaborations or strategic partnership agreements related to our current or future product candidates could delay the development and commercialization of our current or future product candidates in certain geographies or for certain indications, which would harm our business prospects, financial condition and results of operations.
As discussed elsewhere in this Annual Report on Form 10-K, our collaboration partner, Sanofi, is conducting a randomized Phase 2 clinical trial evaluating KT-474 in HS and a second randomized Phase 2 trial in AD.
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Our commercial success depends in part on our ability to obtain and maintain patent or other intellectual property protection in the U.S.
−Removed: and other countries for our current or future product candidates and our core technologies, including our proprietary Pegasus TM platform, our initial IRAK4, STAT3 and MDM2 programs, which are our most advanced development programs, as well as our proprietary compound library and other know-how.
+Added: and other countries for our current or future product candidates and our core technologies, including our proprietary TPD expertise, our, STAT6, TYK2 and IRAK4 programs, which are our most advanced development programs, as well as our proprietary compound library, and other know-how.
We seek to protect our proprietary and intellectual property position by, among other methods, filing patent applications in the U.S.
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We also rely on trade secrets, know-how and continuing technological innovation to develop and maintain our proprietary and intellectual property position.
−Removed: We own patent applications and one patent related to our platform E3 ligase ligand technology and our novel bifunctional degrader compounds, including claims to compositions of matter, pharmaceutical compositions, methods of use, methods of treatment, and other related methods.
−Removed: As of December 31, 2023, our patent portfolio covering novel compounds, and the methods of making and using thereof, included 101 patent families.
−Removed: Patent term adjustments, supplementary protection certificate filings, or patent term extensions could result in later expiration dates in various countries, while terminal disclaimers could result in earlier expiration dates in the U.S.
+Added: We own patent applications and patents related to our TPD technology and our novel bifunctional degrader compounds, including claims to compositions of matter, pharmaceutical compositions, methods of use, methods of treatment, and other related methods.
The patent position of biotechnology and pharmaceutical companies generally is highly uncertain, involves complex legal and factual questions and has in recent years been the subject of much litigation.
−Removed: The degree of patent protection we require to successfully commercialize our current or future product candidates may be unavailable or severely limited in some cases and may not adequately protect our rights or permit us to gain or keep any competitive advantage.
−Removed: We cannot provide any assurances that any of our pending patent applications that mature into issued patents will include claims with a scope sufficient to protect our Pegasus TM platform and our current or future product candidates.
+Added: The degree of patent protection we require to successfully commercialize our current or future product candidates may be unavailable or severely limited in some cases and may not adequately protect our rights or permit us to gain or keep any
+Added: competitive advantage.
+Added: We cannot provide any assurances that any of our pending patent applications that mature into issued patents will include claims with a scope sufficient to protect our TPD expertise and our current or future product candidates.
In addition, if the breadth or strength of protection provided by our patent applications or any patents we may own or in-license is threatened, it could dissuade companies from collaborating with us to license, develop or commercialize current or future product candidates.
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Patent and Trademark Office, or USPTO, the European Patent Office, or EPO, or in other countries.
−Removed: In addition, we may be subject to
−Removed: third-party submissions to the USPTO, the EPO, or elsewhere, that may reduce the scope or preclude the granting of claims from our pending patent applications.
+Added: In addition, we may be subject to third-party submissions to the USPTO, the EPO, or elsewhere, that may reduce the scope or preclude the granting of claims from our pending patent applications.
Competitors may challenge our issued patents or may file patent applications before we do.
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An adverse determination in any such submission or proceeding may result in loss of exclusivity or freedom to operate or in patent claims being narrowed, invalidated or held unenforceable, in whole or in part, which could limit our ability to stop others from using or commercializing similar or identical technology and drugs, without payment to us, or could limit the duration of the patent protection covering our technology and current or future product candidates.
−Removed: Such challenges may also result in our inability to manufacture or commercialize our current or future product candidates without infringing third-party patent rights.
+Added: Such challenges may also result in our inability to manufacture or commercialize our current or future product candidates without infringing third-party
+Added: patent rights.
In addition, if the breadth or strength of protection provided by our patents and patent applications is threatened, it could dissuade companies from collaborating with us to license, develop or commercialize current or future product candidates.
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We will not obtain patent or other intellectual property protection for all current or future product candidates in all jurisdictions throughout the world, and we may not be able to adequately enforce our intellectual property rights even in the jurisdictions where we seek protection.
−Removed: We may not be able to pursue patent coverage of our current or future product candidates, the Pegasus TM platform, or other technologies in all countries.
−Removed: Filing, prosecuting and defending patents on current or future product candidates, the Pegasus TM platform, and other technologies in all countries throughout the world would be prohibitively expensive, and intellectual property rights in some countries outside the U.S.
+Added: We may not be able to pursue patent coverage of our current or future product candidates, our TPD expertise, or other technologies in all countries.
+Added: Filing, prosecuting and defending patents on current or future product candidates, our TPD expertise, and other technologies in all countries throughout the world would be prohibitively expensive, and intellectual property rights in some countries outside the U.S.
can be less extensive than those in the U.S.
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Many companies have encountered significant problems in protecting and defending intellectual property rights in foreign jurisdictions.
−Removed: The legal systems of certain countries, particularly certain developing countries, do not favor the enforcement of patents, trade secrets and other intellectual property protection, particularly those relating to pharmaceutical products, which
−Removed: could make it difficult for us to stop the infringement of any patents we may own or in-license or marketing of competing products in violation of our proprietary rights generally.
+Added: The legal systems of certain countries, particularly certain developing countries, do not favor the enforcement of patents, trade secrets and other intellectual property protection, particularly those relating to pharmaceutical products, which could make it difficult for us to stop the infringement of any patents we may own or in-license or marketing of competing products in violation of our proprietary rights generally.
Proceedings to enforce any rights we may have in our patent applications or any patents we may own or in-license in foreign jurisdictions could result in substantial costs and divert our efforts and attention from other aspects of our business, could put any patents we may own or in-license at risk of being invalidated or interpreted narrowly and our patent applications at risk of not issuing, and could provoke third parties to assert claims against us.
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In these countries, the patent owner may have limited remedies, which could materially diminish the value of such patent.
−Removed: If we are forced to grant a license to third parties with respect to any patents we may own or license that are relevant to our business, our competitive position may be impaired, and our business, financial condition, results of operations, and prospects may be adversely affected.
+Added: If we are forced to grant a license to third parties with respect to any patents we may own or license that are relevant to our
+Added: business, our competitive position may be impaired, and our business, financial condition, results of operations, and prospects may be adversely affected.
We may not obtain or grant licenses or sublicenses to intellectual property rights in all markets on equally or sufficiently favorable terms with third parties.
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Sanofi and other collaborators may have the right to terminate their respective license agreements in full in the event that we materially breach or default in the performance of any of the obligations under such license agreements.
−Removed: Any termination of these licenses, or if the underlying patents fail to provide the intended exclusivity, could result in the loss of significant rights and could harm our ability to commercialize our current or future product candidates, the Pegasus TM platform, or other technologies, competitors or other third parties would have the freedom to seek regulatory approval of, and to market, products identical to ours, and we may be required to cease our development and commercialization of certain of our current or future product candidates.
+Added: Any termination of these licenses, or if the underlying patents fail to provide the intended exclusivity, could result in the loss of significant rights and could harm our ability to commercialize our current or future product candidates, our TPD expertise, competitors or other third parties would have the freedom to seek regulatory approval of, and to market, products identical to ours, and we may be required to cease our development and commercialization of certain of our current or future product candidates.
Any of the foregoing could have a material adverse effect on our competitive position, business, financial conditions, results of operations, and prospects.
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In addition, the agreements under which we may license intellectual property or technology from third parties are likely to be complex, and certain provisions in such agreements may be susceptible to multiple interpretations.
−Removed: The resolution of any contract interpretation disagreement that may arise could narrow what we believe to be the scope of our rights to the relevant intellectual property or technology, or increase what we believe to be our financial or other obligations under the relevant agreement, either of which could have a material adverse effect on our business, financial condition, results of operations and prospects.
+Added: The resolution of any contract interpretation disagreement that may arise could narrow what we believe to be the scope of our rights to the relevant intellectual property or technology, or increase what we believe to be our financial or other obligations under the relevant agreement, either of which could have a material adverse effect on our business, financial condition, results of operations and
Moreover, if disputes over intellectual property that we may license prevent or impair our ability to maintain current or future licensing arrangements on acceptable terms, we may be unable to successfully develop and commercialize the affected current or future product candidates or technologies, which could have a material adverse effect on our business, financial conditions, results of operations and prospects.
23 unchanged sentences
The USPTO and foreign governmental patent agencies require compliance with a number of procedural, documentary, fee payment and other similar provisions during the patent application process and after issuance of any patent.
−Removed: In addition, periodic maintenance fees, renewal fees, annuity fees and/or various other government fees are required to be paid periodically.
