−Removed: We are a clinical stage biotechnology company seeking to develop differentiated biologics for the treatment of atopic dermatitis (AD), asthma, chronic obstructive pulmonary disease (COPD) and related inflammatory and immunology (I&I) indications with high unmet need.
+Added: We are a clinical stage biotechnology company advancing novel biologics with the potential for differentiated efficacy and dosing in the largest inflammatory and immunology (“I&I”) markets, including for the treatment of atopic dermatitis (“AD”), asthma, eosinophilic esophagitis (“EoE”), chronic obstructive pulmonary disease (“COPD”), and other I&I indications.
Our antibody programs are designed to overcome limitations of existing therapies by targeting well-established mechanisms of action and incorporating advanced antibody engineering to optimize half-life and other properties.
−Removed: Our two most advanced programs are APG777 and APG808, which we are initially developing for the treatment of AD and COPD, respectively.
−Removed: With our broad pipeline and depth of expertise, we believe we can deliver value and meaningful benefit to patients underserved by today’s standard of care.
−Removed: See the section titled “—Recent Developments” for program updates.
+Added: Our pipeline comprises four antibody programs being developed initially for the treatment of I&I indications as monotherapies and combinations.
+Added: Our most advanced programs are APG777, APG990, APG333, and APG808.
+Added: With four validated targets in our portfolio, we are seeking to achieve best-in-class efficacy and dosing through monotherapies and combinations of our novel antibodies.
+Added: Based on a broad pipeline and depth of expertise, we believe we can deliver value and meaningful benefit to patients underserved by today’s standard of care.
+Added: Our programs incorporate advanced antibody engineering to optimize half-life and other properties designed to overcome limitations of existing therapies.
+Added: We believe each of our programs has potential for broad application across multiple I&I indications, including in combination.
+Added: In March 2024, we announced positive interim safety, pharmacokinetic (“PK”) and pharmacodynamic (“PD”) data from our Phase 1 trial of APG777 in healthy volunteers and in May 2024, we initiated a Phase 2 trial of APG777 in patients with moderate-to-severe AD.
+Added: In February 2025, we announced that the last patient in Part A of the Phase 2 trial had been dosed and that we had commenced dosing of Part B.
+Added: In August 2024, we initiated a Phase 1 trial of APG990 in healthy volunteers and in March 2025, we announced positive interim safety and PK data from that trial.
+Added: In December 2024, we initiated a Phase 1 trial of APG333 in healthy volunteers.
+Added: In March 2024, we initiated a Phase 1 trial of APG808 in healthy volunteers and in December 2024, we announced positive interim safety, PK and PD data from that trial.
+Added: Our pipeline comprises four programs being developed initially for the treatment of I&I indications, as shown below.
+Added: Our programs incorporate advanced antibody engineering to optimize half-life and other properties designed to overcome limitations of existing therapies.
+Added: We believe each of our programs has potential for broad application across multiple I&I indications.
+Added: APG777 – anti-IL13 antibody, same mechanism of action as EBGLYSS (lebrikizumab)
APG777 is a subcutaneous (“SQ”) extended half-life monoclonal antibody (“mAb”) targeting IL-13.
−Removed: AD is a chronic inflammatory skin disorder that affects approximately 40 million adults and 18 million children in the United States, France, Germany, Italy, Japan, Spain and the United Kingdom, 40% of which have moderate-to-severe disease.
−Removed: Based on our preclinical studies, we believe APG777 can be dosed either every two or every three months in maintenance, which, if our clinical trials are successful, would represent a significant improvement compared to first generation IL-13 antibodies that are dosed every two to four weeks.
−Removed: In August 2023, we announced the dosing of our first participant in our first clinical trial for APG777 in Australia.
−Removed: The APG777 Phase 1 trial is a double-blind, placebo-controlled study in healthy volunteers and consists of a single-ascending dose (SAD) component and a multiple-ascending dose (MAD) component.
−Removed: The trial enrolled 40 healthy adult subjects into three SAD and two MAD cohorts.
−Removed: The primary endpoint is safety and a key secondary endpoint is pharmacokinetics (PK).
−Removed: The Phase 1 trial is ongoing and we have announced initial safety and PK data from this trial.
−Removed: We have filed an investigational new drug application (IND) in support of a Phase 1 trial in healthy volunteers in the United States for subjects of Japanese descent and have received a “study may proceed” letter from the FDA for the trial.
−Removed: We anticipate initiating a Phase 2 trial in AD in the United States and internationally in the first half of 2024.
−Removed: Based on our initial clinical data, we may initiate a Phase 2 trial in asthma and expect to further evaluate opportunities to develop APG777 for other I&I indications, including alopecia areata (AA), chronic rhinosinusitis with nasal polyps (CRSwNP), chronic spontaneous urticaria (CSU), eosinophilic esophagitis (EoE) and prurigo nodularis (PN).
+Added: In August 2023, we announced the dosing of our first participant in our first clinical trial for APG777.
+Added: In 2024, we announced positive interim safety and PK data from this trial with APG777 demonstrating a potential best-in-class PK profile, including a half-life of 77 days, supporting the potential for every three- to six- month maintenance dosing in AD.
+Added: Single doses of APG777 demonstrated a deep and sustained effect on PD markers out to approximately 12 months.
+Added: APG777 was well-tolerated across all dose groups.
+Added: In May 2024, we commenced dosing in the Phase 2 clinical trial of APG777 in patients with moderate-to-severe AD.
+Added: In February 2025, we announced that the last patient in the Part A portion of the trial had been dosed with 16-week topline data from Part A expected in mid-2025.
+Added: In February 2025, we also announced that we had commenced dosing of Part B of the Phase 2 trial.
+Added: All patients benefiting from treatment will have the opportunity to continue to APG777 maintenance treatment, which will evaluate three- to six-month dosing intervals.
+Added: We anticipate maintenance data from Part A in the first half of 2026 and 16-week topline data from Part B in the second half of 2026.
+Added: Based on our initial clinical data, we plan to advance the development of APG777 in asthma and EoE by initiating a Phase 1b trial in asthma in the first half of 2025, followed by a Phase 2b trial in asthma in the second half of 2025, and a Phase 2 trial in EoE in 2026.
+Added: Based on our clinical data, we expect to further evaluate additional opportunities to develop APG777 for other I&I indications, including alopecia areata (“AA”), chronic rhinosinusitis with nasal polyps (“CRSwNP”), chronic spontaneous urticaria (“CSU”), and prurigo nodularis (“PN”).
+Added: In addition, we plan to evaluate APG777 in combination with other investigational therapies within our pipeline to potentially enable greater efficacy for I&I conditions.
+Added: We plan to initiate our first combination study, a Phase 1b trial of APG777 and APG990, a novel, SQ, half-life extended mAb targeting OX40L, in 2025.
+Added: This combination study is designed to evaluate the coformulation of APG777 and APG990 (“APG279”) against DUPIXENT in patients with moderate-to-severe AD, with readout expected in the second half of 2026.
+Added: APG990 – anti-OX40L antibody, same mechanism of action as amlitelimab;
+Added: potential combination therapy with APG777
+Added: APG990 is an SQ extended half-life mAb that utilizes advanced antibody engineering to target OX40L.
+Added: We plan to develop APG777 and APG990 together as a potential first-in-class coformulation for the treatment of AD by combining deep and sustained inhibition of Type 2 inflammation via APG777’s inhibition of IL-13 with broader inhibition of Type 1-3 inflammation through APG990’s inhibition of OX40L.
+Added: APG279 has been shown to retain stability, injectability, and convenience of individual components in preclinical studies.
+Added: In preclinical studies, APG279 has also demonstrated broad inhibition of Type 1, Type 2 and Type 3 inflammation, similar to what was seen with Janus kinase (“JAK”) inhibition, but with potential for better tolerability than JAK inhibitors.
+Added: We believe these combined mechanisms offer the potential for improved clinical responses over monotherapy while our planned approach of coformulating two extended half-life mAbs holds the potential for best-in-class dosing.
+Added: In August 2024, we initiated a Phase 1 clinical trial of APG990 in healthy volunteers to establish safety, tolerability and PK profile, which could enable the combination with APG777.
+Added: In March 2025, we announced positive interim safety and PK data from the APG990 Phase 1 clinical trial.
+Added: PK data showed a half-life of approximately 60 days across doses tested.
+Added: APG990, in single doses up to 1,200mg, was well tolerated and showed a favorable safety profile, consistent with other assets targeting OX40L.
+Added: In addition, preclinical toxicology studies of the combination of APG777 and APG990 showed no findings at any dose level, including the highest dose tested of 150 mg/kg per agent.
+Added: Based on these results, we plan to submit an Investigational New Drug application or foreign equivalent for APG279.
+Added: Following clearance, we plan to initiate in 2025 a Phase 1b trial of APG279 against DUPIXENT in approximately 50 to 75 patients with moderate-to-severe AD with a data readout expected in the second half of 2026.
+Added: APG333 – anti-TSLP antibody, same mechanism of action as TEZPIRE (tezepelumab);
+Added: potential combination therapy with APG777
+Added: APG333 is a fully-human mAb against thymic stromal lymphopoietin (“TSLP”), an epithelial cell-derived cytokine that has emerged as an attractive validated target for the treatment of people living with asthma and COPD.
+Added: In preclinical studies, the combination of APG777 and APG333 has been shown to impact both central inflammation and local airway responses.
+Added: This has the potential to improve clinical outcomes compared to approved or in-development biologics which only target peripheral or central inflammation, not both, and retains the potential for a significantly less frequent dosing schedule.
+Added: In December 2024, we initiated a Phase 1 trial of APG333 in healthy volunteers and we expect interim data from the trial in the second half of 2025.
+Added: We plan to evaluate APG777 and APG333 monotherapies in respective Phase 1b trials in patients with asthma in 2025 to support advancement into future combination trials in asthma and COPD.
+Added: Subject to positive data, we plan to study APG777 in combination with APG333 to drive potential best-in-class efficacy in respiratory conditions.
+Added: APG808 – anti-IL4Rα antibody, same mechanism of action as DUPIXENT
APG808 is an SQ extended half-life mAb targeting IL-4Rα, a target with clinical validation across eight different Type 2 allergic diseases.
−Removed: COPD is a heterogenous, progressive respiratory condition characterized by cough, dyspnea and airflow obstruction that affects approximately 32 million adults 40 years of age and older in the United States, France, Germany, Italy, Japan, Spain and the United Kingdom.
−Removed: Based on our preclinical studies, we believe APG808 can be dosed either every six weeks or every two months in maintenance, which, if our clinical trials are successful, would represent a significant improvement compared to first generation IL-4Rα antibodies that are dosed every two weeks.
−Removed: In November 2023, we finalized the nomination of a development candidate for our APG808 program for the treatment of COPD.
−Removed: Since then, we have completed a toxicology program that included a one-month GLP toxicology study in mice with the NOAEL observed at 1,000 mg/kg/dose.
−Removed: In February 2024, we received regulatory approval to commence a first-in-human clinical trial in Australia.
−Removed: We expect to enter the clinic with APG808 in healthy volunteers followed by a potential Phase 1b trial in asthma and/or a Phase 2 trial in COPD (pending data from the Phase 1 trial and following the submission of an IND or foreign equivalent to support such trials).
−Removed: Our earlier-stage programs, APG990 and APG222, utilize advanced antibody engineering to target OX40L and both IL-13 and OX40L, respectively, which we are initially developing for the treatment of AD.
−Removed: OX40L occurs higher up in the inflammatory pathway than IL-13 or IL-4Rα and potentially broadens the impact on the inflammatory cascade.
−Removed: With current approved biologics only targeting two mechanisms of action (IL-13 and IL4Rα) in AD, OX40L could represent another therapeutic option for patients, especially the portion of patients who do not benefit from currently available treatments.
−Removed: We expect to nominate a development candidate for APG990 in 2024.
−Removed: In addition, we believe that blocking multiple targets, such as simultaneous inhibition of IL-13 and OX40L in APG222, could allow us to provide benefit to patients with AD and other I&I indications.
−Removed: We recently added a new program that also utilizes advanced antibody
−Removed: engineering for an undisclosed target.
−Removed: We believe that each of our programs has the potential to impact multiple additional I&I indications.
−Removed: Recent Developments
−Removed: APG777 Positive Interim Phase 1 Data
−Removed: On March 5, 2024, we announced positive interim Phase 1 data from our first-in-human study of APG777, one of our lead product candidates being developed as a frontline treatment for moderate-to-severe AD and other inflammatory diseases.
−Removed: Pharmacokinetic (PK) data showed a half-life of approximately 75 days across doses tested and Pharmacodynamic (PD) data showed deep and sustained inhibition of key AD biomarkers pSTAT6 and TARC for approximately three months (longest available follow-up available, with inhibition still ongoing at time of the data cut).
−Removed: Results from the trial exceeded our trial objectives and support the potential for APG777, a novel anti-IL-13 antibody, to optimize exposure levels in 16-week induction and be dosed once every three or six months in maintenance.
−Removed: These findings represent the potential for improved clinical responses from greater exposures in induction and significantly less frequent dosing in maintenance compared to currently approved biologic therapies, which are dosed at every two to four weeks, a potential major advancement for patients with AD and other inflammatory diseases.
−Removed: APG777, in single doses up to 1,200mg and multiple doses of 300mg, was well tolerated and showed a favorable safety profile, in line with the existing body of third-party evidence for the safety of the anti-IL-13 class.
−Removed: Based on these data, we plan to initiate a randomized, placebo-controlled, Phase 2 clinical trial in patients with moderate-to-severe AD in the first half of 2024 ahead of schedule.
−Removed: Key Phase 1 Interim Findings
−Removed: The Phase 1 trial is a first-in-human, randomized, double-blind, placebo-controlled study designed to evaluate safety and PK of APG777 in healthy volunteers.
−Removed: The study enrolled 40 healthy adult participants into three SAD and two MAD cohorts.
−Removed: Doses of subcutaneous APG777 evaluated in the study included 300mg, 600mg and 1,200mg.
−Removed: APG777’s PK differentiation supports further development of APG777 as a treatment for moderate-to-severe AD and other inflammatory diseases.
−Removed: APG777’s potentially best-in-class PK profile, including a half-life of approximately 75 days, supports testing higher exposures of drug in induction to potentially achieve improved clinical responses;
−Removed: and testing of maintenance dosing of every three or six months, representing two to four injections per year compared to the current treatment paradigm of 13 to 26 injections per year.
−Removed: Dose-proportional increases in serum concentrations and key parameters (e.g., Cmax, AUC) were observed in the Phase 1 trial.
−Removed: PK was consistent across subjects with low variability.
−Removed: Figures A and B show single- and multi-dose concentration-time profiles, respectively, from the ongoing Phase 1 trial.
−Removed: Figure A—Single-dose concentration-time profile
−Removed: Figure B—Multi-dose concentration-time profile
−Removed: Single doses of APG777 demonstrated a deep and sustained effect on PD markers for approximately three months (longest follow-up available with inhibition still ongoing at time of data cut).
−Removed: Single doses of APG777 suppressed pSTAT6,
−Removed: one of the first downstream markers of IL-13 pathway inhibition, with near-complete inhibition (both in terms of median and mean percent change from baseline) for approximately three months.
−Removed: Single doses of APG777 suppressed TARC, an inflammatory mediator and the most strongly correlated biomarker to AD severity, with deep and sustained inhibition for approximately three months.
−Removed: Figure C shows pSTAT6 and TARC as biomarkers of IL-13 engagement and AD severity.
−Removed: Figure C—pSTAT6 and TARC are biomarkers of IL-13 target engagement and AD severity
−Removed: Figure D shows pSTAT6 inhibition data for APG777 from our Phase 1 trial.
−Removed: Figure D—Median percent change from baseline in pSTAT6
−Removed: Figure E shows TARC inhibiton data for APG777 from our Phase 1 trial in 6 healthy volunteers receiving a single SC injection of 300mg of APG777.
−Removed: Figure E—Median % changes from baseline in TARC inhibition
−Removed: Figure F shows TARC inhibition for DUPIXENT using data derived from a third–party Phase 1 trial with 6 healthy volunteers receiving a single SC injection of 300 mg DUPIXENT.
−Removed: Figure F—Median % changes from baseline in TARC inhibition
−Removed: Single doses of APG777 up to 1,200mg and multiple doses of 300mg were well tolerated with a favorable safety profile consistent with the existing third-party data supporting the safety of the anti-IL-13 class.
−Removed: The most common treatment-emergent adverse events (TEAEs) were vascular access site pain, vessel puncture site bruise, headache, and vascular access bruising.
−Removed: 60% of participants observed at least one TEAE;
−Removed: 15% of participants observed at least one drug-related adverse event (AE).
−Removed: There were no Grade 3 TEAEs or severe adverse events related to study drug.
−Removed: No AEs led to discontinuation of the study.
−Removed: Phase 2 Trial in AD
−Removed: Following our positive interim results, we plan to advance APG777 into a randomized, placebo-controlled, 16-week Phase 2 clinical trial in patients with moderate-to-severe AD.
−Removed: The integrated Phase 2 AD trial is expected to initiate in the first half of 2024 with 16-week topline data from Part A expected in the second half of 2025.
−Removed: Part A is expected to enroll approximately 110 patients randomized 2:1 to APG777 and placebo with primary endpoint of mean percentage changes in EASI score from baseline to Week 16.
−Removed: Part B of the Phase 2 trial is a randomized, placebo-controlled dose optimization with approximately 360 patients randomized 1:1:1:1 to high, medium, or low dose APG777 and placebo with primary endpoint of mean percentage changes in EASI score from baseline to Week 16.
−Removed: All patients benefiting from treatment will continue to APG777 maintenance, which will evaluate three- to six-month dosing.
−Removed: The integrated design is expected to provide for significant timeline acceleration by combining Phase 2a and Phase 2b elements into a single study protocol.
−Removed: All Part A sites are also expected to participate in Part B, which should avoid delays for site startup between the two parts.
−Removed: Doses in the Phase 2 trial are enabled by APG777’s potentially best-in-class PK profile, extended half-life, and high-concentration formulation.
−Removed: Our 180mg/mL formulation enables a 44% higher dose of APG777 compared to lebrikizumab in the same volume.
−Removed: The APG777 Phase 2 induction regimen is designed to exceed lebrikizumab (an IL-13 inhibitor with an overlapping epitope with APG777) exposures by approximately 30 to 40% with potential for improved clinical outcomes
−Removed: and maintenance regimen is designed to equal lebrikizumab’s exposures.
−Removed: In Phase 3 studies, approximately 30% higher exposure seen in lebrikizumab low bodyweight group resulted in numerically higher efficacy than the overall study population across all key endpoints, including EASI-75 and more stringent endpoints such as EASI-90 and IGA 0/1.
−Removed: Approximately 30 to 40% higher induction exposures for APG777 than lebrikizumab are based on a planned six injection induction regimen given in the first sixteen weeks of APG777 treatment.
−Removed: This is approximately half as many of the 11 injections of lebrikizumab given during the same period.
−Removed: At 52 weeks, exposures of APG777 dosed every three months are designed to exceed those of lebrikizumab and exposures of APG777 dosed every six months are designed to equal those of lebrikizumab.
−Removed: We also may evaluate APG777 in expansion indications including initiating a Phase 2 trial in asthma in 2025.
−Removed: APG808 Phase 1 Trial
−Removed: On March 5, 2024, we also announced that our Phase 1 APG808 healthy volunteer clinical trial is expected to enter the clinic ahead of scheduled in the first half of 2024 following receipt of regulatory clearance in February 2024.
−Removed: In addition, we expect interim Phase 1 PK and safety data in healthy volunteers in the second half of 2024, ahead of prior guidance, and initial proof-of-concept data in asthma in the first half of 2025.
−Removed: We expect to initiate a proof-of-concept clinical trial in patients with COPD in 2025, pending positive data from Phase 1 trial and regulatory clearance.
−Removed: APG990 and APG222
−Removed: On March 5, 2024, we also announced that our early-stage programs, APG990 and APG222, are progressing to candidate selection.
−Removed: We expect to nominate a candidate for APG990 in 2024 and initiate a Phase 1 trial in healthy volunteers in 2025.
−Removed: We plan to provide more detailed updates on our earlier pipeline programs and combination strategy in an R&D Day in the fourth quarter of 2024.
+Added: In March 2024, we commenced dosing of the first healthy volunteers in the APG808 Phase 1 trial and in September 2024, we commenced dosing of the first asthma patients as a cohort in that Phase 1 trial.
+Added: In December 2024, we announced positive interim safety, PK and PD data from the Phase 1 trial.
+Added: APG808 demonstrated a potential best-in-class PK profile, including a half-life of approximately 55 days at projected, clinically relevant steady state exposures, supporting the potential for every two- to three-month maintenance dosing.
+Added: Single doses of APG808 demonstrated a deep and sustained effect on PD markers out to approximately three months (longest follow-up available at time of data cut).
+Added: APG808 was well-tolerated across all dose groups.
+Added: We are also now evaluating APG808 in a Phase 1b trial in patients with asthma, with data expected in the first half of 2025.
Our goal is to discover and develop new therapies for a range of I&I indications.
We aim to accomplish this goal by focusing on known biologic drivers of disease and utilizing advanced antibody engineering to develop product candidates with optimized properties that have the potential to overcome limitations of existing therapies.
−Removed: For instance, our two most advanced programs, APG777 and APG808, bind to the same epitopes, or binding sites, on IL-13 and IL-4Rα as lebrikizumab and DUPIXENT (dupilumab), respectively, based on our head-to-head preclinical studies, but are designed to include extended half-life technologies and other optimized properties.
+Added: For instance, each of our programs, APG777, APG990, APG333 and APG808, bind to the same epitopes, or binding sites, on IL-13, OX40L, TSLP and IL-4Rα as EBGLYSS (lebrikizumab), amlitelimab, TEZPIRE (tezepelumab), and DUPIXENT (dupilumab), respectively, based on our head-to-head preclinical studies, but are designed to include extended half-life technologies and other optimized properties.
When designing our programs, we test multiple half-life extension technologies, including YTE and LS amino acid modifications, to identify the optimal candidate to advance against each target.
4 unchanged sentences
We believe our approach will enable us to develop a portfolio of therapies that are differentiated compared to the currently available standards of care and address unmet medical needs for I&I indications, including the potential for improved dosing and/or efficacy.
−Removed: Biologics Are Common Treatments for I&I Diseases
−Removed: Over the last two decades, biologics have become more common for the treatment of a wide range of I&I indications and remain the core therapeutic modality today.
−Removed: New treatments for I&I indications have largely been driven by biologics, which accounted for nearly 90% of I&I product revenues.
−Removed: Given the overlapping mechanistic drivers of many I&I indications, indication expansion remains a consistent hallmark of many I&I products.
−Removed: Broadly, mAbs have been developed to target both diseases driven by T helper type 1 (Th1) immune responses, which involve IL-2, interferon-γ and lymphotoxin-α and an associated neutrophilic response, and diseases driven by T helper type 2 (Th2) immune responses, which involve IL-4, IL-5 and IL-13 and an associated eosinophilic response.
−Removed: As one example, psoriasis, with a moderate-to-severe population estimated to be approximately 9.2 million patients, had the first biologic approved in 2008 and an additional six biologics approved from that time to 2023.
−Removed: Only one other indication, psoriatic arthritis, has more approved biologics.
−Removed: By contrast, the moderate-to-severe AD population, which is estimated to be approximately 25.1 million patients, has only two approved biologics, which leaves a large unmet need for patients with AD.
−Removed: DUPIXENT is an example of the success of approved therapeutics.
−Removed: Since its approval for the treatment of AD in 2017, DUPIXENT has also been approved in asthma, CRSwNP, EoE and PN and is being clinically developed in allergic bronchopulmonary aspergillosis, allergic fungal rhinosinusitis, bullous pemphigoid, chronic pruritis of unknown origin, cold inducible urticaria, COPD, chronic rhinosinusitis sans nasal polyps and CSU, and is expected to reach peak sales of $21 billion in 2031 based on consensus estimates.
−Removed: Although our most advanced program APG777 targets the same mechanism of action as DUPIXENT, there is no assurance that our clinical trial results will achieve similar clinical trial results with respect to safety and/or efficacy or that APG777 will achieve FDA approval or commercial success.
−Removed: AD Background and Current Treatment Limitations
−Removed: AD, the most common subtype of eczema, is a chronic inflammatory skin disorder that affects individuals of all ages and races.
−Removed: AD affects individuals living in geographic regions worldwide.
−Removed: AD is characterized by pruritic (itchy), erythematous (red) and often excoriated (damaged) skin lesions, which are most often located on the neck, inner elbows and behind the knees.
−Removed: The specific cause of AD is unknown;
−Removed: however, research has shown that genetics, the immune system and the environment all play a role in the disease.
−Removed: AD can significantly impact quality of life, leading to sleep disturbance, psychological distress, elevated infection risk and chronic pain.
−Removed: AD is frequently associated with other atopic manifestations such as food allergy, allergic rhinitis (also known as hay fever) and asthma.
−Removed: AD is characterized by a Th2 response, which describes Th2 cells, a subset of white blood cells, that produce small proteins called cytokines, like IL-13, which regulate inflammation, immune response and tissue repair.
−Removed: AD usually begins in childhood;
−Removed: however, anyone can become affected with this inflammatory disease at any age.
−Removed: It is estimated that 40 million adults and 18 million children in the United States, France, Germany, Italy, Japan, Spain and the United Kingdom are affected by AD.
−Removed: Approximately 40% of all patients have moderate-to-severe disease.
−Removed: The incidence of AD has increased two to three-fold in industrialized nations since the 1970s, with approximately 15% to 20% of children and 1% to 3% of adults affected worldwide.
−Removed: There is no cure for AD and many people have difficulty controlling the disease.
−Removed: AD patients work with a dermatologist to determine treatment options that can bring their symptoms under control.
−Removed: For less extensive disease (i.e., mild-to-moderate AD), treatment is primarily topical corticosteroids and targeted topical treatments (e.g., a topical Janus kinase (JAK) inhibitor).
−Removed: For more extensive disease (i.e., moderate-to-severe AD), mAbs have emerged as the preferred frontline therapy in most adult and pediatric patients that is not controlled by topical therapies.
−Removed: Avoiding environmental and stress triggers, increased skin care regimen and dietary and lifestyle changes may also be part of the treatment recommendations.
−Removed: There are two FDA-approved mAbs, Regeneron and Sanofi’s DUPIXENT (dupilumab), a mAb targeting IL-4Rα, and LEO Pharma’s ADBRY (tralokinumab-ldrm), a mAb targeting IL-13, labeled to treat moderate-to-severe AD.
−Removed: Lebrikizumab is an investigational mAb targeting IL-13 being developed by Eli Lilly and Company and currently under regulatory review for approval in the United States and has been approved in the European Union and Japan.
−Removed: Despite recent advancements in AD treatment, a significant number of patients continue to suffer from active disease.
−Removed: Today’s treatments are associated with many challenges, including a high frequency of injections that may lead to poor patient compliance.
−Removed: Based on a peer-reviewed third-party study of real world use published in the Journal of the American Academy of Dermatology, more than 20% of patients discontinue treatment with DUPIXENT within six months of starting therapy.
−Removed: The dosing schedule of biologics for AD is driven by the half-life for these agents, which provides a meaningful opportunity for a new treatment option with improved administration due to less frequent dosing.
−Removed: COPD Background and Current Treatment Limitations
−Removed: COPD is a heterogenous, progressive respiratory condition characterized by cough, dyspnea and airflow obstruction.
−Removed: It is estimated that approximately 10% of the global population 40 years of age and older have COPD, and in 2019 (prior to the COVID–19 pandemic), COPD was the third leading cause of death globally.
−Removed: In the United States, over 150,000 people die of COPD each year.
−Removed: Three symptoms of COPD are dyspnea (difficulty breathing), cough and sputum (coughed-up phlegm) production.
−Removed: There are several possible linked risk factors to COPD including cigarette smoke, environmental factors (e.g., pollution and occupational exposures), airway responsiveness, atopy, asthma, infections and genetics.
−Removed: COPD has historically been thought of as driven by Th1 immune responses, which are driven by IL-2, interferon-γ and lymphotoxin-α and associated with a neutrophilic response.
−Removed: However, more recent third-party data has demonstrated that Th2 immune responses, which are driven by IL-4, IL-5 and IL-13 and associated with an eosinophilic response, are prominent in a subset of COPD patients.
−Removed: Th2 immune responses have been shown to be associated with increased airway inflammation and appear to underlie COPD in a subset of patients and related cytokines have been shown to be upregulated during exacerbations.
−Removed: For stable COPD, inhaled bronchodilators (drugs that increase the size of the airways) are the mainstay of treatment.
−Removed: These include short-and long-acting beta-agonists (e.g., albuterol, salmeterol and formoterol), muscarinic agonists (e.g., tiotropium and aclidinium), and inhaled glucocorticoids (e.g., fluticasone and budesonide).
−Removed: For patients with refractory COPD, treatment options include chronic antibiotic use and DALIRESP (roflumilast).
