−Removed: We are a clinical stage global biopharmaceutical company aiming to develop and deliver novel oral therapeutics to treat a wide range of chronic diseases with unmet medical need.
−Removed: Our differentiated technology platform leverages structure-based drug discovery and computational chemistry expertise and enables us to develop oral small molecule therapeutics for the treatment of various diseases including those impacting the metabolic, cardiovascular, and pulmonary systems.
−Removed: In February 2023, we completed our Initial Public Offering (“IPO”) for net proceeds of approximately $166.7 million, after deducting the underwriting discounts and commissions and estimated offering expenses payable by us.
−Removed: In September 2023, we entered into a share purchase agreement with certain institutional investors (the “Purchase Agreement”), pursuant to which we issued and sold an aggregate of 21,617,295 ordinary shares and 2,401,920 non-voting ordinary shares for net proceeds of approximately $281.5 million (the “Private Placement”).
−Removed: Our initial focus is on G-protein coupled receptors (“GPCRs”) as a therapeutic target class.
−Removed: GPCRs regulate numerous diverse physiological and pathological processes, and approximately one in every three marketed medicines targets GPCR-associated pathways.
−Removed: By leveraging our world-class GPCR know-how, we aim to design differentiated small molecule therapies to overcome the limitations of biologics and peptide therapies targeting this family of receptors.
−Removed: We are developing GSBR-1290, our oral small molecule product candidate targeting the validated glucagon-like-peptide-1 receptor (“GLP-1R”) for the treatment of type 2 diabetes mellitus (“T2DM”) and obesity.
−Removed: We completed our Phase 1 single ascending dose (“SAD”) study of GSBR-1290 in September 2022.
−Removed: GSBR-1290 was generally well tolerated and demonstrated dose- dependent pharmacokinetic (“PK”) and pharmacodynamic (“PD”) activity.
−Removed: We submitted an investigational new drug (“IND”) application to the FDA to support initiation of a Phase 1b study in T2DM and obesity and received FDA allowance in September 2022.
−Removed: We initiated the Phase 1b multiple ascending dose (“MAD”) study of
−Removed: GSBR-1290 in January 2023 and completed dosing in otherwise healthy overweight subjects in March 2023.
−Removed: In May 2023, we submitted a protocol amendment to the FDA and initiated dosing of the Phase 2a proof-of-concept study in T2DM and obesity.
−Removed: We reported topline data for the 28-day Phase 1b MAD study in September 2023, in which GSBR-1290 was generally well-tolerated with no adverse event (“AE”)-related discontinuations and demonstrated an encouraging safety profile and significant weight loss of up to 4.9% placebo-adjusted, supporting once-daily dosing.
−Removed: In December 2023, we reported clinically meaningful topline data from our Phase 2a T2DM cohort, interim results from our Phase 2a obesity cohort and topline data from a Japanese ethno-bridging study of GSBR-1290.
−Removed: These data demonstrated that GSBR-1290 was generally well-tolerated, with no treatment-related SAEs over 12 weeks, with only one participant discontinuing the study due to adverse events in the T2DM cohort and none in the obesity cohort.
−Removed: GSBR-1290 also showed significant reductions in weight in the obesity cohort at 8 weeks, and significant reductions in hemoglobin A1c (“HbA1c”) and weight in the T2DM cohort.
−Removed: We expect to report the full 12-week Phase 2a obesity data in the latter half of the second quarter of 2024 with additional 24 participant data.
−Removed: We also fully enrolled a formulation bridging and titration optimization study to evaluate capsule versus tablet PK and explore different titration regimens of GSBR-1290.
−Removed: We expect to report topline results from this study in the latter half of the second quarter of 2024, in preparation for the global Phase 2b study for obesity which we expect to initiate in the second half of 2024.
−Removed: A Phase 2 study in T2DM is also planned for the fourth quarter of 2024.
−Removed: A number of GPCR properties contribute to its importance as a drug target class, including interaction with a diverse set of signaling molecules, involvement in a vast array of physiological and pathological processes, and cell surface expression that enables extracellular drug binding.
−Removed: As such, GPCRs have emerged as the largest family of targets for approved drugs, have provided significant benefit to patients and have achieved blockbuster sales in a number of therapeutic indications, including diabetes (Victoza), bipolar disorders (Abilify, Seroquel), asthma (Singulair), hypertension (Diovan, Lopressor), and cardiovascular disease (Plavix).
−Removed: Despite this success, there remain a number of challenges to continued innovation in this target class, including (i) low expression levels on cell surfaces, (ii) the complexity of the multi-subunit peptide GPCR receptor, (iii) difficulties in obtaining relevant crystal structures as a basis for drug design, and (iv) non-specific signaling through multiple intracellular signaling pathways, a concept known as non-biased signaling, which can limit activity and increase side effects.
−Removed: We have developed a platform designed to address these key challenges, enabling us to discover small molecule drugs to effectively target GPCRs.
−Removed: Further, our platform has been designed to develop novel drugs against other targets where traditional drug discovery methods have not been adequate.
−Removed: Our next generation structure-based drug discovery platform is based on techniques that our founders have evolved for over 25 years, which enables us to generate small molecule product candidates designed to overcome the historical limitations of GPCR drug development.
−Removed: As shown below, we believe our insights and capability to visualize the three-dimensional protein structures of the target and the ligands combined with the computational chemistry capabilities of our co-founder and strategic partner, Schrödinger, give us significant competitive advantages in highly efficient and rational drug design.
+Added: We are a clinical stage global biopharmaceutical company developing novel oral small molecule therapeutics to treat a wide range of chronic diseases with unmet medical need.
+Added: Our differentiated technology platform leverages both structure-based drug discovery and our expertise in computational chemistry to discover and develop small molecule therapeutics against G-protein coupled receptors (“GPCRs”).
+Added: These important receptors regulate numerous and diverse physiological and pathological processes.
+Added: In fact, approximately one in every three marketed medicines targets GPCR-associated pathways for the treatment of various metabolic, cardiovascular and pulmonary disorders.
+Added: By leveraging our world-class GPCR know-how, we are designing differentiated small molecule therapies to overcome the limitations of biologics and peptide therapies that target this family of receptors.
+Added: Our most advanced product candidate to date is aleniglipron, also known as GSBR-1290, an oral small molecule selective glucagon-like-peptide-1 receptor (“GLP-1R”) agonist currently in two Phase 2 clinical trials for the treatment of obesity, overweight and related conditions.
+Added: Our obesity pipeline also includes ACCG-2671, an oral small molecule amylin receptor agonist development candidate in investigational new drug (“IND”)-enabling studies, multiple preclinical discovery stage small molecules targeting glucose-dependent insulinotropic polypeptide (“GIP”) and glucagon (“GCG”) receptors, as well as ANPA-0073, an oral small molecule agonist targeting the apelin (“APJ”) receptor in GLP-toxicology studies and Phase 2 ready.
+Added: Importantly, these programs have the potential to be developed as monotherapy as well as in fixed dose combination with our backbone therapeutics aleniglipron or ACCG-2671, as demonstrated below.
+Added: combination products enable us to potentially address diseases beyond obesity including type 2 diabetes mellitus (“T2DM”), heart failure, sleep apnea, chronic kidney disease (“CKD”), osteoarthritis, metabolic dysfunction-associated steatotic liver disease (“MASH”) and potentially even addiction and Parkinson’s disease and Alzheimer’s disease, areas where we are starting to see encouraging data with GLP-1Rs.
+Added: Our product candidates, as oral small molecules, have the potential to be more accessible medicines than biologics and peptide therapies with potential potentially differentiated effectiveness and safety and, from a manufacturing standpoint, more scalable towards meeting global demand.
+Added: Metabolic Franchise Strategy:
+Added: Fixed-Dose Combinations and Potential Indication Expansion
+Added: Obesity Market
+Added: Obesity is a complex, heterogeneous, chronic, and progressive disease, which substantially affects health, quality of life and mortality.
+Added: “’Obesity” and “severe obesity” are defined by a body mass index (“BMI”) of greater than 30 and 40 kg/m 2 , respectively, with abnormal or excessive fat accumulation.
+Added: “Overweight” is defined by a BMI of greater than 25 kg/m 2 .
+Added: Obesity has wide-ranging consequences on the health and wellbeing of individuals.
+Added: The metabolic consequences of obesity include, but are not limited to, T2DM, MASH, hypercholesterolemia, chronic kidney disease, atherosclerotic cardiovascular disease, heart failure, osteoarthritis and sleep apnea.
+Added: In the United States, 58% of adults with obesity have high blood pressure, a risk factor for heart disease and approximately 23% of adults with obesity have diabetes.
+Added: According to the Centers for Disease Control and Prevention, the prevalence of overweight and obesity in the United States between 2017 – 2020 was more than 100 million adults, representing approximately 42% of the population.
+Added: During the same time, the prevalence of severe obesity was more than 22 million adults, representing approximately 9% of the population.
+Added: Globally, obesity affects more than 890 million (13%) adults and has continued to increase in prevalence worldwide since the World Health Organization declared a global obesity epidemic.
+Added: This deeply rooted and global health crisis represents a total addressable market of more than $100 billion annually.
+Added: Global Obesity Epidemic:
+Added: Prevalence of Obesity and Overweight and Total Addressable Market
+Added: Currently Approved Peptide Treatments have Limitations
+Added: Currently approved GLP-1R agonists provide multiple beneficial effects in patients with T2DM, including excellent glycemic control with low risk of hypoglycemia, weight loss and protection against cardiovascular and renal complications.
+Added: However, approved GLP-1R agonists have several shortcomings in terms of patient convenience, ease of dosing and cost.
+Added: Injectable peptide GLP-1R agonists require patients to self-inject, require inconvenient refrigerated storage and are costly.
+Added: In addition, long acting GLP-1R agonists typically require long titration periods to reach an optimal dose for disease management in order to avoid treatment-associated gastrointestinal side effects, including nausea and vomiting.
+Added: Unfortunately, most patients today do not stay on therapy past a year, with discontinuation rates of 65% with injectable GLP-1R agonists after one year and up to 85% after two years as shown below.
+Added: This means that patients are not benefitting from sustained weight loss and the long-term cardiometabolic benefits that GLP-1R agonist can provide.
+Added: Discontinuation Rates of Approved GLP-1R Agonist Treatment Over First Two Year of Treatment
+Added: Oral Small Molecules:
+Added: A Solution for Long-Term Maintenance Therapy
+Added: We believe there is a significant opportunity for oral small molecules to enable patients to continue GLP-1R agonist treatment for sustained weight loss and long-term cardiometabolic benefits.
+Added: For example, oral semaglutide (Rybelsus), the first approved oral GLP-1R peptide agonist, provides an option for patients who are unable or unwilling to self-administer injectable therapies.
+Added: However, Rybelsus requires a stringent dosing protocol and dosing with up to four ounces of water and no food or beverage within 30 minutes.
+Added: Additionally, the product’s absorption enhancer may affect the absorption of other concomitantly administered oral medications.
+Added: Thus, we believe there is a significant unmet medical need for orally administered GLP-1R agonists that meet or exceed efficacy and safety parameters of available drugs with less stringent preparation requirements.
+Added: Existing constraints that should be eliminated or minimized include:
+Added: restrictive food or fluid dosing protocols, refrigeration and maintenance of effective concentrations throughout the dosing interval without interfering with the absorption of concomitant medications while offering the potential for combination products with other glucose-lowering agents or other commonly co-administered therapies.
+Added: In addition, the high prevalence of obesity and overweight together with the broad interest in currently approved GLP-1R peptides have contributed to past drug shortages for Wegovy and Zepbound.
+Added: Moreover, the scalability of weekly GLP-1R peptide injectables may be limited by fill-finish capacity and device requirements, while the scalability to large populations of oral GLP-1R analog peptides, including oral semaglutide, may be limited by large drug substance requirements arising from their poor bioavailability.
+Added: We believe we are well-positioned to overcome the limitations of existing peptide therapies through the development of novel oral small molecule therapeutics via our differentiated technology platform and approach.
+Added: Our Technology Platform and Approach
+Added: Our next generation, structure-based drug discovery platform is based on techniques that our founders have evolved over 25 years, which enables us to generate small molecule product candidates designed to overcome the historical limitations of GPCR drug development (see subsection titled “Challenges of GPCR Therapeutics Discovery and Development” below).
+Added: As shown below, we believe our insights and capabilities for visualizing three-dimensional ligand and target protein structures combined with computational chemistry capabilities of our co-founder and strategic partner, Schrödinger, give us significant competitive advantages in highly efficient and rational drug design.
We design our novel compounds by combining our knowledge of GPCR structures together with advanced physics-based computational methods, which we believe allows us to predict the binding affinity of molecules to the target site with a high degree of accuracy.
−Removed: Advantages of GPCR oral small molecule therapeutic
−Removed: OPPORTUNITIES
−Removed: Limited cellular and tissue permeability
−Removed: Customizable pharmaceutic properties
−Removed: Scalability and costs
−Removed: Orally available, better patient compliance
−Removed: Limited stability
−Removed: No cold-chain requirements
−Removed: Cold supply chain requirements
−Removed: Large scale manufacturing capability
+Added: Our Technology Platform Repeatedly Delivers New Oral Small Molecules
We believe the strengths of our platform position us to develop oral small molecule drugs that can deliver biologic-like activity and specificity.