+Added: periodic maintenance fees, renewal fees, annuity fees and/or various other government fees are required to be paid periodically.
While an inadvertent lapse can in some cases be cured by payment of a late fee or by other means in accordance with the applicable rules, there are situations in which noncompliance can result in abandonment or lapse of the patent or patent application, resulting in partial or complete loss of patent rights in the relevant jurisdiction.
20 unchanged sentences
Risks Related to Our Trademarks, Trade Names and Trade Secrets
−Removed: If our trademarks and trade names for our products or company name are not adequately protected in one or more countries where we intend to market our products, we may delay the launch of product brand names, use different or less effective trademarks or tradenames in different countries, or face other potentially adverse consequences to building our product brand recognition.
+Added: If our trademarks for our products or company name are not adequately protected in one or more countries where we intend to market our products, we may delay the launch of product brand names, use different or less effective trademarks or tradenames in different countries, or face other potentially adverse consequences or impediments to building our product brand recognition.
Our trademarks or trade name may be challenged, infringed, diluted, circumvented, declared generic, or determined to be infringing on other marks.
1 unchanged sentence
In addition, during the trademark registration process, we may receive Office Actions from the USPTO or from comparable agencies in foreign jurisdictions refusing registration of our trademarks.
−Removed: For example, in April 2021 and October 2022, respectively, the USPTO issued preliminary office action refusals against our applications to register E3 LIGASE WHOLE BODY ATLAS and E3 HUMAN ATLAS and our K & Design logo mark.
−Removed: While E3 LIGASE WHOLE BODY ATLAS and E3 HUMAN ATLAS have since been published and notices of allowance issued, we do not yet know whether the USPTO will issue a subsequent office action against our application for our logo mark, to which we will have to respond, and which we may not ultimately be able to overcome, or if this application will be approved for publication as well.
In the USPTO and in comparable agencies in many foreign jurisdictions, third parties are also given an opportunity to oppose pending trademark applications and/or to seek the cancellation of registered trademarks.
1 unchanged sentence
and European Union trademark offices opposing our applications to register KYMERA and KYMERA THERAPEUTICS for pharmaceuticals and drug development services on the basis of its claimed rights in the KYMRIAH mark.
−Removed: This dispute was amicably settled in October 2020 and the involved applications for KYMERA and KYMERA THERAPEUTICS are now registered or allowed in the United States and have proceeded to registration in the European Union.
+Added: This dispute was amicably settled in October 2020 and the involved applications for KYMERA
+Added: and KYMERA THERAPEUTICS are now registered or allowed in the United States and have proceeded to registration in the European Union.
If we are unable to adequately protect and enforce our trade secrets, our business and competitive position would be harmed.
12 unchanged sentences
Although we require all of our employees to assign their inventions to us, we may be unsuccessful in executing such an agreement with each party who, in fact, conceives or develops intellectual property that we regard as our own.
−Removed: The assignment of intellectual property rights may not be self-executing, or the assignment agreements may be breached, and we may be forced to bring claims against third parties, or defend claims that they may bring against us, to determine the ownership of what we regard as our intellectual
+Added: The assignment of intellectual property rights may not be self-executing, or the assignment agreements may be breached, and we may be forced to bring claims against third parties, or defend claims that they may bring against us, to determine the ownership of what we regard as our intellectual property.
Such claims could have a material adverse effect on our business, financial condition, results of operations, and prospects.
11 unchanged sentences
Some of our competitors may be able to sustain the costs of such litigation or proceedings more effectively than we can because of their greater financial resources and more mature and developed intellectual property portfolios.
−Removed: Uncertainties resulting from the initiation and continuation of patent litigation or other proceedings could have a material adverse effect on our ability to compete in the marketplace.
+Added: Uncertainties resulting from the initiation and
+Added: continuation of patent litigation or other proceedings could have a material adverse effect on our ability to compete in the marketplace.
Post-grant proceedings provoked by third parties or brought by the USPTO may be necessary to determine the validity or priority of inventions with respect to our patent applications or any patents we may own or in-license.
15 unchanged sentences
Even if resolved in our favor, litigation or other legal proceedings relating to intellectual property claims may cause us to incur significant expenses, and could distract our technical and management personnel from their normal responsibilities.
−Removed: In August 2021, we initiated a US patent office
−Removed: proceeding, a post-grant review, to challenge a third-party patent unrelated to our current product candidates.
+Added: In August 2021, we initiated a US patent office proceeding, a post-grant review, to challenge a third-party patent unrelated to our current product candidates.
In response, the owner of the challenged third-party patent disclaimed that patent in full.
6 unchanged sentences
Any of the foregoing events would harm our business, financial condition, results of operations and prospects.
−Removed: We may be subject to damages or settlement costs resulting from claims that we or our employees hav
+Added: We may be subject to damages or settlement costs resulting from claims that we or our employees have violated the intellectual property rights of third parties, or are in breach of our agreements.
+Added: We may be accused of, allege or otherwise become party to lawsuits or disputes alleging wrongful disclosure of third-party confidential information by us or by another party, including current or former employees, contractors or consultants.
+Added: In addition to diverting attention and resources, such disputes could adversely impact our business reputation and/or protection of our proprietary technology.
+Added: The intellectual property landscape relevant to our product candidates and programs is crowded, and third parties may initiate legal proceedings alleging that we are infringing, misappropriating or otherwise violating their intellectual property rights, the outcome of which would be uncertain and could have a material adverse effect on the success of our business.
+Added: Our commercial success depends upon our ability to develop, manufacture, market and sell our current and future product candidates
+Added: and use our proprietary technologies without infringing, misappropriating or otherwise violating the intellectual property rights of third parties.
+Added: There is a substantial amount of litigation involving patents and other intellectual property rights in the biotechnology and pharmaceutical industries, as well as administrative proceedings for challenging patents, including derivation, interference, reexamination, inter partes review and post grant review proceedings before the USPTO or oppositions and other comparable proceedings in foreign jurisdictions.
+Added: We or any of our current or future licensors or strategic partners may be party to, exposed to, or threatened with, future adversarial proceedings or litigation by third parties having patent or other intellectual property rights alleging that our current or future product candidates and/or proprietary technologies infringe, misappropriate or otherwise violate their intellectual property rights.
+Added: We cannot assure you that our current or future product candidates, our TPD expertise, and other technologies that we have developed, are developing or may develop in the future do not or will not infringe, misappropriate or otherwise violate existing or future patents or other intellectual property rights owned by third parties.
+Added: For example, many of our employees were previously employed at other biotechnology or pharmaceutical companies.
+Added: Although we try to ensure that our employees, consultants and advisors do not use the proprietary information or know-how of others in their work for us, we may be subject to claims that we or these individuals have used or disclosed intellectual property, including trade secrets or other proprietary information, of any such individual’s former employer.
+Added: We may also be subject to claims that patents and applications we have filed to protect inventions of our employees, consultants and advisors, even those related to one or more of our current or future product candidates, our TPD expertise, or other technologies, are rightfully owned by their former or concurrent employer.
+Added: Litigation may be necessary to defend against these claims.
+Added: While certain activities related to development and preclinical and clinical testing of our current or future product candidates may be subject to safe harbor of patent infringement under 35 U.S.C.
+Added: §271(e)(1), upon receiving FDA approval for such candidates we or any of our future licensors or strategic partners may immediately become party to, exposed to, or threatened with, future adversarial proceedings or litigation by third parties having patent or other intellectual property rights alleging that such product candidates infringe, misappropriate or otherwise violate their intellectual property rights.
+Added: Numerous U.S.
+Added: and foreign issued patents and pending patent applications, which are owned by third parties, exist in the fields in which we are developing our current or future product candidates.
+Added: As the biotechnology and pharmaceutical industries expand and more patents are issued, the risk increases that our current or future product candidates may give rise to claims of infringement of the patent rights of others.
+Added: Moreover, it is not always clear to industry participants, including us, which patents cover various types of drugs, products or their methods of use or manufacture.
+Added: Thus, because of the large number of patents issued and patent applications filed in our fields, there may be a risk that third parties may allege they have patent rights encompassing our current or future product candidates, technologies or methods.
+Added: If a third party claims that we infringe, misappropriate or otherwise violate its intellectual property rights, we may face a number of issues, including, but not limited to:
+Added: • infringement, misappropriation and other intellectual property claims which, regardless of merit, may be expensive and time-consuming to litigate and may divert our management’s attention from our core business and may impact our reputation;
+Added: • substantial damages for infringement, misappropriation or other violations, which we may have to pay if a court decides that the product candidate or technology at issue infringes, misappropriates or violates the third party’s rights, and, if the court finds that the infringement was willful, we could be ordered to pay treble damages and the patent owner’s attorneys’ fees;
+Added: • a court prohibiting us from developing, manufacturing, marketing or selling our current or future product candidates, or from using our proprietary technologies, including our TPD expertise, unless the third-party licenses its product rights to us, which it is not required to do on commercially reasonable terms or at all;
+Added: • if a license is available from a third party, we may have to pay substantial royalties, upfront fees and other amounts, and/or grant cross-licenses to intellectual property rights for our products, or the license to us may be non-exclusive, which would permit third parties to use the same intellectual property to compete with us;
+Added: • redesigning our current or future product candidates or processes so they do not infringe, misappropriate or violate third-party intellectual property rights, which may not be possible or may require substantial monetary expenditures and time;
+Added: • there could be public announcements of the results of hearings, motions or other interim proceedings or developments, and, if securities analysts or investors perceive these results to be negative, it could have a substantial adverse effect on the price of our common stock.