−Removed: DALIRESP is the only systemic therapy approved to reduce the risk of COPD exacerbations in patients with severe COPD and a history of frequent COPD exacerbations.
−Removed: However, the effect is modest.
−Removed: A pooled analysis from two Phase 3 trials of DALIRESP in COPD patients 40 years of age and older with severe airflow limitation, bronchitis symptoms and a history of exacerbations showed a 17% reduction in moderate or severe exacerbations.
−Removed: Despite recent advancements in COPD treatment, 9.4 million patients in the United States, Japan, Germany, France, Italy, Spain and the United Kingdom with moderate-to-severe disease continue to suffer and die from the disease.
−Removed: No biologics are currently approved for the treatment of COPD, with ensifentrine, a nebulized PDE3/4 treatment under FDA review.
−Removed: Given the complexity of COPD, we believe biologics targeting Th2 immune response in patients with high peripheral eosinophils show the greatest promise, as supported by DUPIXENT’s 2023 positive Phase 3 data in COPD.
−Removed: However, even if approved, biologics for the treatment of COPD will be associated with many challenges, including a high frequency of injections.
−Removed: The dosing schedule of current biologics in development for COPD is driven by the short half-life for these agents, which provides a meaningful opportunity for a new treatment option with improved administration due to less frequent dosing.
−Removed: Of the biologics in development for COPD, we are not aware of any programs that have the potential to reduce dosing frequency past four weeks and the related burden of administration on patients.
−Removed: Asthma Background and Current Treatment Limitations
−Removed: Asthma is one of the most common non-communicable diseases and, for a substantial number of patients, has an impact on quality of life.
−Removed: Asthma is estimated to affect 40 million adults and 12 million children in the United States, France, Germany, Italy, Japan, Spain and the United Kingdom, with prevalence rates of 5% to 8% in many countries.
−Removed: Currently, the asthma market is greater than $10 billion in these seven major markets.
−Removed: Asthma is a complex multifactorial disease, attributed to interactions between genetic susceptibility, host factors and environmental exposures, which result in airway inflammation, control of airway tone and reactivity.
−Removed: The resulting clinical presentation can vary, but can result in shortness of breath, chest tightness or pain, coughing and wheezing.
−Removed: In the United States, asthma accounts for approximately five million physician visits, one million emergency room visits and thousands of deaths annually.
−Removed: Treatment of asthma focuses on control of asthma symptoms and reduction of asthma exacerbations.
−Removed: Exact treatments are based on severity and can include short-acting inhalers (e.g., short-acting beta agonists) used as needed,
−Removed: long-acting inhalers (e.g., long-acting beta agonists, inhaled corticosteroids) given daily or systemic medications, such as biologics.
−Removed: Biologics, specifically, have begun to play an important role in the treatment of the 15.2 million patients with moderate-to-severe disease, largely as an add-on to inhaled medication.
−Removed: XOLAIR was the first biologic approved for asthma in 2003 and subsequently, an additional five biologics have been approved since 2015 (NUCALA, CINQAIR, FASENRA, DUPIXENT and TEZSPIRE).
−Removed: All have shown reductions in annualized exacerbation rates of approximately 50% to 60% and are dosed every two to eight weeks.
−Removed: Despite advances in care, including biologics, there is still high unmet medical need for patients suffering from asthma, both in terms of reduced injection burden as well as improved efficacy.
−Removed: Our pipeline comprises four programs being developed initially for the treatment of I&I indications, as shown below.
−Removed: Our two most advanced programs, APG777 and APG808, which we are initially developing for the treatment of AD and COPD, respectively, target the same mechanism of action as lebrikizumab and DUPIXENT (dupilumab), respectively.
−Removed: Moreover, we are evaluating APG777 in additional I&I indications, including asthma, AA, CRSwNP, CSU, EoE and PN.
−Removed: Our earlier-stage programs, APG990 and APG222, utilize advanced antibody engineering to target OX40L and both IL-13 and OX40L, respectively.
−Removed: We recently added a new program that also utilizes advanced antibody engineering for an undisclosed target.
−Removed: Our programs incorporate advanced antibody engineering to optimize half-life and other properties designed to overcome limitations of existing therapies.
−Removed: We believe each of our programs has potential for broad application across multiple I&I indications.
−Removed: (1) Based on data from our Phase 1 trial of APG777 in healthy volunteers, we may initiate a Phase 2 trial in asthma and expect to further evaluate opportunities to develop APG777 for other I&I indications, including alopecia areata, chronic rhinosinusitis with nasal polyps, chronic spontaneous urticaria, eosinophilic esophagitis and prurigo nodularis.
−Removed: Our most advanced program, APG777, is an SQ mAb with YTE half-life extension technology targeting IL-13.
−Removed: In our head-to-head preclinical assays, our leads have demonstrated equivalent or better potency to lebrikizumab in the inhibition of IL-13 signaling.
−Removed: In our head-to-head studies of APG777 and lebrikizumab in non-human primates (NHPs) (cynomolgus monkeys), APG777 showed a significantly longer half-life than lebrikizumab.
−Removed: We expect APG777 to have
−Removed: a human half-life of approximately 80 to 110 days based on data from other YTE antibodies for soluble targets, which showed half-lives in humans that is three to four times greater than in NHPs, as shown in Figure 1 below.
−Removed: Figure 1 — NHP and human half-life data of mAbs with and without the YTE amino acid modification
−Removed: (1) As reported in studies conducted by the sponsor of each of these product candidates or in the label of approved products.
−Removed: Based on our PK modeling, with only a 33 day human half-life (which, to our knowledge, would be lower than the lowest half-life for a mAb with the YTE amino acid modifications reported to date), we believe we can achieve an every two-month maintenance dosing schedule at our target exposures, which are modeled based on lebrikizumab’s exposures.
−Removed: With only a 50 day half-life, we believe we can achieve an every three-month maintenance dosing schedule at our target exposures, which are modeled based on lebrikizumab’s exposures, each as shown in Figure 2 below.
−Removed: Figure 2 — APG777 NHP half-life, predicted human half-life and predicted dosing interval
−Removed: (1) Based on steady state PK simulations made with parameters for APG777 identical to lebrikizumab except changes in dose and kelimination.
−Removed: Compared to more frequent dosing schedules associated with existing AD therapies, every three or six month dosing, should our clinical trials be successful in demonstrating the requisite efficacy and safety profile, has the potential to be significantly more convenient for patients, enabling them to better adhere to their dosing schedule.
−Removed: Additionally, every three or six month dosing is expected to improve quality of life given that many patients experience “needle fatigue” and pediatric patients in particular often suffer from fear of needles.
−Removed: In August 2023, we announced the dosing of our first participant in our first clinical trial for APG777 in Australia.
−Removed: The trial enrolled 40 healthy adult subjects into three SAD and two MAD cohorts.
−Removed: The primary endpoint is safety and a key secondary endpoint is PK.
−Removed: The Phase 1 trial is ongoing and we have announced initial safety and PK data from this trial.
−Removed: Generally, the half-life of mAbs is consistent between healthy volunteers and patients, since mAbs are degraded by endogenous catabolic processes that are not affected by disease.
−Removed: This gives us confidence that the PK parameters derived from the Phase 1 trial in healthy volunteers can be used effectively to model dosing regimens for subsequent Phase 2 and Phase 3 safety and efficacy trials in patients with AD and other indications.
−Removed: We have filed an IND in support of a Phase 1 trial in healthy volunteers in the United States for subjects of Japanese descent and have received a “study may proceed” letter from the FDA for the trial.
−Removed: We anticipate initiating a Phase 2 trial in AD in the United States and internationally in the first half of 2024.
−Removed: Pending data from the Phase 1 trial, we expect to enroll moderate-to-severe AD patients in a randomized, placebo-controlled Phase 2 trial.
−Removed: The primary data readout will be after 16 weeks on trial, which is common among other agents studied in AD.
−Removed: Primary efficacy outcomes will include, but will not be limited to, percent change from baseline in Eczema Area and Severity Index (EASI) and proportion of patients achieving an IGA scale 0/1 (assessment of clear or almost clear) and EASI-75 (change in EASI score from baseline of at least 75%).
−Removed: Based on our initial clinical data, we may initiate a Phase 2 trial in asthma, and expect to further evaluate opportunities to develop APG777 for other I&I indications, including AA, CRSwNP, CSU, EoE and PN.
−Removed: Our second most advanced program, APG808, is an SQ extended half-life mAb targeting IL-4Rα, a target with clinical validation across eight Type 2 allergic diseases.
−Removed: In our head-to-head preclinical assays, our leads have demonstrated equivalent potency to DUPIXENT in the inhibition of IL-4Rα signaling.
−Removed: In addition, based on our preclinical studies, we believe APG808 can be dosed either every six weeks or every two months in maintenance, which, if our clinical trials are successful, would represent a significant improvement compared to first generation IL-4Rα antibodies that are dosed every two weeks.
−Removed: In November 2023, we finalized the nomination of a development candidate for APG808 and we have received regulatory approval to commence a first-in-human clinical trial in Australia.
−Removed: We anticipate that APG808 will enter the clinic in healthy volunteers in the first half of 2024 followed by a potential Phase 1b trial in asthma and/or a Phase 2 trial in COPD (pending data from the Phase 1 trial and following the submission of an IND or foreign equivalent to support such trials).
−Removed: Our third program, APG990, is an SQ extended half-life mAb targeting OX40L for the treatment of AD.
−Removed: OX40L occurs higher up in the inflammatory pathway than IL-13 or IL4Rα and potentially broadens the impact on the inflammatory cascade.
−Removed: With current approved biologics only targeting two mechanisms of action (IL-13 and IL4Rα) in AD, OX40L could represent another therapeutic option for patients, especially the portion of patients who do not benefit from currently available treatments.
−Removed: We expect to nominate a development candidate in 2024 if we observe equivalent or better in vitro potency to other mAbs targeting OX40L in head-to-head preclinical studies, and an improved PK profile, including half-life extension, in head-to-head studies in NHPs.
−Removed: Our fourth program, APG222, is one or more extended half-life SQ antibodies targeting both IL-13 and OX40L, which we believe has the potential to improve outcomes in AD over current standard of care biologic therapies.
−Removed: We believe that the mechanism of action of APG222, which combines blockage of OX40L and IL-13, could simultaneously decrease OX40L signaling, helping to rebalance the immune system and decrease immune cell differentiation and cytokine release, and further reduce IL-13, resulting even less immune signaling.
−Removed: This, in turn, could prevent certain disease-related signs and symptoms that are driven by IL-13 signaling and the downstream inflammatory cascade.
−Removed: We believe that blocking multiple targets, such as simultaneous inhibition of IL-13 and OX40L, could allow us to provide benefit to patients with AD and other I&I indications.
−Removed: Additional Opportunities
−Removed: We believe that each of our programs has the potential to impact multiple additional I&I indications beyond AD and COPD, including asthma, as well as AA, CRSwNP, CSU, EoE and PN.
−Removed: Initial structured indication prioritization has identified asthma as a leading expansion opportunity given the significant overlap with AD and the clinical unmet need for extended dosing biologics that do not sacrifice clinical benefit.
−Removed: Based on third-party claims data, 31% of AD patients also carry an asthma diagnosis.
−Removed: Based on feedback from dermatologists, we believe that there is significant value in having both indications on a label because of this overlap.
−Removed: Asthma is estimated to affect 40 million adults and 12 million children in the United States, France, Germany, Italy, Japan, Spain and the United Kingdom.
−Removed: Our Team, Investors and Paragon Collaboration
−Removed: We were founded in 2022 by leading healthcare investors Fairmount Funds and Venrock Healthcare Capital Partners and have since assembled a management team of drug developers with significant experience in clinical development.
−Removed: Our management team comprises industry veterans with extensive experience at biopharmaceuticals companies and proven track records in the discovery, development, manufacturing and commercialization of numerous approved therapeutics in I&I indications, including DALIRESP (Roflumilast), ILUMYA (tildrakizumab), KORSUVA (difelikafalin) and OTEZLA (apremilast), as well as more than a dozen other approved products.
−Removed: The team additionally has clinical and regulatory experience with late-stage I&I products currently under regulatory review, including etrasimod and lebrikizumab, manufacturing experience of biologics from IND through commercialization and financial, operational, legal and transactional experience across the biopharmaceutical industry.
−Removed: Since our inception, we have raised approximately $484.4 million in net proceeds from the issuance of preferred units and sale of common stock in our initial public offering (IPO).
−Removed: In July 2023, we completed our IPO in which we issued and sold an aggregate of 20,297,500 shares of common stock (inclusive of 2,647,500 shares pursuant to the exercise in full of the underwriters’ option to purchase additional shares) at a public offering price of $17.00 per share, for aggregate net proceeds of $315.4 million after deducting underwriting discounts and commissions and other offering expenses.
−Removed: We have exclusive development and commercialization rights to our programs through a strategic collaboration with Paragon Therapeutics, Inc.
−Removed: Together with Paragon, we intend to evaluate additional opportunities and can select additional targets as part of our discovery research collaboration.
−Removed: Paragon was founded by Fairmount Funds in 2021 as the firm’s discovery engine for biologics that potentially overcome limitations of existing therapies.
−Removed: Paragon leverages a dedicated in-house team of scientific experts in antibody development, as well as its partnership with FairJourney Biologics, to pursue unique therapeutic concepts and enable their rapid proof-of-concept validation.
−Removed: We consider Paragon to be a related party.
−Removed: See the section titled “Certain Relationships and Related Party Transactions — Our Relationship with Paragon” for additional information.
−Removed: Our Strengths
−Removed: We believe that our company and differentiated programs possess the following attributes that will help us successfully develop and commercialize new therapies:
−Removed: ● Incorporate advanced antibody engineering to optimize half-life and other properties to potentially overcome limitations of existing therapies.
−Removed: We are focused on engineering therapies with potential for improved dosing, efficacy and safety profiles.
−Removed: We implement YTE or LS amino acid modifications, which have the potential to significantly improve PK profile and reduce injection burden compared to existing agents.
−Removed: Our antibody engineering programs are designed to improve antibody candidate attributes, including in vitro potency, bioavailability and decreased PK variability, as well as those attributes essential for manufacturability and high concentration formulation (i.e.
−Removed: viscosity, solubility and stability) to generate optimized antibodies.
−Removed: ● Leverage validated targets and mechanisms of action.
−Removed: Our antibody programs are designed to overcome limitations of existing therapies by targeting well-established mechanisms of action and incorporating advanced antibody engineering to optimize half-life and other properties.
−Removed: advanced programs, APG777 and APG808, which we are initially developing for the treatment of AD and COPD, respectively, target IL-13 and IL-4Rα, respectively.
−Removed: ● Address a clear initial opportunity in AD driven by patient burden in a large addressable market.
−Removed: There is a large adult and pediatric patient population, with AD affecting over 40 million adults and 18 million children in the United States, France, Germany, Italy, Japan, Spain and the United Kingdom, and market penetration from existing biologics has been hindered in part due to the burden of frequent injections.
−Removed: Many patients experience “needle fatigue” and pediatric patients in particular often suffer from fear of needles.
−Removed: Estimates show that as many as two in three children and one in four adults have strong fears around needles.
−Removed: We believe there is clear unmet need for a new therapy that improves the clinical profile of existing agents and allows for less frequent dosing.
−Removed: ● Address a large unmet need in COPD, a leading cause of death with no approved biologics.
−Removed: COPD affects more than 32 million adults 40 years of age and older in the United States, France, Germany, Italy, Japan, Spain and the United Kingdom and is a leading cause of death worldwide.
−Removed: COPD patients are also much more likely to become severely ill when they are infected with other respiratory diseases, which further compounds the significant health care burden.
−Removed: While bronchodilators improve symptoms of COPD, they do not address the underlying inflammatory processes.
−Removed: There are no approved biologics available for the treatment of COPD.
−Removed: We believe there is a significant unmet need for a novel therapy that can effectively target an underlying source of inflammation that may be a root cause of COPD, in order to limit COPD events and improve lung capacity.
−Removed: ● Potential for expansion into a broad range of I&I indications, including asthma.
−Removed: We believe there is a path to indications beyond AD and COPD based on the common biology underlying multiple I&I indications.
−Removed: Based on current biologic understanding, we are evaluating APG777 in additional I&I indications, including asthma, as well as AA, CRSwNP, CSU, EoE and PN.
−Removed: Moreover, we believe that our programs beyond APG777 also have the potential to impact multiple additional I&I indications, including AA, CRSwNP, CSU, EoE and PN.
−Removed: ● Strong leadership in I&I discovery, development and commercialization, as well as manufacturing of biologics overall.
−Removed: We were founded in 2022 by leading healthcare investors, Fairmount Funds and Venrock Healthcare Capital Partners, and have since assembled a management team comprising industry veterans with extensive experience at biopharmaceuticals companies and with proven track records in the discovery, development, manufacturing and commercialization of numerous approved therapeutics, as well as clinical and regulatory experience with dermatologic products, including lebrikizumab.
Our goal is to become a leader in developing novel therapies for I&I indications.
1 unchanged sentence
The key elements of our strategy include:
−Removed: ● Advancing APG777, our most advanced program, through clinical development and regulatory filings for AD.
−Removed: We are developing APG777 as a frontline treatment for patients with moderate-to-severe AD who have failed or have an inadequate response to topical corticosteroids.
−Removed: APG777 is an SQ extended half-life mAb targeting IL-13 that has been engineered to have differentiated attributes, including an extended half-life, which we expect will result in a more favorable dosing schedule, including either an every three or six months maintenance dosing schedule.
−Removed: In our head-to-head preclinical studies, APG777 was observed to be as potent as lebrikizumab in terms of IL-13 inhibition but with a significantly longer half-life.
−Removed: Based on these preclinical studies and our interim Phase 1 data we believe APG777 can be dosed either every three or six months in maintenance, which, if our clinical trials are successful, would represent a significant improvement compared to first generation IL-13 antibodies that are dosed every two to four weeks.
−Removed: In addition, we believe the low-volume SQ delivery
−Removed: of APG777 and effector-silent backbone of the APG777 mAb will contribute to an optimized product.
−Removed: In August 2023, we announced the dosing of our first participant in our first clinical trial for APG777.
−Removed: The trial enrolled 40 healthy adult subjects into three SAD and two MAD cohorts.
−Removed: The primary endpoint is safety and a key secondary endpoint is PK.
−Removed: The Phase 1 trial is ongoing and we have announced initial safety and PK data from this trial.
−Removed: We anticipate initiating a Phase 2 trial in AD in the United States and internationally in the first half of 2024.
−Removed: We have completed GLP-compliant toxicology studies up to six months in duration, with no adverse findings at any dose level, including the highest tested dose, which was the maximum feasible dose.
−Removed: The completed toxicology studies were designed to facilitate moving from Phase 1 to Phase 2 clinical trials, pending regulatory approval.
−Removed: A primary readout at 16 weeks is common among AD agents and is recognized as an important time point for FDA approval of biologics for AD.
−Removed: ● Leveraging our approach of targeting known biologic drivers of I&I indications to advance APG808, our second most advanced program, into clinical development for COPD.
−Removed: APG808 is an SQ extended half-life mAb targeting IL-4Rα, a target with clinical validation across eight different Type 2 allergic diseases, that has been engineered to have an extended half-life as well as maintain similar potency as compared to DUPIXENT in our head-to-head in vitro assays.
−Removed: COPD is a heterogenous, progressive respiratory condition characterized by cough, dyspnea and airflow obstruction that affects approximately 32 million adults 40 years of age and older in the United States, France, Germany, Italy, Japan, Spain and the United Kingdom.
−Removed: Based on our preclinical studies, we believe APG808 can be dosed either every six weeks or every two months in maintenance, which would represent a significant improvement compared to first generation IL-4Rα antibodies, that are dosed every two weeks.
−Removed: In November 2023, we finalized the nomination of a development candidate for APG808 and we have received regulatory approval to commence a first-in-human clinical trial in Australia.
−Removed: We anticipate that APG808 will enter the clinic in healthy volunteers in the first half of 2024 followed by a potential Phase 1b trial in asthma and/or a Phase 2 trial in COPD (pending data from the Phase 1 trial and following the submission of an IND or foreign equivalent to support such trials).
−Removed: ● Advancing our programs targeting OX40L and the dual inhibition of OX40L and IL-13.
−Removed: Our third program, APG990, is a mAb targeting OX40L for the treatment of AD.
−Removed: OX40L occurs higher up in the inflammatory pathway than IL-13 or IL-4Rα and potentially broadens the impact on the inflammatory cascade.
−Removed: With current approved biologics only targeting two mechanisms of action (IL-13 and IL4Rα) in AD, OX40L could represent another therapeutic option for patients, especially the portion of patients who do not benefit from currently available treatments.
−Removed: We are engineering APG990 to have additional favorable properties compared to other mAbs targeting OX40L, including an extended half-life.
−Removed: We believe we are the only company applying half-life extension technology to the OX40L class.
−Removed: We plan on nominating a development candidate in this program in 2024.
−Removed: Our fourth program, APG222, is focused on the dual inhibition of OX40L and IL-13, which we believe could result in a more durable response than inhibition of either target alone across a broader range of I&I indications.
−Removed: We believe that blocking multiple targets, such as simultaneous inhibition of IL-13 and OX40L, could allow us to provide benefit to patients with AD and other I&I indications.
−Removed: ● Maximizing the potential of our programs through indication expansion beyond AD and COPD.
−Removed: We believe our APG777 and APG808 programs have the potential to treat I&I indications driven by Th2 immune response, such as asthma, as well as AA, CRSwNP, CSU, EoE and PN.
−Removed: In addition, we believe our APG990 and APG222 programs have the potential to treat I&I indications driven by both Th1 and Th2 immune responses.
−Removed: Other therapies with which our most advanced programs share a mechanism of action have demonstrated success in targeting indications driven by Th2 immune response.
−Removed: Leveraging different mechanisms of action for the same indications may allow us to treat a broader patient population.
−Removed: We have taken a systematic approach to prioritizing indications and plan on leveraging clinical data and knowledge from our Phase 1 trials in APG777 to launch proof-of-concept Phase 2 trials in indications with strong scientific rationale in large markets or areas of unmet need.
−Removed: Based on our initial clinical data, we may initiate a Phase 2 trial in asthma, and expect to further evaluate
−Removed: opportunities to develop APG777 for other I&I indications, including AA, CRSwNP, CSU, EoE and PN.
+Added: • Advancing APG777 targeting IL-13 through clinical development and regulatory filings for AD;
+Added: • Advancing APG990 targeting OX40L and APG279 for the dual inhibition of OX40L and IL-13;
+Added: • Advancing APG333 targeting TSLP and the combination of APG777 and APG333 for the dual inhibition of TSLP and IL-13;
+Added: • Maximizing the potential of our programs through indication expansion beyond AD, including asthma, EoE and COPD;
• Expanding existing and evaluating new collaborations to broaden the impact we can have for patients living with I&I indications.
−Removed: Our strategic collaboration with Paragon has resulted in us obtaining exclusive development and commercialization rights for our initial programs.
−Removed: Together with Paragon, we intend to evaluate additional opportunities and can select additional targets as part of the discovery research collaboration.
−Removed: In addition, we plan to evaluate additional opportunities to enhance our capabilities and expand our development pipeline or provide development or commercialization capabilities that complement our own.
−Removed: We recently added a new program that also utilizes advanced antibody engineering for an undisclosed target.
−Removed: Biologics are Common Treatments for I&I Diseases
−Removed: Over the last two decades, biologics have become more common for the treatment of a wide range of I&I indications and remain the core therapeutic modality today.
−Removed: New treatments for I&I indications have largely been driven by biologics, which accounted for nearly 90% of these I&I product revenues.
−Removed: Given the overlapping mechanistic drivers of many I&I indications, indication expansion remains a consistent hallmark of many I&I products.
−Removed: Broadly, mAbs have been developed to target both diseases driven by T helper type 1 (Th1) immune responses, which involve IL-2, interferon-γ and lymphotoxin-α and an associated neutrophilic response, and diseases driven by T helper type 2 (Th2) immune responses, which involve IL-4, IL-5 and IL-13 and an associated eosinophilic response.
−Removed: As one example, psoriasis, with a moderate-to-severe population estimated to be approximately 9.2 million patients, had the first biologic approved in 2008 and an additional six biologics approved from that time to 2023.
−Removed: Only one other indication, psoriatic arthritis, has more approved biologics.
−Removed: By contrast, the moderate-to-severe AD population, which is estimated to be approximately 25.1 million patients, has only two approved biologics, which leaves a large unmet need for patients with AD.
−Removed: DUPIXENT is an example of the success of approved therapeutics.
−Removed: Since its approval for the treatment of AD in 2017, DUPIXENT has also been approved in asthma, CRSwNP, EoE and PN and is being clinically developed in allergic bronchopulmonary aspergillosis, allergic fungal rhinosinusitis, bullous pemphigoid, chronic pruritis of unknown origin, cold inducible urticaria, COPD, chronic rhinosinusitis sans nasal polyps and CSU.
−Removed: Although our most advanced program APG777 targets the same mechanism of action as DUPIXENT, there is no assurance that our clinical trial results will achieve similar clinical trial results with respect to safety and/or efficacy or that APG777 will achieve FDA approval or commercial success.
Overview of AD
11 unchanged sentences
For some people, AD improves by adulthood, but for many, it can be a lifelong illness.
−Removed: It is estimated that 40 million adults and 18 million children in the United States, France, Germany, Italy, Japan, Spain and the United Kingdom are
−Removed: affected by AD.
+Added: It is estimated that 81.6 million people suffer from moderate to severe AD worldwide.
Approximately 40% of all patients have moderate-to-severe disease.
3 unchanged sentences
AD patients work with a dermatologist to determine treatment options that can bring their symptoms under control.
−Removed: For less extensive disease (i.e., mild-to-moderate AD), treatment is primarily topical corticosteroids and targeted topical treatments (e.g., a topical Janus kinase (JAK) inhibitor).
+Added: For less extensive disease (i.e., mild-to-moderate AD), treatment is primarily topical corticosteroids and targeted topical treatments (e.g., a topical JAK inhibitor).
For more extensive disease (i.e., moderate-to-severe AD), mAbs have emerged as the preferred frontline therapy in most adult and pediatric patients that is not controlled by topical therapies.
22 unchanged sentences
mAbs have emerged as the preferred frontline therapy in most adult and pediatric patients with moderate-to-severe AD that is not controlled by topical therapies.
−Removed: There are two FDA-approved mAbs, DUPIXENT and ADBRY, labeled to treat moderate-to-severe AD that is inadequately controlled by topical corticosteroids.
−Removed: Additionally, lebrikizumab is an investigational mAb being developed by Eli Lilly and Company designed to inhibit the IL-13 pathway and is currently under review for approval by the FDA and has been approved by the European Medicines Agency (EMA) and the Pharmaceuticals and Medical Devices Agency (PMDA), in Japan.
+Added: There are four U.S.
+Added: Food and Drug Administration (“FDA”)-approved mAbs, DUPIXENT, ADBRY, EBGLYSS, and NEMLUVIO, labeled to treat moderate-to-severe AD that is inadequately controlled by topical corticosteroids.
DUPIXENT is indicated for the treatment of adult and pediatric patients aged six months and older with moderate-to-severe AD whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.
8 unchanged sentences
It selectively inhibits IL13, preventing IL13 induced immune responses in the skin.
−Removed: It is dosed via SQ injection with an initial loading dose requiring four injections, followed by two injections every two weeks for 16 weeks and then, for select patients, maintenance injections every month may be considered.
+Added: It is dosed via SQ injection with an initial loading dose requiring either (i) in the case of prefilled syringes, four injections, followed by two injections every two weeks for 16 weeks then, for select patients, maintenance injections every month may be considered;
+Added: or (ii) in the case of
+Added: autoinjectors, two injections, followed by one injection every two weeks for 16 weeks then, for select patients, maintenance injections every month may be considered.
ADBRY was evaluated in nearly 2,000 patients with AD in three pivotal trials.
Across the three trials, ADBRY demonstrated improvements in both skin clearance and lesion extent and severity at Week 16.
−Removed: Lebrikizumab is an emerging treatment with a similar mechanism of action to both DUPIXENT and ADBRY.
−Removed: It is an investigational mAb being developed by Eli Lilly and Company that is designed to inhibit the IL-13 pathway and currently under regulatory review for approval in the United States and has been approved in the European Union and Japan.
−Removed: In three Phase 3 clinical trials, SQ administration of lebrikizumab was dosed every two weeks in the induction phase (first 16 weeks of treatment) and every two or four weeks in the maintenance phase (from 16 weeks to 52 weeks).
−Removed: Lebrikizumab met all primary and key secondary endpoints at Week 16 in Phase 3 trials.
−Removed: The most commonly reported adverse events (AE) were conjunctivitis, common cold and headache.
−Removed: For patients for which biologics such as DUPIXENT or ADBRY do not provide adequate control of moderate-to-severe AD, systemic JAK inhibitors may be recommended.