1 unchanged sentence
We believe this is particularly important for the most prevalent chronic diseases including those involving the metabolic, cardiovascular and pulmonary systems.
−Removed: Our lead product candidate, GSBR-1290, is an oral and biased small molecule agonist of GLP-1R, a validated GPCR drug target for T2DM and obesity, currently in Phase 2 development.
−Removed: There are currently ten marketed peptide molecules that target GLP-1R;
−Removed: collectively, these peptide therapies generated worldwide sales of $65 billion in 2023.
−Removed: However, there are currently no approved oral small molecule therapies targeting GLP-1R.
−Removed: In non-human primate (“NHP”), studies, GSBR-1290 demonstrated glucose-dependent insulin secretion and suppressed food intake, resulting in weight reduction.
−Removed: Given these findings and other compelling preclinical data, we completed a Phase 1 study in healthy volunteers for GSBR-1290 in September 2022, a Phase 2a study development in diabetes in December 2023 and expect to complete a Phase 2a study in obesity in the latter half of the second quarter of 2024.
−Removed: To date GSBR-1290 has demonstrated generally favorable safety, tolerability and efficacy results in clinical trials.
−Removed: Beyond GSBR-1290, we are developing next generation GLP-1R candidates, including dual GLP-1R/glucose-dependent insulinotropic polypeptide receptor (“GIPR”) agonists and amylin agonists, each designed with customized properties to achieve additional benefit.
−Removed: We are also developing oral small molecule therapeutics targeting other GPCRs for the treatment of pulmonary and cardiovascular diseases.
−Removed: Specifically, we are advancing ANPA-0073, our biased agonist, targeting the apelin receptor (“APJR,”) a GPCR that has been implicated in idiopathic pulmonary fibrosis (“ IPF”).
−Removed: In September 2022, we completed a Phase 1 SAD and MAD study evaluating ANPA-0073 in healthy human volunteers, in which it was generally well tolerated.
−Removed: Additionally, we are developing an antagonist that targets lysophosphatidic acid 1 receptor (“ LPA1R”), a GPCR implicated in responses to tissue injury and pro-fibrotic processes.
−Removed: We have demonstrated substantial anti-fibrotic activity of our LPA1R antagonists in mouse models of fibrotic lung disease and we selected a development candidate, LTSE-2578, in January 2023 and expect to initiate a first-in-human study in the second quarter of 2024.
−Removed: We are also dedicated to fueling our pipeline and pursuing drug discovery partnerships.
−Removed: Through our discovery engine, we leverage the power of cryo-electron microscopy (“cryo-EM”) machine learning and X-ray crystallography, as the basis for our molecular designs.
−Removed: We employ state-of-the-art small molecule hit identification, including DNA encoded library technology and affinity mass spectrometry selections for membrane proteins.
+Added: Oral small molecules have large-scale manufacturing advantages and are generally more cost-effective to produce than peptides.
+Added: As shown below, we have a current manufacturing capacity of 6,000 tons/year of aleniglipron, which is enough to supply treatment to more than 120 million patients per year.
+Added: Potential Differentiation for Aleniglipron on Scalable Manufacturing
+Added: Our Pipeline and Programs
+Added: We pursue opportunities to target GPCRs in human diseases on the basis of validated biology, safety, development feasibility and market potential.
+Added: We are building a pipeline of wholly-owned oral small molecule drugs targeting chronic diseases with unmet medical need and commercial potential.
+Added: Our initial focus is in areas of metabolic, cardiovascular and pulmonary diseases.
+Added: The following table summarizes key information on our current product candidates:
Our mission is to discover and develop broadly accessible oral therapeutics to treat a wide range of chronic diseases with unmet medical need through advancements in structure-based drug discovery and computational chemistry.
5 unchanged sentences
We intend to expand into other key emerging areas where we can leverage our platform to develop orally-available molecules against targets that historically have been limited to peptides or biologics.
−Removed: ● Advance our GLP-1R franchise of metabolic focused assets, establishing a foundation for additional opportunities.
−Removed: Our franchise approach involves developing next generation GLP-1R agonists, including dual GLP-1R/GIPR agonists, each designed with customized properties to achieve maximum benefit.
−Removed: Based on compelling data generated from our preclinical studies, we believe that our lead GLP-1R candidate, GSBR-1290, has the potential to be a differentiated treatment for T2DM and obesity.
−Removed: In obesity, we expect to complete the Phase 2a study in the latter half of the second quarter of 2024 and initiate a Phase 2b study in the fourth quarter of 2024.
−Removed: In T2DM, we have completed the Phase 2a study and expect to initiate a Phase 2 study in the second half of 2024.
−Removed: In addition, our next generation GLP-1R program is focused on the development of orally-available small molecules in combination with GLP-1R, including GIPR, amylin, as well as the APJR for selective or muscle-sparing weight loss.
+Added: • Advance our metabolic franchise including our GLP-1R and amylin backbone therapies, establishing a foundation for additional opportunities.
+Added: Our franchise approach involves developing next generation GLP-1R and amylin receptor agonists, designed with customized properties to achieve maximum benefit.
+Added: Based on compelling data generated from our clinical and preclinical studies, we believe that our lead GLP-1R candidate, aleniglipron, has the potential to be a differentiated treatment for obesity.
+Added: Based on preclinical data, we believe that our lead oral small molecule amylin development candidate, ACCG-2671, has the potential to be the first-in-class oral small molecule amylin treatment option for obesity.
+Added: In addition, our program is
+Added: focused on the development of orally-available small molecules in combination with GLP-1R and/or amylin, including glucose-dependent insulinotropic polypeptide receptor (“GIPR”), GCG receptor (“GCGR”), as well as the APJ receptor for selective or muscle-sparing weight loss.
• Pursue additional opportunities in chronic diseases.
Chronic diseases pose a major burden to patients and healthcare systems worldwide and there is an urgent need for effective and more accessible treatment options.
−Removed: Our APJR agonist product candidate, ANPA-0073 is in development for the treatment of cardiopulmonary and cardiometabolic conditions.
−Removed: In addition, we are evaluating LPA1R antagonism in IPF, and selected a development candidate (LTSE-2578) in January 2023 and expect to initiate a first-in-human study in the second quarter of 2024.
−Removed: We plan to continue to harness insights on GPCR targets, particularly among metabolic, endocrine, pulmonary, and cardiovascular indications, and leverage our platform to fuel our pipeline through our discovery engine at Basecamp Bio Inc.
−Removed: (“Basecamp Bio”).
+Added: We are evaluating LPA1R antagonism in idiopathic pulmonary fibrosis, or IPF and are currently conducting a Phase 1 first-in-human study.
+Added: We plan to continue to harness insights on GPCR targets, particularly among metabolic, endocrine, pulmonary and cardiovascular indications, and leverage our platform to fuel our pipeline.
• Maximize the potential of our platform and portfolio through strategic partnerships.
2 unchanged sentences
We plan to leverage our platform for external opportunities where partners bring additional disease biology understanding, drug development and commercial expertise, regional insights or other complementary capabilities.
−Removed: Our Pipeline and Programs
−Removed: We pursue opportunities to target GPCRs in human diseases on the basis of validated biology, safety, development feasibility and market potential.
−Removed: We are building a pipeline of wholly-owned oral small molecule drugs targeting chronic diseases with unmet medical need and commercial potential.
−Removed: Our initial focus is in areas of metabolic, cardiovascular and pulmonary diseases.
−Removed: The following table summarizes key information on our current product candidates:
−Removed: Metabolic Diseases
−Removed: We are initially advancing our GLP-1R franchise as a treatment for obesity and T2DM , conditions affecting approximately 764 million and 537 million people worldwide, respectively.
−Removed: We believe our GLP-1R programs have demonstrated qualities that offer the potential to differentiate them from current approved and development stage programs.
−Removed: ● Selective GLP-1R Program.
−Removed: GSBR-1290 is a biased GLP-1R agonist which has demonstrated dose-dependent activation of the G-protein pathway.
−Removed: GSBR-1290 has also demonstrated glucose-dependent insulin secretion and suppressed food intake with similar activity to an approved injectable peptide GLP-1R agonist in preclinical models.
−Removed: The product candidate is designed to be orally administered, without restrictions on diet or concomitant therapy .
−Removed: ● GLP-1R Combination.
−Removed: Our combination and next generation small molecule program is focused on GLP-1R candidates, including GLP-1R/GIPR agonists and amylin agonists, each designed with customized properties to achieve additional benefits like enhanced metabolic control .
−Removed: Our APJR agonist, ANPA-0073, is being evaluated for selective or muscle-sparing weight loss.
−Removed: ANPA-0073, is a G-protein biased APJR agonist for which we completed a Phase 1 SAD and MAD study, in which it was generally well tolerated as a single dose from 2mg to 600 mg, and at doses from 75 mg to 500 mg once daily dosing for seven days, with no SAEs reported.
−Removed: Pulmonary and Cardiovascular Diseases
−Removed: We are evaluating our LPA1R program, LTSE-2578 for IPF and PPF .
−Removed: Our LPA1R program, LTSE-2578, is an investigational oral small molecule LPA1R antagonist.
−Removed: We believe LTSE-2578 is a differentiated molecule because it demonstrated potent in vitro and in vivo activity in preclinical IPF models and dose dependent inhibition of histamine release as the PD marker.
−Removed: We plan to initiate a first-in-human study in the second quarter of 2024.
−Removed: GPCRs as a Therapeutic Target Family
−Removed: GPCRs form the largest human membrane protein family, consisting of approximately 800 identified members as illustrated below.
−Removed: GPCRs are involved in several vital physiological functions, such as immune system regulation and inflammation, autonomic nervous system transmission, behavioral and mood regulation, sensory transmission, and maintenance of homeostasis, making them important targets for numerous therapeutics.
−Removed: To date, there are approximately 475 drugs on the market acting at over 100 unique GPCRs.
−Removed: Additionally, more than 220 GPCRs have not yet been explored as clinical targets, hence representing broad untapped therapeutic potential for addressing global healthcare needs.
−Removed: Phylogenetic tree of GPCR targets
−Removed: GPCR targeting drugs have successfully delivered significant patient benefit resulting in large market opportunities in many therapeutic areas.
−Removed: Examples include liraglutide (Victoza for T2DM), aripiprazole (Abilify for schizophrenia, bipolar disorder and depression), montelukast (Singulair for asthma), valsartan (Diovan for hypertension), metoprolol (Lopressor for hypertension, angina, and myocardial infarction), and clopidogrel (Plavix for myocardial infarction and stroke).
−Removed: GPCR related drugs are the largest drug class accounting for approximately 27% of global pharmaceutical sales with estimated aggregate sales of $890 billion between 2011 and 2015.
−Removed: GPCRs are proteins that span the entire width of cell membranes.
−Removed: Their primary function is to recognize extracellular substances, primarily ligands, and transmit signals across the cell membrane to the inside of the cell.
−Removed: Schematic of a GPCR
−Removed: As shown above, the binding of extracellular ligands to GPCRs elicits conformational changes that impact the intracellular side of the receptor, resulting in the formation of a GPCR complex with signal transducers, particularly G-proteins.
−Removed: These signal transducers go on to interact with second messengers, ultimately either stimulating or inhibiting certain cellular processes.
−Removed: GPCRs signal not only through G-proteins, but also through β-arrestins and other non-G-protein transducers.
−Removed: Β-arrestins play an essential role in many physiological and pathological processes, and are involved in the desensitization, internalization, sequestration, and trafficking of GPCRs.
−Removed: Certain GPCR ligands are capable of simultaneously activating both G-protein and non-G-protein mediated signaling pathways, which can lead to a variety of physiologic as well as pathologic effects.
−Removed: Challenges of GPCR Therapeutic Discovery and Development
−Removed: Despite tremendous advancements in structure-based drug design and development, GPCR drug discovery and development remains challenging.
−Removed: ● Similarity between the binding sites of GPCRs and related receptors can cause off-target toxicities:
−Removed: All GPCRs have the same overall three-dimensional architecture but the specific endogenous binding site is unique due to the placement of amino acid side chains shaping the binding site.
−Removed: For instance, the early sphingosine-1-phosphate 1 receptor (“S1P1R”) agonist Gilenya led to the development of a new class of therapy for the treatment of multiple sclerosis, but had exhibited bradycardia as a side effect due in part to sphingosine-1-phosphate 3 receptor (“S1P3R”) activity, a very closely related S1P1 receptor subtype.
−Removed: The next generation S1P1R agonist Zeposia was designed using structural information by Receptos, Inc.
−Removed: to remove the S1P3 and other activities and therefore did not have the same side effect profile as Gilenya.
−Removed: ● GPCRs are involved in diverse downstream signaling pathways which can result in side effects:
−Removed: GPCRs interact with a range of molecules, including G-protein and non-G-protein
−Removed: transducers including β-arrestin.
−Removed: Signaling pathway selectivity results from agonist-induced specific receptor conformation and when targeting GPCRs involved in multiple signaling pathways, both therapeutic benefits and side effect issues may arise.