+Added: Some of our competitors may be able to sustain the costs of litigation more effectively than we can because they have substantially greater resources.
+Added: In addition, any uncertainties resulting from the initiation and continuation of any litigation could have a material adverse effect on our ability to raise the funds necessary to continue our operations or could otherwise have a material adverse effect on our business, results of operations, financial condition and prospects.
+Added: The occurrence of any of the foregoing could have a material adverse effect on our business, financial condition, results of operations or prospects.
+Added: Third parties may assert that we are employing their proprietary technology without authorization.
+Added: Patents issued in the U.S.
+Added: by law enjoy a presumption of validity that can be rebutted in U.S.
+Added: courts only with evidence that is “clear and convincing,” a heightened standard of proof.
+Added: There may be issued third-party patents of which we are currently unaware with claims to compositions, formulations, methods of manufacture or methods for treatment related to the use or manufacture of our current or future product candidates.
+Added: Patent applications can take many years to issue.
+Added: In addition, because some patent applications in the U.S.
+Added: may be maintained in secrecy until the patents are issued, patent applications in the U.S.
+Added: and many foreign jurisdictions are typically not published until 18 months after their earliest priority filing date, and publications in the scientific literature often lag behind actual discoveries, we cannot be certain that others have not filed patent applications covering our current or future product candidates or technology.
+Added: If any such patent applications issue as patents, and if such patents have priority over our patent applications or patents we may own or in-license, we may be required to obtain rights to such patents owned by third parties which may not be available on commercially reasonable terms or at all, or may only be available on a non-exclusive basis.
+Added: There may be currently pending third-party patent applications which may later result in issued patents that our current or future product candidates may infringe.
+Added: It is also possible that patents owned by third parties of which we are aware, but which we do not believe are relevant to our current or future product candidates or other technologies, could be found to be infringed by our current or future product candidates or other technologies.
+Added: In addition, third parties may obtain patents in the future and claim that use of our technologies infringes upon these patents.
+Added: Moreover, we may fail to identify relevant patents or incorrectly conclude that a patent is invalid, not enforceable, exhausted, or not infringed by our activities.
+Added: If any third-party patents were held by a court of competent jurisdiction to cover the manufacturing process of our current or future product candidates, molecules used in or formed during the manufacturing process, or any final product itself, the holders of any such patents may be able to block our ability to commercialize the product candidate unless we obtained a license under the applicable patents, or until such patents expire or they are finally determined to be held invalid or unenforceable.
+Added: Similarly, if any third-party patent were held by a court of competent jurisdiction to cover aspects of our formulations, processes for manufacture or methods of use, including combination therapy or patient selection methods, the holders of any such patent may be able to block our ability to develop and commercialize the product candidate unless we obtained a license or until such patent expires or is finally determined to be held invalid or unenforceable.
+Added: In either case, such a license may not be available on commercially reasonable terms or at all.
+Added: If we are unable to obtain a necessary license to a third-party patent on commercially reasonable terms, or at all, our ability to commercialize our current or future product candidates or TPD expertise may be impaired or delayed, which could in turn significantly harm our business.
+Added: Even if we obtain a license, it may be nonexclusive, thereby giving our competitors access to the same technologies licensed to us.
+Added: Parties making claims against us may seek and obtain injunctive or other equitable relief, which could effectively block our ability to further develop and commercialize our current or future product candidates.
+Added: Defense of these claims, regardless of their merit, could involve substantial litigation expense and would be a substantial diversion of employee resources from our business.
+Added: In the event of a successful claim of infringement, misappropriation or other violation against us, we may have to pay substantial damages, including treble damages and attorneys’ fees for willful infringement, obtain one or more licenses from third parties, pay royalties or redesign our infringing products, which may be impossible or require substantial time and monetary expenditure.
+Added: We cannot predict whether any such license would be available at all or whether it would be available on commercially reasonable terms.
+Added: Furthermore, even in the absence of litigation, we may need or may choose to obtain licenses from third parties to advance our research or allow commercialization of our current or future product candidates.
+Added: We may fail to obtain any of these licenses at a reasonable cost or on reasonable terms, if at all.
+Added: In that event, we would be unable to further develop and commercialize our current or future product candidates or technologies, which could harm our business significantly.
+Added: We may not identify relevant third-party patents or may incorrectly interpret the relevance, scope or expiration of a third-party patent, which might subject us to infringement claims or adversely affect our ability to develop and market our current or future product candidates.
+Added: We cannot guarantee that any of our or our licensors’ patent searches or analyses, including the identification of relevant patents, the scope of patent claims or the expiration of relevant patents, are complete or thorough, nor can we be certain that we have identified each and every third-party patent and pending patent application in the U.S.
+Added: and abroad that is relevant to or necessary for the commercialization of our current or future product candidates in any jurisdiction.
+Added: For example, U.S.
+Added: patent applications filed before November 29, 2000, and certain U.S.
+Added: patent applications filed after that date that will not be filed outside the U.S.
+Added: remain confidential until patents issue.
+Added: As mentioned above, patent applications in the U.S.
+Added: and elsewhere are
+Added: published approximately 18 months after the earliest filing for which priority is claimed, with such earliest filing date being commonly referred to as the priority date.
+Added: Therefore, patent applications covering our current or future product candidates could have been filed by third parties without our knowledge.
+Added: Additionally, pending patent applications that have been published can, subject to certain limitations, be later amended in a manner that could cover our current or future product candidates or the use of our current or future product candidates.
+Added: The scope of a patent claim is determined by an interpretation of the law, the written disclosure in a patent and the patent’s prosecution history.
+Added: Our interpretation of the relevance or the scope of a patent or a pending application may be incorrect, which may negatively impact our ability to market our current or future product candidates.
+Added: We may incorrectly determine that our current or future product candidates are not covered by a third-party patent or may incorrectly predict whether a third party’s pending application will issue with claims of relevant scope.
+Added: Our determination of the expiration date of any patent in the U.S.
+Added: or abroad that we consider relevant may be incorrect, which may negatively impact our ability to develop and market our current or future product candidates.
+Added: Our failure to identify and correctly interpret relevant patents may negatively impact our ability to develop and market our current or future product candidates.
+Added: If we fail to identify and correctly interpret relevant patents, we may be subject to infringement claims.
+Added: We cannot guarantee that we will be able to successfully settle or otherwise resolve such infringement claims.
+Added: If we fail in any such dispute, in addition to being forced to pay damages, which may be significant, we may be temporarily or permanently prohibited from commercializing any of our current or future product candidates or technologies that are held to be infringing.
+Added: We might, if possible, also be forced to redesign current or future product candidates so that we no longer infringe the third-party intellectual property rights.
+Added: Any of these events, even if we were ultimately to prevail, could require us to divert substantial financial and management resources that we would otherwise be able to devote to our business and could adversely affect our business, financial condition, results of operations and prospects.
+Added: Risks Related to Employee Matters, Managing Growth and Other Risks Related to Our Business
+Added: Risks Related to Employee Matters and Managing Growth
+Added: Our future success depends on our ability to retain key executives and to attract, retain and motivate qualified personnel.
+Added: We are highly dependent on the research and development, clinical and business development expertise of Nello Mainolfi, Ph.D., our President and Chief Executive Officer, Jared Gollob, M.D., our Chief Medical Officer, Bruce Jacobs, our Chief Financial Officer, Ellen Chiniara, our Chief Legal Officer and Jeremy Chadwick, our Chief Operating Officer, as well as the other principal members of our management, scientific and clinical teams.
+Added: Although we have entered into employment letter agreements with our executive officers, each of them may terminate their employment with us at any time.
+Added: We do not maintain “key person” insurance for any of our executives or other employees.
+Added: In addition, we rely on consultants and advisors, including scientific and clinical advisors, to assist us in formulating our research and development and commercialization strategy.
+Added: Our consultants and advisors may be employed by employers other than us and may have commitments under consulting or advisory contracts with other entities that may limit their availability to us.
+Added: If we are unable to continue to attract and retain high quality personnel, our ability to pursue our growth strategy will be limited.
+Added: Recruiting and retaining qualified scientific, clinical, manufacturing and sales and marketing personnel will also be critical to our success.
+Added: The loss of the services of our executive officers or other key employees could impede the achievement of our research, development and commercialization objectives and seriously harm our ability to successfully implement our business strategy.