−Removed: RINVOQ (upadacitinib) or CIBINQO (abrocitinib) are both FDA-approved treatments for AD that may be prescribed to patients who do not respond to topical prescription treatments.
+Added: EBGLYSS is indicated for the treatment of moderate-to-severe AD in adult patients whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.
+Added: It can also be used with or without topical corticosteroids.
+Added: EBGLYSS is designed to inhibit the IL-13 pathway.
+Added: In three Phase 3 clinical trials, SQ administration of EBGLYSS was dosed every two weeks in the induction phase (first 16 weeks of treatment) and every two or four weeks in the maintenance phase (from 16 weeks to 52 weeks).
+Added: EBGLYSS met all primary and key secondary endpoints at Week 16 in Phase 3 trials.
+Added: The most commonly reported adverse events (“AEs”) were conjunctivitis, common cold and headache.
+Added: In Phase 3 studies, ~30% higher exposure was seen in the low body weight group (less than 60kg), which also had numerically higher efficacy than the overall study population across all key endpoints, including EASI-75 and more stringent endpoints such as EASI-90 and IGA 0/1.
+Added: NEMLUVIO is indicated for the treatment of moderate-to-severe AD patients aged 12 and over in combination with topical corticosteroids and/or calcineurin inhibitors when the disease is not adequately controlled with topical prescription therapies.
+Added: NEMLUVIO is a humanized IgG2 mAb that inhibits IL-31 signaling by binding selectively to IL-31Rα.
+Added: It is dosed via SQ injection with an initial loading dose requiring two injections, followed by one injection every four or eight weeks in maintenance.
+Added: NEMLUVIO was evaluated in combination with topical corticosteroids and/or calcineurin inhibitors in over 1,700 patients with AD in two pivotal trials.
+Added: Across the two trials, NEMLUVIO in combination with topical corticosteroids and/or calcineurin inhibitors demonstrated improvements in both skin clearance and lesion extent and severity at Week 16.
+Added: For patients for which biologics such as DUPIXENT, ADBRY, EBGLYSS, or NEMLUVIO do not provide adequate control of moderate-to-severe AD, systemic JAK inhibitors may be recommended.
+Added: RINVOQ (upadacitinib) or CIBINQO (abrocitinib) are both FDA-approved treatments for AD that may be prescribed to patients who do not respond to topical prescription treatments or systemic drugs, including biologics.
Despite their effectiveness and convenient oral administration, these therapies are associated with serious risk of life-threatening side effects and carry boxed warnings.
3 unchanged sentences
Systemic JAK inhibitors represented just 7% of the AD market in 2022.
−Removed: An emerging mechanism in treatments for AD is targeting OX40 or OX40L, which occur higher up in the inflammatory pathway than IL-13 or IL-4Rα and potentially broadens the impact on the inflammatory cascade.
+Added: An emerging mechanism in treatments for AD is targeting OX40L, which occurs higher up in the inflammatory pathway than IL‑13 or IL‑4Rα and potentially broadens the impact on the inflammatory cascade.
OX40L is the ligand for OX40.
−Removed: OX40L is expressed on antigen presenting cells and its interaction with OX40 causes the accumulation of T cells by providing a survival signal.
−Removed: OX40L, by playing a role in activating T cells and reprogramming them into inflammatory subsets, contributes to immune overactivation in AD and other inflammatory conditions.
−Removed: Additionally, OX40L activation of OX40 inhibits the expression of FOXP3 and the inhibitory function of regulatory T (Treg) cells.
−Removed: Treg cells suppress immune response, which leads to worse symptoms in inflammatory conditions.
−Removed: Therefore, OX40L blockade may lead to clinical benefit in AD and other inflammatory conditions by first suppressing inflammatory T cell activation, and next by increasing the proliferation of Treg cells, which can serve to further reduce inflammatory cells.
−Removed: Amlitelimab, which targets OX40L, and rocatinlimab, which targets OX40, have both demonstrated promising Phase 2 data in AD.
+Added: Amlitelimab, which targets OX40L, has demonstrated activity in Phase 2 trials in AD.
Addressing the Limitations of Current Biologics
7 unchanged sentences
Dermatologists were selected based on years of experience in the field (four or more years of practice post residency or fellowship training), number of AD patients treated (30 or more AD patients seen per month), experience prescribing biologic therapies in AD (10% or more of AD patients on biologics) and no previous contact with us.
−Removed: We conducted approximately 30-minute interviews using standardized questions to solicit sentiments towards a potential new product offering with every three month dosing in maintenance and the same efficacy and safety as DUPIXENT, which was presented as a blinded Target Product Profile (the TPP).
+Added: We conducted approximately 30‑minute interviews using standardized questions to solicit sentiments towards a potential new product offering with every three-month dosing in maintenance and the same efficacy and safety as DUPIXENT, which was presented as a blinded Target Product Profile (“TPP”).
The dermatologists selected for the survey have an average of 20 years in practice, treat an average of 88 AD patients per month and see a mix of both adult and pediatric patients.
In the interviews, dermatologists described how they would incorporate the TPP in treatment algorithms for biologic naïve patients (i.e., patients who have never taken a biologic treatment, but qualify based on failure to topical therapies) and biologic-experienced patients (i.e., patients who are either currently or have previously used a biologic therapy for AD).
−Removed: On average, dermatologists indicated they expect approximately 92% of their biologic patients would start a product with the TPP as frontline treatment.
+Added: On average, dermatologists indicated they expect that approximately 92% of their biologic patients would start a product with the TPP as frontline treatment.
For patients currently or previously on biologic therapy, dermatologists estimated approximately 57% would switch to a product with the TPP.
+Added: Likewise, patients were given APG777 TPP and two other available treatments.
+Added: When asked their preference, 94% of patients preferred a Q3M dosing regimen.
+Added: Finally, payers were asked how they might cover a product with the TPP, at a similar net price, and most see this product as a first line biologic product.
Dermatologists were then asked how their intent to use a product with the TPP would change if (i) it was dosed every two months in the maintenance setting, or (ii) it was dosed every six months in the maintenance setting.
3 unchanged sentences
With every six-month dosing, dermatologists on average indicated they would prescribe a product with the TPP to 91% of their biologic naïve patients and they estimated 68% of patients currently or previously on biologic therapy would switch to a product with the TPP.
−Removed: Figure 5 — Intent to use a product with the APG777 Target Product Profile with every two, three or six month maintenance dosing and equivalent efficacy and safety to DUPIXENT
+Added: Figure 3 — Intent to use a product with the APG777 Target Product Profile with every three- or six-month maintenance dosing and equivalent efficacy and safety to DUPIXENT
We are not aware of any programs in development in AD that have the potential to reduce dosing frequency past four weeks and the related burden of administration on patients.
A more convenient dosing schedule is especially important for pediatric patients, which has the potential to expand the market significantly.
−Removed: Overview of COPD
−Removed: Disease Overview
−Removed: COPD is a heterogenous, progressive respiratory condition characterized by cough, dyspnea and airflow obstruction.
−Removed: It is estimated that approximately 10% of the global population 40 years of age and older have COPD, and in 2019 (prior to the COVID–19 pandemic), COPD was the third leading cause of death globally.
−Removed: In the United States, over 150,000 people die of COPD each year.
−Removed: Three symptoms of COPD are dyspnea (difficulty breathing), cough and sputum (coughed-up phlegm) production.
−Removed: There are several possible linked risk factors to COPD including cigarette smoke, environmental factors (e.g., pollution and occupational exposures), airway responsiveness, atopy, asthma, infections and genetics.
−Removed: COPD has historically been thought of as driven by Th1 immune responses, which are driven by IL-2, interferon-γ and lymphotoxin-α and associated with a neutrophilic response.
−Removed: However, more recent third-party data has demonstrated that Th2 immune responses, which are driven by IL-4, IL-5 and IL-13 and associated with an eosinophilic response, are prominent in a subset of COPD patients.
−Removed: Th2 immune responses have been shown to be associated with increased airway inflammation and appear to underlie COPD in a subset of patients and related cytokines have been shown to be upregulated during exacerbations.
−Removed: Overview of Current Treatment Options
−Removed: For stable COPD, inhaled bronchodilators (drugs that increase the size of the airways) are the mainstay of treatment.
−Removed: These include short-and long-acting beta-agonists (e.g., albuterol, salmeterol and formoterol), muscarinic agonists (e.g., tiotropium and aclidinium), and inhaled glucocorticoids (e.g., fluticasone and budesonide).
−Removed: For patients with refractory COPD, treatment options include chronic antibiotic use and DALIRESP (roflumilast).
−Removed: DALIRESP is the only systemic therapy approved to reduce the risk of COPD exacerbations in patients with severe COPD and a history of frequent COPD exacerbations.
−Removed: However, the effect is modest.
−Removed: A pooled analysis from two Phase 3 trials of DALIRESP in COPD patients 40 years of age and older with severe airflow limitation, bronchitis symptoms and a history of exacerbations showed a 17% reduction in moderate or severe exacerbations.
−Removed: Despite recent advancements in COPD treatment, a significant number of patients continue to suffer and die from the disease.
−Removed: No biologics are currently approved for the treatment of COPD, with ensifentrine, a nebulized PDE3/4 treatment under FDA review.
−Removed: Given the complexity of COPD, we believe biologics targeting Th2 immune response in patients with high peripheral eosinophils show the greatest promise, as supported by DUPIXENT’s recent positive Phase 3 data in COPD.
−Removed: Specifically, the topline data from DUPIXENT’s Phase 3 BOREAS trial, which enrolled COPD patients with elevated peripheral eosinophils (≥300 cell/μL), showed a significant reduction of 30% in moderate-to-severe acute exacerbations of COPD (p=0.0005), as well as improved lung function and quality of life.
−Removed: NOTUS, the second Phase 3 trial, confirmed the BOREAS findings with a 34% reduction in moderate-to-severe exacerbations at 52 weeks (p=0.0002).
−Removed: Addressing the Limitations of Current Biologics
−Removed: However, even if approved, biologics for the treatment of COPD will be associated with many challenges, including a high frequency of injections.
−Removed: The dosing schedule of current biologics in development for COPD is driven by the short half-life for these agents, which provides a meaningful opportunity for a new treatment option with improved administration due to less frequent dosing.
−Removed: Of the biologics in development for COPD, we are not aware of any programs that have the potential to reduce dosing frequency past four weeks and the related burden of administration on patients.
Overview of Asthma
12 unchanged sentences
All have shown reductions in annualized exacerbation rates of approximately 50% to 60% and are dosed every two to eight weeks.
−Removed: Despite advances in care, including biologics, there is still high unmet medical need for patients suffering from asthma, both in terms of reduced injection burden as well as improved efficacy
+Added: Overview of Eosinophilic Esophagitis
+Added: Disease Overview
+Added: EoE is a chronic inflammatory condition of the esophagus, with the hallmark histological finding being eosinophilic infiltrates (i.e., presences of eosinophils in the tissue).
+Added: When not treated appropriately, EoE progresses to cause scarring and strictures of the esophagus, which gives patients significant trouble with eating and drinking and potential nutritional compromise.
+Added: Once considered a rare condition, incidence and prevalence rates have rapidly increased with EoE now being the most common cause of upper-gastrointestinal morbidity.
+Added: The overall prevalence in the United States is approximately 1 in 700, up from 1 in 2,000 in 2014, with more than 400,000 Americans currently suffering from the condition.
+Added: Overview of Current Treatment Options
+Added: The only available biologic for the treatment of EoE is DUPIXENT, which was first approved for this indication in 2022 and later approved for patients aged 1 and older in 2024, and requires weekly dosing.
+Added: DUPIXENT’s approval in EoE further supports the scientific rationale for IL-13/IL-4Rα targeting agents in treating EoE.
+Added: DUPIXENT was studied in approximately 300 EoE patients across two pivotal trials and demonstrated clinically meaningful improvements in histological remission defined as peak esophageal intraepithelial eosinophil count in adult, adolescent, and pediatric patients.
+Added: In adults and adolescents, DUPIXENT demonstrated clinically meaningful reduction in dysphagia symptoms as measured by reduction in Dysphagia Symptom Questionnaire score.
+Added: In pediatric patients (1-11 years of age), DUPIXENT demonstrated clinically meaningful reduction in symptoms as measured by reduction in Pediatric EoE Sign/Symptom Questionnaire-Caregiver score.
+Added: Overview of COPD
+Added: Disease Overview
+Added: COPD is a heterogenous, progressive respiratory condition characterized by cough, dyspnea and airflow obstruction.
+Added: It is estimated that approximately 10% of the global population 40 years of age and older have COPD, and in 2019 (prior to the COVID–19 pandemic), COPD was the third leading cause of death globally.
+Added: In the United States, over 150,000 people die of COPD each year.
+Added: Overview of Current Treatment Options
+Added: For stable COPD, inhaled bronchodilators (drugs that increase the size of the airways) are the mainstay of treatment.
+Added: These include short-and long-acting beta-agonists (e.g., albuterol, salmeterol and formoterol), muscarinic agonists (e.g., tiotropium and aclidinium), and inhaled glucocorticoids (e.g., fluticasone and budesonide).
+Added: For patients with refractory COPD, treatment options include chronic antibiotic use and DALIRESP (roflumilast).
+Added: A pooled analysis from two Phase 3 trials of DALIRESP in COPD patients 40 years of age and older with severe airflow limitation, bronchitis symptoms and a history of exacerbations showed a 17% reduction in moderate or severe exacerbations.
+Added: In 2024, the FDA approved DUPIXENT as the first biologic treatment for add-on maintenance for inadequately controlled COPD and an eosinophilic phenotype.
+Added: Two Phase 3 studies demonstrated that DUPIXENT dosed every 2 weeks reduced exacerbations by an average of 31% compared to placebo in patients with elevated peripheral eosinophils (≥300 cell/μL).
+Added: TEZSPIRE (tezepelumab) is a biologic being developed in COPD.
+Added: Tezspire dosed as 420 mg monthly, showed a 37% reduction in annualized exacerbations in a subset (n=92) of moderate to very severe COPD patients with eosinophils ≥150 cell/μL in an initial Phase 2 trial.
+Added: OHTUVAYRE (ensifentrine), a twice daily nebulized treatment for moderate to severe COPD, was approved in 2024.
+Added: However, the trials did not require a recent history of exacerbations.
+Added: Despite these recent advancements in COPD treatment, a significant number of patients continue to suffer and die from the disease.
+Added: Given the complexity of COPD, we believe biologics targeting Th2 immune response in patients with high peripheral eosinophils show the greatest promise, as supported by DUPIXENT’s approval in COPD and TEZSPIRE’s encouraging Phase 2 data in COPD.
Our Solution:
Building Differentiated Biologics
−Removed: We are engineering therapies for AD, COPD, asthma and other related I&I indications.
−Removed: Our two most advanced programs, APG777 and APG808, target IL-13 and IL4Rα, respectively, and are designed to overcome limitations of frequent dosing associated with currently available treatments.
−Removed: With respect to our earlier-stage programs, APG990 utilizes advanced antibody engineering to target OX40L, a target with potentially broad application for inflammatory conditions, and APG222 utilizes advanced antibody engineering to target both IL-13 and OX40L.
−Removed: We recently added a new program that also utilizes advanced antibody engineering for an undisclosed target.
+Added: We are engineering therapies for AD, asthma, EoE, COPD, and other related I&I indications.
+Added: Our programs, APG777, APG990, APG333 and APG808, target IL-13, OX40L, TSLP, and IL4Rα, respectively, and are designed to overcome limitations of frequent dosing associated with currently available treatments.
+Added: We believe that each of our programs has potential for broad application across multiple I&I indications, including the potential for higher efficacy either through an improved monotherapy or via rationale combinations.
+Added: Despite advances in care, there is still high unmet medical need for patients suffering from the I&I indications that we are targeting, both in terms of reduced injection burden as well as improved efficacy.
Our programs incorporate advanced antibody engineering approaches, and are designed to optimize for half-life extension, in vitro potency, bioavailability and decreased PK variability, as well as those attributes essential for manufacturability and high concentration formulation (i.e.
2 unchanged sentences
YTE amino acid modifications are a triple modification (M252 Y /S254 T /T256 E ) introduced into the antibody, while LS amino acid modifications are a double modification (M428 L /N434 S ).
−Removed: Our most advanced program, APG777, leverages YTE amino acid modification half-life extension technology and is SQ mAb targeting IL-13.
−Removed: After regulatory approval, we initiated a Phase 1 clinical trial of APG777 in healthy volunteers in August 2023.
−Removed: Our second most advanced program, APG808, leverages half-life extension technology and is an SQ mAb targeting IL-4Rα.
−Removed: In November 2023, we finalized the nomination of a development candidate for APG808 based on equivalent in vitro potency compared to DUPIXENT and other improved drug properties, including half-life extension in
−Removed: our head-to-head preclinical studies and we have received regulatory approval to commence a first-in-human clinical trial in Australia.
−Removed: Our third program, APG990, leverages half-life extension technology and is an SQ mAb targeting OX40L.
−Removed: We expect to nominate a development candidate in 2024 if we observe equivalent or better in vitro potency compared to other mAbs targeting OX40L and other improved drug properties, including half-life extension in our head-to-head preclinical studies.
−Removed: Our fourth program, APG222, targets both IL-13 and OX40L using one or more SQ mAbs that leverage half-life extension technology.
−Removed: We believe targeting both IL-13 and OX40L has the potential to improve clinical outcomes in AD over current standard of care biologic therapies.
+Added: APG777, leverages YTE amino acid modification half-life extension technology and is an SQ mAb targeting IL-13.
+Added: APG777 demonstrated a 77-day half-life in a Phase 1 clinical trial in healthy volunteers.
+Added: We initiated a Phase 2 clinical trial in patients with moderate-to-severe AD in May 2024.
+Added: The Phase 2 trial is designed to combine the
+Added: typical Phase 2a and 2b portions of a clinical trial into a single protocol.
+Added: In February 2025, we announced that the last patient in the Part A portion had been dosed and that we had commenced dosing of the Part B portion.
+Added: We anticipate maintenance data from Part A in the first half of 2026 and 16-week topline data from Part B in the second half of 2026.
+Added: APG990, leverages half-life extension technology and is an SQ mAb targeting OX40L.
+Added: We initiated a Phase 1 clinical trial of APG990 in healthy volunteers in August 2024 and announced positive interim safety and PK data in March 2025.
+Added: In 2025, we plan to initiate a Phase 1b trial designed to evaluate APG279 against DUPIXENT in approximately 50 to 75 patients with moderate-to-severe AD with a data readout expected in the second half of 2026.
+Added: APG333, leverages half-life extension technology and is an SQ mAb targeting TSLP.
+Added: We initiated a Phase 1 clinical trial of APG333 in healthy volunteers in December 2024 and expect a data readout in the second half of 2025.
+Added: Subject to positive data and required regulatory approvals, we plan to evaluate the combination of APG777 and APG333.
+Added: APG808, leverages half-life extension technology and is an SQ mAb targeting IL-4Rα.
+Added: We initiated a Phase 1 clinical trial of APG808 in March 2024 and announced positive interim safety, PK and PD data in December 2024.
+Added: We are also now evaluating APG808 in a Phase 1b trial in patients with asthma, with data expected in the first half of 2025.
Half-Life Extension and Antibody Engineering Technologies
42 unchanged sentences
Similarly, administration of mAbs bearing LS amino acid modifications does not appear to confer any additional safety risk or immunogenicity risk.
−Removed: For example, ULTOMIRUS (ravulizumab) is an LS modified version of SOLIRIS (eculizumab).
−Removed: In third-party clinical trials, the AE profile of ULTOMIRUS and SOLIRIS were shown to be a similar in a head-to-head study and one ADA-positive sample was found in each treatment arm.
−Removed: Our most advanced program, APG777, leverages YTE amino acid modifications half-life extension technology and is an SQ mAb targeting IL-13.
−Removed: We plan to evaluate APG777 in AD, as well as a number of expansion indications, including asthma.
−Removed: In our head-to-head preclinical studies of APG777 and lebrikizumab in NHPs APG777 showed a significantly longer half-life than lebrikizumab.
−Removed: In these studies, APG777’s half-life was 27.6 days, as compared to 18.0 days for lebrikizumab based on cumulative fit models across SQ and IV groups for each compound and as shown in Figure 7 below.
−Removed: Figure 7 — Head-to-head comparison of NHP PK for APG777 and lebrikizumab
−Removed: N=3 per group.
−Removed: Two of three NHPs in the lebrikizumab arm developed ADAs by day 40 (datapoints associated with ADAs are excluded).
−Removed: We expect APG777 to have a human half-life of approximately 80 to 110 days based on data from other YTE antibodies for soluble targets, which provided evidence that half-life in humans is three to four times greater than in NHPs.
−Removed: As shown in Figure 8 below, this is largely consistent with previous clinical observations of mAbs with YTE amino acid modification, however, there can be no assurance that APG777 will have similar or comparable results.
−Removed: Figure 8 — YTE mAbs extended half-life in NHPs has consistently translated to significantly greater human half-life than non-YTE mAbs
−Removed: Based on our PK modeling, with only a 33-day human half-life (which, to our knowledge, would be lower than the lowest half-life for a mAb with the YTE amino acid modifications reported to date), we believe we can achieve an every two month maintenance dosing schedule at our target exposures, which are modeled based on lebrikizumab’s exposures.
−Removed: With only a 50-day half-life, we believe we can achieve an every three month maintenance dosing schedule at our target exposures, which are modeled based on lebrikizumab’s exposures.
−Removed: Compared to more frequent dosing schedules associated with existing AD therapies, every three or six month dosing, should our clinical trials be successful in demonstrating the requisite efficacy and safety profile, has the potential to be significantly more convenient for patients, enabling them to better adhere to their dosing schedule.
−Removed: Additionally, every three or six month dosing improves quality of life given that many patients experience “needle fatigue” and pediatric patients in particular often suffer from fear of needles.
−Removed: In August 2023, we initiated a Phase 1 trial of APG777 in healthy volunteers in Australia.
−Removed: We have announced initial SQ PK and safety data from this trial.
+Added: For example, ULTOMIRIS (ravulizumab) is an LS modified version of SOLIRIS (eculizumab).
+Added: In third-party clinical trials, the AE profile of ULTOMIRIS and SOLIRIS were shown to be a similar in a head-to-head study and one ADA-positive sample was found in each treatment arm.
+Added: APG777 leverages YTE amino acid modifications half-life extension technology and is an SQ mAb targeting IL-13.
+Added: We are evaluating APG777 in AD, and plan to evaluate APG777 in a number of expansion indications, including asthma and EoE and in combination with certain of our other programs.
+Added: In our head-to-head preclinical studies of APG777 and lebrikizumab in non-human primates (“NHPs”).
+Added: APG777 showed a significantly longer half-life than lebrikizumab.
+Added: In these studies, APG777’s half-life was 27.6 days, as compared to 18.0 days for lebrikizumab based on cumulative fit models across SQ and IV groups for each compound.
+Added: In 2024, we announced interim safety, PK and PD data from our Phase 1 trial of APG777 in healthy volunteers.
+Added: PK data showed a half-life of 77 days across doses tested.
Generally, the half-life of mAbs is consistent between healthy volunteers and patients since mAbs are degraded by endogenous catabolic processes and are not subject to the same drug-drug interaction potential of many traditional small molecules.
Consequently, this gives us confidence that the PK parameters derived from the Phase 1 trial in healthy volunteers can be used to effectively model dosing regimens in the subsequent Phase 2 and Phase 3 safety and efficacy trials in patients with AD and other I&I indications.
−Removed: We plan to initiate a Phase 2 trial in patients with AD in the first half of 2024.
−Removed: We plan to enroll moderate-to-severe AD patients in a randomized, placebo-controlled Phase 2 trial.
−Removed: The primary data readout will be after 16 weeks on trial, which is common among other agents studied in AD.
−Removed: Primary outcomes will include, but will not be limited to,
−Removed: percent change from baseline in EASI and proportion of patients achieving an IGA scale 0/1 and EASI-75.
−Removed: At the end of the primary 16-week trial, patients will rollover to continue treatment on either a maintenance or open-label extension trial.
−Removed: In addition, based on our initial clinical data, we may initiate a Phase 2 trial in asthma, and expect to further evaluate opportunities to develop APG777 for other I&I indications, including AA, CRSwNP, CSU, EoE and PN.
+Added: We are testing three- and six-month dosing in our Phase 2 clinical trial of APG777.
+Added: Compared to more frequent dosing schedules associated with existing AD therapies, every three- or six-month dosing, should our clinical trials be successful in demonstrating the requisite efficacy and safety profile, has the potential to be significantly more convenient for patients, enabling them to better adhere to their dosing schedule.
+Added: Additionally, every three- or six-month dosing improves quality of life given that many patients experience “needle fatigue” and pediatric patients in particular often suffer from fear of needles.
APG777’s target, IL‑13, has no known non-disease function
66 unchanged sentences
In our similar head-to-head preclinical study, ADBRY was found to have a binding response, suggesting that it has a different epitope on IL‑13 than lebrikizumab.
−Removed: APG777 matched the in vitro potency of lebrikizumab and DUPIXENT across all relevant assays in our head-to-head preclinical studies
+Added: APG777 matched the in vitro potency of lebrikizumab and dupilumab across all relevant assays in our head-to-head preclinical studies
APG777 was engineered to demonstrate similar preclinical activity to available therapies in our head-to-head studies.
1 unchanged sentence
Measuring downstream functional inhibition of the pathway is critical as this measures the mAb’s impact not only on IL‑13, but also the impacts of the resulting inflammatory cascade that causes the features, signs and symptoms associated with AD.
−Removed: To measure these
−Removed: parameters, APG777 was tested in vitro across four assays:
+Added: To measure these parameters, APG777 was tested in vitro across four assays:
Human Affinity by SPR, Inhibition of pSTAT6 Induction, Inhibition of TF‑1 Proliferation and Inhibition of TARC Secretion.
These assays are described in detail below and outputs are measured in IC90, the concentration or amount of drug it takes to cause a 90% inhibition in the assay.
−Removed: Results from our head-to-head preclinical studies demonstrated that each of ADBRY, lebrikizumab and APG777 had similar affinity for IL-13 (see Figure 12 below).
+Added: Results from our head-to-head preclinical studies demonstrated that each of ADBRY, lebrikizumab and APG777 had similar affinity for IL‑13.
Notably, since DUPIXENT does not target IL‑13, it cannot be compared in this assay, but can be tested in assays on pSTAT6, TF‑1 proliferations and TARC release as these assays measure inhibition in the IL‑13/IL‑4 pathway downstream.
1 unchanged sentence
This provides preclinical evidence of similar in vitro potency among DUPIXENT, lebrikizumab and APG777 across a variety of in vitro assays.
−Removed: Figure 12 — Head-to-head studies of APG777, ADBRY, DUPIXENT and lebrikizumab in our preclinical assays
−Removed: APG777 Dosing
+Added: APG777 Preclinical Dosing
APG777 has demonstrated significantly extended half-life in NHPs
−Removed: To demonstrate APG777’s potential to improve dosing over current and anticipated standard of care mAbs in AD, among other diseases, we studied APG777 in female NHPs following a single bolus dose of 3 mg/kg, given SQ.
−Removed: Blood samples were collected serially starting with a sample pre-dose and subsequently at 0.167, 1, 4, 8, 24, 48, 96, 168, 336, 504, 674, 840, 1334, 1680 and 2160 hours post-dose.
−Removed: Data was analyzed to show mean serum concentration with standard deviation over time and a regression fit was performed.
In our head-to-head studies of APG777 and lebrikizumab in NHPs, APG777 showed a significantly longer half-life than lebrikizumab.
−Removed: In these studies, APG777’s half-life was 27.6 days, as compared to 18.0 days for lebrikizumab, based on cumulative fit models across SQ and IV groups for each compound as shown in Figure 13 below.
−Removed: Figure 13 — Head-to-head comparison of NHP PK for APG777 and lebrikizumab
−Removed: N=3 per group.
−Removed: 2 of 3 animals in the lebrikizumab arm developed ADAs by day 40 (datapoints associated with ADAs are excluded).
−Removed: In a non-head-to-head comparison against third-party NHP data, APG777 demonstrated the highest normalized AUC0-∞ (Cnorm*day), or area under the curve (AUC) from dosing to infinity, among antibodies with the YTE modification, as shown in Figure 14.
−Removed: We believe this showed that APG777’s PK profile provided the greatest sustained concentrations, or levels of drug in the blood stream, relative to other antibodies with the YTE modification.
−Removed: Figure 14 — NHP PK and AUC for mAbs with YTE modification
−Removed: We expect this NHP half-life data to translate to a human half-life of approximately 80 to 110 days based on comparable mAbs with YTE amino acid modification
−Removed: Given that half-life extension for mAbs with YTE amino acid modification is dependent on the type of target (receptor versus soluble), we examined the translation of NHP half-life data to human half-life data for mAbs with soluble targets and found that human half-life is approximately three to four times longer than NHP half-life (mean:
−Removed: 3.5x, median:
−Removed: 3.1x), as shown in Figure 15 below.