−Removed: ● Expression levels of GPCRs are low and create significant hurdles to structural and PD characterization:
−Removed: Recombinant protein expression of GPCRs remains extremely challenging.
−Removed: Expression levels of GPCRs are low and improvement of expression level continues to be mainly empirical and resource-consuming.
−Removed: GPCRs are complex membrane proteins that require a stable membrane environment throughout the purification process to avoid destabilization and aggregation.
−Removed: ● GPCR structural visualization is complex making GPCR structure-based drug discovery challenging:
−Removed: Structure-based drug design requires rapid iterations of GPCR structures in complex with specific new ligands to determine their effects on conformation.
−Removed: This is well established through robust crystallography platforms for soluble drug targets.
−Removed: Cryo-EM has helped accelerate the membrane protein field, but the methods still require substantial expertise and execution.
−Removed: Drug discovery approaches targeting GPCRs have evolved from traditional approaches including high throughput screening to rational design for enhanced activity, tailor-made signaling response, and improved selectivity, which leads to improved safety and tolerability profiles.
−Removed: Our Platform and Approach
−Removed: Our platform is based on techniques that our founders have been evolving for over 25 years, which have enabled them to deliver multiple marketed medicines.
−Removed: Our approach enables us to generate small molecule product candidates that are designed to overcome the historical limitations of GPCR drug development.
−Removed: Our insights and capabilities enable us to visualize the three-dimensional protein structures of the target and the ligands.
−Removed: We believe this visualization combined with the computational chemistry capabilities of Schrödinger gives us significant competitive advantages in highly efficient and rational drug design.
−Removed: We design our novel compounds by combining our knowledge of GPCR structures together with advanced physics-based computational methods, which we believe allows us to predict the binding affinity of molecules to the target site with a high degree of accuracy.
−Removed: As shown below, our technology platform allows us to determine feasibility, optimize the design of, and efficiently generate families of potent and highly selective small molecule candidates.
−Removed: Structure Therapeutics integrated technology platform from target to IND
−Removed: Oral small molecules have the potential to address the key limitations of biologic and peptide drugs, such as high cost and patient inconvenience, thereby significantly improving patient access.
−Removed: We believe this is particularly important for the most prevalent chronic diseases including those involving the endocrine, cardiovascular, and pulmonary systems.
−Removed: We believe the strengths of our technology platform will enable us to develop oral small molecule drugs that can deliver biologic-like activity and specificity.
−Removed: Strategic GPCR Target Prioritization
−Removed: We start with target prioritization by focusing on validated GPCR targets that do not have attractive small molecule solutions.
−Removed: We then prioritize by assessing the feasibility of a small molecule solution for these targets and market opportunities of their respective target indication.
−Removed: Expertise in GPCR Structure-Based Drug Discovery
−Removed: GPCRs are difficult to characterize structurally because they are composed of seven transmembrane domains, have low expression, and are unstable outside of the cell membrane environment.
−Removed: While structure-based approaches have been utilized for decades in soluble protein drug discovery, recent breakthrough advancements in computational chemistry, artificial intelligence, machine learning and electron microscopy are redefining the field of GPCR structure-based drug discovery.
−Removed: Visualization of GPCR Structure and binding site interactions
−Removed: As shown above, our structure-based technology platform combines direct visualization of protein receptor binding interactions with advanced simulation of molecular motion and signal transduction.
−Removed: Site 1 is considered to be the orthosteric or primary binding site for receptor activation.
−Removed: Site 2 is on the surface of the receptor, often referred to as the allosteric site and may potentially regulate receptor activation signaling.
−Removed: By visualizing and analyzing how different ligands bind to a particular target and specific sites and affect their conformational dynamics, we believe we are able to efficiently convert biologics and peptides into more accessible, patient-accommodating oral small molecules.
−Removed: In addition, we can enhance the pharmaceutic properties of our small molecules with the aim to elicit the desired function while maintaining superior pharmaceutical properties.
−Removed: Non-biased vs biased GPCR agonists
−Removed: Additionally, GPCR signaling can follow several pathways and molecules can be designed such that their pharmacology is selected to create “biased signaling” as illustrated above.
−Removed: GPCRs are known to signal not only through G-proteins, but also through β-arrestins, intracellular proteins that “arrest” the signal and stop the receptor from becoming over-stimulated through a receptor internalization mechanism.
−Removed: Using the three-dimensional structures of GPCRs and selection methods, we can potentially design highly selective “biased”
−Removed: molecules that preferentially activate G-protein and not β-arrestin pathways, which could lead to enhanced clinical activity as well as an improved safety profile due to lower dosage requirements.
−Removed: GPCR Experience
−Removed: Robust and Integrated Medicinal Chemistry to Generate and Optimize Hits on GPCR Targets
−Removed: We have extensive medicinal chemistry know-how on the discovery and development of novel molecules that target GPCRs.
−Removed: When coupled with our deep understanding of GPCR biology, we have the potential to design appropriate chemotypes for each GPCR function as illustrated below.
−Removed: Family members with determined structures are
−Removed: highlighted within the tree, and their binding pockets with the ligand
−Removed: Four character code at end of each image is Protein Data Bank ID.
−Removed: Further optimization of compounds powered by our excellence in medicinal chemistry lead us to identify potent and selective oral small molecule product candidates.
−Removed: Partnership with Schrödinger Leveraging its Cutting-Edge Computational Chemistry Capability
−Removed: We have collaborations with Schrödinger on the iteration and optimization of GPCR lead compounds using various next-generation physics-based computational technologies.
−Removed: Schrödinger is a scientific leader in chemical simulation, accurate physics-based methods, which includes among many technologies, Free Energy Perturbation (“FEP”) and in silico drug discovery.
−Removed: Its computational platforms integrate predictive physics-based methods with machine learning to evaluate billions of compounds in silico , achieving experimental accuracy on properties such as binding affinity and solubility.
−Removed: Through this iterative process, we can accelerate evaluation and optimization of molecules in silico ahead of synthesis and assay, and then further optimize them through additional cycles of computation analysis.
−Removed: Structure Therapeutics Integrated Platform
−Removed: As shown above, our collaborations with Schrödinger in our computational and chemistry module enables us to accelerate our lead optimization drug discovery process and reduce development costs.
−Removed: In our partnership with Schrödinger on GPCR drug discovery, we retain the full product rights on the compounds under development.
−Removed: Safety Assays
−Removed: We have proactively used cell and animal-based safety assays to better screen out unwanted side effects, such as liver, cardiovascular and central nervous system toxicity at the initial stages of lead optimization, and we have designed molecules to help minimize safety risks at every step.
−Removed: Our in-depth understanding of GPCR signaling pathway provide us insights to design biased molecules when necessary to mitigate any unwanted liabilities while maintaining the desired activities.
−Removed: Other Proprietary In-House Development Tools for Drug Synthesis and Screening
−Removed: Basecamp Bio focuses specifically on technology development and early discovery and continues to innovate new methods, particularly in hit discovery.
−Removed: Basecamp Bio early discovery
−Removed: In addition to our robust iterative structure-based drug discovery platform shown above, Basecamp Bio is optimizing proprietary in-house drug discovery tools including DNA-Encoded Library technology and Affinity Mass Spectrometry technology to enable the synthesis and screening of vast numbers of small molecule product candidates at a scale that is not possible to achieve by traditional methods.
−Removed: Our Lead GPCR Programs
−Removed: By leveraging our unique platform capabilities, we are building a pipeline of oral small molecule product candidates designed to have patient impact and broad commercial opportunity in therapeutic areas traditionally dominated by biologics and peptide medicines.
−Removed: We are initially focusing on chronic metabolic, cardiovascular, and pulmonary diseases with unmet medical need.
−Removed: Our GLP-1R Focused Franchise for Metabolic Disorders
−Removed: To unlock the full potential of our drug discovery platform across a broad range of metabolic indications, we intend to build out our franchise approach for GLP-1R.
−Removed: Our franchise approach involves developing next generation GLP-1R candidates, with each exhibiting customized properties to achieve additional benefit.
−Removed: Our lead GLP-1R product candidate, GSBR-1290, has the potential to be a differentiated treatment for T2DM and obesity based on preclinical data.
−Removed: GSBR-1290 is an oral and biased agonist of the GLP-1R, a validated GPCR drug target involved in a variety of metabolic conditions.
−Removed: We completed a Phase 1 SAD study for GSBR-1290 in healthy volunteers in September 2022.
−Removed: We initiated the Phase 1b MAD study in January 2023 and completed dosing in otherwise healthy overweight subjects in March 2023.
+Added: Aleniglipron (GSBR-1290) – Oral Small Molecule Selective GLP-1R Agonist for Obesity
+Added: Overview and Timeline
+Added: Our most advanced product candidate, aleniglipron, is an oral and biased small molecule agonist of GLP-1R, a validated GPCR drug target for obesity, currently in two Phase 2 clinical studies for the treatment of obesity, overweight and related conditions.
+Added: We completed our Phase 1 single ascending dose (“SAD”) study of aleniglipron in September 2022.
+Added: Aleniglipron was generally well tolerated and demonstrated dose-dependent pharmacokinetic (“PK”) and pharmacodynamic (“PD”) activity.
+Added: We submitted an IND application to the FDA to support initiation of a Phase 1b study in T2DM and obesity and received FDA allowance in September 2022.
+Added: We initiated the Phase 1b multiple ascending dose (“MAD”) study of aleniglipron in January 2023 and completed dosing in otherwise healthy overweight subjects in March 2023.
In May 2023, we submitted a protocol amendment to the FDA and initiated dosing of the Phase 2a proof-of-concept study in T2DM and obesity.
−Removed: We reported topline data for the 28-day Phase 1b MAD study in September 2023, in which GSBR-1290 was generally well-tolerated with no adverse event-related discontinuations and demonstrated an encouraging safety profile and significant weight loss of up to 4.9% placebo-adjusted, supporting once-daily dosing.
−Removed: In December 2023, we reported clinically meaningful topline data from our Phase 2a T2DM cohort, interim results from our Phase 2a obesity cohort and topline data from our Japanese ethno-bridging study of GSBR-1290.
−Removed: These data demonstrated
−Removed: that GSBR-1290 was generally well-tolerated, with no treatment-related SAEs over 12 weeks, with only one participant discontinuing the study due to adverse events in the T2DM cohort and none in the obesity cohort.
−Removed: GSBR-1290 also showed significant reduction in weight in the obesity cohort, and significant reductions in HbA1c and weight in the T2DM cohort.
−Removed: We expect to report the full 12-week Phase 2a obesity data in the latter half of the second quarter of 2024 with additional 24 participant data.
−Removed: We also fully enrolled a formulation bridging and titration optimization study to evaluate capsule versus tablet PK and explore different titration regimens of GSBR-1290.
−Removed: This study is expected to be completed in the latter half of the second quarter of 2024, in preparation for the global Phase 2b study for obesity which we expect to initiate in the fourth quarter of 2024.
−Removed: A Phase 2 study in T2DM is also planned for the second half of 2024.
−Removed: Based on our preclinical and clinical data, we believe that GSBR-1290 and our next-generation product candidates have the potential to have highly differentiated profiles versus currently approved therapies and those in development.
−Removed: Diabetes Disease Background
−Removed: Diabetes mellitus (“DM”) is an endocrine related disorder of glucose regulation with subsequent hyperglycemia, or high blood sugar, which develops following pancreatic β-cell destruction or dysfunction resulting in severe loss of insulin production, also known as type 1 diabetes, or β-cell dysfunction and loss of insulin sensitivity, also known as T2DM.
−Removed: T2DM is more common in adults and accounts for around 90% of all diabetes cases.
−Removed: In T2DM, the loss of insulin sensitivity is often preceded by being overweight or obese, and manifests along with hypertension and dyslipidemia.
−Removed: Regardless of etiology, once hyperglycemia develops, patients with diabetes share a common disease course characterized by atherosclerotic diseases such as coronary heart disease, stroke, peripheral vascular disease and/or, microvascular diseases such as nephropathy, retinopathy, and neuropathy.
−Removed: Additionally, hyperglycemia is associated with metabolic dysfunction, chronic inflammation, and an increase in infections.
−Removed: According to the 2021 International Diabetes Federation Diabetes Atlas, more than one in ten adults are now living with diabetes globally.
−Removed: The estimated prevalence of diabetes in adults aged 20 to 79 years has more than tripled since 2000, from an estimated 151 million (4.6% of the global population in this age group at the time) to 537 million (10.5%) today.
−Removed: If trends continue, the number will jump to a staggering 783 million (12.2%) by 2045.
−Removed: The number of adults with diabetes in the United States reached 32.2 million in 2021, while China has the largest numbers of adults with diabetes at 140.9 million.
−Removed: In 2021, approximately 6.7 million adults aged 20 to 79 are estimated to have died as a result of diabetes or its complications.
−Removed: According to American Diabetes Association (“ADA”), the total estimated cost of diagnosed diabetes in the United States increased to $327 billion in 2017, which included $237 billion in direct medical costs and $90 billion in reduced productivity.
−Removed: In newly diagnosed T2DM patients, treatment is focused on improving modifiable risk factors such as obesity, low physical activity and high caloric diet through patient education that includes instruction on maintaining a healthy lifestyle including nutritional counseling, avoiding excessive calories and rapidly absorbed carbohydrates, and physical exercise.