+Added: Furthermore, replacing executive officers and key employees may be difficult and may take an extended period of time because of the limited number of individuals in our industry with the breadth of skills and experience required to successfully develop, gain regulatory approval of and commercialize drugs.
+Added: Competition to hire from this limited pool is intense, and we may be unable to hire, train, retain or motivate these key personnel on acceptable terms given the competition among numerous pharmaceutical and biotechnology companies for similar personnel.
+Added: We also experience competition for the hiring of scientific and clinical personnel from universities and research institutions.
+Added: Failure to succeed in clinical trials may make it more challenging to recruit and retain qualified scientific personnel.
+Added: We will need to continue to develop and expand our company, and we may encounter difficulties in managing this development and expansion, which could disrupt our operations.
+Added: As of December 31, 2024, we had 188 full-time employees, and we expect to increase our number of employees and the scope of our operations.
+Added: To manage our anticipated development and expansion, we must continue to implement and improve our managerial, operational and financial systems, expand our facilities and continue to recruit and train additional qualified personnel.
+Added: Our management may need to divert a disproportionate amount of its attention away from its day-to-day activities and devote a substantial amount of time to managing these development activities.
+Added: Due to our limited resources, we may not
+Added: be able to effectively manage the expansion of our operations or recruit and train additional qualified personnel.
+Added: This may result in weaknesses in our infrastructure, give rise to operational mistakes, loss of business opportunities, loss of employees and reduced productivity among remaining employees.
+Added: The expansion of our operations may lead to significant costs and may divert management’s time and financial resources from other projects, such as the development of our current or future product candidates.
+Added: If our management is unable to effectively manage our expected development and expansion, our expenses may increase more than expected, our ability to generate or increase our revenue could be reduced and we may not be able to implement our business strategy.
+Added: Our future financial performance and our ability to commercialize our current or future product candidates, if approved, and compete effectively will depend, in part, on our ability to effectively manage the future development and expansion of our company.
+Added: We or the third parties upon whom we depend may be adversely affected by unforeseen global events, natural disasters, and our business continuity and disaster recovery plans may not adequately protect us from a serious disaster.
+Added: Unforeseen global events, such as macroeconomic conditions, outbreaks of violence, or geopolitical instability could adversely impact our business.
+Added: Such conflicts could lead to sanctions, embargoes, supply shortages, regional instability, geopolitical shifts, cyberattacks, other retaliatory actions, and adverse effects on macroeconomic conditions, currency exchange rates, and financial markets, which could adversely impact our operations and financial results, as well as those of third parties with whom we conduct business.
+Added: Additionally, any unplanned event, such as flood, fire, explosion, earthquake, extreme weather condition, medical epidemics or pandemics, power shortage, telecommunication failure or other natural or man-made accidents or incidents that result in us being unable to fully utilize our facilities, or the manufacturing facilities of our third-party contract manufacturers, may have a material and adverse effect on our ability to operate our business and have significant negative consequences on our financial and operating conditions.
+Added: Loss of access to these facilities may result in increased costs, delays in the development of our product candidates or interruption of our business operations.
+Added: Natural disasters or pandemics could further disrupt our operations, and have a material and adverse effect on our business, financial condition, results of operations and prospects.
+Added: If a natural disaster, power outage or other event occurred that prevented us from using all or a significant portion of our headquarters, that damaged critical infrastructure, such as our research facilities or the manufacturing facilities of our third-party contract manufacturers, or that otherwise disrupted operations, it may be difficult or, in certain cases, impossible, for us to continue our business for a substantial period of time.
+Added: The disaster recovery and business continuity plans we have in place may prove inadequate in the event of a serious disaster or similar event.
+Added: We may incur substantial expenses as a result of the limited nature of our disaster recovery and business continuity plans, which could have a material adverse effect on our business.
+Added: As part of our risk management policy, we maintain insurance coverage at levels that we believe are appropriate for our business.
+Added: However, in the event of an accident or incident at these facilities, we cannot assure our investors that the amounts of insurance will be sufficient to satisfy any damages and losses.
+Added: If our facilities or the manufacturing facilities of our third-party contract manufacturers are unable to operate because of an accident or incident or for any other reason, even for a short period of time, any or all of our research and development programs may be harmed.
+Added: Any business interruption may have a material and adverse effect on our business, financial condition, results of operations and prospects.
+Added: We intend to sublease our former space in Watertown, Massachusetts for occupancy now that we have moved to our new facility.
+Added: If we are unable to sublease our space on favorable terms or if our subtenants are unable to meet their obligations under any sublease, we may be responsible for unexpected costs, which could impact our financial performance.
+Added: We currently lease 34,522 square feet of research and development and office space in Watertown, Massachusetts, which lease expires on March 31, 2030.
+Added: In December 2021, we entered into a lease for 100,624 square feet of office and laboratory space in Watertown, Massachusetts, which we began occupying in February 2024.
+Added: We intend to sublease our original space and are actively marketing the space to third parties.
+Added: In the event that we are unable to sublease our original space on favorable terms, or at all, or if we are able to sublease our space but our subtenants fail to make lease payments to us or otherwise default on their obligations to us, we could incur unanticipated payment obligations or further impairment.
+Added: Risks Related to Data and Privacy
+Added: Our internal computer systems, or those of our third-party CROs or other contractors or consultants, may fail or suffer security breaches, which could result in a material disruption of our current or future product candidates’ development programs.
+Added: Despite the implementation of security measures, our internal computer systems and those of our third-party CROs and other contractors and consultants are vulnerable to damage from computer viruses, unauthorized access, natural disasters, terrorism, war and telecommunication and electrical failures.
+Added: While we have not experienced any such system failure, accident, or security breach to date, if such an event were to occur and cause interruptions in our operations, it could result in a material disruption of our programs.
+Added: For example, the loss of data from preclinical studies or clinical trials for our current or future product candidates could result in delays in our regulatory approval efforts and significantly increase our costs to recover or reproduce the data.
+Added: To the extent that any disruption or security breach results in a loss of or damage to our data or applications, other data or applications relating to our technology or current or future product candidates, or inappropriate disclosure of confidential or proprietary information, we could incur liabilities and the further development of our current or future product candidates could be delayed.
+Added: We may be unable to adequately protect our information systems from cyberattacks, security incidents, or compromises, which could result in the disclosure of confidential or proprietary information, including personal data, damage our reputation, and subject us to significant financial and legal exposure.
+Added: We rely on information technology systems that we or our third-party providers operate to process, transmit and store electronic information in our day-to-day operations.
+Added: In connection with our product discovery efforts, we may collect and use a variety of personal data, such as names, mailing addresses, email addresses, phone numbers and clinical trial information.
+Added: A successful cyberattack, security incident, or compromise could result in the theft or destruction of intellectual property, data or other misappropriation of assets, or otherwise compromise our confidential or proprietary information and disrupt our operations.
+Added: Cyberattacks are increasing in their frequency, sophistication and intensity, and have become increasingly difficult to detect.
+Added: Cyberattacks could include wrongful conduct by hostile foreign governments, industrial espionage, wire fraud and other forms of cyber fraud, the deployment of harmful malware, denial-of-service, social engineering fraud or other means to threaten data security, confidentiality, integrity and availability.
+Added: A successful cyberattack could cause serious negative consequences for us, including, without limitation, the disruption of operations, the misappropriation of confidential business information, including financial information, trade secrets, financial loss and the disclosure of corporate strategic plans.
+Added: Although we devote resources to protect our information systems, we realize that cyberattacks are a threat, and there can be no assurance that our efforts will prevent information security breaches that would result in business, legal, financial or reputational harm to us, or would have a material adverse effect on our results of operations and financial condition.
+Added: Any failure to prevent or mitigate security breaches or improper access to, use of, or disclosure of our clinical data or patients’ personal data could result in significant liability under state (e.g., state breach notification laws), federal (e.g., HIPAA, as amended by HITECH), and international law (e.g., the EU General Data Protection Regulation, or GDPR) and may cause a material adverse impact to our reputation, affect our ability to use collected data, conduct new studies and potentially disrupt our business.
+Added: We and certain of our service providers have experienced and may in the future experience cyberattacks.
+Added: We rely on our third-party providers to implement effective security measures and identify and correct for any such failures, deficiencies or breaches.
+Added: We also rely on our employees and consultants to safeguard their security credentials and follow our policies and procedures regarding use and access of computers and other devices that may contain our sensitive information.
+Added: If we or our third-party providers fail to maintain or protect our information technology systems and data integrity effectively or fail to anticipate, plan for or manage significant disruptions to our information technology systems, we or our third-party providers could have difficulty preventing, detecting and controlling such cyber-attacks and any such attacks could result in losses described above, as well as disputes with physicians, patients and our partners, regulatory sanctions or penalties, increases in
+Added: operating expenses, expenses or lost revenues or other adverse consequences, any of which could have a material adverse effect on our business, results of operations, financial condition, prospects and cash flows.