−Removed: Figure 15 — NHP and human half-life data of mAbs with and without the YTE amino acid modification
−Removed: We expect APG777 to have a human half-life of approximately 80 to 110 days based on data from other YTE antibodies for soluble targets, which showed a half-life in humans that is three to four times greater than in NHPs, as shown in Figure 16 below, however, there can be no assurance that APG777 will have similar or comparable results.
−Removed: Figure 16 — NHP and human half-life Data of mAbs with and without the YTE amino acid modification
−Removed: (1) As reported in studies conducted by the sponsor of each of these product candidates or in the label of approved products.
−Removed: Based on our PK modeling, with only a 33-day human half-life (which, to our knowledge, would be lower than the lowest half-life for a mAb with the YTE amino acid modifications reported to date), we believe we can achieve an every two month maintenance dosing schedule at our target exposures, which are modeled based on lebrikizumab’s exposures.
−Removed: With only a 50-day half-life, we believe we can achieve an every three month maintenance dosing schedule at our target exposures, which are modeled based on lebrikizumab’s exposures, each as shown in Figure 17 below.
−Removed: Figure 17 — APG777 NHP half-life, predicted human half-life and predicted dosing interval
−Removed: (1) Based on steady state PK simulations made with parameters for APG777 identical to lebrikizumab except changes in dose and kelimination.
−Removed: APG777 can achieve every two month dosing if it demonstrates a half-life of at least 33 days and every three month dosing if it demonstrates a half-life of at least 50 days
−Removed: To understand the maintenance dosing schedule that APG777 may be able to achieve, we used known PK parameters for lebrikizumab.
−Removed: These PK parameters provide an understanding of how lebrikizumab is distributed throughout the body and cleared.
−Removed: Based on these known parameters, we built a two-compartment PK model with first-order absorption, which is standard for mAbs, to predict both lebrikizumab’s and APG777’s concentration, or drug levels,
−Removed: Key parameters included 0.156 L/day for clearance (CL), 4.10 L for central volume (Vc), 0.239 day-1 for absorption rate (ka) and 85.6% for bioavailability.
−Removed: We believe that efficacy in inflammatory conditions, such as AD, is driven by Ctrough, or the minimal concentration of the mAb.
−Removed: Therefore, based on the model described above, we set APG777’s target Ctrough to be equal to lebrikizumab’s Ctrough in maintenance with every four weeks dosing, which was 31.3 mg/L.
−Removed: Given the overlapping epitopes of lebrikizumab and APG777, and similarity in potency across multiple in vitro assays, as described above, we believe this provides a reasonable target drug concentration for APG777.
−Removed: By modeling kelimination, the elimination rate constant or the fraction of drug eliminated in a given time, and half-life to maintain APG777 concentrations above 31.3 mg/L, we approximate at least a 33-day half-life would be required to dose APG777 every two months in maintenance and at least a 50-day half-life would be required to dose APG777 every three months in maintenance assuming a dose of 300 mg.
−Removed: Thus, based on our PK modeling, with only a 33-day human half-life (which, to our knowledge, would be lower than the lowest half-life for a mAb with the YTE amino acid modifications reported to date), we believe we can achieve an every two month maintenance dosing schedule at our target exposures, which are modeled based on lebrikizumab’s exposures.
−Removed: In addition, with only a 50-day half-life, we believe we can achieve an every three month maintenance dosing schedule at our target exposures, which are modeled based on lebrikizumab’s exposures.
+Added: In these studies, APG777’s half-life was 27.6 days, as compared to 18.0 days for lebrikizumab, based on cumulative fit models across SQ and IV groups for each compound.
An Extensive Nonclinical Program Has Been Completed to Characterize the Toxicology, Toxicokinetics and ADA Profile of APG777 in NHPs
3 unchanged sentences
These included a single-dose non-GLP dose-range finding study, as well as 29-day and six-month GLP toxicology studies.
−Removed: Our single-dose, non-GLP study in NHPs was completed with no adverse findings in all cohorts, including the highest dose tested
Our single-dose non-GLP study in NHPs was conducted to select doses for the subsequent one-month and six-month studies in NHPs.
No adverse findings were observed at doses up to the maximum feasible dose and the highest dose tested.
−Removed: Our multi-dose, 29-day GLP study in NHPs was completed with no adverse findings in all cohorts, including the highest cohort tested, which was considered the NOAEL
We have conducted a 29‑day repeat-dose, GLP-compliant toxicology study in NHPs, in support of our Phase 1 clinical trial in healthy volunteers.
1 unchanged sentence
No adverse findings were observed up to the highest dose tested (150mg/kg), which was the maximum feasible dose and was considered the no observed adverse effect level (NOAEL) in this study.
−Removed: Our multi-dose, 6-month GLP study in NHPs was completed with no adverse findings in all cohorts, including the highest cohort tested, which was considered the NOAEL
In support of dosing in clinical trials longer than one month in duration, we completed a six-month GLP-compliant toxicology study in NHPs.
2 unchanged sentences
We believe the results of this study will support progression from Phase 1 to Phase 2 trials of extended duration.
−Removed: Clinical Development of APG777
−Removed: In August 2023, we initiated a Phase 1 trial of APG777 in healthy volunteers in Australia and we have announced initial SQ PK and safety data from this trial.
−Removed: The APG777 Phase 1 trial is a double-blind, placebo-controlled study in healthy volunteers and consists of a SAD component and a MAD component.
−Removed: Eight healthy volunteers, six treated with APG777 and two treated with placebo, will be enrolled in each cohort, and we enrolled a total of 40 healthy adult subjects in the trial.
−Removed: The primary endpoint is safety and a key secondary endpoint is PK.
+Added: APG777 Development
+Added: Phase 1 Trial in Healthy Volunteers
+Added: In August 2023, we initiated a Phase 1 trial of APG777 in healthy volunteers.
+Added: The APG777 Phase 1 trial was a double-blind, placebo-controlled study in healthy volunteers and consisted of a single-ascending dose (“SAD”) component and a MAD component.
+Added: Eight healthy volunteers, six treated with APG777 and two treated with placebo, were enrolled in each cohort, and we enrolled a total of 40 healthy adult subjects in the trial.
+Added: In March 2024, we announced positive interim safety and PK data and, in October and December 2024, we announced positive updated data from this trial.
+Added: Interim PK data for APG777 showed a half-life of 77 days across doses tested and PD data showed near complete inhibition of key AD biomarker pSTAT6 for approximately twelve months after a single administration and sustained TARC inhibition.
+Added: Results from the trial exceeded our trial objectives and support the potential for APG777, a novel anti-IL-13 antibody, to optimize exposure levels in 16-week induction and be dosed once every three or six months in maintenance.
+Added: These findings represent the potential for improved clinical responses from greater exposures in induction and significantly less frequent dosing in maintenance compared to currently approved monotherapy biologic therapies, which are dosed at every two to four weeks, a potential major advancement for patients with AD and other inflammatory diseases.
+Added: APG777’s PK differentiation supports further development of APG777 as a treatment for moderate-to-severe AD and other inflammatory diseases.
+Added: APG777’s PK profile supports testing higher exposures of drug in induction to potentially achieve improved clinical responses;
+Added: and testing of maintenance dosing of every three or six months,
+Added: representing two to four injections per year compared to the current treatment paradigm of 13 to 26 injections per year.
+Added: Dose-proportional increases in serum concentrations and key parameters (e.g., C max , AUC) were observed in the Phase 1 trial.
+Added: PK was generally consistent across subjects with low variability.
+Added: Single doses of APG777 demonstrated a deep and sustained effect on PD markers for approximately twelve months.
+Added: As shown in Figure 8 below, single doses of APG777 suppressed pSTAT6, one of the first downstream markers of IL-13 pathway inhibition, with near-complete inhibition (both in terms of median and mean percent change from baseline) for approximately twelve months.
+Added: Figure 8 — Mean percent pSTAT6 inhibition data for APG777 from our Phase 1 trial
+Added: As shown in Figure 9 below, single doses of APG777 suppressed TARC, an inflammatory mediator and the most strongly correlated biomarker to AD severity, with deep and sustained inhibition for approximately three months.
+Added: Figure 9 —TARC inhibition data for APG777 from our Phase 1 trial in 6 healthy volunteers receiving a single SC injection of 300mg of APG777;
+Added: median percent change from baseline in TARC
+Added: In addition, as shown in Figure 10 below, multiple doses of APG777 suppressed TARC with deep and sustained inhibition for approximately six months.
+Added: Figure 10 — TARC inhibition data for APG777 from our Phase 1 trial in receiving a multi-dose injection of 300mg D1, D15 of APG777
+Added: In March 2024, we reported that single doses of APG777 up to 1,200 mg and multiple doses of 300 mg were well-tolerated with a favorable safety profile consistent with the existing third-party data supporting the safety of the anti-IL-13 class.
+Added: In December 2024, we confirmed that safety data were consistent with the data reported in March 2024.
+Added: The most common treatment-emergent adverse events (“TEAEs”) were vascular access site pain, vessel puncture site bruise, headache, and vascular access bruising.
+Added: 83.3% of participants observed at least one TEAE;
+Added: 16.7% of participants observed at least one drug-related AE.
+Added: There were no Grade 3 TEAEs or severe adverse events related to study drug.
+Added: No AEs led to discontinuation of the study.
+Added: The last participant visit in the Phase 1 trial occurred in January 2025.
+Added: In the first quarter of 2024, we filed an IND for APG777.
+Added: In the first quarter of 2024, we also initiated a Phase 1 trial in healthy volunteers in the United States for subjects of Japanese descent and have completed dosing in that trial.
+Added: Phase 2 Trial in AD
+Added: In May 2024, we initiated APEX, a randomized, placebo-controlled, 16-week Phase 2 clinical trial of APG777 in patients with moderate-to-severe AD.
+Added: The trial is designed to combine the typical Phase 2a and 2b portions of a clinical trial into a single protocol.
A schematic of the trial design is shown in Figure 11 below.
−Removed: Figure 18 — Phase 1 trial design evaluating APG777 in healthy volunteers
−Removed: The Phase 1 trial is ongoing and we have announced initial safety and PK data from this trial.
+Added: Figure 11 — Phase 2 trial design evaluating APG777 in patients with AD
+Added: 16-week topline data from Part A of the integrated Phase 2 AD trial are expected in mid-2025.
+Added: We enrolled 123 patients randomized 2:1 to APG777 and placebo with a primary endpoint of mean percentage changes in EASI score from baseline to Week 16 and secondary endpoints include EASI75 and IGA0/1 at week 16.
+Added: In February 2025, we announced that the last patient in the Part A portion of the APEX trial had been dosed and we expect 16-week topline data from Part A portion in mid-2025.
+Added: Also in February 2025, we announced that we had commenced dosing of the Part B portion of the APEX Phase 2 trial, which is a randomized, placebo-controlled dose optimization with approximately 280 patients randomized 1:1:1:1 to high, medium, or low dose APG777 and placebo with primary endpoint of mean percentage changes in EASI score from baseline to Week 16.
+Added: All patients benefiting from treatment will have the opportunity to continue to APG777 maintenance, which will evaluate three- to six-month dosing.
+Added: The integrated design is expected to provide for significant timeline acceleration by combining Phase 2a and Phase 2b elements into a single study protocol and we were able to transition from completing enrollment in Part A to enrolling Part B within one week.
+Added: We expect that Part A sites will participate in Part B, which we anticipate will avoid delays for site startup between the two parts.
+Added: Doses in the Phase 2 trial are enabled by APG777’s potentially best-in-class PK profile, extended half-life, and high-concentration formulation.
+Added: Our 180mg/mL formulation enables a 44% higher dose of APG777 compared to EBGLYSS in the same volume.
Generally, the half-life of mAbs is consistent between healthy volunteers and patients.
Consequently, we believe that the PK parameters derived from the Phase 1 trial in healthy volunteers can be used to model dosing regimens in the subsequent Phase 2 and Phase 3 trials in patients with AD and other I&I indications.
−Removed: We have filed an IND in support of a Phase 1 trial in healthy volunteers in the United States for subjects of Japanese descent and have received a “study may proceed” letter from the FDA for the trial.
−Removed: We anticipate initiating a Phase 2 trial in patients with AD in the first half of 2024.
−Removed: Broadly, the Phase 2 trial is planned to include moderate-to-severe AD patients in a randomized, placebo-controlled design.
−Removed: Primary data readout will be after 16 weeks of treatment, which is common among other agents studied in AD.
−Removed: Endpoints will include, but not be limited to, percent change from baseline in EASI and proportion of patients achieving IGA 0/1 and EASI-75.
−Removed: At the end of the primary 16-week trial, patients will rollover to continue treatment on either a maintenance or open-label extension trial.
+Added: The APG777 Phase 2 induction regimen is designed to exceed EBGLYSS (lebrikizumab) exposures by approximately 30 to 40% with potential for improved clinical outcomes and maintenance regimen is designed to equal lebrikizumab’s exposures.
+Added: In third-party Phase 3 trials of lebrikizumab, approximately 30% higher exposure was seen in the low bodyweight group (less than 60 kg), which also had numerically higher efficacy than the overall study population across all key endpoints, including EASI-75 and more stringent endpoints such as EASI-90 and IGA 0/1.
+Added: APG777’s higher induction exposures are based on a planned six injection induction regimen given in the first sixteen weeks of APG777 treatment.
+Added: This is approximately half as many of the 11 injections of lebrikizumab given during the same period.
+Added: Modeling of the targeted induction exposures are shown in Figure 12 below.
+Added: Figure 12 — Modeled target induction exposures in APG777 Phase 2 trial
+Added: At 52 weeks, exposures of APG777 dosed every three or six months are designed to approximately equal those of EBGLYSS.
Expansion opportunities for APG777
IL-13 has been found to be elevated in other inflammatory conditions.
−Removed: Based on our initial clinical data, we may initiate a Phase 2 trial in asthma, and expect to further evaluate opportunities to develop APG777 for other I&I indications, including AA, CRSwNP, CSU, EoE and PN.
+Added: Based on our initial clinical data, we plan to advance the development of APG777 in asthma and EoE, by initiating a Phase 1b trial in asthma in the first half of 2025, followed by a Phase 2b trial in asthma in the second half of 2025, and launching a Phase 2 trial in EoE in 2026.
We believe asthma to be an important expansion opportunity for APG777 given the significant overlap with AD (31% according to third-party market research studies) and unmet need for extended dosing biologics that do not sacrifice clinical benefit.
−Removed: Patients with moderate-to-severe asthma who qualify and require biologic treatment have a serious condition that, when not treated appropriately, can lead to additional exacerbations and unnecessary emergency room and
−Removed: hospital visits.
+Added: Patients with moderate-to-severe asthma who qualify and require biologic treatment have a serious condition that, when not treated appropriately, can lead to additional exacerbations and unnecessary emergency room and hospital visits.
Extended duration therapies may lead to increased adherence rates with better control and outcomes for these patients.
5 unchanged sentences
Currently, the asthma market is greater than $10 billion in the seven major markets.
−Removed: Pending data from our Phase 1 trial in healthy volunteers, we plan to initiate a Phase 2 trial of APG777 in asthma to further explore this opportunity.
−Removed: Our second most advanced program, APG808, is an SQ extended half-life mAb targeting IL-4Rα.
−Removed: We plan to evaluate APG808 in COPD with the potential to evaluate additional I&I indications at a later date.
+Added: We plan to advance the development of APG777 in asthma by initiating a Phase 1b trial in asthma in the first half of 2025, followed by a Phase 2b trial in asthma in the second half of 2025.
+Added: We expect data from the Phase 1b trial in 2026.
+Added: Eosinophilic Esophagitis
+Added: EoE is a chronic inflammatory condition of the esophagus, with the hallmark histological finding being eosinophilic infiltrates (i.e., presences of eosinophils in the tissue).
+Added: When not treated appropriately, EoE progresses to cause scarring and strictures of the esophagus, which gives patients significant trouble with eating and drinking and potential nutritional compromise.
+Added: The only available biologic for the treatment of EoE is DUPIXENT, which was approved for this indication in 2022, and requires weekly dosing.
+Added: DUPIXENT’s approval in EoE further supports the scientific rationale for IL-13/IL-4Rα targeting agents in treating EoE.
+Added: We plan to initiate a Phase 2 trial in EoE in 2026.
+Added: Other Indications
+Added: We expect to further evaluate opportunities to develop APG777 for other I&I indications, including AA, CRSwNP, CSU, and PN.
+Added: APG990 is an SQ extended half-life mAb targeting OX40L.
+Added: OX40L is the ligand for OX40 expressed on antigen presenting cells.
+Added: Its interaction with OX40 causes the accumulation of T cells by providing a survival signal.
+Added: T cells are important types of white blood cells of the immune system that play a central role in the immune response.
+Added: OX40L, by playing a role in activating T cells and reprogramming them into inflammatory subsets, contributes to immune overactivation in AD and other inflammatory conditions.
+Added: OX40-OX40L interaction has been implicated in a broad range of inflammatory and autoimmune diseases, including Inflammatory Bowel Disease, asthma, diabetes, arthritis, atherosclerosis, transplant rejection, GVHD and Systemic Lupus Erythematosus.
+Added: Additionally, OX40L activation of OX40 inhibits the expression of FOXP3 and the inhibitory function of regulatory T (Treg) cells.
+Added: Treg cells can suppress the immune response that leads to worsening symptoms in inflammatory conditions.
+Added: OX40L blockade therefore has two mechanisms by which it might have impact on the pathology associated with inflammatory conditions, first by suppressing inflammatory T cell activation, and second by increasing the proliferation of Treg cells, which can serve to further reduce effector T cell function.
+Added: Currently, there are only two mechanisms of action targeted by approved biologic agents in atopic dermatitis, IL-13 and IL-4Rα.
+Added: Targeting OX40L could represent a third mechanism of action.
+Added: OX40L, which is positioned further upstream in the inflammatory pathway than IL-13, allowing for a potentially broader impact on the inflammatory cascade by inhibiting Type 1, Type 2, and Type 3 pathways.
+Added: APG990 Development
+Added: In May 2024, we finalized the nomination of a development candidate for APG990 and in August 2024, we commenced dosing of the first participants in the Phase 1 clinical trial in healthy volunteers.
+Added: In our head-to-head preclinical assays, APG990 has demonstrated similar or improved potency to amlitelimab, an OX40L antibody candidate in late-stage clinical development.
+Added: Figure 13 below depicts a 3D rendering of human OX40L generated from our head-to-head preclinical studies.
+Added: The blue highlights the epitope, or binding site, of amlitelimab, which overlaps with APG990’s epitope, also highlighted with hatch marks.
+Added: Figure 13 — Binding site of APG990 against amlitelimab
+Added: In our head-to-head studies of APG990 and amlitelimab in NHPs, APG990 demonstrated half-life of 26 days versus 21 days for amlitelimab.
+Added: In addition, based on our preclinical studies, we believe APG990 can be dosed every three to six months in maintenance, which, if our clinical trials are successful, would represent a significant improvement compared to first generation OX40L antibodies that are expected to be dosed every four to twelve weeks.
+Added: Our APG990 Phase 1 clinical trial is designed as a double-blind, placebo-controlled, first-in-human, single-ascending dose trial designed to evaluate the safety and PK of APG990 in 40 healthy adult participants across five cohorts.
+Added: Doses of subcutaneous APG990 evaluated in the study included 75mg, 150mg, 300mg, 600mg and 1,200mg.
+Added: In March 2025, we announced data from our APG990 Phase 1 clinical trial.
+Added: APG990 interim Phase 1 pharmacokinetic (PK) data showed a half-life of approximately 60 days across doses tested, supporting the potential for testing every three- and six-month maintenance dosing with as little as 50 mg.
+Added: APG990 generally demonstrated dose proportionality and low variability.
+Added: Figure 14 below depicts the single-dose concentration-time profile from the ongoing APG990 Phase 1 trial.
+Added: Figure 14—Single-dose concentration-time profile
+Added: APG990 was well tolerated across all cohorts, with doses up to 1,200mg.
+Added: The most common (≥10%) treatment-emergent adverse events (TEAEs) were headache.
+Added: 53% of participants observed at least one TEAE and there were no Grade 3 TEAEs related to study drug or severe adverse events.
+Added: No adverse events led to study discontinuation.
+Added: There have been no cases of pyrexia or chills.
+Added: Potential clinical benefit of targeting both IL-13 and OX40L
+Added: Multiple studies have demonstrated that the upregulation of type 2 cytokines in the skin, particularly IL-13, is a key driver of inflammation in AD.
+Added: However, other pathways that are activated in AD include Type 1 (e.g., interferon-gamma [IFNγ]) and Type 3 (e.g., IL-22, IL-17) responses.
+Added: Therefore, due to the heterogeneity of inflammatory involvement in AD, we believe that blocking multiple targets, such as simultaneous inhibition of IL-13 and OX40L, could allow us to provide benefit to patients with AD and other I&I indications.
+Added: More specifically, we believe that inhibition of IL-13 with APG777 could provide depth of inhibition for the core driver of inflammation in AD, namely Type 2 inhibition, while inhibition of OX40L with APG990 could provide breadth of inhibition across a broader range of inflammatory subtypes (Types 1-3) and cytokines, but with less depth, addressing AD heterogeneity.
+Added: This dual mechanism could, therefore, improve the breadth or depth (or both) of clinical outcomes.
+Added: We have generated preclinical data to support our approach to targeting both IL-13 and OX40L.
+Added: In our preclinical ex vivo human allogeneic lymphocyte reaction assay, we demonstrated that APG279 targets all inflammatory types, including near-complete Type 2 inhibition, with the potential for every 3-month (or less frequent) dosing.
+Added: We plan to develop APG279 as a potential first-in-class coformulation for the treatment of AD combining deep and sustained inhibition of Type 2 inflammation via APG777’s inhibition of IL-13 with broader inhibition of Type 1-3 inflammation through APG990’s inhibition of OX40L.
+Added: APG279 has been shown to retain stability, injectability, and convenience of individual components.
+Added: In preclinical studies it has demonstrated broad inhibition of Type 1, Type 2 and Type 3 inflammation, similar to what was seen with JAK inhibition, but with potential for better tolerability than JAK inhibitors.
+Added: We believe these combined mechanisms offer the potential for improved clinical responses over monotherapy while our planned approach of coformulating two extended half-life mAbs holds the potential for best-in-class dosing.
+Added: Following our positive interim results from the APG990 Phase 1 clinical trial, we believe that APG990’s PK profile supports the potential for a single 2 mL co-formulated injection of APG279 (APG777 + APG990) administered every three- and six- months in maintenance.
+Added: In addition, preclinical toxicology studies of the combination of APG777 and APG990 showed no findings at any dose level, including the highest dose tested of 150 mg/kg per agent.
+Added: Based on these results, we plan to submit an IND application or foreign equivalent for APG279.
+Added: Following clearance, we plan to initiate a Phase 1b clinical trial designed to evaluate APG279 against DUPIXENT in approximately 50 to 75 patients with moderate-to-severe AD with a readout expected in the second half of 2026.
+Added: APG279 will be co-administered in the proof-of-concept Phase 1b trial with coformulation planned for future clinical studies.
+Added: APG333 is a fully-human mAb against TSLP.
+Added: TSLP is an epithelial cell-derived cytokine that has emerged as an attractive validated target for the treatment of people living with asthma and COPD, with the potential for extended half-life and to be used in combination with other mAbs for potentially greater efficacy in broader populations.
+Added: TSLP plays important roles in Type 2 and Type 3 inflammation and TSLP inhibition has shown clinical benefit in both eosinophilic and non-eosinophilic asthma.
+Added: TSLP inhibition has been clinically validated, with the only approved product on the market for the treatment of severe asthma without biomarker or phenotype restrictions.
+Added: APG333 has similar binding as a first generation mAb, TEZSPIRE, for TSLP across our head-to-head preclinical assays.
+Added: Figure 15 below depicts a 3D rendering of human TSLP generated from our head-to-head preclinical studies.
+Added: The gray highlights the epitope, or binding site, of TEZSPIRE, which overlaps with APG333’s epitope, also highlighted with blue hatch marks.
+Added: Additionally, in our head-to-head studies of APG333 and TEZSPIRE in NHPs, APG333 showed a significantly longer half-life than TEZSPIRE.
+Added: In these preclinical studies, APG333’s half-life was 24 days, as compared to 11 days for TEZSPIRE.
+Added: Based on these preclinical studies, we believe that the longer half-life could support dosing every three to six months in the clinic.
+Added: Figure 15 — Binding site of APG333 against tezepelumab (TEZSPIRE)
+Added: APG333 Development
+Added: In October 2024, we finalized the nomination of a development candidate for APG333 and in December 2024 we initiated a Phase 1 clinical trial of APG333 in healthy volunteers.
+Added: The APG333 Phase 1 clinical trial is designed as a double-blind, placebo controlled, first-in-human, SAD trial in healthy volunteers.
+Added: The study will evaluate the safety, tolerability and pharmacokinetics of APG333 and is expected to enroll approximately 32 healthy adults into four cohorts.
+Added: We expect interim data from the APG333 Phase 1 trial in the second half of 2025.
+Added: Potential clinical benefit of targeting both IL-13 and TSLP
+Added: In preclinical studies, the combination of APG777 and APG333 has been shown to drive both inhibition of inflammation centrally and local airway responses compared to approved or in-development biologics, which only target central or local inflammation, with the potential for a significantly less frequent dosing schedule.
+Added: In our preclinical studies, we showed that APG777 activates bronchial smooth muscle cells that promote local airway responses to inflammation while APG333 targeted inflammation centrally and more broadly, showing inhibition of both Type 2 and non-Type 2 cytokines.
+Added: We believe targeting both central and local inflammation for respiratory diseases has the potential to improve clinical outcomes for patients.
+Added: We plan to evaluate APG777 and APG333 monotherapies in respective Phase 1b trials in patients with asthma in 2025 to support advancement into future combination trials in asthma and COPD.
+Added: Subject to positive data, we plan to study APG777 in combination with APG333 to drive potential best-in-class efficacy in respiratory conditions.
+Added: APG808 is an SQ extended half-life mAb targeting IL-4Rα, a target with clinical validation across eight different Type 2 allergic diseases.
Based on our head-to-head preclinical studies of APG808, we have demonstrated the potential to increase the half-life of IL-4Rα-targeting mAbs using half-life extension modifications.
−Removed: In our head-to-head studies of APG808 and DUPIXENT in NHPs, APG808 demonstrated half-life of 27 days versus 11 days for DUPIXENT, an increase of 145%, as shown in Figure 19 below.
+Added: In our head-to-head studies of APG808 and DUPIXENT in NHPs, APG808 demonstrated half-life of 27 days versus 11 days for DUPIXENT.
Moreover, in our head-to-head preclinical assay, APG808 demonstrated equivalent potency of IL-4Rα inhibition compared to DUPIXENT in a head-to-head in vitro assay.
−Removed: Figure 19 — Head-to-head comparison of NHP PK for APG808 and DUPIXENT
−Removed: In November 2023, we finalized the nomination of a development candidate for APG808 and we received regulatory approval to commence a first-in-human clinical trial in Australia.
−Removed: We anticipate that APG808 will enter the clinic in healthy volunteers in the first half of 2024 followed by a potential Phase 1b trial in asthma and/or a Phase 2 trial in COPD (pending data from the Phase 1 trial and following the submission of an IND or foreign equivalent to support such trials).
−Removed: IL-4R α is a known driver of COPD pathogenesis and broader I&I indications
+Added: In March 2024, we initiated a Phase 1 clinical trial of APG808 in healthy volunteers and announced positive interim safety, PK and PD data from the Phase 1 trial in December 2024 demonstrating a potential best-in-class PK
+Added: profile, including a half-life of approximately 55 days, supporting the potential for every two- to three-month maintenance dosing.
+Added: IL-4Rα is a known driver of disease pathology in I&I indications
APG808’s target, IL-4Rα, is a known driver of pathogenesis for a number of diseases.
By blocking IL-4Rα, we believe APG808 will prevent formation of the IL-13Rα1-IL-4Rα heterodimer, which is understood to be a key pathogenic step in multiple Th2-driven diseases such as AD, asthma, COPD and CRSwNP.
−Removed: As shown in Figure 20 below, blocking IL-4Rα can prevent signaling through both IL-4 and IL-13.
Preventing the formation of the IL-13Rα1-IL-4Rα heterodimer in turn prevents recruitment of members of the JAK family of enzymes and prevents the signaling cascade that results in the expression of pro-inflammatory cytokines and leads to an immune response by the body in these diseases.
−Removed: Figure 20 — APG808 is designed to disrupt IL-13 signaling by preventing the formation of the IL-13Rα1-IL-4Rα heterodimer
−Removed: COPD has historically been thought of as driven by Th1 immune responses, which are driven by IL-2, interferon-γ and lymphotoxin-α and an associated neutrophilic response.
−Removed: However, more recent third-party data has demonstrated that Th2 immune responses, which are driven by IL-4, IL-5 and IL-13 and associated with an eosinophilic response, are prominent in a subset of COPD patients.