−Removed: Patients who are unable to achieve glycemic control through weight loss and/or lifestyle modifications should be started on single or combination glucose-lowering medications to lower their glycemic burden and reduce the risk of cardiovascular and other complications.
−Removed: Obesity Disease Background
−Removed: Obesity, defined as a body mass index (“BMI”) of > 30 kg/m 2 , is a major independent risk factor for T2DM.
−Removed: Approximately 90% of T2DM patients are considered either overweight with a BMI between 25.0 kg/m 2 and 29.9 kg/m 2 , or obese with a BMI of 30 kg/m 2 or greater.
−Removed: Worldwide obesity has nearly tripled between 1975 and 2016.
−Removed: As of 2020, 1.9 billion (39%) adults were overweight, including over 764 million (15%) adults who were obese.
−Removed: In men, being slightly overweight increased diabetes risk seven-fold and in women, being slightly overweight increased diabetes risk twelve-fold.
−Removed: Being obese increased the risk to 60-fold.
−Removed: Obesity affects nearly one third of all adults in the United States and is associated with a range of comorbidities, such as T2DM, cardiovascular disease, obstructive sleep apnea, and cancer.
−Removed: Importantly, even
−Removed: modest weight reduction, on the order of five to ten percent, can significantly reduce comorbidities and improve health-related outcomes and has been recently recommended by the major scientific societies (European Association of the Study of Diabetes (“EASD”) and ADA).
−Removed: Obesity therefore represents an immense commercial opportunity with very few approved therapies on the market.
−Removed: The GLP-1R agonist semaglutide, approved for use in T2DM, has also been approved for weight management for which it is marketed under the brand name Wegovy, which is estimated to reach peak sales of $6.7 billion in 2026.
−Removed: Relationship Between T2DM and Obesity
−Removed: T2DM and obesity are not independent conditions, as the majority of patients with T2DM are obese.
−Removed: Observed increases in the prevalence of T2DM are related to the increasing prevalence of obesity and multiple mechanisms have been proposed through which they may be linked pathophysiologically.
−Removed: Upper body and visceral fat are associated with T2DM, metabolic syndrome and cardiovascular disease.
−Removed: Obesity is a major contributor to poor metabolic control in patients with T2DM.
−Removed: Increasingly, weight reduction is seen as an important goal of therapy for patients with T2DM.
−Removed: Weight loss in the first year of treatment of T2DM has been associated with an increase in life expectancy.
−Removed: According to the ADA Standards of Medical Care in Diabetes—2022, management of obesity is an important factor in the treatment of diabetes since even a small degree of weight loss can improve control of blood sugar levels, resulting in a decreased need for glucose-lowering medications.
−Removed: Given this information, a therapy that can both lower blood glucose and help with weight management in T2DM could have near-term benefits in glycemic control and longer-term benefits in increased insulin sensitivity and reduction of cardiovascular risk.
−Removed: Current Treatments for T2DM and Obesity
−Removed: First-line treatment for patients with T2DM involves lifestyle modifications and metformin.
−Removed: If glycemic control remains inadequate, an additional oral glucose lowering medication should be added.
−Removed: Options include sodium-glucose transport protein 2 inhibitors, dipeptidyl peptidase-4 inhibitors, and GLP-1R agonists.
−Removed: Current treatment algorithms suggest that GLP-1R agonists should be preferentially used after metformin failure in patients who are at high risk for, or who have established, atherosclerotic cardiovascular disease.
−Removed: Several scientific societies, including the EASD and ADA, recommend GLP-1R agonists as first line therapy in patients with established atherosclerotic cardiovascular disease or in those at high risk of developing disease.
−Removed: According to Global Data, Eli Lilly and Company (“Eli Lilly”), Novo Nordisk, Merck and Sanofi S.A.
−Removed: (“Sanofi”), have captured significant market share in the approximately $65.4 billion market for glucose-lowering agents in 2023, which is projected to grow to $115.4 billion by 2027 as depicted below.
−Removed: Historical and projected global obesity and type-2 diabetes drug sales by class
−Removed: Overview of GLP-1R Signaling Pathway and Target Biology
−Removed: GLP-1 is an incretin peptide secreted in the intestinal tract in response to food intake.
−Removed: GLP-1 stimulates insulin secretion from pancreatic β-cells and inhibits glucagon secretion from pancreatic α-cells.
−Removed: GLP-1 receptors are located on various cell and tissue types including pancreatic β-cells, central and peripheral neurons, cells of the intestinal tract, vascular smooth muscle and endothelial cells, coronary arteries, and the sino-atrial node of the heart.
−Removed: Through actions at these receptors, GLP-1 and GLP-1R agonists have demonstrated widespread therapeutic effects in patients with diabetes, including stimulating insulin secretion and lowering blood glucose levels, slowing gastric emptying, reducing caloric intake, promoting weight loss, improving lipoprotein metabolism, lowering systolic blood pressure, improving complications from arteriosclerotic cardiovascular diseases, and reducing cardiovascular disease morbidity and mortality, as illustrated below.
−Removed: GLP-1R pathway and target biology
−Removed: Endogenous GLP-1 is rapidly degraded in vivo by DPP-4, with a half-life of one to two minutes.
−Removed: The development of GLP-1R agonists for the treatment of diabetes and obesity has involved modifications to the GLP-1 peptide and/or conjugation to carrier compounds or matrices that delay degradation after subcutaneous administration.
−Removed: The six marketed GLP-1R and GLP-1R/GIPR agonists are synthetic peptides and include liraglutide and semaglutide marketed by Novo Nordisk;
−Removed: dulaglutide and tirzepatide marketed by Eli Lilly;
−Removed: exenatide marketed primarily by AstraZeneca plc (“AstraZeneca”);
−Removed: and lixisenatide marketed by Sanofi.
−Removed: According to Global Data, these six GLP-1R and GLP-1R/GIPR peptides approved for T2DM and obesity collectively generated approximately $65.4 billion in worldwide sales in 2023, which is projected to reach $115 billion by 2027.
−Removed: Rybelsus is an oral formulation of semaglutide co-formulated with sodium N-8-(2-hydroxybenzoyl) amino caprylate to limit degradation and improve oral absorption.
−Removed: To date, there are no approved oral small molecule therapies targeting this pathway.
−Removed: Common side effects of GLP-1R and GLP-1R/GIPR agonists include nausea, vomiting, and diarrhea, which are most pronounced when starting therapy or increasing the dose.
−Removed: Generally, these effects correlate with times of maximum drug concentrations and ameliorate with continued therapy.
−Removed: Typically, slow up-titration to the desired dose can mitigate these side effects.
−Removed: However, once-weekly injectable GLP-1R and GLP-1R/GIPR agonists typically require a long titration period to achieve an optimal dose, potentially delaying therapeutic benefit.
−Removed: Once-daily therapy with an oral small molecule may provide flexibility in titration and allow a combined approach with other oral therapies.
−Removed: The Unmet Medical Need for Improved GLP-1R Therapeutics in Diabetes and Obesity
−Removed: GLP-1R agonists provide multiple beneficial effects in patients with T2DM, including excellent glycemic control with low risk of hypoglycemia, weight loss and protection against cardiovascular and renal complications.
−Removed: However, we believe approved GLP-1R agonists have shortcomings in terms of patient convenience, ease of dosing, and cost.
−Removed: Injectable peptide GLP-1R agonist peptides require patients to self-inject, require inconvenient refrigerated storage and are costly.
−Removed: In addition, long acting GLP-1R agonists typically require long titration periods to
−Removed: reach an optimal dose for disease management in order to avoid treatment-associated gastrointestinal side effects.
−Removed: Oral semaglutide (Rybelsus), the first approved oral GLP-1R peptide agonist, provides an option for patients who are unable or unwilling to self-administer.
−Removed: However, Rybelsus requires a stringent dosing protocol and dosing with up to four ounces of water with no food or beverage within 30 minutes.
−Removed: Additionally, the product’s absorption enhancer may affect the absorption of other concomitantly administered oral medications.
−Removed: We believe there is an unmet medical need for orally administered GLP-1R agonists that meet or exceed efficacy and safety parameters of available drugs with less stringent preparation requirements.
−Removed: Such existing constraints include restrictive food or fluid dosing protocols, refrigeration, maintenance of effective concentrations throughout the dosing interval, without interfering with the absorption of concomitant medications and that offer the potential for combination products with other glucose lowering agents or other commonly co-administered therapies.
−Removed: In addition to glycemic control, weight management is increasingly viewed as important to the management of T2DM.
−Removed: Injectable GLP-1R agonists, liraglutide and semaglutide result in weight loss at doses approved for treatment of T2DM, while higher doses of each drug, indicated for chronic weight management, result in greater weight loss.
−Removed: At an appropriate dose, an oral GLP-1R agonist may play a role in managing both blood glucose and weight.
−Removed: Our Solution:
−Removed: Small Molecule GLP-1R Agonist
−Removed: GLP-1, along with GIPR, comprise the incretin family, peptide hormones secreted into the blood by enteroendocrine cells in the gut, which play a role in glycemic control.
−Removed: We are taking a franchise approach to our GLP-1R programs by developing next generation GLP-1 agonists and potential GIPR modulators.
−Removed: Leveraging the depth of our GLP-1R/GIPR structure platform, proprietary compound library and deep biology and disease insights, we are advancing multiple generations of structurally distinct GLP-1R agonist molecules through lead optimization.
−Removed: Each molecule is designed to have a different tissue penetration profile and other incretin activities in order to maximize the value and/or realize the full potential offered by our in-house platform.
−Removed: GSBR-1290 Selective GLP-1R Agonist Program
−Removed: We are developing GSBR-1290, a biased orally-available small molecule GLP-1R agonist, initially as a treatment for T2DM and obesity.
−Removed: Due to its significant preclinical activity and oral availability, we believe that GSBR-1290 has the potential to be a differentiated treatment with no restrictions on diet or concomitant therapies.
−Removed: GSBR-1290 analog bound GLP-1R cryo-EM structure
−Removed: GSBR-1290 was designed through our internal structure-based drug discovery platform.
+Added: We reported topline data for the 28-day Phase 1b MAD study in September 2023, in which aleniglipron was generally well-tolerated with no adverse event-related discontinuations and demonstrated an encouraging safety profile and significant weight loss of up to 4.9% placebo-adjusted, supporting once-daily dosing.
+Added: In December 2023, we reported clinically meaningful topline
+Added: data from our Phase 2a T2DM cohort, interim results from our Phase 2a obesity cohort and topline data from a Japanese ethno-bridging study of aleniglipron.
+Added: These data demonstrated that aleniglipron was generally well-tolerated, with no treatment-related serious adverse events (“SAEs”) over 12 weeks, with only one participant discontinuing the study due to adverse events in the T2DM cohort and none in the obesity cohort.
+Added: Aleniglipron also showed significant reduction in weight in the obesity cohort at 8 weeks and significant reductions in hemoglobin A1c (“HbA1c”) and weight in the T2DM cohort.
+Added: In June 2024, we reported positive topline data from our Phase 2a obesity study, in which aleniglipron demonstrated a clinically meaningful and statistically significant placebo-adjusted mean decrease in weight of 6.2% at 12 weeks (p<0.0001, using least-squares means (“LSM”) and analyzed based on the primary efficacy estimand using a mixed model for repeated measures) and demonstrated generally favorable safety and tolerability results following repeated, daily dosing up to 120 mg.
+Added: Furthermore, we explored a new tablet formulation of aleniglipron in a capsule to tablet PK study, which demonstrated a placebo-adjusted mean weight loss of up to 6.9% with the tablet formulation at 12 weeks (p<0.0001, using LSM and analyzed based on the primary efficacy estimand using a mixed model for repeated measures).
+Added: In July 2024, we submitted an IND to the FDA to support the initiation of a Phase 2b study in chronic weight management and received FDA allowance in August 2024.
+Added: In the fourth quarter of 2024, we initiated the Phase 2b ACCESS study, a randomized, double-blind, placebo-controlled, dose-range finding study of aleniglipron in approximately 220 adult participants living with obesity (BMI ≥ 30 kg/m 2 ), or overweight (BMI ≥ 27 kg/m 2 ) with at least one weight-related comorbidity.
+Added: Participants start at 5 mg of aleniglipron (or placebo) with a 4-week titration schedule, reaching target doses of 45 mg, 90 mg and 120 mg.
+Added: The primary endpoint is percent change in body weight from baseline to week 36.
+Added: Secondary endpoints include safety and tolerability of the monthly titration scheme, as well as PK of aleniglipron.
+Added: In the fourth quarter of 2024, we initiated a randomized, double-blind, placebo-controlled dose-range finding Phase 2 study of aleniglipron, known as ACCESS II, in approximately 82 adult participants living with obesity or overweight with at least one weight-related comorbidity.
+Added: The study is designed to evaluate two higher doses of aleniglipron.
+Added: Participants start at 5 mg of aleniglipron (or placebo) and follow a 4-week titration schedule up to target doses of 120 mg, 180 mg and 240 mg.
+Added: In February 2025, we completed enrollment in the ACCESS and ACCESS II studies, and we expect to report topline data from both studies in the fourth quarter of 2025.