+Added: Any failure by such third parties to prevent or mitigate security breaches or improper access to or disclosure of such information could have similarly adverse consequences for us.
+Added: If we are unable to prevent or mitigate the impact of such security or data privacy breaches, we could be exposed to litigation and governmental investigations, which could lead to a potential disruption to our business.
+Added: We, our collaborators and our service providers may be subject to a variety of privacy and data protection laws, regulations and contractual obligations, which may require us to incur substantial compliance costs, and any failure or perceived failure by us to comply with them could expose us to fines or other penalties and otherwise harm our business and operations.
+Added: We may be subject to data privacy and protection laws and regulations that apply to the collection, transmission, storage and use of sensitive information and personally-identifying information, which among other things, imposes certain requirements relating to the privacy, security and transmission of certain individually identifiable information.
+Added: In addition, numerous other federal and state laws, including state security breach notification laws, state health information privacy laws and federal and state consumer protection laws, govern the collection, use, disclosure and security of personal information.
+Added: These laws continue to change and evolve and are increasing in breadth and impact.
+Added: For example, with respect to the collection and processing of personal data relating to the European Union (“EU”), European Economic Area (“EEA”) and United Kingdom (“UK”), we are subject to the EU General Data Protection Regulation (EU GDPR), the UK General Data Protection Regulation (UK GDPR), as well as applicable data protection laws in effect in the Member States of the EEA and in the UK (including the UK Data Protection Act 2018) which govern the processing of personal data in connection with (a) the offering of goods or services to/the monitoring of the behavior of individuals in the UK and EEA;
+Added: or (b) the activities of our establishments in the UK and any EEA Member State.
+Added: The UK’s data protection regime is independent from but aligned to the EU’s data protection regime.
+Added: In this Form 10-K, “GDPR” refers to both the EU GDPR and the UK GDPR, unless specified otherwise.
+Added: The GDPR is wide-ranging in scope and imposes numerous requirements on companies that process personal data, including imposing special requirements in respect of the processing of health and other sensitive data, requiring that consent of individuals to whom the personal data relates is obtained in certain circumstances, requiring additional disclosures to individuals regarding data processing activities, requiring that safeguards are implemented to protect the security and confidentiality of personal data, limiting retention periods for personal data, creating mandatory data breach notification requirements in certain circumstances, and requiring that certain measures (including contractual requirements) are put in place when engaging third-party service providers.
+Added: The GDPR also imposes strict rules on the transfer of personal data to countries outside of the UK and EEA that do not ensure an adequate level of protection, including the United States in certain circumstances, unless derogation exists or a valid GDPR transfer mechanism (for example, the European Commission approved Standard Contractual Clauses (SCCs) and the UK International Data Transfer Agreement or Addendum (UK IDTA)) have been put in place, and transfer impact assessments conducted.
+Added: Any inability to transfer personal data from the UK or EEA to the United States in compliance with data protection laws may impede our operations and may adversely affect our business and financial position.
+Added: Following the UK’s exit from the EU, or Brexit, there will be increasing scope for divergence in application, interpretation and enforcement of the data protection laws between these territories.
+Added: For example, the UK has introduced the Data Reform Bill into the UK legislative process with the intention for this bill to reform the UK’s data protection regime following Brexit.
+Added: If passed, the final version of the Data Reform Bill may have the effect of further altering the similarities between the UK and EEA data protection regimes and threaten the UK adequacy decision from the EU Commission allowing the free flow of personal data from the UK to the EEA, which may lead to additional compliance costs and could increase our overall risk.
+Added: This lack of clarity on future UK laws and regulations and their interaction with those of the EEA could add legal risk, uncertainty, complexity, and cost to our handling of European personal data and our privacy and security compliance programs, and could require us to implement different compliance measures for the UK and EEA.
+Added: Failure to comply with the requirements of the GDPR and the related national data protection laws of the EEA Member States and the UK may result in fines up to €20 million (17.5 million for the UK GDPR) or 4% of a company’s global annual revenues for the preceding financial year, whichever is higher.
+Added: The GDPR also confers a private right of action on data subjects and consumer associations to lodge complaints with supervisory authorities, seek judicial remedies, and obtain compensation for damages resulting from violations of the GDPR.
+Added: Complying with these European data protection laws may impose significant costs or otherwise require us to divert resources or implement changes to our business processes, and any actual or perceived non-compliance could result in significant penalties, claims and reputational damage.
+Added: In the United States, several layers of federal and state data protection laws and regulations may apply to our business, including HIPAA, the Federal Trade Commission (“FTC”) Act and state consumer privacy and health data privacy laws.
+Added: For example, the California Consumer Privacy Act (“CCPA”) is a comprehensive privacy law that creates individual privacy rights and increased privacy and security obligations on businesses handling the personal data of California residents.
+Added: The CCPA requires covered businesses to provide certain disclosures to consumers about data collection, use and sharing practices, to allow California residents to opt out of certain sales and disclosures of personal information, and to opt out of certain uses of
+Added: sensitive personal information, including health information.
+Added: The law also created a regulatory agency in California, and that agency’s finalized and proposed regulations are continuing to change the standard of privacy protection we may be required to meet.
+Added: Numerous other states have passed similar consumer privacy laws that are or will be implemented and enforced by various state regulators.
+Added: Like the CCPA, these laws grant consumers rights in relation to their personal information and impose new obligations on regulated businesses, including, in some instances, broader data security requirements.
+Added: In addition, federal and state legislators and regulators are imposing new and heightened protections for health and other sensitive information that could impact our business.
+Added: For example, the Federal Trade Commission (“FTC”) has imposed stringent requirements on the collection and disclosure of sensitive categories of personal information, including health information, and has expanded the application of its Health Breach Notification Rule.
+Added: Through executive and legislative action, the federal government has also taken steps to restrict data transactions involving certain sensitive data categories – including health data, genetic data, and biospecimens – with persons affiliated with China, Russia, and other countries of concern.
+Added: Washington’s My Health My Data Act, which went into effect in March 2024, requires regulated entities to obtain consent to collect health information, grants consumers certain rights, including to request deletion, and provides for robust enforcement mechanisms, including enforcement by the state attorney-general and by litigants through a private right of action for consumer claims.
+Added: These current and future data privacy laws and regulations may require us to modify our data collection or processing practices and policies, incur substantial costs and expenses in an effort to comply and increase our potential exposure to regulatory enforcement, reputational damage, and/or litigation.
+Added: Issues relating to the use of artificial intelligence and machine learning could adversely affect our business and operating results.
+Added: In our ongoing efforts to innovate and develop product candidates, we have integrated artificial intelligence (“AI”) and machine learning into virtual screening, hit validation and optimization technologies.
+Added: While AI and machine learning presents opportunities for enhanced productivity and innovation, it also introduces inherent risks, including legal and regulatory, that could adversely impact our business and reputation.
+Added: Proper use of AI and machine learning can lead to improved decision-making, cost reduction, and competitive advantage.
+Added: However, improper use, including algorithmic biases, ethical considerations, data privacy issues, and potential regulatory non-compliance, could result in reputational damage, legal liabilities, and financial losses.
+Added: The rapidly evolving regulatory landscape surrounding AI also poses a risk, as new laws and regulations could impose additional compliance burdens, resulting in increased operational costs to comply with U.S.
+Added: laws concerning the use of AI, the nature of which cannot be determined at this time.
+Added: In addition, the European Union recently passed the Artificial Intelligence Act, whose regulations will be developed over the coming year and, in the U.S., the recent Executive Order concerning artificial intelligence may result in extensive new federal rule-making.
+Added: We are committed to implementing governance and control mechanisms to mitigate these risks, but there can be no assurance that such measures will adequately prevent or mitigate the adverse effects that the integration and use of AI may have on our business, financial condition, and results of operations.
+Added: Risks Related to Our Common Stock
+Added: The price of our common stock has been and may continue to be volatile and fluctuate substantially, and investors may lose all or part of their investment.
+Added: Our stock price has been volatile and may continue to be subject to wide fluctuations in response to various factors.
+Added: The stock market in general and the market for biopharmaceutical companies in particular have experienced extreme volatility that has often been unrelated to the operating performance of particular companies, including in connection with conflicts in various regions of the world, increasing inflation rates, and interest rate changes, which have resulted in decreased stock prices for many companies notwithstanding the lack of a fundamental change in their underlying business models or prospects.
+Added: As a result of this volatility, you may lose all or part of your investment.
+Added: The market price for our common stock may be influenced by many factors, including:
+Added: • the success of competitive drugs or technologies;
+Added: • results of preclinical studies and clinical trials of our current or future product candidates or those of our competitors;
+Added: • regulatory or legal developments in the U.S.