−Removed: Th2 immune responses have been shown to be associated with increased airway inflammation and appear to underlie COPD in a subset of patients and related cytokines have been shown to be upregulated during exacerbations.
−Removed: The exact mechanism of Th2 immune response leading to airway inflammation is unknown, but is in part driven by allergens driving the adaptive immune response inducing differentiation toward Th2 cells, as well as pollutants, microbes and glycolipids activating ILC2s (Type 2 innate lymphoid cells) to produce Th2-associated cytokines IL-5 and IL-13.
−Removed: Eosinophils have been shown to contribute to bronchoconstriction, fibrosis and mucus production in animal models
−Removed: Further, overexpression of IL-13 has been shown in mice lungs to lead to emphysema (air-filled spaces in the lungs), elevated mucus production and inflammation reminiscent of human COPD.
−Removed: Therefore, while still not fully elucidated, Th2 immune response produces some of the hallmark pathologies of COPD.
−Removed: Third-party clinical trials have demonstrated that up to 52% of patients with COPD have an increased eosinophil count, which is a marker of Th2 immune response.
−Removed: Studies have further demonstrated an association between eosinophilic airway inflammation and severe exacerbations of COPD.
−Removed: There is also epidemiological evidence of a correlation between eosinophils and mortality from COPD exacerbations.
−Removed: We do not yet have clinical data regarding patients with COPD and there can be no assurance that our trials will have similar or comparable results.
−Removed: In our preclinical studies, APG808 binned with DUPIXENT
−Removed: As described previously, epitope binning is a technique used to cluster different mAbs based on the specific region of the antigen (in this case IL-4Rα) that is recognized by the antibody.
−Removed: To characterize the binning of APG808 and DUPIXENT, we studied APG808 and DUPIXENT in head-to-head preclinical studies.
−Removed: In binning studies with immobilized DUPIXENT, no response was observed for APG808.
−Removed: This indicated that APG808 and DUPIXENT binned together and provided evidence that the two mAbs likely bind to a similar or the same epitope on IL-4Rα.
APG808 has demonstrated equivalent potency to DUPIXENT in head-to-head in vitro assays
1 unchanged sentence
Specifically, an assay was performed to measure downstream functional inhibition of the IL-13/IL-4 pathway, meaning after IL-13Rα1 and IL-4Rα heterodimerization.
−Removed: Measuring downstream functional inhibition of the pathway is critical, as this measures the mAb’s impact on the inflammatory cascade that causes the features, signs, and symptoms associated with I&I indications, including COPD.
−Removed: More specifically, three in vitro assays were performed showing inhibition of pSTAT6 induction, TF-1 proliferation and TARC Secretion.
−Removed: STAT6-mediated signaling is required for the development of Th2 cells and the Th2 immune response and is primarily activated by IL-4 and IL-13.
−Removed: TF-1 is a human erythroblast cell line that proliferates in response to IL-4 or IL-13.
−Removed: This cell line is a widely used “workhorse” system for several functional immune assays owing to its expression of a myriad of cell-surface receptors as well as intracellular signaling mediators that are endogenous to most immune cell-types.
−Removed: Lastly, TARC secretion is a critical step in Th2 inflammation, with TARC recruiting skim-homing Th2 cells and eosinophils into skin tissues where they amplify inflammation-mediated tissue damage.
−Removed: Outputs of these assays were measured in IC90, the concentration or amount of drug it takes to cause a 90% inhibition in the assay.
+Added: Measuring downstream functional inhibition of the pathway is critical, as this measures the mAb’s impact on the inflammatory cascade that causes the features, signs, and symptoms associated with I&I indications.
In our head-to-head preclinical study, DUPIXENT and APG808 showed similar binding, with femtomolar affinity for IL-4Rα, and similar inhibition across the three in vitro assays which measure downstream functional inhibition of the IL-13/IL-4 pathway (pSTAT6 induction, inhibition of TF-1 proliferation, and inhibition of TARC secretion).
−Removed: As shown in Figure 21 below, in the TF-1 assay for STAT-6 phosphorylation, the IC90 was 1.11 nM for APG808 compared to 1.93 nM for DUPIXENT and for TARC secretion the IC90 was 1.25 for APG808 and 1.67 for DUPIXENT.
−Removed: These results provide preclinical evidence of similar in vitro potency among DUPIXENT and APG808.
−Removed: Figure 21 — Head-to-head comparison of APG808 versus DUPIXENT in the TF-1 proliferation assay
+Added: Figure 16 below depicts a 3D rendering of human IL-4Rα generated from our head-to-head preclinical studies.
+Added: The gray highlights the epitope, or binding site, of dupilumab (DUPIXENT), which overlaps with APG808’s epitope, also highlighted with hatch marks.
+Added: Figure 16 — APG808's epitope on IL-4Rα overlaps with dupilumab and leverages proven mechanism of action and biology
APG808 Dosing
−Removed: We have demonstrated the potential to increase APG808’s half-life approximately two times over DUPIXENT’s half-life in NHPs
−Removed: In our single-dose NHP studies, we have demonstrated the potential to increase the half-life of IL-4Rα-targeting mAbs using half-life extension modifications.
−Removed: In our head-to-head studies in NHPs, APG808 demonstrated half-life of 27 days versus 11 days for DUPIXENT, an increase of 145%.
−Removed: Analogous antibodies with half-life extension modifications have shown half-lives extension over NHP data of approximately two to three times
−Removed: We have incorporated half-life extension technology in APG808 based on antibody recycling, such as YTE or LS amino acid modifications, as was used in the tool compound data shown above.
−Removed: Antibody recycling through increased affinity for FcRn, as described in the sections above, impacts degradation via pinocytosis, but not elimination via TMDD.
−Removed: Therefore, to understand APG808’s potential half-life in the clinic, we concluded analogs with membrane-bound targets would be the most informative.
−Removed: Figure 22 below shows the NHP and human half-life data of mAbs for membrane-bound targets with and without the YTE amino acid modification.
−Removed: Figure 22 — NHP and human half-life data of mAbs for membrane-bound targets with and without the YTE amino acid modification
−Removed: As reported in studies conducted by the sponsor of each of these product candidates or in the label of approved products.
−Removed: As one example, CDX-0159 is an antibody targeting KIT (c-KIT/CD117) receptor tyrosine kinase with YTE amino acid modifications for half-life extension currently in clinical development.
−Removed: In NHPs, half-life was shown to be 22 days for CDX-0159 compared to 4.8 days for CDX-0158, a non-half-life extended antibody directed at the same target.
−Removed: Clinically, CDX-0159 showed a 32-day half-life, suggesting an approximately one-and-a-half times increase over NHP data.
−Removed: Further, CDX-0159 has shown a human half-life that is approximately five times greater than CDX-0158, the non-half-life extended antibody directed at the same target (half-life of CDX-0159 was 32 days versus 6 days for CDX-0158).
−Removed: As another example, VRDN-002 is an antibody targeting anti-IGF-1 receptor with recycling-based FC modifications for half-life extension (i.e., YTE or LS or similar amino acid modifications) currently in clinical development.
−Removed: In NHPs, half-life was shown to be 14 days for VRDN-002 compared to 6.4 days for teprotumumab, a non-half-life extended antibody directed at the same target.
−Removed: Clinically, VRDN-002 showed an approximately 30-to 40-day half-life in an interim analysis, suggesting an approximately two to three times increase over NHP data.
−Removed: Further, VRDN-002 has shown a human half-life that is approximately three to four times greater than teprotumumab, the non-half-life extended antibody directed at the same target (half-life of VRDN-002 was approximately 30 to 40 days compared to approximately 10 to 11 days for teprotumumab).
−Removed: As a third example, VRDN-003 is an antibody targeting anti-IGF-1 receptor with recycling-based Fc modifications for half-life extension (i.e.
−Removed: YTE or LS or similar amino acid modifications) currently in clinical development.
−Removed: In NHPs, half-life was shown to be 13 days.
−Removed: Clinically, VRDN-002 showed an approximately 40-to 50-day half-life, suggesting an increase of approximately three to four times over NHP data.
−Removed: Therefore, as shown in Figure 23 below, we expect that APG808 would have a human half-life of approximately 39 to 104 days based on two estimation methods.
−Removed: Via the first method, we estimate APG808’s human half-life to be approximately 41 to 103 days based on APG808’s 27 day NHP half-life and a one-and-a-half to approximately four times factor going from NHPs to humans as observed for other membrane-bound half-life extended mAbs.
−Removed: Via the second method, we estimate APG808’s human half-life to be approximately 45 to 75 days based on DUPIXENT’s 15-day human half-life and a three to five times factor going from non-half-life extended antibodies to half-life extended antibodies directed at the same receptor target.
−Removed: Figure 23 — APG808 NHP half-life, predicted human half-life and predicted dosing interval
−Removed: Based on steady state PK simulations made with parameters for APG808 identical to DUPIXENT except changes in dose and kelimination.
−Removed: APG808 can achieve every six weeks dosing if it demonstrates a half-life of at least 42 days and every two month dosing if it demonstrates a half-life of at least 59 days
−Removed: To understand the maintenance dosing schedule that APG808 may be able to achieve, we used known PK parameters for DUPIXENT.
−Removed: These PK parameters provide an understanding of how DUPIXENT is distributed throughout the body and cleared.
−Removed: Based on these known parameters, we built a two-compartment model with first-order absorption and parallel linear and Michaelis-Menten elimination, the latter corresponding to TMDD effects associated with targeting membrane-bound IL-4Rα, to predict both DUPIXENT’s and APG808’s concentration, or drug levels, over time.
−Removed: Key parameters included 0.0447 day-1 for elimination rate (ke), 2.74 L for central volume (Vc), 0.306 day-1 for absorption rate (ka) and 64.2% for bioavailability.
−Removed: We believe that efficacy in inflammatory conditions, such as COPD, is driven by Ctrough, or the minimal concentration of the mAb.
−Removed: Therefore, based on the model described above, we set APG808’s target Ctrough to be equal to DUPIXENT’s Ctrough with every two weeks dosing, which was approximately 75 mg/L.
−Removed: Given the planned overlapping epitopes of DUPIXENT and APG808 and similarity in potency across multiple in vitro assays, we believe this provides a reasonable target drug concentration for APG808.
−Removed: By modeling kelimination and half-life to maintain APG808 concentrations above approximately 75 mg/L, we approximate at least a 42 day half-life would be required to dose APG808 every six weeks and at least a 59-day half-life would be required to dose APG808 every two months based on our planned dose and formulation.
−Removed: Thus, with a minimum of 42-or 59-day half-life, which is in range for most mAbs with half-life extension targeting receptors, we believe we can achieve either an every six week or an every two month dosing schedule, respectively, at our target exposures, which are modeled based on DUPIXENT’s exposures.
−Removed: Development Plan for APG808
−Removed: In November 2023, we finalized the nomination of a development candidate for APG808 and we received regulatory approval to commence a first-in-human clinical trial in Australia.
−Removed: The APG808 Phase 1 trial is designed as a double-blind, placebo-controlled study in healthy volunteers with single ascending doses.
−Removed: Eight healthy volunteers, six treated with APG808 and two treated with placebo, will be enrolled in each cohort, and we expect to enroll a total of approximately 32 healthy adult subjects in the trial.
−Removed: The primary endpoint is safety and a key secondary endpoint is PK.
−Removed: Pending data from our Phase 1 trial in healthy volunteers and following the submission of an IND or foreign equivalent to support a Phase 2 trial in COPD, we plan to initiate a Phase 2 trial in patients with COPD.
+Added: In our head-to-head preclinical studies of APG808 and DUPIXENT in NHPs, APG808 showed a significantly longer half-life than DUPIXENT.
+Added: In these preclinical studies, APG808’s half-life was up to 27 days, as compared to 11 days for DUPIXENT.
+Added: APG808 Development
+Added: In March 2024, we commenced dosing of the first healthy volunteers in the APG808 Phase 1 trial and in September 2024, we commenced dosing of the first asthma patients as a cohort in that Phase 1 trial.
+Added: The APG808 Phase 1 trial was designed as a double-blind, placebo-controlled study in healthy volunteers with single ascending doses.
+Added: The APG808 Phase 1 trial enrolled 32 healthy adult participants into four SAD cohorts.
+Added: In December 2024, we shared positive interim safety, PK and PD data from the Phase 1 trial.
+Added: APG808 demonstrated a potential best-in-class PK profile, including a half-life of approximately 55 days, supporting the potential for every two- to three- month maintenance dosing.
+Added: Single doses of APG808 demonstrated a deep and sustained effect on PD markers out to approximately three months (longest follow-up available at time of data cut).
+Added: APG808 was well-tolerated across all dose groups.
+Added: We are also now evaluating APG808 in a Phase 1b trial in patients with asthma, with data expected in the first half of 2025.
Expansion opportunities for APG808
−Removed: IL-4Rα biology has been implicated in a number of different indications, including AD, asthma, CRSwNP, EoE, PN and CSU.
+Added: IL-4Rα biology has been implicated in a number of different indications, including AD, asthma, COPD, CRSwNP, EoE, PN and CSU.
We intend to evaluate additional expansion opportunities in one or more of such indications.
1 unchanged sentence
DUPIXENT, which also targets IL-4Rα but is dosed every other week, is approved in asthma in patients six years of age or older with moderate-to-severe-asthma with eosinophilic phenotype or oral corticosteroids dependent regardless of phenotype and has shown a 46% reduction in the rate of annualized exacerbations in pivotal studies, which we believe validates targeting IL-4Rα as an approach to treating asthma.
−Removed: Pending data from our Phase 1 trial in healthy volunteers, we may initiate a Phase 1b trial of APG808 in a small cohort of asthma patients to further explore this opportunity.
−Removed: Our third program, APG990, is an SQ extended half-life mAb targeting OX40L.
−Removed: We expect to nominate a development candidate in 2024 if we observe equivalent or better in vitro potency compared to other mAbs targeting OX40L and an improved PK profile, including half-life extension, in head-to-head studies.
−Removed: OX40L is the ligand for OX40 expressed on antigen presenting cells.
−Removed: Its interaction with OX40 causes the accumulation of T cells by providing a survival signal.
−Removed: T cells are important types of white blood cells of the immune system that play a central role in the immune response.
−Removed: OX40L, by playing a role in activating T cells and reprogramming them into inflammatory subsets, contributes to immune overactivation in AD and other inflammatory conditions.
−Removed: OX40-OX40L interaction has been implicated in a broad range of inflammatory and autoimmune diseases, including Inflammatory Bowel Disease (IBD), asthma, diabetes, arthritis, atherosclerosis, transplant rejection, GVHD and Systemic Lupus Erythematosus.
−Removed: Additionally, OX40L activation of OX40 inhibits the expression of FOXP3 and the inhibitory function of regulatory T (Treg) cells.
−Removed: Treg cells can suppress the immune response that leads to worsening symptoms in inflammatory conditions.
−Removed: OX40L blockade therefore has two mechanisms by which it might have impact on the pathology associated with inflammatory conditions, first by suppressing inflammatory T cell activation, and second by increasing the proliferation of Treg cells, which can serve to further reduce effector T cell function.
−Removed: The mechanism of action of APG990 is shown in Figure 24 below.
−Removed: Figure 24 — Mechanism of action of APG990
−Removed: Currently, there are only two MOAs targeted by approved biologic agents in atopic dermatitis, IL-13 and IL-4Rα.
−Removed: Targeting OX40L could represent a third MOA.
−Removed: OX40L occurs higher up in the inflammatory pathway than IL-13 or IL-4Rα and potentially broadens the impact on the inflammatory cascade, which may have benefits for certain patients.
−Removed: Specifically, OX40L could represent another therapeutic option for the portion of patients who do not benefit from currently available treatments.
−Removed: Development plan for APG990
−Removed: We intend to nominate a development candidate in 2024 if we observe equivalent or better in vitro potency compared to other mAbs targeting OX40L and an improved PK profile, including half-life extension, in head-to-head studies.
−Removed: Following nomination of a development candidate, we plan to conduct the appropriate nonclinical toxicology studies to support initiation of a Phase 1 clinical trial in healthy volunteers and file an IND or foreign equivalent required to initiate such trial.
−Removed: Our fourth program, APG222, is one or more extended half-life SQ antibodies targeting both IL-13 and OX40L, which we believe has the potential to improve outcomes in AD over current standard of care biologic therapies.
−Removed: Potential clinical benefit of targeting both IL-13 and OX40L
−Removed: We believe that blocking multiple targets, such as simultaneous inhibition of IL-13 and OX40L, could allow us to provide benefit to patients with AD and other I&I indications.
−Removed: Data from a third-party Phase 2a trial of amlitelimab, an antibody targeting OX40L, demonstrated a decrease in circulating IL-13 with treatment, but not a complete obliteration of IL-13.
−Removed: OX40L signaling promotes immune cells to differentiate and produce cytokines, including IL-13.
−Removed: Thus, we hypothesize that blocking IL-13 will lead to less immune cell differentiation leading to lower levels of IL-13 production.
−Removed: We believe that the mechanism of action of APG222, which combines blockage of OX40L and IL-13 (as shown in Figure 25 below), could simultaneously decrease OX40L signaling, helping to rebalance the immune system and decrease immune cell differentiation and cytokine release, and further reduce IL-13, resulting even less immune signaling.
−Removed: This, in turn, could prevent certain disease-related signs and symptoms that are driven by IL-13 signaling and the downstream inflammatory cascade.
−Removed: Figure 25 — Mechanism of action of APG222
−Removed: Development plan for APG222
−Removed: We are generating preclinical data to support our approach to targeting both IL-13 and OX40L.
−Removed: If such preclinical data supports our approach, subject to completion of the Phase 1 healthy volunteer trials for each of APG777 and APG990, we intend to file an IND or foreign equivalent and initiate a trial targeting both IL-13 and OX40L in AD thereafter.
Additional Expansion Opportunities
−Removed: In addition to the currently planned expansion opportunities for APG777 and APG808, we are evaluating opportunities to develop our programs for other I&I indications, including AA, CRSwNP, CSU, EoE and PN.
+Added: We believe that each of our programs has the potential to impact multiple additional I&I indications beyond AD and COPD, including asthma and EoE as well as AA, CRSwNP, CSU, and PN.
+Added: Initial structured indication prioritization has identified asthma as a leading expansion opportunity given the significant overlap with AD and the clinical unmet need for extended dosing biologics that do not sacrifice clinical benefit.
+Added: Based on third-party claims data, 31% of AD patients also carry an asthma diagnosis.
+Added: Based on feedback from dermatologists, we believe that there is significant value in having both indications on a label because of this overlap.
+Added: Asthma is estimated to affect 40 million adults and 12 million children in the United States, France, Germany, Italy, Japan, Spain and the United Kingdom.
We do not yet have clinical data showing the ability of our programs to treat other indications and there can be no assurance that our programs will have similar or comparable results to any products or later-stage product candidates for these indications.
9 unchanged sentences
Further, we believe the positive Phase 3 data for DUPIXENT in patients with CSU that is not adequately controlled with the current standard of care suggests the role of the IL-4/IL-13 heterodimer signaling complex’s involvement in CSU.
−Removed: Eosinophilic Esophagitis
−Removed: EoE is a chronic inflammatory condition of the esophagus, with the hallmark histological finding being eosinophilic infiltrates (i.e., presences of eosinophils in the tissue).
−Removed: When not treated appropriately, EoE progresses to cause scarring and strictures of the esophagus, which gives patients significant trouble with eating and drinking and potential nutritional compromise.
−Removed: The only available biologic for the treatment of EoE is DUPIXENT, which was approved for this indication in 2022, and requires weekly dosing.
−Removed: DUPIXENT’s approval in EoE further supports the scientific rationale for IL-13/IL-4Rα targeting agents in treating EoE.
Prurigo Nodularis
10 unchanged sentences
From time to time, we can choose to add additional targets to the collaboration by mutual agreement with Paragon.
−Removed: Pursuant to the terms of the 2022 Option Agreement, the parties will initiate certain research programs that will generally be focused on a particular target (each, a Research Program).
+Added: Pursuant to the terms of the 2022 Option Agreement, the parties initiated certain research programs that generally focused on a particular target (each, a “Research Program”).
Each Research Program is aimed at discovering, generating, identifying and/or characterizing antibodies directed to the respective target.
7 unchanged sentences
Under the 2022 Option Agreement, on a Research Program-by-Research Program basis following the finalization of the Research Plan for each respective Research Program, we are required to pay Paragon a nonrefundable fee in cash of $0.5 million.
−Removed: obligated to compensate Paragon on a quarterly basis for its services performed under each Research Program based on the actual costs incurred.
+Added: We are also obligated to compensate Paragon on a quarterly basis for its services performed under each Research Program based on the actual costs incurred.
In November 2023, we entered into an additional antibody discovery and option agreement with Paragon (the “2023 Option Agreement” and together with the 2022 Option Agreement, collectively, the “Option Agreements”).
Under the terms of the 2023 Option Agreement, Paragon identifies, evaluates and develops antibodies directed against certain mutually agreed therapeutic targets of interest to us.
−Removed: The 2023 Option Agreement initially includes one undisclosed target.
+Added: The 2023 Option Agreement initially includes one target, TSLP.
Under the 2023 Option Agreement, we have the exclusive option to, on a research program-by-research program basis, be granted an exclusive, worldwide license to all of Paragon’s right, title and interest in and to the intellectual property resulting from the applicable research program to develop, manufacture and commercialize the antibodies and products directed to the selected targets.
1 unchanged sentence
Pursuant to the terms of the 2023 Option Agreement, the parties may initiate Research Programs.
−Removed: Each Research Program is aimed at discovering, generating, identifying and/or characterizing antibodies directed to the respective target.
+Added: Each Research Program will be aimed at discovering, generating, identifying and/or characterizing antibodies directed to the respective target.
For each Research Program, the parties must establish a Research Plan.
−Removed: We and Paragon will agree on an initial Research Plan that outlines the services that will be performed commencing at inception of the arrangement related to the undisclosed target.
+Added: In January 2024, we agreed on an initial Research Plan with Paragon that outlines the services that will be performed commencing at inception of the arrangement related to TSLP.
Our exclusive option with respect to each Research Program is exercisable at our sole discretion at any time during the period beginning on the initiation of activities under the associated Research Program and ending a specified number of days following the delivery of the data package from Paragon related to the results of the Research Plan activities.
There is no payment due upon exercise of an Option pursuant to the 2023 Option Agreement.
−Removed: Following entry into the 2023 Option Agreement, we and Paragon will negotiate a form of License Agreement to be entered into in the event that we exercise our exclusive option with respect to each Research Program, which License Agreement will include certain pre-agreed economic and other business terms.
Under the 2023 Option Agreement, on a Research Program-by-Research Program basis following the finalization of the Research Plan for each respective Research Program, we are required to pay Paragon a nonrefundable fee in cash of $2.0 million.
−Removed: In the first quarter of 2024, we paid Paragon $2.0 million fee for a Research Program for an undisclosed target.
We are also obligated to compensate Paragon on a quarterly basis for its services performed under each Research Program based on the actual costs incurred.
We expense the service fees as the associated costs are incurred when the underlying services are rendered.
+Added: In January 2024, we finalized the Research Plan with Paragon related to the TSLP target.
+Added: As such, we made a one-time non-refundable payment of $2.0 million to Paragon in the first quarter of 2024.
Unless terminated earlier, the Option Agreements shall continue in force on a Research Program-by-Research Program basis until the earlier of:
4 unchanged sentences
Each party has the right to terminate either Option Agreement or any Research Program upon (i) 30 days’ prior written notice of the other party’s material breach that remains uncured for the 30-day period and (ii) the other party’s bankruptcy.
−Removed: Paragon IL-13 License Agreement
+Added: Paragon License Agreements
In November 2022, we exercised our option available under the 2022 Option Agreement with respect to the IL-13 Research Program.
−Removed: Upon such exercise, we entered into an associated license agreement with Paragon (the IL-13 License Agreement).
−Removed: Under the terms of the IL-13 License Agreement, Paragon granted to us an exclusive, worldwide, royalty-bearing, sublicensable right and license with respect to certain information, patent rights and sequence information related to antibodies directed at the IL-13 target to use, make, sell, import, export and otherwise exploit the antibodies directed at the IL-13 target.
−Removed: Pursuant to the IL-13 License Agreement, we granted to Paragon a similar license (except that such license we granted to Paragon is non-exclusive) to the IL-13 license with respect to multispecific antibodies that are directed at the IL-13 target and one or more other antibodies.
−Removed: We were also granted a right of first negotiation with Paragon
−Removed: concerning the development, license and grant of rights to certain multispecific antibodies.
−Removed: We are solely responsible for the continued development, manufacture and commercialization of products at our own cost and expense.
−Removed: We are obligated to pay Paragon up to $3.0 million upon the achievement of specific development and clinical milestones for the first product under the IL-13 License Agreement that achieves such specified milestones.
−Removed: Upon execution of the IL-13 License Agreement, we paid Paragon a $1.0 million fee for nomination of a development candidate.
−Removed: In August 2023, we announced the dosing of our first participant in the Phase 1 trial of APG777 and incurred a milestone payment of $2.0 million to Paragon in the third quarter of 2023.
−Removed: We are also obligated to pay royalties to Paragon equal to a low-single digit percentage of net sales of any products under the IL-13 License Agreement, and Paragon has a similar obligation to pay royalties to us with respect to the IL-13 multispecific license.
−Removed: Royalties are due on a product-by-product and country-by-country basis beginning upon the first commercial sale of each product and ending on the later of (i) 12 years after the first commercial sale of such product in such country and (ii) expiration of the last valid claim of a patent covering such product in such country (Royalty Term).
−Removed: No royalty payments had become due to Paragon through December 31, 2023.
−Removed: Unless earlier terminated, the IL-13 License Agreement remains in effect until the expiration of the last-to-expire Royalty Term for any and all products.
−Removed: We may terminate the agreement in its entirety or on a country-by-country or product-by-product at any time for any or no reason upon 60 days advance written notice to Paragon, and either party may terminate for (i) the other party’s material breach that remains uncured for 90 days (or 30 days with respect to any failure to make payments) following notice of such breach and (ii) the other party’s bankruptcy.
−Removed: Upon any termination prior to the expiration of an agreement, all licenses and rights granted pursuant to the agreement will automatically terminate and revert to the granting party and all other rights and obligations of the parties will terminate.
−Removed: Paragon IL-4Rα License Agreement
−Removed: In April 2023, we exercised our option available under the 2022 Option Agreement with respect to the IL-4Rα Research Program.
−Removed: Upon such exercise, we entered into an associated license agreement with Paragon (the IL-4Rα License Agreement).
−Removed: Under the terms of the IL-4Rα License Agreement, Paragon granted to us an exclusive, worldwide, royalty-bearing, sublicensable right and license with respect to certain information, patent rights and sequence information related to antibodies directed at the IL-4Rα target to use, make, sell, import, export and otherwise exploit the antibodies directed at the IL-4Rα target.
−Removed: Pursuant to the IL-4Rα License Agreement, we granted to Paragon a similar license (except that such license we granted to Paragon is non-exclusive) to the IL-4Rα license with respect to multispecific antibodies that are directed at the IL-4Rα target and one or more other antibodies.
−Removed: We also granted a right of first negotiation with Paragon concerning the development, license and grant of rights to certain multispecific antibodies.
−Removed: We are solely responsible for the continued development, manufacture and commercialization of products at our own cost and expense.
−Removed: We are obligated to pay Paragon up to $3.0 million upon the achievement of specific development and clinical milestones for the first product under the IL-4Rα License Agreement that achieves such specified milestones.
−Removed: In November 2023, the Company finalized the nomination of a development candidate under the IL-4Rα License Agreement and made a milestone payment of $1.0 million to Paragon in the fourth quarter of 2023.
−Removed: Thereafter, we are obligated to make a further milestone payment of $2.0 million upon the first dosing of a human patient in a Phase 1 trial.
−Removed: We are also obligated to pay royalties to Paragon equal to a low-single digit percentage of net sales of any products under the IL-4Rα License Agreement, and Paragon has a similar obligation to pay royalties to us with respect to the IL-4Rα multispecific license.
−Removed: Royalties are due on a product-by-product and country-by-country basis beginning upon the first commercial sale of each product and ending on the later of (i) 12 years after the first commercial sale of such product in such country and (ii) expiration of the last valid claim of a patent covering such product in such country.
−Removed: Unless earlier terminated, the IL-4Rα License Agreement remains in effect until the expiration of the last-to-expire Royalty Term for any and all products.
−Removed: We may terminate the agreement in its entirety or on a country-by-country or product-by-product at any time for any or no reason upon 60 days advance written notice to Paragon, and either party may terminate for (i) the other party’s material breach that remains uncured for 90 days (or 30 days with respect to any
−Removed: failure to make payments) following notice of such breach and (ii) the other party’s bankruptcy.
−Removed: Upon any termination prior to the expiration of an agreement, all licenses and rights granted pursuant to the agreement will automatically terminate and revert to the granting party and all other rights and obligations of the parties will terminate.