+Added: Aleniglipron Design and Discovery
+Added: We are developing aleniglipron, a biased orally-available small molecule GLP-1R agonist, initially as a treatment for obesity and related diseases.
+Added: Due to its significant preclinical activity and oral availability, we believe that aleniglipron has the potential to be a differentiated treatment with no restrictions on diet or concomitant therapies.
+Added: Aleniglipron Analog Bound GLP-1R Cryo-EM Structure
+Added: Aleniglipron was designed through our internal structure-based drug discovery platform.
As shown above, multiple small molecules bound to GLP-1R structures have been generated to guide iterative chemistry design efforts.
−Removed: GSBR-1290 is also designed to be a biased GPCR agonist, which only activates the G-protein pathway without β-arrestin signaling at therapeutic doses, thereby avoiding receptor internalization and de-sensitization.
−Removed: In an intravenous glucose tolerance test (“ivGTT”) in NHPs, GSBR-1290 increased glucose-dependent insulin secretion to a similar level achieved by liraglutide, an approved injectable GLP-1R agonist.
−Removed: In a repeat food intake study in NHPs, GSBR-1290 showed a significant decrease in body weight relative to the placebo and surpassed that seen with liraglutide.
−Removed: GSBR-1290 Preclinical Data, Pharmacology, and Biomarker Data
−Removed: In NHP ivGTT studies, glucose was injected five minutes following intravenous administration of either GSBR-1290 (0.05 mg/kg) or liraglutide (0.1 mg/kg).
−Removed: Plasma samples were taken at indicated timepoints to evaluate insulin and glucose levels.
−Removed: GSBR-1290 demonstrated statistically significant decreases in blood glucose concentration via stimulation of insulin secretion in a glucose-dependent manner, similar to liraglutide which was dosed at an equivalent approved human dose.
−Removed: Robust activity in non-human primate acute ivGTT studies
−Removed: Data were presented as mean ± standard error of the mean (“SEM”);
−Removed: one-way ANOVA followed by Dunnett’s multiple comparisons test.
−Removed: *p<0.05, **p<0.01, ***p<0.001 vs vehicle
−Removed: As shown below, in a seven day repeat oral dosing study in NHPs, GSBR-1290 was evaluated at once-daily oral doses of 2 mg/kg, 6 mg/kg, and 10 mg/kg and compared to placebo and liraglutide.
−Removed: Food intake was measured each day over the first six days of the study and reported as an average of these measurements.
−Removed: ivGTT and body weight were performed before dosing and on the sixth day (body weight) or seventh day (ivGTT) of post-dosing.
−Removed: At all doses of GSBR-1290, glucose reduction was shown to be statistically significantly different versus vehicle and comparable to liraglutide.
−Removed: Similarly, all doses increased insulin secretion significantly except at 6 mg/kg dose, which only achieved statistical p value at 0.055 due to a slightly greater data variability.
−Removed: At 6 mg/kg and 10 mg/kg, a statistically significant reduction of average food intake measured over the first six days of the study compared to vehicle was observed.
−Removed: At 10 mg/kg of GSBR-1290, the average food intake from Day 1 to Day 6 was only 59% relative to liraglutide group.
−Removed: GSBR-1290 at 6 mg/kg and 10 mg/kg also showed a significant decrease in body weight relative to placebo and surpassed liraglutide, with the highest dose of GSBR-1290 achieving more than eight percent reduction in average body weight versus baseline in one week.
−Removed: Seven day repeat oral dosing study in non-human primates
−Removed: Data were presented as mean ± SEM;
−Removed: one-way ANOVA followed by Dunnett’s multiple comparisons test.
−Removed: *p<0.05, **p<0.01, ***p<0.001 vs vehicle
−Removed: In the description of our clinical trials and preclinical studies below and elsewhere in this Annual Report, n represents the number of participants in a particular group and p or p-values represent the probability that random chance caused the result (e.g., a p-value of 0.01 means that there is a 0.1% probability that the difference between the placebo group and the treatment group is purely due to random chance).
−Removed: A p-value of less than or equal to 0.05 is a commonly used criterion for statistical significance, and may be supportive of a finding of efficacy by regulatory authorities.
−Removed: In addition, we conducted a preclinical comparison study of GSBR-1290 and PF-06882961, a clinical stage compound in development by Pfizer.
−Removed: Unlike GSBR-1290, PF-06882961 is a partially biased GLP-1R agonist, which could lead to de-sensitization of the receptor in vivo .
−Removed: In an experiment conducted in-house, GSBR-1290 demonstrated comparable in vivo activity to PF-06882961 at a lower exposure.
−Removed: In the acute ivGTT studies, GSBR-1290 achieved similar activity to liraglutide at average concentration around 34 nanomolar (“nM”) (0.05 mg intravenous), comparing to a similar activity achieved by PF-06882961 in an in-house experiment at an average concentration around 442 nM (0.3 mg intravenous).
−Removed: This suggests that the concentration needed to achieve full activity for GSBR-1290 is at a level much lower than that for PF-06882961.
−Removed: PF-06882961 has been studied in SAD and MAD studies with a maximum dose of 200 mg/BID to achieve maximum HbA1c activity and weight management.
−Removed: In-house data showed that PF-06882961 was positive in a glutathione trapping assay.
−Removed: GSBR-1290 was inactive in this assay, suggesting reduced risks with long-term use.
−Removed: In addition, GSBR-1290 also did not show activity as a time dependent inhibitor (“TDI”) for cytochrome P450 3A4 (“CYP3A4”).
−Removed: PF-06882961 was reported as a CYP3A4 TDI, which, if confirmed in clinical trials, suggests the potential for interactions with the 30–50% of marketed drugs metabolized through this pathway.
−Removed: GSBR-1290 Phase 1 Healthy Volunteer Trial
−Removed: In September 2022, we completed a first-in-human Phase 1 SAD study for GSBR-1290 in 48 healthy adult volunteers between the ages of 18 and 55.
−Removed: The objective was to assess drug safety, tolerability and PK.
−Removed: The study enrolled six cohorts of eight participants assigned to receive a single dose of GSBR-1290 or placebo in a 3:1 ratio.
−Removed: Doses ranged from 1 mg to 90 mg across the six cohorts.
−Removed: The fourth cohort received 15 mg administered either under a fed condition, which consisted of a standardized high fat breakfast, and under a fasted condition, in each case to characterize the effect of food on the PK of GSBR-1290.
−Removed: A schema of our Phase 1 SAD study is presented below:
−Removed: Schema of our GSBR-1290 Phase 1 SAD study in healthy volunteers
−Removed: GSBR-1290 Phase 1 PK and PD Data in Healthy Volunteers
−Removed: In the study, PK parameters of systemic exposure, C max and AUC, increased with doses of GSBR-1290 across the dose range from 1 mg to 90 mg GSBR-1290.
−Removed: GSBR-1290 exhibited supra dose proportionality from 1 mg to 30 mg followed by less than dose-proportional from 30 mg to 90 mg.
−Removed: The 30mg dose AUC provided more than double the effective AUC0-24h required for glycemic control, derived from non-human primate PK/PD data.
−Removed: Food intake (high fat meal) was associated with a ~36% decrease in the geometric mean C max but no significant change in mean AUC value, with 80% relative bioavailability, based on AUC compared with the fasted state.
−Removed: GSBR-1290 Phase 1 Safety Data in Healthy Volunteers
−Removed: GSBR-1290 was shown to be generally well tolerated at all dose levels administrated in this Phase 1 SAD study.
−Removed: No SAEs and no adverse changes in laboratory tests (including hematology, chemistry and coagulation) were observed.
−Removed: No trial stopping criteria were met.
−Removed: Adverse events (“AEs”) did not result in any early terminations or subject discontinuations from participation in this study.
−Removed: Treatment-emergent AEs (“TEAEs”) were reported for 32 of 36 participants (89%) following fasted administration of GSBR-1290 and for 7 of 12 participants (58%) following administration of placebo, with a total of 109 TEAEs.
−Removed: Following administration of GSBR-1290 in the fasted state, most TEAEs were classified as mild (69 of 109, or 63% of all TEAEs) in severity, with 34 TEAEs (31% of all TEAEs) classified as moderate in severity.
−Removed: Six TEAEs (6%) were classified as severe, including four events of vomiting, one event of nausea and one event of catheter site infection.
−Removed: There was an apparent dose-related trend in the severity of TEAEs following single doses of GSBR-1290, with severe TEAEs reported following the 60 mg and 90 mg doses of GSBR-1290, but not following low doses (1 mg, 10 mg, 15 mg).
−Removed: Occurrences in TEAEs of moderate intensity were also higher following higher dose range of GSBR-1290.
−Removed: The following table shows an overall summary of TEAEs that were reported in the study.
−Removed: Low dose GSBR-1290 includes 1 mg, 10 mg and 15 mg fasted and high dose GSBR-1290 includes 30 mg, 60 mg and 90 mg fasted.
−Removed: If a participant had multiple occurrences of a TEAE, the participant was presented only once in the Participant count for a given Preferred Term.
−Removed: Occurrences were counted each time.
−Removed: There was no notable difference in the overall incidence or severity of treatment-related AEs under fasted and fed administration of GSBR-1290 at a dose level of 15 mg.
−Removed: There was a higher incidence of related TEAEs of vomiting and headache following fasted administration (three of six participants, or 50%) compared to fed administration (one of six participants, or 17%).
−Removed: The most common TEAEs reported in at least four of 36 participants (>10%) who received GSBR-1290 were nausea, headache, vomiting, dehydration, decreased appetite, dizziness, and diarrhea.
−Removed: Across the various dose levels, there were apparent dose-related trends in the overall incidence of common TEAEs.
−Removed: The incidence of the TEAEs described above was notably higher following fasted administration of the high dose GSBR-1290 treatments (30 mg, 60 mg, 90 mg) than the low dose GSBR-1290 treatments (1
−Removed: mg, 10 mg, 15 mg) and placebo, with a similar observation in treatment-related AEs of nausea, vomiting, dehydration, and headache of at least moderate severity.
−Removed: We believe all TEAEs observed during the study are in line with the proposed treatment mechanism and typically derive from impacts on appetite, nausea, and vomiting.
−Removed: There was an apparent increasing trend in heart rate over time in both low (1 mg, 10 mg, 15 mg) and high dose (30 mg, 60 mg, 90 mg) GSBR-1290 groups.
−Removed: This increase appeared to peak at 12 hours post-dose and was notably larger in the high dose GSBR-1290 groups.
−Removed: Increases in heart rate over time were observed in the pooled placebo group but to a much lesser extent.
−Removed: In summary, GSBR-1290 was shown to be generally well tolerated when administered as a single dose of up to 90 mg.
−Removed: However, there were dose-related trends in the incidence, severity and causality of TEAEs, particularly GI related TEAEs, consistent with what has been previously reported in clinical trials involving the GLP-1RA class of drugs.
−Removed: There were no treatment-related AEs reported in patients who received placebo.
−Removed: PK parameters of systemic exposure increased with dose of GSBR-1290 across the dose range from 1 mg to 90 mg GSBR-1290.
−Removed: GSBR-1290 Non-clinical Safety Pharmacology and Toxicology Studies
−Removed: A standard battery of nonclinical safety pharmacology studies (central nervous system, cardiovascular and respiratory) has been completed with GSBR-1290 with no findings anticipated to be of clinical relevance.
+Added: Aleniglipron is also designed to be a biased GPCR agonist, which only activates the G-protein pathway without β-arrestin signaling at therapeutic doses, thereby avoiding receptor internalization and de-sensitization.
+Added: In an intravenous glucose tolerance test in non-human primates (“NHPs”), aleniglipron increased glucose-dependent insulin secretion to a similar level achieved by liraglutide, an approved injectable GLP-1R agonist.
+Added: In a repeat food intake study in NHPs, aleniglipron showed a significant decrease in body weight relative to the placebo and surpassed that seen with liraglutide.
+Added: Aleniglipron Non-clinical Safety Pharmacology and Toxicology Studies
+Added: A standard battery of nonclinical safety pharmacology studies (central nervous system, cardiovascular and respiratory) has been completed with aleniglipron with no findings anticipated to be of clinical relevance.
Genotoxicity assessments demonstrated an absence of genotoxicity potential.
In the 4-week and 13-week GLP toxicology study in rats, the no-observed-adverse-effect level (“NOAEL”) dose was considered to be 1000 mg/kg/day, the highest dose tested.
−Removed: In the 4-week and 13-week GLP toxicology study in NHPs, GSBR-1290 showed pharmacologically related events such as inappetence and bodyweight loss, which were reversible with sufficient recovery periods.
−Removed: There were no GSBR-1290-related deaths during the course of study and no GSBR-1290-related changes in organ weights, gross and histopathology examinations at the end of the dosing and recovery periods.
+Added: In the 4-week and 13-week GLP toxicology study in NHPs, aleniglipron showed pharmacologically related events such as inappetence and bodyweight loss, which were reversible with sufficient recovery periods.
+Added: There were no aleniglipron related deaths during the course of study and no aleniglipron related changes in organ weights, gross and histopathology examinations at the end of the dosing and recovery periods.
In the 13-week study, NHPs of both sexes in all dose groups, including in the control group, had minimal to moderate multifocal necrosis/infiltration in the liver.