+Added: and other countries;
+Added: • developments or disputes concerning patent applications, issued patents or other proprietary rights;
+Added: • the recruitment or departure of key personnel;
+Added: • the level of expenses related to any of our current or future product candidates or clinical development programs;
+Added: • the results of our efforts to discover, develop, acquire or in-license additional current or future product candidates or drugs;
+Added: • actual or anticipated changes in estimates as to financial results, development timelines or recommendations by securities analysts;
+Added: • variations in our financial results or those of companies that are perceived to be similar to us;
+Added: • changes in the structure of healthcare payment systems;
+Added: • market conditions in the pharmaceutical and biotechnology sectors;
+Added: • announcements regarding our collaboration agreements, including announcements regarding our collaboration agreement with Sanofi;
+Added: • general economic, industry and market conditions;
+Added: • the other factors described in this “Risk Factors” section.
+Added: These and other market and industry factors may cause the market price and demand for shares of our common stock to fluctuate substantially, regardless of our actual operating performance, which may limit or prevent investors from selling their shares at or above the price paid for the shares and may otherwise negatively affect the liquidity of our common stock.
+Added: The realization of any of the above risks or any of a broad range of other risks, including those described in this section, could have a significant and material adverse impact on the market price of our common stock.
+Added: The price of our common stock may be disproportionately affected as investors may favor traditional profit-making industries and companies during the times of market uncertainty and instability.
+Added: Unstable global economic and geopolitical conditions may have serious adverse consequences on our business, financial condition, stock price and results of operations.
+Added: As widely reported, global credit and financial markets have experienced extreme volatility and disruptions in the past several years, including severely diminished liquidity and credit availability, declines in consumer confidence, declines in economic growth, increases in unemployment rates and uncertainty about economic stability.
+Added: The financial markets and the global economy may also be adversely affected by the potential for significant changes in U.S policies or regulatory environment given the new administration, military conflict, including the ongoing conflicts between Russia and Ukraine, and in the Middle East, terrorism, or other geopolitical events.
+Added: Sanctions imposed by the United States and other countries in response to such conflicts, including in Ukraine, may also continue to adversely impact the financial markets and the global economy, and any economic countermeasures by the affected countries or others could exacerbate market and economic instability.
+Added: There can be no assurance that further deterioration in credit and financial markets and confidence in economic conditions will not occur.
+Added: Our general business strategy may be adversely affected by any such economic downturn, volatile business environment or continued unpredictable and unstable market conditions.
+Added: If the current equity and credit markets deteriorate, or do not improve, it may make any necessary debt or equity financing more difficult, more costly, and more dilutive.
+Added: Furthermore, our stock price may decline due in part to the volatility of the stock market and the general economic downturn.
+Added: Failure to secure any necessary financing in a timely manner and on favorable terms could have a material adverse effect on our growth strategy, financial performance and stock price and could require us to delay, scale back or discontinue the development and commercialization of one or more of our product candidates or delay our pursuit of potential in-licenses or acquisitions.
+Added: In addition, there is a risk that one or more of our current service providers, manufacturers and other partners may not survive these difficult economic times, which could directly affect our ability to attain our operating goals on schedule and on budget.
+Added: Changes in U.S.
+Added: federal policy that affect the geopolitical landscape could give rise to circumstances outside our control that could have negative impacts on our business operations.
+Added: For example, during the prior Trump administration, increased tariffs were implemented on goods imported into the U.S., particularly from China, Canada, and Mexico.
+Added: On February 1, 2025, the U.S.
+Added: imposed a 25% tariff on imports from Canada and Mexico, which were subsequently suspended for a period of one month, and a 10% additional tariff on imports from China.
+Added: Historically, tariffs have led to increased trade and political tensions, between not only the U.S.
+Added: and China, but also between the U.S.
+Added: and other countries in the international community.
+Added: In response to tariffs, other countries have implemented retaliatory tariffs on U.S.
+Added: Political tensions as a result of trade policies could reduce trade volume, investment, technological exchange and other economic activities between major international economies, resulting in a material adverse effect on global economic conditions and the stability of global financial markets.
+Added: in political, trade, regulatory, and economic conditions, including U.S.
+Added: trade policies, could have a material adverse effect on our financial condition or results of operations.
+Added: If securities analysts do not publish research or reports about our business or if they publish negative evaluations of our stock, the price of our stock could decline.
+Added: The trading market for our common stock relies in part on the research and reports that industry or financial analysts publish about us or our business.
+Added: We do not have control over these analysts.
+Added: Although we have obtained research coverage from certain analysts, there can be no assurance that analysts will continue to cover us or provide favorable coverage.
+Added: If one or more of the analysts covering our business downgrade their evaluations of our stock, the price of our stock could decline.
+Added: In addition, if one or more of these analysts cease to cover our stock, we could lose visibility in the market for our stock, which in turn could cause our stock price to decline.
+Added: Our executive officers, directors, principal stockholders and their affiliates exercise significant influence over our company, which will limit your ability to influence corporate matters and could delay or prevent a change in corporate control.
+Added: As of December 31, 2024, the existing holdings of our executive officers, directors, principal stockholders and their affiliates represent beneficial ownership, in the aggregate, of approximately 25% of our outstanding common stock.
+Added: As a result, these stockholders, if they act together, will be able to influence our management and affairs and the outcome of matters submitted to our stockholders for approval, including the election of directors and any merger, consolidation or sale of all or substantially all of our assets.
+Added: This may prevent or discourage unsolicited acquisition proposals or offers for our common stock that you may feel are in your best interest as one of our stockholders.
+Added: Some of these persons or entities may have interests different than yours.
+Added: For example, because many of these stockholders purchased their shares at prices substantially below the current trading price of our stock and have held their shares for a longer period, they may be more interested in selling our Company to an acquirer than other investors or they may want us to pursue strategies that deviate from the interests of other stockholders.
+Added: Additionally, from time to time, any of our non-affiliated shareholders may accumulate or acquire significant positions in our common stock and may similarly be able to influence our business or matters submitted to our stockholders for approval.
+Added: The concentration of voting power among these stockholders may also have an adverse effect on the price of our common stock by delaying, deferring or preventing a change of control of us;
+Added: impeding a merger, consolidation, takeover or other business combination involving us;
+Added: or discouraging a potential acquirer from making a tender offer or otherwise attempting to obtain control of us.
+Added: We have issued a substantial number of warrants and equity awards from our equity plans which are exercisable into shares of our common stock which could result in substantial dilution to the ownership interests of our existing stockholders.
+Added: As of December 31, 2024, approximately 15,159,753 shares of our common stock were reserved for issuance upon exercise of pre-funded warrants.
+Added: Additionally, 10,197,394 shares of our common stock were reserved for issuance upon exercise of outstanding stock options and vested restricted stock units.
+Added: The exercise or conversion of these securities will result in a significant increase in the number of outstanding shares and substantially dilute the ownership interests of our existing stockholders.
+Added: The shares underlying the equity awards from our equity plans are registered on a Form S-8 registration statement.
+Added: As a result, upon vesting these shares can be freely exercised and sold in the public market upon issuance, subject to volume limitations applicable to affiliates.
+Added: The exercise of options and the subsequent sale of the underlying common stock could cause a decline in our stock price.
+Added: Sales of a substantial number of shares of our common stock in the public market could cause our stock price to fall.
+Added: Sales of a substantial number of shares of our common stock in the public market could occur at any time.
+Added: These sales or the perception in the market that the holders of a large number of shares of common stock intend to sell shares, could reduce the market price of our common stock.
+Added: Persons who were our stockholders prior to our initial public offering continue to hold a substantial number of shares of our common stock that many of them are now able to sell in the public market.
+Added: Significant portions of these shares are held by a relatively small number of stockholders, none of whom have entered into agreements restricting their ability to sell their shares.
+Added: Sales by our stockholders of a substantial number of shares or distributions of their holdings to their respective limited partners and other equity holders, or the expectation that such sales or distributions, or the expectation that such sales may occur, could significantly reduce the market price of our common stock.
+Added: Shares issued upon the exercise of stock options outstanding or settlement of restricted stock units under our equity incentive plans or pursuant to future awards granted under those plans will become available for sale in the public market to the extent permitted by the provisions of applicable vesting schedules, any applicable market standoff and lock-up agreements, and Rule 144 and Rule 701 under the Securities Act.
+Added: Certain holders of our common stock have rights, subject to conditions, to require us to file registration statements covering their shares or to include their shares in registration statements that we may file for ourselves or other stockholders.
+Added: We have also filed registration statements on Form S-8 registering the issuance of shares of common stock issued or reserved for future issuance under our equity compensation plans.
+Added: Shares registered under this registration statement on Form S-8 can be freely sold in the public market upon issuance and once vested, subject to volume limitations applicable to affiliates.
+Added: If any of these additional shares are sold, or if it is perceived that they will be sold, in the public market, the market price of our common stock could decline.
+Added: Pursuant to our prior sales agreement, or Cowen Sales Agreement, with Cowen and Company, LLC, or Cowen, we had the ability to offer and sell up to an aggregate amount of $250.0 million of our common stock from time to time in “at-the-market” offerings, subject to the limitations thereof.