−Removed: Paragon OX40L License Agreement
−Removed: In April 2023, we exercised our option available under the 2022 Option Agreement with respect to the OX40L Research Program.
−Removed: Upon such exercise, we entered into an associated license agreement with Paragon (the OX40L License Agreement).
−Removed: Under the terms of the OX40L License Agreement, Paragon granted to us an exclusive, worldwide, royalty-bearing, sublicensable right and license with respect to certain information, patent rights and sequence information related to antibodies directed at the OX40L target to use, make, sell, import, export and otherwise exploit the antibodies directed at the OX40L target.
−Removed: Pursuant to the OX40L License Agreement, we granted to Paragon a similar license (except that such license we granted to Paragon is non-exclusive) to the OX40L license with respect to multispecific antibodies that are directed at the OX40L target and one or more other antibodies.
−Removed: We also granted a right of first negotiation with Paragon concerning the development, license and grant of rights to certain multispecific antibodies.
−Removed: We are solely responsible for the continued development, manufacture and commercialization of products at our own cost and expense.
−Removed: We are obligated to pay Paragon up to $3.0 million upon the achievement of specific development and clinical milestones for the first product under the OX40L License Agreement that achieves such specified milestones.
−Removed: The first specified milestone payment of $1.0 million under the agreement is due upon the nomination of a development candidate, which has not yet occurred.
−Removed: Thereafter, we are obligated to make a further milestone payment of $2.0 million upon the first dosing of a human patient in a Phase 1 trial.
−Removed: We are also obligated to pay royalties to Paragon equal to a low-single digit percentage of net sales of any products under the OX40L License Agreement, and Paragon has a similar obligation to pay royalties to us with respect to the OX40L multispecific license.
+Added: Upon such exercise, the parties entered into an associated license agreement (the “IL-13 License Agreement”).
+Added: In April 2023, we exercised our option available under the 2022 Option Agreement with respect to the IL-4Rα Research Program and the OX40L Research Program.
+Added: Upon such exercise, the parties entered into associated license agreements (the “IL-4Rα License Agreement” and the “OX40L License Agreement,” respectively).
+Added: In August 2024, we exercised our option available under the 2023 Option Agreement with respect to the TSLP Research Program and entered into the associated license agreement (the “TSLP License Agreement,” and collectively with the IL-13 License Agreement, the IL-4Rα License Agreement and the OX40L License Agreement, the “License Agreements”).
+Added: Under the terms of the License Agreements, Paragon granted to us an exclusive, worldwide, royalty-bearing, sublicensable right and license with respect to certain information, patent rights and sequence information related to antibodies directed at the respective target to use, make, sell, import, export and otherwise exploit the antibodies
+Added: directed at the respective target.
+Added: Pursuant to the License Agreements, we granted to Paragon a similar license (except that such license we granted to Paragon is non-exclusive) to the respective licenses with respect to multispecific antibodies that are directed at the respective targets and one or more other antibodies.
+Added: We were also granted a right of first negotiation with Paragon concerning the development, license and grant of rights to certain multispecific antibodies associated with each respective license.
+Added: We are solely responsible for the continued development, manufacture and commercialization of products at our own cost and expense for each licensed target.
+Added: Under the IL-13 License Agreement, the IL-4Rα License Agreement and the OX40L License Agreement, we are obligated to pay Paragon up to $3.0 million upon the achievement of specific development and clinical milestones for the first product under each of the License Agreements that achieves such specified milestones, including a payment of $1.0 million upon the nomination of a development candidate and $2.0 million upon the first dosing of a human patient in a Phase 1 trial.
+Added: Under the TSLP License Agreement, we are obligated to pay Paragon up to $28.0 million upon the achievement of specific development and clinical milestones for the first product, including a payment of $3.0 million upon the nomination of a development candidate and $5.0 million upon the first dosing of a human patient in a Phase 1 trial.
+Added: Upon execution of the IL-13 License Agreement, we paid Paragon a $1.0 million fee for the nomination of a development candidate.
+Added: In August 2023, we announced the dosing of our first participants in the Phase 1 trial of APG777 and made a milestone payment of $2.0 million in the fourth quarter of 2023.
+Added: In November 2023, we finalized the nomination of a development candidate under the IL-4Rα License Agreement and made a milestone payment of $1.0 million to Paragon in the fourth quarter of 2023.
+Added: In March 2024, we announced the dosing of our first participants in a Phase 1 trial of APG808 and made a milestone payment of $2.0 million to Paragon in the first quarter of 2024.
+Added: In May 2024, we finalized the nomination of a development candidate under the OX40L License Agreement and made a milestone payment of $1.0 million to Paragon in the second quarter of 2024.
+Added: In August 2024, we announced the dosing of our first participants in the Phase 1 trial of APG990 and made a milestone payment of $2.0 million in the third quarter of 2024.
+Added: In October 2024, we finalized the nomination of a development candidate under the TSLP License Agreement and made a milestone payment of $3.0 million to Paragon in the fourth quarter of 2024.
+Added: In December 2024, we announced the dosing of our first participant in the Phase 1 trial of APG333 and made a milestone payment of $5.0 million in the fourth quarter of 2024.
+Added: We are also obligated to pay royalties to Paragon equal to a low-single digit percentage of net sales of any products under each of the respective License Agreements, and Paragon has a similar obligation to pay royalties to us with respect to each of the multispecific licenses.
Royalties are due on a product-by-product and country-by-country basis beginning upon the first commercial sale of each product and ending on the later of (i) 12 years after the first commercial sale of such product in such country and (ii) expiration of the last valid claim of a patent covering such product in such country.
−Removed: Unless earlier terminated, the OX40L License Agreement remains in effect until the expiration of the last-to-expire Royalty Term for any and all products.
−Removed: We may terminate each agreement in its entirety or on a country-by-country or product-by-product at any time for any or no reason upon 60 days advance written notice to Paragon, and either party may terminate for (i) the other party’s material breach that remains uncured for 90 days (or 30 days with respect to any failure to make payments) following notice of such breach and (ii) the other party’s bankruptcy.
−Removed: Upon any termination prior to the expiration of an agreement, all licenses and rights granted pursuant to the agreement will automatically terminate and revert to the granting party and all other rights and obligations of the parties will terminate.
Biologics Master Services Agreement — WuXi Biologics (Hong Kong) Limited
In June 2022, Paragon and WuXi Biologics (Hong Kong) Limited (“WuXi Biologics”) entered into a biologics master services agreement (the “WuXi Biologics MSA”), which was subsequently novated to us by Paragon in the second quarter of 2023.
−Removed: The WuXi Biologics MSA governs all development activities and GMP manufacturing and testing for our APG777, APG808 and APG990 programs, as well as potential future programs, on a work order basis.
+Added: The WuXi Biologics MSA governs all development activities and GMP manufacturing and testing for our APG777, APG990, APG333 and APG808 programs, as well as potential future programs, on a work order basis.
Under the WuXi Biologics MSA, we are obligated to pay WuXi Biologics a service fee and all non-cancellable obligations in the amount specified in each work order associated with the agreement for the provision of services.
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We can terminate the WuXi Biologics MSA or any work order at any time upon 30 days’ prior written notice and immediately upon written notice if WuXi Biologics fails to obtain or maintain required material governmental licenses or approvals.
−Removed: Either party may terminate a work order (i) at any time upon six months’ prior notice with reasonable cause, provided however that if WuXi Biologics terminates a work order in such manner, no termination or cancellation fees shall be paid by us and (ii) immediately for cause upon (a) the other party’s material breach that remains uncured for 30 days after notice of such
−Removed: breach, (b) the other party’s bankruptcy or (c) a force majeure event that prevents performance for a period of at least 90 days.
+Added: Either party may terminate a work order (i) at any time upon six months’ prior notice with reasonable cause, provided however that if WuXi Biologics terminates a work order in such manner, no termination or cancellation fees shall be paid by us and (ii) immediately for cause upon (a) the other party’s material breach that remains uncured for 30 days after notice of such breach, (b) the other party’s bankruptcy or (c) a force majeure event that prevents performance for a period of at least 90 days.
Cell Line License Agreement — WuXi Biologics (Hong Kong) Limited
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Under the Cell Line License Agreement, we received a non-exclusive, worldwide, sublicensable license to certain of WuXi Biologics’ know-how, cell line, biological materials (the “WuXi Biologics Licensed Technology”) and media and feeds to make, have made, use, sell and import certain therapeutic products produced through the use of the cell line licensed by WuXi Biologics under the Cell Line License Agreement (the “WuXi Biologics Licensed Products”).
−Removed: Specifically, the WuXi Biologics Licensed Technology is used to manufacture a component of our APG777 and APG808 product candidates.
−Removed: In consideration for the license, we agreed to pay WuXi Biologics a non-refundable license fee of $150,000.
+Added: Specifically, the WuXi Biologics Licensed Technology is used to manufacture a component of the APG777, APG990, APG333 and APG808 programs.
+Added: In consideration for the license, we have paid WuXi Biologics a non-refundable license fee of $150,000.
Additionally, if we manufacture all of our commercial supplies of bulk drug product with a manufacturer other than WuXi Biologics or its affiliates, we are required to make royalty payments to WuXi Biologics in an amount equal to a fraction of a single digit percentage of global net sales of WuXi Biologics Licensed Products manufactured by a third-party manufacturer (the “Royalty”).
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Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.
−Removed: These competitors also compete with us in recruiting and retaining qualified scientific and management personnel, establishing clinical trial sites, patient enrollment for clinical trials as well as in acquiring technologies complementary to, or necessary for, our programs.
+Added: These competitors also compete with us in recruiting and retaining qualified scientific, clinical and management personnel, establishing clinical trial sites, patient enrollment for clinical trials as well as in acquiring technologies complementary to, or necessary for, our programs.
Key competitive factors affecting the success of all our product candidates that we develop, if approved, are likely to be efficacy, safety, convenience, presentation, price, the level of generic competition and the availability of reimbursement from government and other third-party payors.
Our competitors may also obtain FDA or other regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market.
−Removed: Specifically, there are several companies developing or marketing treatments that may be approved for the same indications and/or disease as our two most advanced programs, APG777 and APG808, and third and fourth programs, APG990 and APG222, including major pharmaceutical companies.
+Added: Specifically, there are several companies, including major pharmaceutical companies, developing or marketing treatments that may be approved for the same indications and/or disease as our programs.
We do not yet have clinical data for any of our programs and there can be no assurance that our programs will have similar or comparable results.
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While the AD market has shown similarities to the psoriasis market to date, there can be no assurance that the AD market will develop in a similar or comparable manner to psoriasis.
−Removed: There are several approved products for moderate-to-severe AD, such as dupilumab, an IL-4Rα mAb marketed as DUPIXENT by Sanofi/Regeneron, tralokinumab-ldrm, an IL-13 mAb marketed as ADBRY by LEO Pharmaceuticals, and nemolizumab, an anti-IL-31 mAb marketed in Japan as MITCHGA by Maruho Co., Ltd.
+Added: There are several approved products for moderate-to-severe AD, such as dupilumab, an IL-4Rα mAb marketed as DUPIXENT by Sanofi/Regeneron, lebrikizumab, an IL-13 mAb marketed as EBGLYSS by Lilly, tralokinumab-ldrm, an IL-13 mAb marketed as ADBRY by LEO Pharmaceuticals, and nemolizumab, an anti-IL-31Rα mAb marketed as NEMLUVIO in the U.S.
+Added: and the European Union (“EU”) by Galderma and MITCHGA in Japan by Maruho Co., Ltd.
There are several approved treatments that target JAK1 and/or JAK2 to treat AD, including abrocitinib, marketed as CIBINQO by Pfizer, and upadacitinib, marketed as RINVOQ by AbbVie.
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For example, the percentage of patients achieving EASI 75 on a placebo-adjusted basis in Phase 2 and average of Phase 3 monotherapy trials in AD were 59% and 62%, respectively, for upadacitinib at 30mg dosed daily, 42% and 51%, respectively, for upadacitinib at 15mg dosed daily, 36% and 38%, respectively, for lebrikizumab at 250mg dosed every two weeks, 40% and 34%, respectively, for DUPIXENT at 300mg dosed every two weeks, 49% and 51%, respectively, for abrocitinib at 200mg dosed daily, and 25% and 21%, respectively, for abrocitinib at 100mg dosed daily.
−Removed: With respect to biologics with global Phase 3 data in AD, DUPIXENT, ADBRY, and lebrikizumab have all demonstrated statistically significant results.
+Added: With respect to biologics with global Phase 3 data in AD, DUPIXENT, EBGLYSS, ADBRY, and NEMLUVIO have all demonstrated statistically significant results.
In two Phase 3 trials of DUPIXENT dosed every two weeks in patients with AD, at 16 weeks, DUPIXENT showed 38.0% and 36.1% of treated patients achieved IGA 0/1 compared to 10.3% and 8.5% on placebo, respectively.
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Of the 16‑week responders who received DUPIXENT every two weeks during the induction period, 44% of patients dosed every four weeks and 54% of patients dosed every two weeks in the maintenance period achieved IGA 0/1 and 58% of patients dosed every four weeks and 72% of patients dosed every two weeks in the maintenance period achieved EASI‑75 at 52 weeks.
−Removed: In two Phase 3 trials of lebrikizumab dosed every two weeks in patients with AD, at 16 weeks, lebrikizumab showed 43.1% and 33.2% of treated patients achieved IGA 0/1 compared to 12.7% and 10.8% on placebo, respectively.
−Removed: Further, 58.8% and 52.1% of patients treated with lebrikizumab achieved EASI-75, compared to 16.2% and 18.1% of patients on placebo, respectively.
+Added: In two Phase 3 trials of EBGLYSS dosed every two weeks in patients with AD, at 16 weeks, EBGLYSS showed 43.1% and 33.2% of treated patients achieved IGA 0/1 compared to 12.7% and 10.8% on placebo, respectively.
+Added: Further, 58.8% and 52.1% of patients treated with EBGLYSS achieved EASI‑75, compared to 16.2% and 18.1% of patients on placebo, respectively.
All differences were statistically significant.
−Removed: Of the 16-week responders who received lebrikizumab every two weeks during the induction period, 78% of patients dosed every four weeks and 71% of patients dosed every two weeks in the maintenance period achieved IGA 0/1 and 82% of patients dosed every four weeks and 78% of patients dosed every two weeks in the maintenance period achieved EASI-75 at 52 weeks.
+Added: Of the 16-week responders who received EBGLYSS every two weeks during the induction period, 78% of patients dosed every four weeks and 71% of patients dosed every two weeks in the maintenance period achieved IGA 0/1 and 82% of patients dosed every four weeks and 78% of patients dosed every two weeks in the maintenance period achieved EASI‑75 at 52 weeks.
In two Phase 3 trials of ADBRY dosed every two weeks in patients with AD, at 16 weeks, ADBRY showed 15.8% and 22.2% of treated patients achieved IGA 0/1 compared to 7.1% and 10.9% on placebo, respectively.
1 unchanged sentence
All differences were statistically significant.
−Removed: We do not yet have clinical data in patients for our programs targeting IL-13 or IL-4Rα and there can be no assurance that our programs will have similar or comparable results.
−Removed: We are also aware of several product candidates in clinical development for AD.
−Removed: Lebrikizumab is an IL-13 mAb from Eli Lilly and Company and Almirall, which is under review for potential approval by the FDA and, in 2023, received approval from the EMA.
−Removed: Nemolizumab is an IL-31R mAb from Galderma which had positive topline results in two Phase 3 trials showing 35.6% and 37.7% IGA 0/1 compared to 24.6% and 26.0% in the placebo group.
+Added: In two Phase 3 trials with topical corticosteroids and topical calcineurin inhibitors, NEMLUVIO dosed every four weeks in patients with AD, showed 35.6% and 37.7% IGA 0/1 compared to 24.6% and 26.0% in the placebo group.
For EASI-75, 43.5% and 42.1% of treated patients achieved the endpoint compared to 29.0% and 30.2% in the placebo group.
+Added: All differences were statistically significant.
+Added: We do not yet have clinical data in patients with AD for our programs and there can be no assurance that our programs will have similar or comparable results.
+Added: We are also aware of several product candidates in clinical development for AD.
Amlitelimab is an OX40L mAb, which is currently being evaluated in a Phase 3 trial by Sanofi and has demonstrated EASI-75 of 61.5% compared to 29.4% in the placebo group at week 16 when dosed every four weeks at 250mg with a 500mg loading dose (LD) in a Phase 2b trial.
22.1% of patients treated with amlitelimab 250mg with LD achieved IGA0/1 at Week 16 compared to 5.1% of placebo patients.
−Removed: CBP-201 is an IL-4Rα mAb, which is currently being evaluated in a Phase 3 trial by Connect Biopharma and has demonstrated EASI-75 of 47% compared to 14% for placebo when dosed every two weeks in a Phase 2b trial.
Rocatinlimab is an OX40 mAb, which is currently being evaluated in a Phase 3 trial by Amgen and Kyowa Kirin Co., Ltd.
and has demonstrated EASI-75 of 54% compared to 11% for placebo in a Phase 2 trial.
−Removed: Eblasakimab, an IL-13Rα1 mAb being developed by ASLAN Pharmaceuticals, showed positive Phase 2b data with 600 mg Q4W leading to 52% of treated patients achieving EASI-75 versus 24.4% in the placebo group.
+Added: The first Phase 3 trial showed EASI-75 of 32.8% compared to 13.7% placebo at week 24.
For IGA 0/1, 19.3% of treated patients achieved the endpoint versus 6.6% in the placebo group.
−Removed: Other agents include ANB032, a BTLA antagonist, which is currently being evaluated in a Phase 2b trial by AnaptysBio;
−Removed: Rezpeg, a rIL-2 in Phase 2 trials by NEKTAR, and RAPT193, a CCR4 antagonist in Phase 2b trials by RAPT Therapeutics.
+Added: Other agents include rezpegaldesleukin, a rIL-2 in Phase 2 trials by NEKTAR, temptokibart, an IL-22R in Phase 2 trials by LEO Pharma, GSK1070806, an IL-18 in Phase 2 trials by GSK, and KT-621, an oral STAT6 degrader in Phase 1 trials, by Kymera.
Advanced therapy penetration in AD is currently expected to ramp up from 8% in 2022 to approximately 25% by 2032.
With more convenient and patient-friendly dosing, and potentially better efficacy, we believe that the market for future penetration of biologics could expand even beyond the projected 25%.
−Removed: There are several approved products for COPD, however, there are no approved biologics.
−Removed: We are aware of several biologics in development, including DUPIXENT, for which Sanofi released positive data from two Phase 3 trials;
−Removed: itepekimab, an IL-33 mAb from Sanofi/Regeneron, which is currently being evaluated in a Phase 3 trial;
+Added: There are several approved products for COPD, including DUPIXENT and OHTUVAYRE (ensifentrine), a PDE3/PDE4 inhibitor marketed as OHTUVAYRE by Verona Pharma.
+Added: We are aware of several other biologics in development, including mepolizumab, an IL-5 mAb from GSK which met its primary endpoint in a Phase 3 trial, itepekimab, an IL-33 mAb from Sanofi/Regeneron, which is currently being evaluated in a Phase 3 trial;
tozorakimab, an IL-33 mAb from AstraZeneca, which is currently being evaluated in Phase 3 trials;
benralizumab, an IL-5R mAb, from AstraZeneca, which is currently being evaluated in a Phase 3 trial;
−Removed: mepolizumab, an IL-5 mAb from GSK, which is currently being evaluated in a Phase 3 trial;
−Removed: tezepelumab, a TSLP mAb from AstraZeneca/Amgen, which is currently being evaluated in a Phase 2 trial;
+Added: tezepelumab, a TSLP mAb from AstraZeneca/Amgen, which is expected to begin a Phase 3 trial;
astegolimab, an ST2 mAb from Roche, which is currently being evaluated in Phase 2/3 trials;
−Removed: and ensifentrine, a PDE3/PDE4 inhibitor from Verona Pharma, which met the primary endpoint in two Phase 3 trials and has had an NDA accepted by the FDA.
+Added: and depemokimab, an IL-5 mAb from GSK, which is expected to begin Phase 3 trials.
Manufacturing and Supply
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APG777 drug substance and drug product have been successfully manufactured at clinical scale with acceptable yields for near-term, planned clinical trials.
−Removed: Our initial formulation for APG777 is suitable for SQ injection.
−Removed: By the time of commercialization, we expect APG777 to be administrated via a pre-filled autoinjector.
−Removed: We use a similar approach to development and supply for our APG808 program.
−Removed: APG808 drug substance and drug product have been successfully manufactured at clinical scale with acceptable yields for use in our initial planned clinical trials.
−Removed: While we expect to continue to devote significant resources to process development, scale-up and registration-enabling validation activities for APG777, we believe the manufacturing processes for mAbs such as APG777 are well established and should not create meaningful impediments to either clinical development or commercial launch.
−Removed: However, we will continue to identify additional second source drug substance and drug product contract manufacturers to ensure that we will have sufficient capacity as well as redundancy within our supply chain to avoid product shortages in the future.
+Added: Our formulation for APG777 is suitable for SQ injection.
+Added: By the time of commercialization, we expect APG777 to be administrated via a pre-filled syringe and/or autoinjector.
+Added: We use a similar approach to development and supply for our APG990, APG333 and APG808 programs.
+Added: APG990, APG333 and APG808 drug substance and drug product have been successfully manufactured at clinical scale with acceptable yields for use in our initial planned clinical trials.
+Added: While we expect to continue to devote significant resources to process development, scale-up, manufacturing resupply and registration-enabling validation activities for APG777, we believe the manufacturing processes for mAbs such as APG777 are well established and should not create meaningful impediments to either clinical development or commercial launch.
+Added: We have created redundancy in our clinical supply by contracting with second source drug substance and drug product manufacturers.
+Added: However, we will continue to identify additional drug substance and drug product contract manufacturers to ensure that we will have sufficient capacity as well as redundancy within our supply chain to avoid product shortages in the future.
We will also continue to invest in development activities to ensure an acceptable cost of goods.
1 unchanged sentence
We believe there are multiple sources for the raw materials required for the manufacture of our programs.
−Removed: While any reduction or halt in the supply of raw materials, drug substance or drug product could limit our ability to develop our programs until a replacement supplier or contract manufacturer is found and qualified, we believe that we have or will be able to manufacture sufficient clinical supply of APG777 and APG808, as well as future pipeline products, to support our near-term planned clinical trials, and have access to sufficient manufacturing capacity to support our planned clinical development program.
+Added: While any reduction or halt in the supply of raw materials, drug substance or drug product could limit our ability to develop our programs until a replacement supplier or contract manufacturer is found and qualified, we believe that we have or will be able to manufacture sufficient clinical supply of APG777, APG990, APG333 and APG808, as well as future pipeline products, to support our planned clinical trials, and have access to sufficient manufacturing capacity to support our planned clinical development program.
In light of the recently introduced BIOSECURE Act, which would prohibit federal agencies from entering into procurement contracts with an entity that uses biotechnology equipment or services from a biotechnology company of concern, we continue to take risk mitigation measures to reduce our supply chain risk in the event that WuXi Biologics or one of our other manufacturers or other supply chain vendors is impacted.
−Removed: We intend to continue to identify and select second source suppliers, including those based in the US and EU, for our contract development, manufacturing, testing, and storage needs.
+Added: Although the BIOSECURE Act did not become law in 2024, it may be proposed again in 2025 and we have secured second source drug product manufacturing in the U.S.
+Added: and have entered into an agreement with Samsung Biologics for drug substance supply.
+Added: We intend to continue to identify and select additional source suppliers, including those based in the U.S.
+Added: and EU, for our contract development, manufacturing, testing, and storage needs.
We will also continue to closely monitor geopolitical risk and implement additional mitigations and supply chain redundancies, as needed.
1 unchanged sentence
If these third parties do not properly and successfully carry out their contractual duties or meet expected deadlines, we may not be able to obtain regulatory approval of or commercialize our programs.
−Removed: For APG990 and APG222, we plan to follow a similar approach to APG777 and APG808 for the development and supply of preclinical, clinical and commercial material.
Intellectual Property
1 unchanged sentence
Patent Rights Relating to Our IL - 13 Program
−Removed: As of March 1, 2024, we own four patent families directed to antibodies that target IL-13, including APG777, pharmaceutical formulations, and methods of using those antibodies.
−Removed: The first patent family is directed to compositions of matter and includes an international (PCT) patent application and patent applications in Argentina and Taiwan.
+Added: As of January 31, 2025, we own eight patent families directed to antibodies that target IL-13, including APG777, pharmaceutical formulations and compositions, and methods of using those antibodies.
+Added: The first patent family is directed to compositions of matter and includes patent applications filed in the U.S.
+Added: and in foreign jurisdictions including Europe, Japan and China.
If issued, we would expect these patents to expire in 2043, absent any applicable patent term extensions.
−Removed: The second patent family is directed to methods of using APG777 and includes seven provisional applications.
−Removed: If the provisional patent applications are pursued non-provisionally and mature into one or more issued patents, we would expect those patents to expire in 2044, absent any applicable patent term extensions.
−Removed: The third patent family is directed to pharmaceutical formulations containing APG777 and includes one provisional application.
−Removed: If the provisional patent application is pursued non-provisionally and matures into one or more issued patents, we would expect those patents to expire in 2044, absent any applicable patent term extensions.
−Removed: The fourth patent family is directed to other APG777 compositions and includes one provisional application.
−Removed: If the provisional patent application is pursued non-provisionally and matures into one or more issued patents, we would expect those patents to expire in 2044, absent any applicable patent term extensions.
+Added: The second patent family is directed to methods of using APG777 and includes an international (PCT) patent application and applications in Argentina and Taiwan.
+Added: If the PCT application is pursued in the U.S.
+Added: or any foreign jurisdictions and matures into one or more issued patents, or the Argentina or Taiwan applications mature into issued patents, we would expect those patents to expire in 2044, absent any applicable patent term extensions.
+Added: The third patent family is directed to pharmaceutical formulations containing APG777 and includes a PCT application.
+Added: If the PCT application is pursued in the U.S.
+Added: or any foreign jurisdictions and matures into one or more issued patents, we would expect those patents to expire in 2044, absent any applicable patent term extensions.
+Added: The fourth patent family is directed to other APG777 compositions and includes a PCT application and applications filed in Argentina and Taiwan.
+Added: If the PCT application is pursued in the U.S.
+Added: or any foreign jurisdictions and matures into one or more issued patents, or the Argentina or Taiwan applications mature into one or more issued patents, we would expect those patents to expire in 2044, absent any applicable patent term extensions.
+Added: The remaining four patent families are directed to other APG777 compositions and methods of using APG777 and each family, as of January 31, 2025, includes between one and three provisional applications.
+Added: If these provisional applications are pursued non-provisionally and mature into one or more issued patents, we would expect those patents to expire in 2045 and 2046, absent any applicable patent term extensions.
Patent Rights Relating to Our IL‑4Ra Program
−Removed: We have licensed one patent family from Paragon directed to antibodies that target IL-4R a , including APG808, and methods of using those antibodies.
−Removed: As of March 1, 2024, this family includes an international (PCT) patent application and patent applications in Argentina and Taiwan.
−Removed: If these applications mature into one or more issued patents, we would expect those patents to expire in 2044, absent any applicable patent term extensions.
+Added: As of January 31, 2025, we own four patent families directed to antibodies that target IL-4Ra, including APG808, and methods of using those antibodies.
+Added: The first patent family includes a PCT application and patent applications in Argentina and Taiwan.
+Added: If the PCT application is pursued in the U.S.
+Added: or any foreign jurisdictions and matures into one or more issued patents, or the Argentina or Taiwan applications mature issued patents, we would expect those patents to expire in 2044, absent any applicable patent term extensions.
+Added: The second patent family is directed to methods of using APG808 and includes a PCT application.
+Added: If the PCT application is pursued in the U.S.
+Added: or any foreign jurisdictions and matures into one or more issued patents, we would expect those patents to expire in 2045, absent any applicable patent term extensions.
+Added: The remaining two patent families are directed to APG808 compositions and methods of using APG808 and as of January 31, 2025, each family includes one provisional patent application.
+Added: If these provisional applications are pursued non-provisionally and mature into one or more issued patents, we would expect those patents to expire in 2045, absent any applicable patent term extensions.
Patent Rights Relating to Our OX40L Program
−Removed: We have licensed one patent family from Paragon directed to antibodies that target OX40L, including APG990, and methods of using those antibodies.
−Removed: As of March 1, 2024, this family includes two pending provisional patent applications.
−Removed: Any patents that grant from this family would be expected to expire in 2044, absent any applicable patent term extensions.
+Added: As of January 31, 2025, we own four patent families directed to antibodies that target OX40L, including APG990, and methods of using those antibodies and formulations thereof.
+Added: The first patent family includes a PCT application and applications in Argentina and Taiwan.
+Added: If the PCT application is pursued in the U.S.
+Added: or any foreign jurisdictions and matures into an issued patent or the Argentina or Taiwan applications are pursued and mature into issued patents, we would expect those patents to expire in 2044, absent any applicable patent term extensions.