−Removed: The root cause of these liver abnormalities was not determined, but these findings were considered unrelated to GSBR-1290.
−Removed: The FDA reviewed our 13-week GLP toxicology studies in rats and NHPs and agreed that these liver abnormalities were not considered a new non-clinical safety signal related to GSBR-1290.
−Removed: In nonclinical animal models, GSBR-1290 demonstrated statistically significant decreases in blood glucose concentration and increases of insulin secretion.
−Removed: In a recent 6-month GLP toxicology study in rats, GSBR-1290 demonstrated a NOAEL dose at 1000 mg/kg/day, which supports an estimated more than 100 fold safety window up to 120 mg human dose.
−Removed: We also conducted a 9-month non-human primate (NHP) GLP toxicology study and found no test article-related change in heart rates or QTc intervals.
+Added: The root cause of these liver abnormalities was not determined, but these findings were considered unrelated to aleniglipron.
+Added: The FDA reviewed our 13-week GLP toxicology studies in rats and NHPs and agreed that these liver abnormalities were not considered a new non-clinical safety signal related to aleniglipron.
+Added: In nonclinical animal models, aleniglipron demonstrated statistically significant decreases in blood glucose concentration and increases of insulin secretion.
+Added: In a recent 6-month GLP toxicology study in rats, aleniglipron demonstrated a NOAEL dose at 1000 mg/kg/day, which supports an estimated more than 100-fold safety window up to 120 mg human dose.
+Added: We also conducted a 9-month NHP GLP toxicology study and found no test article-related change in heart rates or QTc intervals.
No meaningful increases in the liver enzymes, ALT/AST, were observed in either the rat or NHP study.
There were no significant findings in embryo-fetal developmental toxicology studies in rats and rabbits.
−Removed: GSBR-1290 Phase 1b MAD study
−Removed: The Phase 1b MAD study focused on the safety and tolerability of GSBR-1290 in 24 healthy overweight or obese individuals.
−Removed: Participants were randomized 3:1 to GSBR-1290 or placebo across three dose cohorts with target doses of 30mg, 60mg or 90mg.
−Removed: GSBR-1290 demonstrated reductions in mean body weight ranging up to 4.9 kg compared to baseline, and up to 4.9% placebo-adjusted.
−Removed: Percent Weight Change from Baseline to Day 28
−Removed: % weight change from baseline
−Removed: % weight change placebo-adjusted
−Removed: (-3.8 to 1.7)
−Removed: (-6.6 to -2.7)
−Removed: (-7.8 to -1.9)
−Removed: Exploratory p-value vs.
−Removed: GSBR-1290 demonstrated an encouraging safety and tolerability profile following once-daily dosing.
−Removed: No participants discontinued the study drug due to adverse events.
−Removed: The majority of adverse events reported were mild, with no severe or serious adverse events observed.
−Removed: As expected for this class, leading adverse events were gastrointestinal-related, with the two most common gastrointestinal adverse events being nausea and diarrhea, with higher incidences observed in all three cohorts compared to placebo.
−Removed: There were no clinically meaningful changes in liver function tests.
−Removed: Summary of Treatment Emergent Adverse Events
−Removed: Placebo pooled
−Removed: Any TEAE by maximum severity
−Removed: Any Serious Adverse Events
−Removed: GSBR-1290 Phase 2a study in diabetes and obesity
−Removed: The randomized, double-blind, 12-week placebo-controlled Phase 2a clinical trial has enrolled a total of 94 participants to date, including 60 participants randomized to GSBR-1290.
−Removed: The T2DM cohort enrolled 54 participants, randomized to GSBR-1290 at 45 mg (n=10) or 90 mg (n=26), or placebo (n=18), dosed once daily.
−Removed: The obesity cohort initially enrolled 40 participants randomized to GSBR-1290 at 120 mg (n=24) or placebo (n=16), dosed once-daily.
−Removed: An additional 24 participants have been enrolled in the obesity arm as previously announced in September 2023 to replace those for whom 12-week weight data was not collected as a result of a data collection omission.
−Removed: These replacement participants have also been randomized 3:2 to GSBR-1290 or placebo.
−Removed: The primary endpoints of the Phase 2a study are safety and tolerability of GSBR-1290.
−Removed: Key secondary endpoints include reduction in weight for both obesity and T2DM cohorts, as well as reduction in HbA1c for the T2DM cohort.
−Removed: GSBR-1290 Safety and tolerability results
−Removed: GSBR-1290 demonstrated an encouraging safety and tolerability profile following repeated, daily dosing for all doses studied (up to 120 mg) in the obesity and T2DM cohorts, with results summarized as follows:
−Removed: ● The majority (88 to 96%, depending on study arm) of AEs reported were mild to moderate.
+Added: Aleniglipron Phase 2a Study in Obesity and Diabetes
+Added: In June 2024, the Company reported positive topline data from the Phase 2a obesity study in which GSBR-1290 demonstrated a clinically meaningful and statistically significant placebo-adjusted mean weight loss of 6.2% at 12 weeks (p<0.0001) and generally favorable safety and tolerability results following repeated, daily dosing up to 120 mg.
+Added: The Company also reported data from a new tablet formulation of GSBR-1290 in a capsule to tablet PK study, which demonstrated a placebo-adjusted mean weight loss of up to 6.9% with the tablet formulation at 12 weeks.
+Added: PK data support proportional exposure between 60 and 120 mg and once-daily oral dosing of GSBR-1290.
+Added: Phase 2a Body Weight Change from Baseline
+Added: Capsule to Tablet PK Study Body Weight Change from Baseline
+Added: Aleniglipron Safety and Tolerability Results
+Added: Aleniglipron demonstrated an encouraging safety and tolerability profile following repeated, daily dosing for all doses studied (up to 120 mg) in the obesity and T2DM cohorts, with results summarized as follows:
+Added: • The majority (88 to 96%, depending on study arm) of adverse events (“AEs”) reported were mild to moderate.
• There were no SAEs related to study drug.
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This participant was diagnosed with fatty liver disease while in the study.
−Removed: ● Of the 60 participants dosed with GSBR-1290, only one participant discontinued the study due to AEs related to study drug (none in the obesity cohort and one (2.8%) in the T2DM cohort).
+Added: • Of the 60 participants dosed with aleniglipron, only one participant discontinued the study due to AEs related to study drug (none in the obesity cohort and one (2.8%) in the T2DM cohort).
Summary of Treatment Emergent Adverse Events (“TEAEs”)
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Any SAEs related to study drug
−Removed: GSBR-1290 Efficacy result s
−Removed: GSBR-1290 demonstrated clinically meaningful activity in both T2DM and obesity cohorts, with results summarized as follows:
−Removed: ● In the T2DM cohort, there was a statistically significant HbA1c reduction (-1.01 to -1.02%, placebo-adjusted) at Week 12 (Table 1 ).
+Added: Aleniglipron Efficacy Results
+Added: Aleniglipron demonstrated clinically meaningful activity in T2DM cohort.
+Added: There was a statistically significant HbA1c reduction (-1.01 to -1.02%, placebo-adjusted) at Week 12 (Table 1).
The study demonstrated a statistically significant and clinically meaningful reduction in weight at Week 12 (-3.26% to -3.51%, placebo-adjusted) (Table 2).
Weight loss continued to decrease through Week 12.
−Removed: ● Results of the interim analysis in the obesity cohort showed a statistically significant and clinically meaningful decrease in weight at Week 8 (-4.74%, placebo-adjusted) (Table 3 ).
−Removed: Weight loss continued to decrease throughout the eight weeks of treatment.
−Removed: Diabetes cohort least square means difference (LSM) change in HbA1c from baseline to 12 weeks (%)
+Added: T2DM Cohort Least Square Means Difference (“LSM”) Change in HbA1c from Baseline to 12 Weeks (%)*
LSM HbA1c change from baseline (%)
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*LSM, CI and p-value from Mixed Model for Repeated Measures
−Removed: Diabetes cohort LSM change in weight from baseline (%)
+Added: T2DM Cohort LSM Change in Weight from Baseline (%)*
LSM weight change from baseline (%)
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*LSM, CI and p-value from Mixed Model for Repeated Measures
−Removed: Obesity Cohort LSM change in weight from baseline (%) 8 week interim results
−Removed: LSM weight change from baseline (%)
−Removed: % weight change placebo-adjusted (LSM, 90%
−Removed: (-6.74, -3.10)
−Removed: GSBR-1290 Phase 1 Japanese Bridging Study
−Removed: The 4-week Phase 1 Japanese ethnobridging study included healthy lean Japanese participants randomized to GSBR-1290 (n=9) and placebo (n=3), and healthy lean non-Japanese participants receiving GSBR-1290 (n=6).
−Removed: GSBR-1290 demonstrated a substantial weight reduction in Japanese participants (-3.91% on GSBR-1290 vs -1.67% placebo) and in non-Japanese participants (-5.13% not placebo-adjusted), with no discontinuations or dose reductions, and no SAEs.
−Removed: These data will be used for regulatory interactions in Japan in preparation for potential future global studies of GSBR-1290.
−Removed: GSBR-1290 Six- and Nine-Month Toxicology Studies
−Removed: In preparation for Phase 2b development with longer durations of treatment, we have completed six-month (rodent) and nine-month (non-human primate) toxicology studies to evaluate the safety of GSBR-1290.
−Removed: No major findings were observed in either study, with no test article-related changes observed in the liver, including ALT/AST, at all doses, and a more than 100 fold safety window at the 120 mg therapeutic dose.
−Removed: Amylin Receptor Agonist - Combination GLP-1R Program
−Removed: Amylin is co-secreted with insulin from β pancreatic cells upon nutrient delivery to the small intestine as a satiety signal, acts upon sub-cortical homeostatic and hedonic brain regions, slows gastric emptying, and
−Removed: suppresses post-prandial glucagon responses to meals.
+Added: ACCG-2671 – Oral Small Molecule Amylin Receptor Agonist for Obesity
+Added: We are advancing our amylin oral small molecule program and have declared our development candidate, ACCG-2671.
+Added: In preclinical studies, ACCG-2671 demonstrated sub-nanomolar in vitro functional activity on amylin and calcitonin receptors, and in vivo reduction in food intake, resulting in weight loss.
+Added: We expect to initiate Phase 1 clinical study of ACCG-2671 in the fourth quarter of 2025.
+Added: The amylin receptor system is complex, and its complexity is present at various levels as shown here and in the figure below:
+Added: • First (starting from left figure panel):
+Added: At the receptor level, there are three amylin receptors, AMY1/2/3 receptors.
+Added: They are heterodimers formed by the calcitonin receptor CTR and the co-receptor RAMP1/2/3.
+Added: There is an equilibrium between calcitonin receptor and Amylin receptors.
+Added: At the agonist level, there are two types of agonists:
+Added: DACRA and SARA
+Added: DACRA, stands for Dual Amylin and Calcitonin Receptor Agonists, which binds both the amylin receptor and calcitonin receptor.
+Added: SARA, stands for Selective Amylin Receptor Agonist, which preferentially binds to the amylin receptor.
+Added: Different agonists bind to the amylin receptor or calcitonin receptor and form different receptor-agonist complexes.
+Added: These complexes could differ in stability, conformation, G protein/b-arrestin recruitment and activation status and cAMP signaling.
+Added: The amylin receptor pocket is large, making small molecule discovery challenging.
+Added: The amylin receptor pocket is large, making small molecule discovery challenging.
+Added: Despite these challenges, we have successfully discovered what we believe is the first amylin small molecule agonist.
+Added: Amylin is co-secreted with insulin from β pancreatic cells upon nutrient delivery to the small intestine as a satiety signal, acts upon sub-cortical homeostatic and hedonic brain regions, slows gastric emptying and suppresses post-prandial GCG responses to meals.
Therefore, new pharmacological amylin analogues can be used as potential anti-obesity medications in individuals who are overweight or obese.
1 unchanged sentence
In collaboration with Schrödinger, we are taking a structure-based drug discovery approach to identify oral small molecule amylin agonists for daily use either alone or in combination with GLP-1R agonists to treat obesity and T2DM.
−Removed: We have identified two novel lead series with promising potency and PK profiles.
−Removed: We have obtained multiple high quality Cryo-EM structures and established in-house in vivo animal models, which enable us to advance our lead optimization effort with high efficiency.
In an in-house proof-of-concept study in rats, our small molecule amylin tool compound (ACCG-0184) showed additional beneficial effects when used as an add-on treatment to a GLP-1R agonist.
−Removed: We are planning to select a development candidate in the second half of 2024.
−Removed: GenerationGIPR Modulator - Combination GLP-1R Program
−Removed: In our GIPR program, we have identified multiple GIPR agonist, dual GLP-1R/GIRP agonist and GIPR antagonist hits for small molecule GIPR modulation.
−Removed: We believe GLP-1R/GIPR modulation has the potential to provide a differentiated treatment in diabetes and obesity.
+Added: In December 2024, we announced the selection of ACCG-2671 as our lead oral amylin agonist for the treatment of obesity.
+Added: ACCG-2671 was designed as an oral small molecule DACRA and is expected to enter Phase 1 clinical development in the fourth quarter of 2025.