+Added: As of December 31, 2024, approximately $50 million worth of common stock had been sold under the Cowen Sales Agreement.
+Added: From October 1, 2021 through December 31, 2024, we sold 1,519,453 shares of common stock through the Cowen Sales Agreement.
+Added: On October 31, 2024, we entered into an Open Market Sale Agreement SM , or the Jefferies Sales Agreement, with Jefferies LLC pursuant to which we may offer and sell our common stock, subject to certain limitations in the sales agreement and compliance with applicable law, at any time throughout the term of the Jefferies Sales Agreement.
+Added: The number of shares that are sold by Jefferies after delivering a placement notice will fluctuate based on the market price of the common stock during the sales period and limits we set with Jefferies.
+Added: Because the price per share of each share sold will fluctuate based on the market price of our common stock during the sales period, it is not possible at this stage to predict the number of shares that will be ultimately issued.
+Added: Sales to, or through, Jefferies by us could result in substantial dilution to the interests of other holders of our common stock.
+Added: Additionally, the sale of a substantial number of shares of our common stock, or the anticipation of such sales, could make it more difficult for us to sell equity or equity-related securities in the future at a time and at a price that we might otherwise wish to effect sales.
+Added: There have not yet been any sales made pursuant to the Jefferies Sales Agreement.
+Added: Because we do not anticipate paying any cash dividends on our capital stock in the foreseeable future, capital appreciation, if any, will be investors’ sole source of gain.
+Added: We have never declared or paid cash dividends on our capital stock.
+Added: We currently intend to retain all of our future earnings, if any, to finance the growth and development of our business.
+Added: As a result, capital appreciation, if any, of our common stock will be investors’ sole source of gain for the foreseeable future.
+Added: We may be at an increased risk of securities class action litigation.
+Added: Historically, securities class action litigation has often been brought against a company following a decline in the market price of its securities.
+Added: This risk is especially relevant for us because biotechnology and pharmaceutical companies have experienced significant stock price volatility in recent years.
+Added: If we were to be sued, it could result in substantial costs and a diversion of management’s attention and resources, which could harm our business.
+Added: Additionally, any lawsuit to which we are a party, with or without merit, may result in an unfavorable judgment.
+Added: We also may decide to settle lawsuits on unfavorable terms.
+Added: Any such negative outcome could result in payments of substantial damages or fines, damage to our reputation or adverse changes to our business practices.
+Added: Furthermore, during the course of litigation, there could be negative public announcements of the results of hearings, motions or other interim proceedings or developments, which could have a negative effect on the market price of our common stock.
+Added: Risks Related to Tax
+Added: Changes in tax law may adversely affect us or our investors.
+Added: The rules dealing with U.S.
+Added: federal, state and local and non-U.S.
+Added: taxation are constantly under review by persons involved in the legislative process and by the Internal Revenue Service, or IRS, the U.S.
+Added: Treasury Department and other taxing authorities.
+Added: Changes to tax laws (which changes may have retroactive application) could adversely affect us or holders of our common stock.
+Added: These changes could subject us to additional income-based taxes and non-income taxes (such as payroll, sales, use, value-added, net worth, property, and goods and services taxes), which in turn could materially affect our financial position and results of operations.
+Added: Additionally, new, changed, modified, or newly interpreted or applied tax laws could increase our customers’ and our compliance, operating and other costs, as well as the costs of our products.
+Added: In recent years, many such changes have been made and changes are likely to continue to occur in the future.
+Added: As we expand the scale of our business activities, any changes in the U.S.
+Added: taxation of such activities may increase our effective tax rate and harm our business, financial condition and results of operations.
+Added: You are urged to consult your tax advisor regarding the implications of potential changes in tax laws on an investment in our common stock.
+Added: Our ability to utilize our net operating loss carryforwards and certain other tax attributes to offset future taxable income may be subject to certain limitations, and, as a result, unavailable to reduce our future tax liability.
+Added: As of December 31, 2024, we had federal and state net operating loss carryforwards of $221.3 million and $238.3 million, respectively, which begin to expire in various amounts in 2037 (other than federal net operating loss carryforwards arising in taxable years beginning after December 31, 2017, which are not subject to expiration but the deductibility of such federal NOLs may be limited to 80% of our taxable income annually for tax years beginning after December 31, 2020).
+Added: As of December 31, 2024, we also had federal and state research and development tax credit carryforwards of $33.1 million and $12.0 million, respectively, which begin to expire in 2032.
+Added: These net operating loss and tax credit carryforwards could expire unused and be unavailable to offset future income tax liabilities.
+Added: In addition, in general, under Sections 382 and 383 of the Internal Revenue Code of 1986, as amended, or the Code, a corporation that undergoes an “ownership change” is subject to limitations on its ability to utilize its pre-change net operating losses or tax credits, or NOLs or credits, to offset future taxable income or taxes.
+Added: For these purposes, an ownership change generally occurs where the aggregate stock ownership of one or more stockholders or groups of stockholders who own at least 5% of a corporation’s stock increases by more than 50 percentage points over the lowest ownership percentage of such stockholders or groups of stockholders within a specified testing period.
+Added: Our existing NOLs or credits may be subject to limitations arising from previous ownership changes.
+Added: In addition, future changes in our stock ownership, many of which are outside of our control, could result in an ownership change under Sections 382 and 383 of the Code and limit our ability to utilize NOLs or credit.
+Added: Our NOLs or credits may also be impaired under state law.
+Added: Accordingly, we may not be able to utilize a material portion of our NOLs or credits.
+Added: Furthermore, our ability to utilize our NOLs or credits is conditioned upon our attaining profitability and generating U.S.
+Added: federal and state taxable income.
+Added: As described above under “Risk Factors-Risks Related to our Financial Position and Need for Additional Capital,” we have incurred significant net losses since our inception and anticipate that we will continue to incur significant losses for the foreseeable future;
+Added: and therefore, we do not know whether or when we will generate the U.S.
+Added: federal or state taxable income necessary to utilize our NOLs or credit carryforwards that are subject to limitation by Sections 382 and 383 of the Code.
+Added: Risks Related to Our Controls and Reporting Requirements
+Added: If we fail to maintain proper and effective internal control over financial reporting, our operating results and our ability to operate our business could be harmed.
+Added: Our internal control over financial reporting is a process designed to provide reasonable assurance regarding the reliability of financial reporting and the preparation of financial statements in accordance with generally accepted accounting principles.
+Added: Pursuant to Section 404 of the Sarbanes-Oxley Act of 2002, or Section 404, we are required to furnish a report by our management on our internal control over financial reporting, including an attestation report on internal control over financial reporting issued by our independent registered public accounting firm.
+Added: To achieve compliance with Section 404, we have engaged in a process to document and evaluate our internal control over financial reporting, which is both costly and challenging.
+Added: In this regard, we will need to continue to dedicate internal resources, potentially engage outside consultants and adopt a detailed work plan to assess and document the adequacy of internal control over financial reporting, continue steps to improve control processes as appropriate, validate through testing that controls are functioning as documented and implement a continuous reporting and improvement process for internal control over financial reporting.
+Added: Despite our efforts, there is a risk that neither we nor our independent registered public accounting firm will be able to conclude within the prescribed timeframe that our internal control over financial reporting is effective as required by Section 404.
+Added: This could result in an adverse reaction in the financial markets due to a loss of confidence in the reliability of our financial statements.
+Added: In addition, investors’ perceptions that our internal controls are inadequate or that we are unable to produce accurate financial statements on a timely basis may harm our stock price and make it more difficult for us to effectively market and sell any of our present or future product candidates that may receive regulatory approval.
+Added: Our disclosure controls and procedures may not prevent or detect all errors or acts of fraud.
+Added: We are subject to certain reporting requirements of the Exchange Act.
+Added: Our disclosure controls and procedures are designed to reasonably assure that information required to be disclosed by us in reports we file or submit under the Exchange Act is accumulated and communicated to management, recorded, processed, summarized and reported within the time periods specified in the rules and forms of the SEC.
+Added: We believe that any disclosure controls and procedures or internal controls and
+Added: procedures, no matter how well conceived and operated, can provide only reasonable, not absolute, assurance that the objectives of the control system are met.
+Added: These inherent limitations include the realities that judgments in decision-making can be faulty, and that breakdowns can occur because of simple error or mistake.
+Added: Additionally, controls can be circumvented by the individual acts of some persons, by collusion of two or more people or by an unauthorized override of the controls.
+Added: Accordingly, because of the inherent limitations in our control system, misstatements or insufficient disclosures due to error or fraud may occur and not be detected.
+Added: Risks Related to Our Charter and Bylaws
+Added: Anti-takeover provisions under our charter documents and Delaware law could delay or prevent a change of control, which could limit the market price of our common stock and may prevent or frustrate attempts by our stockholders to replace or remove our current management.
+Added: Our fourth amended and restated certificate of incorporation and our second amended and restated bylaws contain provisions that could delay or prevent a change of control of our company or changes in our board of directors that our stockholders might consider favorable.