+Added: The second, third and fourth patent families are directed to pharmaceutical formulations and compositions including APG990 and methods of using APG990 and as of January 31, 2025, each family includes one or two provisional applications.
+Added: If these provisional applications are pursued non-provisionally and mature into one or more issued patents, we would expect those patents to expire in 2045, absent any applicable patent term extensions.
+Added: Patent Rights Relating to Our TSLP Program
+Added: As of January 31, 2025, we have licensed one patent family from Paragon directed to antibodies that target TSLP, including APG333, and methods of using those antibodies.
+Added: As of January 31, 2025, this family includes three provisional applications.
+Added: If these provisional applications are pursued non-provisionally and mature into one or more issued patents, we would expect those patents to expire in 2045, absent any applicable patent term extensions.
+Added: We also own two patent families directed to compositions of TSLP antibodies, including APG333, and methods of using APG333.
+Added: As of January 31, 2025, each of these families includes one provisional application.
+Added: If these provisional applications are pursued non-provisionally and mature into one or more issued patents, we would expect those patents to expire in 2045, absent any applicable patent term extensions.
+Added: Patent Rights Relating to Our Combination Programs
+Added: As of January 31, 2025, we own six patent families directed to combinations of APG777, APG990, APG333 and/or APG808 and pharmaceutical formulations and compositions thereof.
+Added: As of January 31, 2025, each of these families includes between one and three provisional applications.
+Added: If these provisional applications are pursued non-provisionally and mature into one or more issued patents, we would expect those patents to expire in 2045, absent any applicable patent term extensions.
+Added: We have also licensed three patent families from Paragon directed to combinations of APG777, APG990, APG333 and/or APG808 and methods of using those combinations.
+Added: As of January 31, 2025, each of these families includes between one and three provisional applications.
+Added: If these provisional applications are pursued non-provisionally and mature into one or more issued patents, we would expect those patents to expire in 2045, absent any applicable patent term extensions.
As indicated above, some of our owned and licensed patent applications are provisional patent applications.
6 unchanged sentences
In most countries in which we have filed, including the United States, the patent term is 20 years from the earliest filing date of a non-provisional patent application.
−Removed: In the United States, a patent’s term may be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the USPTO in examining and granting a patent, or may be shortened if a patent is terminally disclaimed over an earlier-filed patent.
+Added: In the United States, a patent’s term may be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the United States Patent and Trademark Office (“USPTO”) in examining and granting a patent, or may be shortened if a patent is terminally disclaimed over an earlier-filed patent.
The term of a patent that covers a drug or biological product may also be eligible for patent term extension when FDA approval is granted for a portion of the term effectively lost as a result of the FDA regulatory review period, subject to certain limitations and provided statutory and regulatory requirements are met.
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Moreover, the length of the extension could be less than we request.
−Removed: In the future, if and when our product candidates receive approval from the FDA or foreign regulatory authorities, we expect to apply for patent term extensions on issued patents we may obtain in the future covering those products, depending upon the length of the clinical trials for each product and other factors.
+Added: In the future, if and when our product candidates receive approval from the FDA or foreign regulatory authorities, we expect to apply for patent term extensions in applicable jurisdictions on issued patents we may obtain in the future covering those products, depending upon the length of the clinical trials for each product and other factors.
There can be no assurance that any of our pending patent applications will issue or that we will benefit from any patent term extension or favorable adjustment to the term of any of our patents.
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For more information, see the section entitled “Risk Factors — Risks Related to Intellectual Property”.
+Added: Trademark Rights Relating to the Apogee Therapeutics Name and Logo
+Added: As of January 31, 2025, we own a U.S.
+Added: trademark registration for the Apogee logo and the mark APOGEE THERAPEUTICS for research and development services of new pharmaceutical products.
+Added: We also obtained a Statement of Grant of Protection in the UK for the APOGEE THERAPEUTICS mark for research and development services of new pharmaceutical products.
+Added: The Apogee logo and the APOGEE THERAPEUTICS mark are also pending registration in several other countries.
Employees and Human Capital Resources
−Removed: As of March 1, 2024, we had 91 full-time employees, 22 of whom have Ph.D.
+Added: As of December 31, 2024, we had 196 full-time employees, 47 of whom have Ph.D.
Of these full-time employees, 144 employees are engaged in research and development.
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To that end, we are focused on retaining, developing and engaging our existing employees, and attracting high performing talent to join our team.
−Removed: Our rewards package (cash and equity-based compensation and 401(k) and health and welfare benefits plans) is a key tool in retaining, engaging and rewarding our team.
+Added: Our rewards package (cash and equity-based compensation, 401(k) and health and welfare benefits plans) is a key tool in retaining, engaging and rewarding our team.
We are also committed to the continued learning and development of our employees, which we believe will enable us to do our best work for patients.
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We, along with third-party contractors, will be required to navigate the various preclinical, clinical and commercial approval requirements of the governing regulatory agencies of the countries in which we wish to conduct studies or seek approval or licensure of our product candidates.
+Added: Generally, before a new therapeutic product can be marketed, considerable data demonstrating a biological product candidate’s quality, safety, purity and potency, or a small molecule drug candidate’s quality, safety and efficacy, must be obtained, organized into a format specific for each regulatory authority, submitted for review and approved by the regulatory authority.
+Added: For biological product candidates, potency is similar to efficacy and is interpreted to mean the specific ability or capacity of the product, as indicated by appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner intended, to effect a given result.
+Added: Failure to comply with the applicable U.S.
+Added: requirements at any time during the product development process, approval process or post-marketing may subject an applicant to administrative or judicial sanctions.
+Added: These sanctions could include, among other actions, the FDA’s refusal to approve pending applications from the sponsor, withdrawal of an approval, a clinical hold, untitled or warning letters, product recalls or market withdrawals, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement and civil or criminal penalties.
+Added: Any agency or judicial enforcement action could have a material adverse effect on our company and our products or product candidates.
Biologics Regulation
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Submission of an IND therefore may or may not result in FDA authorization to begin a clinical trial.
−Removed: In addition to the IND submission process, supervision of human gene transfer trials includes evaluation and assessment by an institutional biosafety committee (IBC), a local institutional committee that reviews and oversees research utilizing recombinant or synthetic nucleic acid molecules at that institution.
−Removed: The IBC assesses the safety of the research and identifies any potential risk to public health or the environment and such review may result in some delay before initiation of a clinical trial.
Clinical trials involve the administration of the investigational product to human subjects under the supervision of qualified investigators in accordance with GCPs, which include the requirement that all research subjects provide their informed consent for their participation in any clinical study.
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A separate submission to the existing IND must be made for each successive clinical trial conducted during product development and for any subsequent protocol amendments.
−Removed: Furthermore, an independent IRB for each site proposing to conduct the clinical trial must review and approve the plan for any clinical trial and its informed consent form
−Removed: before the clinical trial begins at that site, and must monitor the study until completed.
+Added: Furthermore, an independent IRB for each site proposing to conduct the clinical trial must review and approve the plan for any clinical trial and its informed consent form before the clinical trial begins at that site, and must monitor the study until completed.
Regulatory authorities, the IRB or the sponsor may suspend a clinical trial at any time on various grounds, including a finding that the subjects are being exposed to an unacceptable health risk or that the trial is unlikely to meet its stated objectives.
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Assuming successful completion of all required testing in accordance with all applicable regulatory requirements, the results of product development, nonclinical studies and clinical trials are submitted to the FDA as part of a BLA requesting approval to market the product for one or more indications.
−Removed: The BLA must include all relevant data available from pertinent preclinical studies and clinical trials, including negative or ambiguous results as well as positive findings, together with detailed information relating to the product’s chemistry, manufacturing, controls, and proposed labeling,
−Removed: among other things.
+Added: The BLA must include all relevant data available from pertinent preclinical studies and clinical trials, including negative or ambiguous results as well as positive findings, together with detailed information relating to the product’s chemistry, manufacturing, controls, and proposed labeling, among other things.
Data can come from company-sponsored clinical studies intended to test the safety and effectiveness of the product, or from a number of alternative sources, including studies initiated and sponsored by investigators.
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In addition, under the Pediatric Research Equity Act (“PREA”), a BLA or supplement to a BLA must contain data to assess the safety and effectiveness of the biological product candidate for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.
−Removed: The Food and Drug Administration Safety and Innovation Act requires that a sponsor who is planning to submit a marketing application for a biological product that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration submit an initial pediatric study plan (PSP) within sixty days after an end-of-Phase 2 meeting or as may be agreed between the sponsor and FDA.
+Added: The Food and Drug Administration Safety and Innovation Act requires that a sponsor who is planning to submit a marketing application for a biological product that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration submit an initial pediatric study plan (“PSP”) within 60 days after an end-of-Phase 2 meeting or as may be agreed between the sponsor and FDA.
Unless otherwise required by regulation, PREA does not apply to any biological product for an indication for which orphan designation has been granted.
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The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.
−Removed: Additionally, before approving a BLA, the FDA will typically inspect one or more clinical sites to assure compliance with GCPs.
+Added: Additionally, before approving a BLA, the FDA will typically
+Added: inspect one or more clinical sites to assure compliance with GCPs.
If the FDA determines that the application, manufacturing process or manufacturing facilities are not acceptable, it will outline the deficiencies in the submission and often will request additional testing or information.
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If regulatory approval of a product is granted, such approval will be granted for particular indications and may entail limitations on the indicated uses for which such product may be marketed.
−Removed: For example, the FDA may approve the BLA with a REMS to ensure the benefits of the product outweigh its risks.
+Added: For example, the FDA may approve the BLA with a risk evaluation and mitigation strategy (“REMS”) to ensure the benefits of the product outweigh its risks.
A REMS is a safety strategy to manage a known or potential serious risk associated with a product and to enable patients to have continued access to such medicines by managing their safe use, and could include medication guides, physician communication plans, or elements to assure safe use, such as restricted distribution methods, patient registries and other risk minimization tools.
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Once approved, the FDA may withdraw the product approval if compliance with pre-and post-marketing requirements is not maintained or if problems occur after the product reaches the marketplace.
−Removed: The FDA may require one
−Removed: or more Phase 4 post-market studies and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization, and may limit further marketing of the product based on the results of these post-marketing studies.
+Added: The FDA may require one or more Phase 4 post-market studies and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization, and may limit further marketing of the product based on the results of these post-marketing studies.
Expedited Development and Review Programs
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A fast track product may also be eligible for rolling review, where the FDA may consider for review sections of the BLA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the BLA, the FDA agrees to accept sections of the BLA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the BLA.
+Added: Additionally, products studied for their safety and effectiveness in treating serious or life-threatening diseases or conditions may receive accelerated approval upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.
+Added: As a condition of accelerated approval, the FDA will generally require the sponsor to perform adequate and well-controlled post-marketing clinical studies to verify and describe the anticipated effect on irreversible morbidity or mortality or other clinical benefit.
+Added: Under the Food and Drug Omnibus Reform Act of 2022, the FDA may require, as appropriate, that such studies be underway prior to approval or within a specific time period after the date of approval for a product granted accelerated approval.
+Added: Products receiving accelerated approval may be subject to expedited withdrawal procedures if the sponsor fails to conduct the required post-marketing studies or if such studies fail to verify the predicted clinical benefit.
+Added: In addition, the FDA currently requires as a condition for accelerated approval pre-approval of promotional materials, which could adversely impact the timing of the commercial launch of the product.
A product intended to treat a serious or life-threatening disease or condition may also be eligible for breakthrough therapy designation to expedite its development and review.
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For original BLAs, priority review designation means the FDA’s goal is to take action on the marketing application within six months of the 60-day filing date (as compared to ten months under standard review).
−Removed: Additionally, products studied for their safety and effectiveness in treating serious or life-threatening diseases or conditions may receive accelerated approval upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.
−Removed: As a condition of accelerated approval, the FDA will generally require the sponsor to perform adequate and well-controlled post-marketing clinical studies to verify and describe the anticipated effect on irreversible morbidity or mortality or other clinical benefit.
−Removed: Under the Food and Drug Omnibus Reform Act of 2022, the FDA may require, as appropriate, that such studies be underway prior to approval or within a specific time period after the date of approval for a product granted accelerated approval.
−Removed: Products receiving accelerated approval may be subject to expedited withdrawal procedures if the sponsor fails to conduct the required post-marketing studies or if such studies fail to verify the predicted clinical benefit.
−Removed: In addition, the FDA currently requires as a condition for accelerated approval pre-approval of promotional materials, which could adversely impact the timing of the commercial launch of the product.
Fast track designation, breakthrough therapy designation and priority review do not change the standards for approval but may expedite the development or approval process.
Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.
+Added: Combination Therapy
+Added: Combination therapy is a treatment modality that involves the use of two or more drugs to be used in combination to treat a disease or condition.
+Added: If those drugs are combined in one dosage form, such as one pill, that is known as a fixed dose combination product and it is reviewed pursuant to the FDA’s Combination Rule at 21 CFR 300.50.
+Added: The rule provides that two or more drugs may be combined in a single dosage form when each component contributes to the claimed effects and the dosage of each component (amount, frequency, duration) is such that the combination is safe and effective for a significant patient population requiring such concurrent therapy as defined in the labeling for the drug.
+Added: But not all combination therapy falls under the category of a fixed dose combination.
+Added: For example, the FDA recognizes that two drugs in separate dosage forms and in separate packaging, that otherwise might be administered as monotherapy for an indication, also may be used in combination for the same indication.
+Added: In 2013, the FDA issued guidance to assist sponsors that were developing the range of combination therapies that fall outside the category of fixed dose combinations.
+Added: That guidance provides recommendations and advice on such topics as:
+Added: (1) assessment at the outset whether two or more therapies are appropriate for use in combination;
+Added: (2) guiding principles for nonclinical and clinical development of the combination;
+Added: (3) options for regulatory pathways to seek marketing approval of the combination;
+Added: and (4) post-marketing safety monitoring and reporting obligations.
+Added: Given the wide range of potential combination therapy variations, the FDA indicated it intends to assess each potential combination on a case-by case basis and encouraged sponsors to engage in early and regular consultation with the relevant review division at the agency throughout the development process for its proposed combination.
Post-Approval Requirements
Any products manufactured or distributed by us pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to record-keeping, reporting of adverse experiences, periodic reporting, product sampling and distribution, and advertising and promotion of the product.
+Added: As part of the manufacturing process, the manufacturer is required to perform certain tests on each lot of the product before it is released for distribution.
+Added: After a BLA is approved for a biological product, the product also may be subject to official lot release.
+Added: If the product is subject to official release by the FDA, the manufacturer submits samples of each lot of product to the FDA together with a release protocol showing a summary of the history of manufacture of the lot and the results of all of the manufacturer’s tests performed on the lot.
+Added: The FDA also may perform certain confirmatory tests on lots of some products before releasing the lots for distribution by the manufacturer.
+Added: In addition, the FDA conducts laboratory research related to the regulatory standards on the safety,
+Added: purity, and potency or effectiveness of biologics.
After approval, most changes to the approved product, such as adding new indications or other labeling claims, are subject to prior FDA review and approval.
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Physicians may believe that such off-label uses are the best treatment for many patients in varied circumstances.
−Removed: The FDA does not regulate the behavior of
−Removed: physicians in their choice of treatments.
+Added: The FDA does not regulate the behavior of physicians in their choice of treatments.
The FDA does, however, restrict manufacturer’s communications on the subject of off-label use of their products.
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Complexities associated with the larger, and often more complex, structures of biological products, as well as the processes by which such products are manufactured, pose significant hurdles to implementation of the abbreviated approval pathway that are still being worked out by the FDA.
−Removed: In September 2021, the FDA issued two guidance documents intended to inform prospective applicants and facilitate the development of proposed biosimilars and interchangeable biosimilars, as well as to describe the FDA’s interpretation of certain statutory requirements added by the BPCIA.
+Added: The FDA has issued guidance documents intended to inform prospective applicants and facilitate the development of proposed biosimilars and interchangeable biosimilars, as well as to describe the FDA’s interpretation of certain statutory requirements added by the BPCIA.
Under the BPCIA, an application for a biosimilar product may not be submitted to the FDA until four years following the date that the reference product was first licensed by the FDA.
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In July 2018, the FDA announced an action plan to encourage the development and efficient review of biosimilars, including the establishment of a new office within the agency that will focus on therapeutic biologics and biosimilars.
−Removed: On December 20, 2020, Congress amended the PHSA as part of the COVID-19 relief bill to further simplify the biosimilar review process by making it optional to show that conditions of use proposed in labeling have been previously approved for the reference product,
−Removed: which used to be a requirement of the application.
+Added: On December 20, 2020, Congress amended the PHSA as part of the COVID‑19 relief bill to further simplify the biosimilar review process by making it optional to show that conditions of use proposed in labeling have been previously approved for the reference product, which used to be a requirement of the application.
In addition, government proposals have sought to reduce the 12‑year reference product exclusivity period.
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The PHSA also prohibits the introduction into interstate commerce of unlicensed or mislabeled biological products.
−Removed: federal Physician Payments Sunshine Act requires certain manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program, with specific exceptions, to annually report to the Centers for Medicaid & Medicare Services (CMS) information related to payments or other transfers of value to various healthcare professionals including physicians, physician
−Removed: assistants, nurse practitioners, clinical nurse specialists, certified nurse anesthetists, certified nurse-midwives, and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members.
+Added: federal Physician Payments Sunshine Act requires certain manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program, with specific exceptions, to annually report to the Centers for Medicaid & Medicare Services (“CMS”) information related to payments or other transfers of value to various healthcare professionals including physicians, physician assistants, nurse practitioners, clinical nurse specialists, certified nurse anesthetists, certified nurse-midwives, and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members.
Beginning on January 1, 2023, California Assembly Bill 1278 requires California physicians and surgeons to notify patients of the Open Payments database established under the federal Physician Payments Sunshine Act.
+Added: We are also subject to federal price reporting laws and federal consumer protection and unfair competition laws.
+Added: Federal price reporting laws require manufacturers to calculate and report complex pricing metrics to government programs, where such reported prices may be used in the calculation of reimbursement and/ or discounts on approved products.
+Added: Federal consumer protection and unfair competition laws broadly regulate marketplace activities and activities that potentially harm consumers.
We are also subject to additional similar U.S.
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To the extent that we submit electronic healthcare claims and payment transactions that do not comply with the electronic data transmission standards established under HIPAA and HITECH, payments to us may be delayed or denied.
−Removed: Even when HIPAA does not apply, according to the FTC, violating consumers’ privacy rights or failing to take appropriate steps to keep consumers’ personal information secure may constitute unfair acts or practices in or affecting commerce in violation of Section 5(a) of the Federal Trade Commission Act.
−Removed: In addition, certain state laws, such as the California Consumer Privacy Act of 2018 (CCPA), as amended by the California Privacy Rights Act of 2020 (CPRA), govern the privacy and security of personal information, including health-related information in certain circumstances, some of which are more stringent than HIPAA and many of which differ
−Removed: from each other in significant ways and may not have the same effect, thus complicating compliance efforts.
−Removed: The CCPA/CPRA applies to personal data of consumers, business representatives, and employees, and imposes obligations on certain businesses that do business in California, including to provide specific disclosures in privacy notices, rights to California residents in relation to their personal information.
−Removed: Health information falls under the CCPA/CPRA’s definition of personal information where it identifies, relates to, describes, or is reasonably capable of being associated with or could reasonably be linked with a particular consumer or household — unless it is subject to HIPAA — and is included under a new category of personal information, “sensitive personal information,” which is offered greater protection.
+Added: In addition, state health information privacy laws, such as California’s Confidentiality of Medical Information Act and Washington’s My Health My Data Act, govern the privacy and security of health-related information, specifically, may apply even when HIPAA does not and impose additional requirements.
+Added: Even when HIPAA and state health information privacy laws do not apply, according to the FTC and state Attorneys General, violating consumers’ privacy rights or failing to take appropriate steps to keep consumers’ personal information secure may constitute unfair acts or practices in or affecting commerce in violation of Section 5(a) of the Federal Trade Commission Act and state consumer protection laws.
+Added: In addition, certain state laws, such as the California Consumer Privacy Act of 2018 (“CCPA”), as amended by the California Privacy Rights Act of 2020, govern the privacy and security of personal information, including health-related information in certain circumstances, some of which are more stringent than HIPAA in various ways.
+Added: Numerous other states have passed similar laws, but many differ from each other in significant ways and may not
+Added: have the same effect, thus complicating compliance efforts.
+Added: The CCPA applies to personal data of consumers, business representatives, and employees, and imposes obligations on certain businesses that do business in California, including to provide specific disclosures in privacy notices, and affords rights to California residents in relation to their personal information.
+Added: Health information falls under the CCPA’s definition of personal information where it identifies, relates to, describes, or is reasonably capable of being associated with or could reasonably be linked, directly or indirectly, with a particular consumer or household — unless it is subject to HIPAA — and is included under a new category of personal information, “sensitive personal information,” which is offered greater protection.
+Added: The numerous other comprehensive privacy laws that have passed or are being considered in other states, as well as at the federal and local levels, also exempt some data processed in the context of clinical trials;
+Added: but others exempt covered entities and business associates subject to HIPAA altogether, further complicating compliance efforts, and increasing legal risk and compliance costs for us and the third parties upon whom we rely.
+Added: Additionally, our use of artificial intelligence and machine learning may be subject to laws and evolving regulations regarding the use of artificial intelligence and machine learning, controlling for data bias, and antidiscrimination.
Failure to comply with these laws, where applicable, can result in the imposition of significant civil and/or criminal penalties and private litigation.
Privacy and security laws, regulations, and other obligations are constantly evolving, may conflict with each other to complicate compliance efforts, and can result in investigations, proceedings, or actions that lead to significant civil and/or criminal penalties and restrictions on data processing.
−Removed: Additionally, our use of artificial intelligence and machine learning may be subject to laws and evolving regulations regarding the use of artificial intelligence/machine learning, controlling for data bias, and antidiscrimination.
−Removed: In addition, the CPRA expands the CCPA’s requirements, including by adding a new right for individuals to correct their personal information and establishing a new regulatory agency to implement and enforce the law.
−Removed: Other states, such as Virginia, Colorado, Connecticut and Utah, have also passed comprehensive privacy laws, and similar laws are being considered in several other states, as well as at the federal and local levels.
−Removed: While the laws in these states, like the CCPA, also exempt some data processed in the context of clinical trials, such developments further complicate compliance efforts, and increase legal risk and compliance costs for us and the third parties upon whom we rely.
Coverage and Reimbursement
+Added: and markets in other countries, patients generally rely on third-party payors to reimburse all or part of the costs associated with their treatment.
+Added: Adequate coverage and reimbursement from governmental healthcare programs, such as Medicare and Medicaid, and commercial payors is critical to new product acceptance.
+Added: 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.
+Added: Even if coverage is provided, the approved reimbursement amount may not be high enough to allow it to establish or maintain pricing sufficient to realize a sufficient return on its investment.
+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 levels.
Significant uncertainty exists as to the coverage and reimbursement status of any pharmaceutical or biological product for which we obtain regulatory approval.
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As a result, the coverage determination process is often a time-consuming and costly process that will require us to provide scientific and clinical support for the use of our product candidates to each payor separately, with no assurance that coverage and adequate reimbursement will be applied consistently or obtained in the first instance.
−Removed: Third-party payors are increasingly challenging the prices charged for medical products and services, examining the medical necessity and reviewing the cost effectiveness of pharmaceutical or biological products, medical devices and medical services, in addition to questioning safety and efficacy.
+Added: Factors payors consider in determining reimbursement are based on whether the product is:
+Added: • a covered benefit under its health plan;
+Added: • safe, effective and medically necessary;
+Added: • cost-effective;
+Added: • neither experimental nor investigational.
+Added: Third-party payors are increasingly challenging the prices charged for medical products and services, examining the medical necessity and reviewing the cost effectiveness of pharmaceutical or biological products, medical devices
+Added: and medical services, in addition to questioning safety and efficacy.
Adoption of price controls and cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures, could further limit sales of any product that receives approval.
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Each year, CMS will select and negotiate a preset number of high-spend drugs and biologics that are covered under Medicare Part B and Part D that do not have generic or biosimilar competition.
−Removed: On August 29, 2023, HHS announced the list of the first ten drugs that will be subject to price negotiations.
−Removed: These price negotiations will begin in 2023, although the Medicare drug price negotiation program is currently subject to legal challenges.
−Removed: The IRA also provides a new “inflation rebate” covering Medicare patients that will take effect in 2023 and is intended to counter certain price increases in prescriptions drugs.
−Removed: The inflation rebate provision will require drug manufacturers to pay a rebate to the federal government if the price for a drug or biologic under Medicare Part B and Part D increases faster than the rate of inflation.
+Added: On August 29, 2023, HHS announced the list of the first ten drugs subject to price negotiations.
+Added: These price negotiations occurred in 2024.
+Added: In January 2025, CMS announced a list of 15 additional Medicare Part D drugs that will be subject to price negotiations.
+Added: The IRA also provides a new “inflation rebate” covering Medicare patients that took effect in 2023 and is intended to counter certain price increases in prescriptions drugs.
+Added: The inflation rebate provision requires drug manufacturers to pay a rebate to the federal government if the price for a drug or biologic under Medicare Part B and Part D increases faster than the rate of inflation.
To support biosimilar competition, beginning in October 2022, qualifying biosimilars may receive a Medicare Part B payment increase for a period of five years.
1 unchanged sentence
Notwithstanding these provisions, the IRA’s impact on commercialization and competition remains largely uncertain.
+Added: In addition, 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 U.S.
+Added: Increasingly, third-party payors are requiring that drug companies provide them with predetermined rebates from list prices.
+Added: We cannot be sure that reimbursement will be available for any product candidate that we may commercialize and, if reimbursement is available, the level of reimbursement.
+Added: In addition, many pharmaceutical manufacturers must calculate and report certain price reporting metrics to the government, such as average sales price and best price.
+Added: Penalties may apply in some cases when such metrics are not submitted accurately and timely.
+Added: Further, these prices for drugs may be reduced by mandatory discounts or rebates required by government healthcare programs.
+Added: Finally, in some foreign countries, the proposed pricing for a drug must be approved before it may be lawfully marketed.
+Added: The requirements governing drug pricing vary widely from country to country.
+Added: For example, the European Union provides options for its member states to restrict the range of medicinal products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use.
+Added: To obtain reimbursement or pricing approval, some of these countries may require the completion of clinical trials that compare the cost effectiveness of a particular product candidate to currently available therapies.
+Added: A member state may approve a specific price for the medicinal product or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the medicinal product on the market.
+Added: 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 of our product candidates.
+Added: Historically, products launched in the European Union do not follow price structures of the U.S.
+Added: and generally prices tend to be significantly lower.
Healthcare Reform
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There is significant interest in promoting changes in healthcare systems with the stated goals of containing healthcare costs, improving quality or expanding access.
−Removed: In the United States, the pharmaceutical industry has been a particular focus of these efforts and has been significantly affected by federal and state legislative initiatives, including those designed to limit the pricing, coverage, and reimbursement of pharmaceutical and biopharmaceutical products, especially under government-funded health care programs, and increased governmental control of drug pricing.
+Added: In the United States, the pharmaceutical industry has been a particular focus of these efforts and has been significantly affected by federal and
+Added: state legislative initiatives, including those designed to limit the pricing, coverage, and reimbursement of pharmaceutical and biopharmaceutical products, especially under government-funded health care programs, and increased governmental control of drug pricing.
The ACA, which was enacted in March 2010, substantially changed the way healthcare is financed by both governmental and private insurers in the United States, and significantly affected the pharmaceutical industry.
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Moreover, there has recently been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in several Congressional inquiries and proposed and enacted federal and state measures designed to, among other things, reduce the cost of prescription drugs, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drug products.
−Removed: For example, in May 2019, CMS adopted a final rule allowing Medicare Advantage Plans the option to use step therapy for Part B drugs, permitting Medicare Part D plans to apply
−Removed: certain utilization controls to new starts of five of the six protected class drugs, and requiring the Explanation of Benefits for Part D beneficiaries to disclose drug price increases and lower cost therapeutic alternatives, which went into effect on January 1, 2021.
+Added: For example, in May 2019, CMS adopted a final rule allowing Medicare Advantage Plans the option to use step therapy for Part B drugs, permitting Medicare Part D plans to apply certain utilization controls to new starts of five of the six protected class drugs, and requiring the Explanation of Benefits for Part D beneficiaries to disclose drug price increases and lower cost therapeutic alternatives, which went into effect on January 1, 2021.
In response to the Biden administration’s October 2022 executive order, on February 14, 2023, HHS released a report outlining three new models for testing by the CMS Innovation Center which will be evaluated on their ability to lower the cost of drugs, promote accessibility, and improve quality of care.
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Specifically, we expect regulators to continue pushing for transparency to drug pricing, reducing the cost of prescription drugs under Medicare, reviewing the relationship between pricing and manufacturer patient programs, and reforming government program reimbursement methodologies for drugs.
+Added: Individual states in the U.S.