+Added: In addition, we have initiated GMP manufacturing to support GLP toxicology studies and early clinical development.
+Added: In preclinical studies, ACCG-2671 demonstrated potent and balanced in vitro activities toward amylin and the calcitonin receptors.
+Added: ACCG-2671 also further demonstrated robust in vivo efficacy and a PK and safety profile supporting once-daily oral dosing in humans.
+Added: ACCG-2671 Demonstrated Sub-nanomolar Potency of DACRA Activity
+Added: ACCG-2671 Achieved Cagrilintide-like Efficacy in Preclinical DIO Rat Model
+Added: Lastly, given our most advanced oral small molecule amylin position, we are continuing to work on multiple generations, and we expect to declare additional development candidates in the future.
+Added: GIP and GCG Receptor Oral Small Molecule Obesity Programs
+Added: Beyond our GLP-1R and amylin receptor programs, we are developing next generation oral incretins for potential combination therapy with GLP-1R or amylin candidates.
+Added: These include small molecule candidates targeting GIPR and GCGR, each designed with customized properties to achieve additional benefit.
+Added: In our GIPR program, we have identified multiple GIPR agonist, dual GLP-1R/GIPR agonist and GIPR antagonist hits for small molecule GIPR modulation.
+Added: We believe GLP 1R/GIPR modulation has the potential to provide a differentiated treatment in obesity.
Recent third-party clinical data showed tirzepatide, a GLP-1R/GIPR modulator, was superior to semaglutide with respect to glycemic control.
4 unchanged sentences
Multiple Structures of Ligand Bound GLP-1R, GIPR, GCGR
−Removed: As shown above, representative three-dimensional structures of the incretin GPCRs ( e.g.
−Removed: , GIPR, GLP-1R, Glucagon receptor) are available for structure-based drug discovery.
−Removed: This structural data enables the ability to design dual and tri modulators of this important class of metabolic GPCRs.
+Added: As shown above, representative three-dimensional structures of the incretin GPCRs (e.g., GIPR, GLP-1R, Glucagon receptor) are available for structure-based drug discovery.
+Added: This structural data enables the design of dual and tri modulators of this important class of metabolic GPCRs.
The GIPR model shown below suggests that one of our dual GLP-1/GIPR agonists may extend to fill the pocket (highlighted in color) occupied by our GLP-1/GIPR agonist hits.
3 unchanged sentences
While displaying different GIPR activity, both compounds still maintained certain levels of GLP-1R activities.
−Removed: We are planning to select a development candidate in the first half of 2025.
+Added: We are planning to select a development candidate in 2025.
GIPR Agonist/dual Agonist/antagonist Hits Identified for Potential GLP-1R Combinations
−Removed: Our LPA1R and APJR Program for the Treatment of IPF
−Removed: We are developing LTSE-2578, an investigational oral small molecule LPA1R antagonist for the treatment of IPF.
+Added: In our GCG program, we have identified multiple GCGR agonist and dual GLP-1R/GCGR agonist hits for small molecule GCGR modulation.
+Added: GCG is primarily expressed in the liver and therefore GCGR agonists could play an important role in liver-mediated diseases, specifically MASH.
+Added: ANPA-0073- Oral Small Molecule APJ Receptor Agonist for Selective Weight Loss
+Added: ANPA-0073 is our biased APJ receptor agonist.
+Added: In September 2022, we completed a Phase 1 SAD and MAD study evaluating ANPA-0073 in healthy human volunteers, in which it was generally well tolerated.
+Added: We are currently conducting long term GLP-toxicology studies of ANPA-0073, which is Phase 2 ready, to be used in combination with weight loss medicines for selective or muscle-sparing weight loss
+Added: Apelin is a peptide hormone that binds to the APJ receptor.
+Added: It is involved in various physiological functions and expressed in human and murine skeletal muscles and widely distributed in the body.
+Added: Depending on the cell type studied, APJ receptor activation enhances extracellular signal-regulated kinases, AMPK, AKT and p70S6 kinases and the inhibition of cAMP production.
+Added: Activation of these pathways would result in worthwhile increases in the protein content of skeletal muscles.
+Added: Apelin has in fact proved beneficial in maintaining muscle and could potentially counteract age-associated atrophy.
+Added: We are currently conducting long term GLP-toxicology studies of ANPA-0073, which is Phase 2 ready, to be used in combination with weight loss medicines for selective or muscle-sparing weight loss.
+Added: APJ Receptor Biased Agonism is a Potential Differentiator for ANPA-0073
+Added: BIASED SELECTIVITY
+Added: SIGNALING/cAMP
+Added: INTERNALIZATION/cAMP
+Added: Apelin Peptide
+Added: ANPA-0073 Phase 1 Safety Data in Healthy Volunteers
+Added: In September 2022, we completed a two-part, 96 subject, first-in-human Phase 1 SAD and MAD study for ANPA-0073 in 48 healthy adult volunteers between the ages of 18 and 55.
+Added: The objective was to assess drug safety and PK.
+Added: The first part of this study was a SAD study, involving eight cohorts of eight participants assigned to receive a single dose of ANPA-0073 or placebo in a 3:1 ratio.
+Added: Doses from 2 mg to 600 mg across the eight cohorts were evaluated.
+Added: The second part of the study was a MAD study, including four cohorts of eight subjects receiving sequential ascending doses of ANPA-0073 daily for seven days, increasing from 75 mg to 500 mg once daily.
+Added: ANPA-0073 was generally well tolerated at all dose levels administrated in the SAD and MAD parts of this Phase 1 study.
+Added: In the study, PK parameters of systemic exposure, Cmax and AUC, increased with doses of ANPA-0073 across the dose range from 75 mg to 500 mg.
+Added: In the SAD cohorts, no SAEs and no adverse changes in laboratory tests were observed.
+Added: Among the AEs reported, five were considered moderate TEAEs and the remaining were mild in severity.
+Added: AEs did not result in any early terminations or subject discontinuations from participation in this study.
+Added: No study stopping criteria were met and no significant changes or trends in hematology, blood chemistries, vital signs or electrocardiogram (“ECG”) measurements were noted.
+Added: The following table shows all TEAEs that were reported:
+Added: ANPA-0073 Phase 1 SAD TEAEs
+Added: In the MAD portion of the Phase 1 study, no SAEs and no adverse changes in laboratory tests were observed.
+Added: Among the AEs reported, twelve were considered moderate TEAEs and the remaining were mild in severity.
+Added: AEs did not result in any early terminations or subject discontinuations from participation in this study.
+Added: No study stopping criteria were met and no significant changes or trends in hematology, blood chemistries, vital signs or ECG measurements were noted.
+Added: The following table shows all TEAEs that were reported:
+Added: ANPA-0073 Phase 1 MAD TEAEs
+Added: We have initiated the 26-week chronic GLP-toxicology studies in rats and 39-week studies in dogs that we believe will be required by regulatory agencies to continue dosing beyond 13 weeks in Phase 2.
+Added: We are also evaluating ANPA-0073 for selective or muscle-sparing weight loss.
+Added: LTSE-2578 – Oral Small Molecule LPA1R Antagonist for IPF
+Added: Additionally, we are developing an antagonist that targets lysophosphatidic acid 1 receptor (“LPA1R”), a GPCR implicated in responses to tissue injury and pro-fibrotic processes, for the treatment of IPF.
+Added: We have demonstrated substantial anti-fibrotic activity of our LPA1R antagonists in mouse models of fibrotic lung disease and we selected a development candidate, LTSE-2578, in January 2023.
+Added: In June 2024, we initiated our first-in-human Phase 1 study of LTSE-2578.
We believe LTSE-2578 is a differentiated molecule because it demonstrated potent in vitro and in vivo activity in preclinical IPF models and dose dependent inhibition of histamine release as the pharmacodynamic marker.
We have completed IND-enabling studies including 28-day GLP-toxicology studies in dogs and rats.
−Removed: We are planning to initiate a first-in-human Phase 1 single and multiple ascending dose study in healthy volunteers in the second quarter of 2024.
−Removed: In addition, we are developing ANPA-0073, an investigational oral small molecule APJR agonist, for the treatment of IPF.
−Removed: When compared to a non-biased APJR agonist (Apelin-12) in a preclinical study, ANPA-0073 avoided hypotension.
−Removed: In September 2022, we completed a Phase 1 SAD and MAD study evaluating ANPA-0073, in which it was generally well tolerated in healthy human volunteers.
−Removed: We expect to conduct additional preclinical studies and are evaluating plans to initiate a Phase 2 study in IPF.
+Added: In June 2024, we initiated a Phase 1 clinical study of LTSE-2578.
+Added: This randomized, double-blind, placebo-controlled first-in-human clinical study is designed to investigate the safety, tolerability and PK of single and multiple ascending doses of LTSE-2578 in approximately 64 healthy participants and expect to report initial data in 2025.
IPF Disease Background
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Pirfenidone exhibits anti-fibrotic, anti-inflammatory and antioxidant properties through down-regulation of key pro-fibrotic growth factors including TGF-β, inhibition of inflammatory cytokines production and release and reduction of lipid peroxidation and oxidative stress.
−Removed: In Phase 3 trials, pirfenidone slowed disease progression and functional decline in patients with IPF and showed a reduced risk of mortality.
+Added: In Phase 3 studies, pirfenidone slowed disease progression and functional decline in patients with IPF and showed a reduced risk of mortality.
Common adverse effects of pirfenidone include gastrointestinal intolerance such as nausea, diarrhea and dyspepsia and skin reactions, including rash and photosensitivity.
8 unchanged sentences
Despite these limitations, these two drugs have generated total sales of $3.6 billion in 2020.
−Removed: Overview of LPA1R Pathway and Target Biology
−Removed: Lysophosphatidic acid (“LPA”) is a bioactive lipid which exerts potent extracellular signaling through its interaction with several GPCRs, mediating important cellular responses, such as proliferation, migration, and cytoskeletal reorganization.
+Added: LPA1R Pathway and Target Biology
+Added: Lysophosphatidic acid (“LPA”) is a bioactive lipid that exerts potent extracellular signaling through its interaction with several GPCRs, mediating important cellular responses, such as proliferation, migration and cytoskeletal reorganization.
LPA/LPA1R in IPF Pathogenesis
2 unchanged sentences
genetic or PD inhibition of LPA1R attenuated bleomycin induced lung fibrosis by mediating fibroblast recruitment and vascular leak.
−Removed: We believe that LPA1R has been clinically validated as a potential target based on proof-of-concept data from a third party, randomized, double blind, placebo-controlled Phase 2 trial of an LPA1R antagonist (BMS-986020) in patients with IPF.
+Added: We believe that LPA1R has been clinically validated as a potential target based on proof-of-concept data from a third party, randomized, double blind, placebo-controlled Phase 2 study of an LPA1R antagonist (BMS 986020) in patients with IPF.
Patients in the 600 mg BID cohort exhibited significantly slower rates of forced vital capacity decline from baseline to 26 weeks versus placebo.
−Removed: Although the compound was generally well tolerated, dose-related hepatobiliary toxicity in some patients led to early termination of the trial.
+Added: Although the compound was generally well tolerated, dose-related hepatobiliary toxicity in some patients led to early termination of the study.
After conducting additional toxicology investigations, BMS reported that hepatobiliary toxicity was likely caused by inhibition of bile acids efflux transporters such as Bile Salt Export Pump (“BSEP”).
−Removed: generation LPA1R antagonists (BMS-986278) with minimal BSEP inhibition by BMS are currently in clinical development.
+Added: Second generation LPA1R antagonists (BMS 986278) with minimal BSEP inhibition by BMS are currently in clinical development.
We believe that LPA1R can also be used to treat progressive pulmonary fibrosis (“PPF”), which is defined as the presence of at least two of the three criteria, which are worsening respiratory symptoms, functional decline and radiological progression in patients with interstitial lung disease with radiological pulmonary fibrosis for known or unknown reasons other than IPF, within the previous year.
1 unchanged sentence
As illustrated below, we utilized the available protein structural information to collaborate with Schrödinger.
−Removed: After validation and customization with an initial set of compounds for retrospective analysis, Schrödinger’s FEP was utilized and suggested potency in the prospective analysis.
+Added: After validation and customization with an initial set of compounds for retrospective analysis, Schrödinger’s Free Energy Perturbation (“FEP”) was utilized and suggested potency in the prospective analysis.
This customized model greatly expedited the iterative lead optimization process and helped us to achieve candidate selection efficiently.
7 unchanged sentences
One month GLP toxicity studies of LTSE-2578 in rats and dogs have been completed to enable the upcoming first time in human study.
−Removed: Overview of APJR Pathway and Target Biology
−Removed: The apelinergic system plays a key role in the maintenance of vascular health and function through regulation of fibrosis, cell proliferation and inflammation.
−Removed: APJR is highly expressed in the pulmonary vascular endothelium and is upregulated on endothelial cells in IPF patients.
−Removed: Further, activation of the apelinergic system through APJR has been shown to protect endothelial cell survival, and is critical for regeneration of the small capillary blood vessels.
−Removed: These findings support the possibility that an APJR agonist may play a beneficial role in interstitial lung disease.