+Added: Some of these provisions include:
+Added: • a board of directors divided into three classes serving staggered three-year terms, such that not all members of the board will be elected at one time;
+Added: • a prohibition on stockholder action through written consent, which requires that all stockholder actions be taken at a meeting of our stockholders;
+Added: • a requirement that special meetings of stockholders be called only by the board of directors acting pursuant to a resolution approved by the affirmative vote of a majority of the directors then in office;
+Added: • advance notice requirements for stockholder proposals and nominations for election to our board of directors;
+Added: • a requirement that no member of our board of directors may be removed from office by our stockholders except for cause and, in addition to any other vote required by law, upon the approval of not less than two-thirds of all outstanding shares of our voting stock then entitled to vote in the election of directors;
+Added: • a requirement of approval of not less than two-thirds of all outstanding shares of our voting stock to amend any bylaws by stockholder action or to amend specific provisions of our certificate of incorporation;
+Added: • the authority of the board of directors to issue preferred stock on terms determined by the board of directors without stockholder approval and which preferred stock may include rights superior to the rights of the holders of common stock.
+Added: In addition, because we are incorporated in Delaware, we are governed by the provisions of Section 203 of the Delaware General Corporate Law, or DGCL, which may prohibit certain business combinations with stockholders owning 15% or more of our outstanding voting stock.
+Added: These antitakeover provisions and other provisions in our fourth amended and restated certificate of incorporation and amended and restated bylaws could make it more difficult for stockholders or potential acquirers to obtain control of our board of directors or initiate actions that are opposed by the then-current board of directors and could also delay or impede a merger, tender offer or proxy contest involving our company.
+Added: These provisions could also discourage proxy contests and make it more difficult for you and other stockholders to elect directors of your choosing or cause us to take other corporate actions you desire.
+Added: Any delay or prevention of a change of control transaction or changes in our board of directors could cause the market price of our common stock to decline.
+Added: Our amended and restated bylaws designate specific courts as the exclusive forum for certain litigation that may be initiated by our stockholders, which could limit our stockholders’ ability to obtain a favorable judicial forum for disputes with us.
+Added: Pursuant to our amended and restated bylaws, unless we consent in writing to the selection of an alternative forum, the Court of Chancery of the State of Delaware is the sole and exclusive forum for any state law claims for (1) any derivative action or proceeding brought on our behalf;
+Added: (2) any action asserting a claim of or based on a breach of a fiduciary duty owed by any director, officer or other employee of ours to us or our stockholders;
+Added: (3) any action asserting a claim pursuant to any provision of the DGCL, our amended and restated certificate of incorporation or our amended and restated bylaws;
+Added: or (4) any action asserting a claim governed by the internal affairs doctrine, or the Delaware Forum Provision.
+Added: The Delaware Forum Provision will not apply to any causes of action arising under the Securities Act or the Exchange Act.
+Added: Our amended and restated bylaws further provide that unless we consent in writing to the selection of an alternative forum, the United States District Court for the District of Massachusetts shall be the sole and exclusive forum for resolving any complaint asserting a cause of action
+Added: arising under the Securities Act, or the Federal Forum Provision.
+Added: In addition, our amended and restated bylaws provide that any person or entity purchasing or otherwise acquiring any interest in shares of our capital stock is deemed to have notice of and consented to the Delaware Forum Provision and the Federal Forum Provision;
+Added: provided, however, that stockholders cannot and will not be deemed to have waived our compliance with the federal securities laws and the rules and regulations thereunder.
+Added: We recognize that the Delaware Forum Provision and the Federal Forum Provision in our amended and restated bylaws may impose additional litigation costs on stockholders in pursuing any such claims, particularly if the stockholders do not reside in or near the State of Delaware or the Commonwealth of Massachusetts, as applicable.
+Added: Additionally, the forum selection clauses in our amended and restated bylaws may limit our stockholders’ ability to bring a claim in a judicial forum that they find favorable for disputes with us or our directors, officers or employees, which may discourage the filing of lawsuits against us and our directors, officers and employees, even though an action, if successful, might benefit our stockholders.
+Added: In addition, while the Delaware Supreme Court ruled, and other state courts have upheld the validity of, that federal forum selection provisions purporting to require claims under the Securities Act be brought in federal court, there is uncertainty as to whether other courts will enforce our Federal Forum Provision.
+Added: If the Federal Forum Provision is found to be unenforceable, we may incur additional costs associated with resolving such matters.
+Added: The Federal Forum Provision may also impose additional litigation costs on stockholders who assert that the provision is not enforceable or invalid.
+Added: The Court of Chancery of the State of Delaware and the United States District Court for the District of Massachusetts may also reach different judgments or results than would other courts, including courts where a stockholder considering an action may be located or would otherwise choose to bring the action, and such judgments may be more or less favorable to us than our stockholders.
+Added: Congress, the Trump administration, or any new administration may make substantial changes to fiscal, tax, and other federal policies that may adversely affect our business.
+Added: In 2017, the U.S.
+Added: Congress and the Trump administration made substantial changes to U.S.
+Added: policies, which included comprehensive corporate and individual tax reform.
+Added: In addition, the Trump administration called for significant changes to U.S.
+Added: trade, healthcare, immigration and government regulatory policy.
+Added: With the transition to the Biden administration in early 2021, changes to U.
+Added: policy occurred and since the start of the Trump Administration in 2025, U.S.
+Added: policy changes have been implemented at a rapid pace and additional changes are likely.
+Added: Changes to U.S.
+Added: policy implemented by the U.S.
+Added: Congress, the Trump administration or any new administration have impacted and may in the future impact, among other things, the U.S.
+Added: and global economy, international trade relations, unemployment, immigration, healthcare, taxation, the U.S.
+Added: regulatory environment, inflation and other areas.
+Added: Although we cannot predict the impact, if any, of these changes to our business, they could adversely affect our business.
+Added: Until we know what policy changes are made, whether those policy changes are challenged and subsequently upheld by the court system and how those changes impact our business and the business of our competitors over the long term, we will not know if, overall, we will benefit from them or be negatively affected by them
+Added: Unresolve d Staff Comments.
+Added: Cybersec urity
+Added: Cyber Risk Management and Strategy
+Added: Kymera uses, stores and processes data for and about our research programs, clinical trials, employees, and suppliers.
+Added: We have developed and maintain an information security program designed to assess, identify, and manage risks from cybersecurity threats, including to our data and systems.
+Added: We conduct periodic assessments of our assets, including internal and external security testing, as part of our risk management process and to evaluate the effectiveness of applicable security controls.
+Added: These assessments are informed by industry standards.
+Added: Our cybersecurity risk management process is a part of our overall risk management program.
+Added: We also have an employee education program that includes training designed to raise awareness of cybersecurity threats.
+Added: We have adopted an Incident Response Policy that outlines the legal and governance process for identifying and managing material cyber risks to our information and information systems and our framework for assessing and responding to cyber incidents, as applicable.
+Added: Although risks from cybersecurity threats have to date not materially affected, and we do not believe they are reasonably likely to materially affect, us, our business strategy, results of operations or financial condition, we could, from time to time, experience threats and communicate security incidents relating to our and our third-party vendors’ information systems.
+Added: For more information, please see Item 1A- Risk Factors.
+Added: Governance Related to Cybersecurity Risks
+Added: Under the ultimate direction of the Chief Executive Officer and our executive management team, the Cybersecurity Supervisory Committee (CSSC) has primary responsibility for overseeing our management of cybersecurity risks, which includes representatives from finance, legal, operations, human resources, and information technology.
+Added: The CSSC meets as circumstances warrant to review and update incident response procedures and to provide oversight of incident response activities of the Cyber Security Incident Response Team.
+Added: The head of information technology and the CSSC have primary responsibility for assessing and managing our cybersecurity program.
+Added: The head of information technology, who reports to the Chief Financial Officer, has more than 25 years of experience in building and leading information technology and security teams.
+Added: The board of directors has ultimate oversight of our risk management program and has delegated oversight of that program, including, oversight of cybersecurity, to the audit committee of the board of directors.
+Added: of Information Technology presents to the audit committee periodically regarding cybersecurity matters.
+Added: The Chief Financial Officer and the Chief Legal Officer are responsible for informing the audit committee in the event of any material cybersecurity incidents and any potential disclosure obligations arising from such incidents .
+Added: We currently occupy approximately 100,624 square feet of office and laboratory space in Watertown, Massachusetts under a lease that expires in March 2035.
+Added: We have two options to extend the lease term, each for five additional years at then-market rates.
+Added: Additionally, we currently lease approximately 34,522 rentable square feet of extra office and laboratory space in Watertown, Massachusetts under a lease that expires in March 2030 that we are not currently occupying.
+Added: We intend to sublease and are actively marketing the original space to third parties.
+Added: We believe that our office and laboratory space is sufficient to meet our current needs and that suitable additional space will be available as and when needed on commercially reasonable terms.
Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.