+Added: have also become increasingly active in passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain drug access and marketing cost disclosure and transparency measures, and designed to encourage importation from other countries and bulk purchasing.
+Added: 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.
+Added: In addition, regional healthcare authorities and individual
+Added: hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription drug and other healthcare programs.
+Added: This could reduce the ultimate demand for its drugs or put pressure on its drug pricing, which could negatively affect our business, financial condition, results of operations and prospects.
Other Government Regulation Outside of the United States
13 unchanged sentences
The GDPR imposes a number of strict obligations and restrictions on the ability to process, including collecting, analyzing and transferring, personal data of individuals, in particular with respect to health data from clinical trials and adverse event reporting.
−Removed: The GDPR includes requirements relating to the legal basis of the processing (such as consent of the individuals to whom the personal data relates), the information provided to the individuals prior to processing their personal data, the notification obligations to the national data protection authorities, and the security and confidentiality of the personal data.
+Added: The GDPR includes requirements relating to the legal basis of the processing (such as consent of the individuals to whom the personal data relates), the information provided to the individuals prior to processing their personal data, the personal data breaches which may have to be notified to the national data protection authorities and data subjects, the measures to be taken when engaging processors, and the security and confidentiality of the personal data.
EU Member States may also impose additional requirements in relation to health, genetic and biometric data through their national legislation.
2 unchanged sentences
Among the appropriate safeguards that can be used, the data exporter may use the standard contractual clauses (“SCCs”).
+Added: When relying on SCCs, data exporters are also required to conduct a transfer risk assessment to verify if anything in the law and/or practices of the third country may impinge on the effectiveness of the SCCs in the context of the transfer at stake and, if so, to identify and adopt supplementary measures that are necessary to bring the level of protection of the data transferred to the EU standard of essential equivalence.
+Added: Where no supplementary measure is suitable, the data exporter should avoid, suspend or terminate the transfer.
With regard to the transfer of data from the EEA to the United States, on July 10, 2023, the EC adopted its adequacy decision for the EU-US Data Privacy Framework.
1 unchanged sentence
companies participating in the framework.
−Removed: Failure to comply with the requirements of the GDPR and the related national data protection laws of the EU Member States may result in significant monetary fines for noncompliance of up to €20 million or 4% of the annual global revenues of the noncompliant company, whichever is greater, other administrative penalties and a number of criminal offenses (punishable by uncapped fines) for organizations and, in certain cases, their directors and officers, as well as civil liability claims from individuals whose personal data was processed.
+Added: With regard to the transfer of data from the EU to the United Kingdom (“UK”), personal data may freely flow from the EEA to the UK since the UK is deemed to have an adequate data protection level.
+Added: However, the adequacy decisions
+Added: include a ‘sunset clause’ which entails that the decisions will automatically expire four years after their entry into force, unless renewed.
+Added: Failure to comply with the requirements of the GDPR and the related national data protection laws of the EU Member States may result in significant monetary fines for noncompliance of up to €20 million or 4% of the annual global revenues of the noncompliant company, whichever is greater, other administrative penalties and a number of criminal offenses for organizations and, in certain cases, their directors and officers, as well as civil liability claims from individuals whose personal data was processed.
Data protection authorities from the different EU Member States may still implement certain variations, enforce the GDPR and national data protection laws differently, and introduce additional national regulations and guidelines, which adds to the complexity of processing personal data in the EU.
−Removed: Guidance developed at both the EU level and at the national level in individual EU Member States concerning implementation and compliance practices are often updated or otherwise revised.
−Removed: Furthermore, there is a growing trend towards the required public disclosure of clinical trial data in the EU, which adds to the complexity of obligations relating to processing health data from clinical trials.
−Removed: Such public disclosure obligations are provided in the new EU Clinical Trials Regulation No.
+Added: Furthermore, there are specific requirements relating to processing health data from clinical trials, including public disclosure obligations provided in the EU Clinical Trials Regulation No.
536/2014 (CTR), EMA disclosure initiatives and voluntary commitments by industry.
Failure to comply with these obligations could lead to government enforcement actions and significant penalties against us, harm to our reputation, and adversely impact our business and operating results.
−Removed: The uncertainty regarding the interplay between different regulatory frameworks, such as the CTR and the GDPR, further adds to the complexity that we face with regard to data protection regulation.
−Removed: With regard to the transfer of personal data from the EEA to the United Kingdom (UK), personal data may now freely flow from the EEA to the UK since the UK is deemed to have an adequate data protection level.
−Removed: However, the adequacy decisions include a ‘sunset clause’ which entails that the decisions will automatically expire four years after their entry into force.
−Removed: Additionally, following the UK’s withdrawal from the EU and the EEA, companies also have to comply with the UK’s data protection laws (including the UK GDPR (as defined in section 3(10) (as supplemented by section 205(4)) of the Data Protection Act 2018 (the DPA 2018)), the DPA 2018, and related data protection laws in the UK).
+Added: Additionally, following the UK’s withdrawal from the EU and the EEA, companies also have to comply with the UK’s data protection laws (including the UK GDPR (as defined in section 3(10) (as supplemented by section 205(4)) of the Data Protection Act 2018 (“DPA 2018”)), the DPA 2018, and related data protection laws in the UK).
Separate from the fines that can be imposed by the GDPR, the UK regime has the ability to fine up to the greater of £17.5 million or 4% of global turnover.
−Removed: Following the UK’s withdrawal from the EU and the EEA, companies are subject to specific transfer rules under the UK regime;
−Removed: personal data may flow freely from the UK to the EEA, since the EEA is deemed to have an adequate data protection level for purposes of the UK regime.
−Removed: These UK international transfer rules broadly mirror the GDPR rules.
+Added: Companies are subject to specific transfer rules under the UK regime which broadly mirror the GDPR rules.
On February 2, 2022, the UK Secretary of State laid before the UK Parliament the international data transfer agreement (“IDTA”) and the international data transfer addendum to the EC’s standard contractual clauses for international data transfers (“Addendum”) and a document setting out transitional provisions.
The IDTA and Addendum came into force on March 21, 2022 and replaced the old SCCs for the purposes of the UK regime.
−Removed: However, the transitional provisions, adopted with the IDTA and the Addendum, provide that contracts concluded on or before September 21, 2022 on the basis of any old SCCs continue to provide appropriate safeguards for the purpose of the UK regime until March 21, 2024, provided that the processing operations that are the subject matter of the contract remain unchanged and reliance on those clauses ensures that the transfer of personal data is subject to appropriate safeguards.
+Added: Regarding transfer from the UK to the EEA, personal data may flow freely since the EEA is deemed to have an adequate data protection level for purposes of the UK regime.
With regard to the transfer of personal data from the UK to the United States, the UK government has adopted an adequacy decision for the United States, the UK-US Data Bridge, which came into force on October 12, 2023.
2 unchanged sentences
Drug and Biologic Development Process
−Removed: Regardless of where they are conducted, all clinical trials included in applications for marketing authorization (MA) for human medicines in the European EU/EEA must have been carried out in accordance with EU regulations.
+Added: Regardless of where they are conducted, all clinical trials included in applications for marketing authorization (“MA”) for human medicines in the EU/EEA must have been carried out in accordance with EU regulations.
This means that clinical trials conducted in the EU/EEA have to comply with EU clinical trial legislation but also that clinical trials conducted outside the EU/EEA have to comply with ethical principles equivalent to those set out in the EEA, including adhering to international good clinical practice and the Declaration of Helsinki.
1 unchanged sentence
The CTR replaced the Clinical Trials Directive 2001/20/EC, (“Clinical Trials Directive”) and introduced a complete overhaul of the existing regulation of clinical trials for medicinal products in the EU.
−Removed: Under the former regime, which will expire after a transition period of three years, as outlined below in more detail, before a clinical trial can be initiated it must be approved in each EU member state where there is a site at which the clinical trial is to be conducted.
−Removed: The approval must be obtained from two separate entities:
−Removed: the National Competent Authority (NCA) and one or more Ethics Committees.
−Removed: The NCA of the EU Member States in which the clinical trial will be conducted must authorize the conduct of the trial, and the independent Ethics Committee must grant a positive opinion in relation to the conduct of the clinical trial in the relevant EU member state before the commencement of the trial.
−Removed: Any substantial changes to the trial protocol or other information submitted with the clinical trial applications must be submitted to or approved by the relevant NCA and Ethics Committees.
−Removed: Under the current regime all suspected unexpected serious adverse reactions to the investigated drug that occur during the clinical trial must be reported to the NCA and to the Ethics Committees of the EU member state where they occur.
−Removed: A more unified procedure will apply under the new CTR.
−Removed: A sponsor will be able to submit a single application for approval of a clinical trial through a centralized EU clinical trials portal.
+Added: Under the new CTR, a sponsor is able to submit a single application for approval of a clinical trial through a centralized EU clinical trials portal (“the Clinical Trials Information System” or “CTIS”).
One national regulatory authority (the reporting EU member state proposed by the applicant) will take the lead in validating and evaluating the application consult and coordinate with the other concerned EU Member States.
3 unchanged sentences
The CTR also aims to streamline and simplify the rules on safety reporting, and introduces enhanced transparency requirements such as mandatory submission of a summary of the clinical trial results to the EU Database.
−Removed: The CTR foresees a three-year transition period.
−Removed: EU Member States will work in CTIS immediately after the system has gone live.
−Removed: Since January 31, 2023, submission of initial clinical trial applications via CTIS is mandatory, and by January 31, 2025, all ongoing trials approved under the former Clinical Trials Directive will need to comply with the CTR and have to be transitioned to CTIS.
+Added: Since January 31, 2023, submission of initial clinical trial applications via CTIS is mandatory and CTIS serves as the single entry point for submission of clinical trial-related information and data.
+Added: By January 31, 2025, all ongoing trials approved under the former Clinical Trials Directive will need to comply with the CTR and have to be transitioned to CTIS.
On July 19, 2023, the EC published guidance concerning the steps to be taken in this transition.
8 unchanged sentences
In the EEA, after completion of all required clinical testing, pharmaceutical products may only be placed on the market after obtaining a MA.
−Removed: To obtain an MA of a drug under European Union regulatory systems, an applicant can submit an MAA through, amongst others, a centralized or decentralized procedure.
+Added: To obtain an MA of a drug under EU regulatory systems, an applicant can submit an MAA through, amongst others, a centralized or decentralized procedure.
To be used or sold in the UK, a drug must have an effective MA obtained by a centralized application through EMA or a national application.
5 unchanged sentences
Health Canada, Swiss Medic, FDA, EMA, among others).
−Removed: The IRP allows medicinal products approved in other jurisdictions that meet certain criteria to undergo a fast-tracked MHRA review to obtain and/or update a MA in the UK or Great Britain.
+Added: The IRP allows medicinal products approved in other jurisdictions that meet certain criteria to undergo a fast-tracked MHRA review to obtain and/or update a MA in the UK.
Applicants can submit initial MAAs to the IRP but the procedure can also be used throughout the lifecycle of a product for post-authorization procedures including line extensions, variations and renewals.
Centralized Authorization Procedure
−Removed: The centralized procedure provides for the grant of a single MA that is issued by the EC following the scientific assessment of the application by the European Medicines Agency (EMA) that is valid for all EU Member States as well as in the three additional EEA Member States.
−Removed: The centralized procedure is compulsory for specific medicinal products, including for medicines developed by means of certain biotechnological processes, products designated as orphan medicinal products, advanced therapy medicinal products (ATMP) and medicinal products with a new active substance indicated for the treatment of certain diseases (AIDS, cancer, neurodegenerative disorders, diabetes, auto-immune and viral diseases).
−Removed: For medicinal products containing a new active substance not yet authorized in the EEA before May 20, 2004 and indicated for the treatment of other diseases, medicinal products that constitute significant therapeutic, scientific or technical innovations or for which the grant of a MA through the centralized procedure would be in the interest of public health at EU level, an applicant may voluntarily submit an application for a MA through the centralized procedure.
+Added: The centralized procedure provides for the grant of a single MA that is issued by the EC following the scientific assessment of the application by the European Medicines Agency (“EMA”) that is valid for all EU Member States as well as in the three additional EEA Member States (Norway, Iceland and Liechtenstein).
+Added: The centralized procedure is compulsory for specific medicinal products, including for medicines developed by means of certain biotechnological processes, products designated as orphan medicinal products, advanced therapy medicinal products (gene therapy, somatic cell therapy, or tissue engineered medicines) and medicinal products with a new active substance indicated for the treatment of certain diseases (HIV/AIDS, cancer, neurodegenerative disorders, diabetes, auto-immune and viral diseases).
+Added: For medicinal products containing a new active substance not yet authorized in the EEA before May 20, 2004 and indicated for the treatment of other diseases, medicinal products that constitute significant therapeutic, scientific or technical innovations or for which the grant of a MA through the centralized procedure would be in the
+Added: interest of public health at EU level, an applicant may voluntarily submit an application for a MA through the centralized procedure.
Under the centralized procedure, the Committee for Medicinal Products for Human Use (“CHMP”) established at the EMA, is responsible for conducting the initial assessment of a drug.
10 unchanged sentences
(ii) they can be authorized under a decentralized procedure where an applicant applies for simultaneous authorization in more than one EU member state;
−Removed: or (iii) they can be authorized in an EU member state in accordance with that state’s national procedures and then be
−Removed: authorized in other EU countries by a procedure whereby the countries concerned agree to recognize the validity of the original, national MA (mutual recognition procedure).
+Added: or (iii) they can be authorized in an EU member state in accordance with that state’s national procedures and then be authorized in other EU countries by a procedure whereby the countries concerned agree to recognize the validity of the original, national MA (mutual recognition procedure).
The decentralized procedure permits companies to file identical MA applications for a medicinal product to the competent authorities in various EU Member States simultaneously if such medicinal product has not received marketing approval in any EU Member State before.
13 unchanged sentences
After these five years, the authorization may subsequently be renewed on the basis of a reevaluation of the risk-benefit balance.
−Removed: Once renewed, the MA is valid for an unlimited period unless the EC or the national competent authority decides, on justified grounds relating to pharmacovigilance, to proceed with only one additional five-year renewal.
+Added: Once renewed, the MA is valid for an unlimited period unless the EC or the national competent authority decides, on justified grounds relating to pharmacovigilance, to proceed
+Added: with only one additional five-year renewal.
Applications for renewal must be made to the EMA at least nine months before the five-year period expires.
−Removed: Additionally, the holder of a MA for an ATMP must put in place and maintain a system to ensure that each individual product and its starting and raw materials, including all substances coming into contact with the cells or tissues it may contain, can be traced through the sourcing, manufacturing, packaging, storage, transport and delivery to the relevant healthcare institution where the product is used.
Any authorization which is not followed by the actual placing of the drug on the EU market (in case of centralized procedure) or on the market of the authorizing member state within three years after authorization ceases to be valid.
For the UK, the period of three years during which the drug has not been marketed in Great Britain will be restarted from the date of conversion to a Great Britain MA.
−Removed: Conversion refers to the procedure by which, as of January 1, 2021, MAs granted on the basis of a centralized procedure in the EU are only valid in Norther Ireland but not in Great Britain, whereas, prior EU authorizations have all been automatically converted into UK MAs effective in Great Britain only.
+Added: Conversion refers to the procedure by which, as of January 1, 2021, MAs granted on the basis of a centralized procedure in the EU are only valid in Northern Ireland but not in Great Britain, whereas, prior EU authorizations have all been automatically converted into UK MAs effective in Great Britain only.
On the other hand, for the EU, in the case the drug has been marketed in the UK, the placing on the UK market before the end of the period starting when the UK left the EU on January 31, 2020 and ending on December 31, 2020 (the Brexit Transition Period) will be taken into account.
1 unchanged sentence
Advanced Therapy Medicinal Products
−Removed: In the EU, medicinal products, including ATMPs are subject to extensive pre-and post-market regulation by regulatory authorities at both the EU and national levels.
+Added: In the EU, medicinal products, including advanced therapy medicinal products (“ATMPs”) are subject to extensive pre-and post-market regulation by regulatory authorities at both the EU and national levels.
ATMPs comprise gene therapy products, somatic cell therapy products and tissue engineered products, which are genes, cells or tissues that have undergone substantial manipulation and that are administered to human beings in order to cure, diagnose or prevent diseases or regenerate, repair or replace a human tissue.
−Removed: Pursuant to the ATMP Regulation, the Committee on Advanced Therapies (CAT) is responsible in conjunction with the CHMP for the evaluation of ATMPs.
+Added: Pursuant to Regulation (EC) No 1394/2007, the Committee for Advanced Therapies (“CAT”) is responsible in conjunction with the CHMP for the evaluation of ATMPs.
The CHMP and CAT are also responsible for providing guidelines on ATMPs.
6 unchanged sentences
(i) the benefit/risk balance of the product is positive, (ii) it is likely that the applicant will be in a position to provide the comprehensive clinical data, (iii) unmet medical needs will be fulfilled by the grant of the MA and (iv) the benefit to public health of the immediate availability on the market of the medicinal product concerned outweighs the risk inherent in the fact that additional data are still required.
−Removed: A conditional MA must be renewed annually.
+Added: Once a conditional MA has been granted, the MA holder must fulfil specific obligations within defined timelines.
+Added: A conditional MA is valid for one year and must be renewed annually, but it can be converted into a standard MA once the MA holder fulfils the obligations imposed and the complete data confirm that the medicine’s benefits continue to outweigh its risks.
Data and Market Exclusivity
As in the United States, it may be possible to obtain a period of market and / or data exclusivity in the EU that would have the effect of postponing the entry into the marketplace of a competitor’s generic, hybrid or biosimilar product (even if the pharmaceutical product has already received a MA) and prohibiting another applicant from relying on the MA holder’s pharmacological, toxicological and clinical data in support of another MA for the purposes of submitting an application, obtaining MA or placing the product on the market.
−Removed: New Chemical Entities (NCE) approved in the EU qualify for eight years of data exclusivity and 10 years of marketing exclusivity.
+Added: Innovative medicinal products, referred to as New Chemical Entities (“NCE”) approved in the EU qualify for eight years of data exclusivity and 10 years of marketing exclusivity.
An additional non-cumulative one-year period of marketing exclusivity is possible if during the data exclusivity period (the first eight years of the 10‑year marketing exclusivity period), the MA holder obtains an authorization for one or more new therapeutic indications that are deemed to bring a significant clinical benefit compared to existing therapies.
4 unchanged sentences
Another year of data exclusivity may be added to the eight years, where a change of classification of a pharmaceutical product has been authorized on the basis of significant pre-trial tests or clinical trials (when examining an application by another applicant for or holder of market authorization for a change of classification of the same substance the competent authority will not refer to the results of those tests or trials for one year after the initial change was authorized).
−Removed: Products may not be granted data exclusivity since there is no guarantee that a product will be considered by the European Union’s regulatory authorities to include a NCE.
+Added: Products may not be granted data exclusivity since there is no guarantee that a product will be considered by the EU’s regulatory authorities to include a NCE.
Even if a compound is considered to be a NCE and the MA applicant is able to gain the prescribed period of data exclusivity, another company nevertheless could also market another version of the medicinal product if such company can complete a full MAA with their own complete database of pharmaceutical tests, preclinical studies and clinical trials and obtain MA of its product.
1 unchanged sentence
The current draft envisages e.g., a shortening of the periods of data exclusivity, however, there is currently neither a final version of this draft nor a date for its entry into force.
+Added: While the European Parliament adopted its approving position on the reform on April 10, 2024, no further required legislative steps have been taken since.
Orphan Designation and Exclusivity
−Removed: The criteria for designating an orphan medicinal product in the European Union are similar in principle to those in the United States.
−Removed: The EMA grants orphan drug designation if the medicinal product is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition affecting no more than five in 10,000 persons in the European Union (prevalence criterion).
−Removed: In addition, Orphan Drug Designation can be granted if, for economic reasons, the medicinal product would be unlikely to be developed without incentives and if there is no other satisfactory method approved in the European Union of diagnosing, preventing, or treating the condition, or if such a method exists, the proposed medicinal product is a significant benefit to patients affected by the condition.
+Added: The criteria for designating an orphan medicinal product in the EU are similar in principle to those in the United States.
+Added: The EMA grants orphan drug designation if the medicinal product is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition affecting no more than five in 10,000 persons in the EU (prevalence criterion).
+Added: In addition, Orphan Drug Designation can be granted if, for economic reasons, the medicinal product would be unlikely to be developed without incentives and if there is no other satisfactory method approved in the EU of diagnosing, preventing, or treating the condition, or if such a method exists, the proposed medicinal product is a significant benefit to patients affected by the condition.
An application for orphan drug designation (which is not a MA, as not all orphan-designated medicines reach the authorization application stage) must be submitted first before an application for MA of the medicinal product is submitted.
19 unchanged sentences
Products with an orphan designation in the EU can be considered for an orphan MA in Great Britain, but a UK-wide orphan MA can only be considered in the absence of an active EU orphan designation.
−Removed: The MHRA will review applications for orphan designation at the time of a MA, and will offer
−Removed: incentives, such as market exclusivity and full or partial refunds for MA fees to encourage the development of medicines in rare diseases.
+Added: The MHRA will review applications for orphan designation at the time of a MA, and will offer incentives, such as market exclusivity and full or partial refunds for MA fees to encourage the development of medicines in rare diseases.
Pediatric Development
22 unchanged sentences
It includes control of compliance with EU good manufacturing practices rules, manufacturing authorizations, pharmacovigilance rules and requirements governing advertising, promotion, sale, and distribution, recordkeeping, importing and exporting of medicinal products.
−Removed: Failure by us or by any of our third-party partners, including suppliers, manufacturers and distributors to comply with EU laws and the related national laws of individual EU Member States governing the conduct of clinical trials, manufacturing approval, MA of medicinal products and marketing of such products, both before and after grant of MA, statutory health insurance, bribery and anti-corruption or other applicable regulatory requirements may result in
−Removed: administrative, civil or criminal penalties.
+Added: Failure by us or by any of our third-party partners, including suppliers, manufacturers and distributors to comply with EU laws and the related national laws of individual EU Member States governing the conduct of clinical trials, manufacturing approval, MA of medicinal products and marketing of such products, both before and after grant of MA, statutory health insurance, bribery and anti-corruption or other applicable regulatory requirements may result in administrative, civil or criminal penalties.
These penalties could include delays or refusal to authorize the conduct of clinical trials or to grant MA, product withdrawals and recalls, product seizures, suspension, withdrawal or variation of the MA, total or partial suspension of production, distribution, manufacturing or clinical trials, operating restrictions, injunctions, suspension of licenses, fines and criminal penalties.
9 unchanged sentences
More generally, non-compliance with pharmacovigilance obligations can lead to the variation, suspension or withdrawal of the MA for the product or imposition of financial penalties or other enforcement measures.
−Removed: The manufacturing process for pharmaceutical products in the European Union is highly regulated and regulators may shut down manufacturing facilities that they believe do not comply with regulations.
−Removed: Manufacturing requires a manufacturing authorization, and the manufacturing authorization holder must comply with various requirements set out in the applicable EU laws, regulations and guidance, including Directive 2001/83/EC, Directive 2003/94/EC, Regulation (EC) No 726/2004 and the European Commission Guidelines for Good Manufacturing Practice (GMP).
−Removed: These requirements include compliance with EU GMP standards when manufacturing pharmaceutical products and active pharmaceutical ingredients, including the manufacture of active pharmaceutical ingredients outside of the European Union with the intention to import the active pharmaceutical ingredients into the European Union.
−Removed: Similarly, the distribution of pharmaceutical products into and within the European Union is subject to compliance with the applicable EU laws, regulations and guidelines, including the requirement to hold appropriate authorizations for distribution granted by the competent authorities of the EU Member States.
−Removed: The manufacturer or importer must have a qualified person who is responsible for certifying that each batch of product has been manufactured in accordance with GMP, before releasing the product for commercial distribution in the European Union or for use in a clinical trial.
+Added: The manufacturing process for pharmaceutical products in the EU is highly regulated and regulators may shut down manufacturing facilities that they believe do not comply with regulations.
+Added: Manufacturing requires a manufacturing authorization, and the manufacturing authorization holder must comply with various requirements set out in the applicable EU laws, regulations and guidance, including Directive 2001/83/EC, Directive 2003/94/EC (repealed by Directive 2017/1572 on January 31, 2022), Regulation (EC) No 726/2004 and the European Commission Guidelines for Good Manufacturing Practice (“GMP”).
+Added: These requirements include compliance with EU GMP standards when manufacturing pharmaceutical products and active pharmaceutical ingredients, including the manufacture of active pharmaceutical ingredients outside of the EU with the intention to import the active pharmaceutical ingredients into the EU.
+Added: Amendments or replacements of at least Directive 2001/83/EC and Regulation (EC) No 726/2004 are part of the reform proposal for European pharmaceutical legislation.
+Added: Similarly, the distribution of pharmaceutical products into and within the EU is subject to compliance with the applicable EU laws, regulations and guidelines, including the requirement to hold appropriate authorizations for distribution granted by the competent authorities of the EU Member States.
+Added: The manufacturer or importer must have a qualified person who is responsible for certifying that each batch of product has been manufactured in accordance with GMP, before releasing the product for commercial distribution in the EU or for use in a clinical trial.
Manufacturing facilities are subject to periodic inspections by the competent authorities for compliance with GMP.
8 unchanged sentences
Direct-to-consumer advertising of prescription-only medicines is also prohibited in the EU.
−Removed: Violations of the
−Removed: rules governing the promotion of medicinal products in the European Union could be penalized by administrative measures, fines and imprisonment.
+Added: Violations of the rules governing the promotion of medicinal products in the EU could be penalized by administrative measures, fines and imprisonment.
These laws may further limit or restrict the advertising and promotion of our products to the general public and may also impose limitations on its promotional activities with healthcare professionals.
4 unchanged sentences
In the EU, interactions between pharmaceutical companies and physicians are also governed by strict laws, regulations, industry self-regulation codes of conduct and physicians’ codes of professional conduct both at EU level and in the individual EU Member States.
−Removed: 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 prohibited in the European Union.
+Added: 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 prohibited in the EU.
The provision of benefits or advantages to physicians is also governed by the national anti-bribery laws of the EU Member States.
14 unchanged sentences
The TCA does not, however, contain wholesale mutual recognition of UK and EU pharmaceutical regulations and product standards.
−Removed: The UK government has adopted the Medicines and Medical Devices Act 2021 to enable the UK’s regulatory frameworks to be updated following the UK’s departure from the EU.
+Added: The UK government has adopted the Medicines and Medical Devices Act 2021 (“MMDA”) to enable the UK’s regulatory frameworks to be updated following the UK’s departure from the EU.
The MMDA introduces regulation-making, delegated powers covering the fields of human medicines, clinical trials of human medicines, veterinary medicines and medical devices.
The MHRA has since been consulting on future regulations for medicines and medical devices in the UK.
−Removed: For other countries outside of the European Union, such as countries in Eastern Europe, Latin America or Asia, the requirements governing the conduct of clinical trials, product licensing, pricing and reimbursement vary from country to country.
+Added: For other countries outside of the EU, such as countries in Eastern Europe, Latin America or Asia, the requirements governing the conduct of clinical trials, product licensing, pricing and reimbursement vary from country to country.
In all cases, again, the clinical trials must be conducted in accordance with GCP and the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki.
If we fail to comply with applicable foreign regulatory requirements, we may be subject to, among other things, fines, suspension of clinical trials, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions and criminal prosecution.
+Added: Additional Regulation
+Added: In addition to the foregoing, local, state and federal laws, including in the United States and Israel, regarding such matters as safe working conditions, manufacturing practices, environmental protection, fire hazard control and hazardous substances, including the Occupational Safety and Health Act, the Resource Conservancy and Recovery Act and the Toxic Substances Control Act, affect our business.
+Added: These and other laws govern our use, handling and disposal of various biological, chemical and radioactive substances used in, and wastes generated by, our operations.
+Added: If our operations result in contamination of the environment or expose individuals to hazardous or biohazardous substances, we could be liable for damages, environmental remediation, and/or governmental fines.
+Added: We believe that we are in material compliance with applicable environmental laws and occupational health and safety laws that continued compliance therewith will not have a material adverse effect on our business.
+Added: We cannot predict, however, how changes in these laws may affect our future operations.
+Added: We may incur significant costs to comply with such laws and regulations now or in the future.
+Added: General Information
+Added: Our internet address is www.apogeetherapeutics.com.
+Added: No portion of our website, or any other website that may be referenced, is incorporated by reference into this Annual Report.
+Added: You are advised to read this Annual Report in conjunction with other reports and documents that we file from time to time with the Securities and Exchange Commission (“SEC”).
+Added: The SEC maintains information for electronic filers (including Apogee) at its website at www.sec.gov.
+Added: We make our annual reports on Form 10-K, our quarterly reports on Form 10-Q, and our current reports on Form 8-K, and amendments to those reports, available on our internet website, free of charge, as soon as reasonably practicable after such material is electronically filed with, or furnished to, the SEC.
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.