−Removed: Apelin binding to APJR activates G-protein second messenger signaling and leads to reduced production of cyclic adenosine monophosphate (“cAMP”).
−Removed: Apelin binding to APJR also initiates a feedback loop that eventually downregulates apelin-APJR signaling by recruitment of β-arrestin and subsequent internalization of APJR.
−Removed: In addition, recruitment of β-arrestin triggers downstream pathways that induce vasorelaxation and cardiomyocyte hypertrophy.
−Removed: Therefore, the degree of activation by designed ligands of G-protein and β-arrestin signaling pathway may lead to both therapeutic benefit and undesirable effects.
−Removed: Importance of endothelial cells on pulmonary fibrosis
−Removed: As shown above, while epithelial cell damage and the inflammatory response are known contributors to fibrosis, recent studies have highlighted the importance of endothelial cells on pulmonary fibrosis.
−Removed: Microvascular injuries are observed in patients with pulmonary fibrosis.
−Removed: Persistent vascular leak may support a pro-inflammatory and pro-fibrotic environment.
−Removed: Endothelial senescence is found in the lung of IPF patients.
−Removed: Senescent endothelial cells could secrete factors that directly stimulate fibroblast activation.
−Removed: Targeting apelin pathway may promote capillary regeneration, ameliorate the inflammatory environment, and reduce endothelial senescence, in this way reducing lung fibrosis.
−Removed: Since an APJR agonist mainly targets endothelial cells, we believe it could be easily combined with the current standard of care, pirfenidone and ninetedanib, which do not target the anti-fibrosis pathway from endothelial cells.
−Removed: Our APJR Program for the Treatment of Obesity
−Removed: APJ is expressed in human and murine skeletal muscles.
−Removed: Apelin and APJ are widely distributed in the body and are involved in various physiological functions as blood pressure regulation.
−Removed: Depending on the cell type studied, APJ activation enhances extracellular signal-regulated kinases, AMPK, AKT, and p70S6 kinases and the inhibition of cyclic AMP (cAMP) production.
−Removed: Activation of these pathways would result in worthwhile increases in the protein content of skeletal muscles.
−Removed: Apelin has in fact proved beneficial in maintaining muscle and could potentially counteract age-associated atrophy.
−Removed: We are evaluating ANPA-0073 which is Phase 2 ready, to be used in combination with weight loss medicines for selective or muscle-sparing weight loss.
−Removed: We are also developing ANPA-0073, an investigational, oral, small molecule APJR agonist, for the treatment of IPF.
−Removed: ANPA-0073 is designed to suppress cAMP production through activation of a G-protein-mediated signaling without significant activation of the β-arrestin pathway in order to avoid APJ internalization, and thereby potentially avoid any desensitization effects of an unbiased APJR agonist.
−Removed: We conducted preclinical in vitro studies on our compounds and third-party compounds to assess arrestin signaling and internalization.
−Removed: As shown below, apelin peptide and clinically tested competitor compounds including AMG-986 and
−Removed: BMS-986224 are all non-biased APJR agonists in these in vitro studies, with low β-arrestin/cAMP and internalization/cAMP ratios.
−Removed: Our molecules, such as ANPA-0073 and ANPA-137, are designed to be biased with much higher β-arrestin/cAMP and internalization/cAMP ratios than apelin peptide and the competitor compounds shown below.
−Removed: APJR biased agonism is a potential differentiator for ANPA-0073
−Removed: BIASED SELECTIVITY
−Removed: SIGNALING/cAMP
−Removed: INTERNALIZATION/cAMP
−Removed: Apelin Peptide
−Removed: ANPA-0073 Preclinical Data
−Removed: In an in vitro study, ANPA-0073 demonstrated high potency in suppressing cAMP production through the G-protein-mediated signaling pathway with a half maximal excitatory concentration (EC50) value of less than 10 nM (n=15), but less potency in triggering the β-arrestin pathway and APJR internalization respectively.
−Removed: These data suggest ANPA-0073 is highly biased.
−Removed: The G-protein agonist potency of ANPA-0073 was similar across different species (rat, dog and monkey).
−Removed: Anti-fibrosis effect of an APJ agonist ANPA-0137 was evaluated in bleomycin induced lung fibrosis model.
−Removed: Seven days after bleomycin challenges, mice received oral ANPA-137 for two weeks.
−Removed: ANPA-137 significantly reduced lung fibrosis Ashcroft scores and inflammatory cells infiltration into lung as quantified by inflammatory score as shown below.
−Removed: APJR agonist demonstrated anti-fibrosis efficacy in therapeutic IPF mouse model
−Removed: Furthermore, ANPA-137 also demonstrated anti-fibrotic activity in an in vivo bleomycin-induced rat lung fibrosis model.
−Removed: Similar to mouse bleomycin study design, seven days after bleomycin challenges, rats
−Removed: received 15 mpk of oral ANPA-137 for two weeks.
−Removed: ANPA-137 significantly reduced lung fibrosis as quantified by Ashcroft score as shown below.
−Removed: APJR agonist demonstrated anti-fibrosis efficacy in therapeutic IPF rat model
−Removed: ANPA-0073 Phase 1 Healthy Volunteer Trial Design
−Removed: In September 2022, we completed a two-part, 96 subject, first-in-human Phase 1 SAD and MAD study for ANPA-0073 in 48 healthy adult volunteers between the ages of 18 and 55.
−Removed: The objective was to assess drug safety and PK.
−Removed: The first part of this study was a SAD study, involving eight cohorts of eight participants assigned to receive a single dose of ANPA-0073 or placebo in a 3:1 ratio.
−Removed: Doses from 2 mg to 600 mg across the eight cohorts were evaluated.
−Removed: The second part of the trial was a MAD study, including four cohorts of eight subjects receiving sequential ascending doses of ANPA-0073 daily for seven days, increasing from 75 mg to 500 mg once daily.
−Removed: A schema of our Phase 1 study is presented below:
−Removed: Schema of our ANPA-0073 Phase 1 study in healthy volunteers
−Removed: ANPA-0073-01 Part A SAD Schema
−Removed: ANPA-0073-01 Part B MAD Schema
−Removed: ANPA-0073 Phase 1 Safety Data in Healthy Volunteers
−Removed: ANPA-0073 was generally well tolerated at all dose levels administrated in the SAD and MAD parts of this Phase 1 study.
−Removed: In the study, PK parameters of systemic exposure, C max and AUC, increased with doses of ANPA-0073 across the dose range from 75 mg to 500 mg.
−Removed: In the SAD cohorts, no SAEs and no adverse changes in laboratory tests were observed.
−Removed: Among the AEs reported, five were considered moderate treatment emergent adverse events and the remaining were mild in severity.
−Removed: AEs did not result in any early terminations or subject discontinuations from participation in this study.
−Removed: No trial stopping criteria were met and no significant changes or trends in hematology, blood
−Removed: chemistries, vital signs or electrocardiogram (“ECG”) measurements were noted.
−Removed: The following table shows all TEAEs that were reported:
−Removed: ANPA-0073 Phase 1 SAD Treatment Emergent Adverse Events
−Removed: In the MAD portion of the Phase 1 study, no SAEs and no adverse changes in laboratory tests were observed.
−Removed: Among the AEs reported, twelve were considered moderate TEAEs and the remaining were mild in severity.
−Removed: AEs did not result in any early terminations or subject discontinuations from participation in this study.
−Removed: No trial stopping criteria were met and no significant changes or trends in hematology, blood chemistries, vital signs or ECG measurements were noted.
−Removed: The following table shows all TEAEs that were reported:
−Removed: ANPA-0073 Phase 1 MAD Treatment Emergent Adverse Events
−Removed: We will initiate the 26-week chronic GLP-toxicology studies in rats and 39-week studies in dogs that we believe will be required by regulatory agencies to continue dosing beyond 13 weeks in Phase 2.
−Removed: We are also evaluating ANPA-0073 for selective or muscle-sparing weight loss.
+Added: GPCRs as a Therapeutic Target Family
+Added: GPCRs form the largest human membrane protein family, consisting of approximately 800 identified members as illustrated below.
+Added: GPCRs are involved in several vital physiological functions, such as immune system regulation and inflammation, autonomic nervous system transmission, behavioral and mood regulation, sensory transmission and maintenance of homeostasis.
+Added: Therefore, they are important targets for numerous therapeutics with approximately 475 drugs on the market to date acting at over 100 unique GPCRs.
+Added: Importantly, more than 220 GPCRs have not yet been explored as clinical targets, hence representing a broad and untapped therapeutic potential for addressing global healthcare needs.
+Added: Phylogenetic Tree of GPCR Targets
+Added: GPCR targeting drugs have successfully delivered significant patient benefit resulting in large market opportunities in many therapeutic areas.
+Added: Examples include liraglutide (Victoza for T2DM), aripiprazole (Abilify for schizophrenia, bipolar disorder and depression), montelukast (Singulair for asthma), valsartan (Diovan for hypertension), metoprolol (Lopressor for hypertension, angina and myocardial infarction) and clopidogrel (Plavix for myocardial infarction and stroke).
+Added: GPCR related drugs are the largest drug class accounting for approximately 27% of global pharmaceutical sales with estimated aggregate sales of $890 billion between 2011 and 2015.
+Added: GPCRs are proteins that span the entire width of cell membranes.
+Added: Their primary function is to recognize extracellular substances, primarily ligands, and transmit signals across the cell membrane to the inside of the cell.
+Added: Schematic of a GPCR
+Added: As shown above, the binding of extracellular ligands to GPCRs elicits conformational changes that impact the intracellular side of the receptor, resulting in the formation of a GPCR complex with signal transducers, particularly G-proteins.
+Added: These signal transducers go on to interact with second messengers, ultimately either stimulating or inhibiting certain cellular processes.
+Added: GPCRs signal not only through G-proteins, but also through β-arrestins and other non-G-protein transducers.
+Added: Β-arrestins play an essential role in many physiological and pathological processes, and they are involved in the desensitization, internalization, sequestration and trafficking of GPCRs.
+Added: Certain GPCR ligands are capable of simultaneously activating both G-protein and non-G-protein mediated signaling pathways, which can lead to a variety of physiologic as well as pathologic effects.
+Added: Challenges of GPCR Therapeutic Discovery and Development
+Added: Despite tremendous advancements in structure-based drug design and development, GPCR drug discovery and development remains challenging.
+Added: • Similarity between the binding sites of GPCRs and related receptors can cause off-target toxicities:
+Added: All GPCRs have the same overall three-dimensional architecture but the specific endogenous binding site is unique due to the placement of amino acid side chains shaping the binding site.
+Added: For instance, the early sphingosine 1 phosphate 1 receptor (“S1P1R”) agonist Gilenya led to the development of a new class of therapy for the treatment of multiple sclerosis, but had exhibited bradycardia as a side effect due in part to sphingosine 1 phosphate 3 receptor (“S1P3R”) activity, a very closely related S1P1 receptor subtype.
+Added: The next generation S1P1R agonist Zeposia was designed using structural information by Receptos, Inc.
+Added: to remove the S1P3 and other activities and therefore did not have the same side effect profile as Gilenya.
+Added: • GPCRs are involved in diverse downstream signaling pathways which can result in side effects:
+Added: GPCRs interact with a range of molecules, including G-protein and non-G-protein transducers including β-arrestin.
+Added: Signaling pathway selectivity results from agonist-induced specific receptor conformation and when targeting GPCRs involved in multiple signaling pathways, both therapeutic benefits and side effect issues may arise.
+Added: • Expression levels of GPCRs are low and create significant hurdles to structural and PD characterization:
+Added: Recombinant protein expression of GPCRs remains extremely challenging.
+Added: Expression levels of GPCRs are low and improvement of expression level continues to be mainly empirical and resource-consuming.
+Added: GPCRs are complex membrane proteins that require a stable membrane environment throughout the purification process to avoid destabilization and aggregation.
+Added: • GPCR structural visualization is complex making GPCR structure-based drug discovery challenging:
+Added: Structure-based drug design requires rapid iterations of GPCR structures in complex with specific new ligands to determine their effects on conformation.
+Added: This is well established through robust crystallography platforms for soluble drug targets.
+Added: Cryo-EM has helped accelerate the membrane protein field, but the methods still require substantial expertise and execution.
+Added: Drug discovery approaches targeting GPCRs have evolved from traditional approaches including high throughput screening to rational design for enhanced activity, tailor-made signaling response and improved selectivity, which leads to improved safety and tolerability profiles.
+Added: Our Structure-Based Drug Discovery Technology Platform
+Added: Our platform is based on techniques that our founders have been evolving for over 25 years, which have enabled them to deliver multiple marketed medicines.
+Added: Our approach enables us to generate small molecule product candidates that are designed to overcome the historical limitations of GPCR drug development.
+Added: Our insights and capabilities enable us to visualize the three-dimensional protein structures of the target and the ligands.
+Added: We believe this visualization combined with the computational chemistry capabilities of Schrödinger gives us significant competitive advantages in highly efficient and rational drug design.
+Added: We design our novel compounds by combining our knowledge of GPCR structures together with advanced physics-based computational methods, which we believe allows us to predict the binding affinity of molecules to the target site with a high degree of accuracy.
+Added: As shown below, our technology platform allows us to determine feasibility, optimize the design of and efficiently generate families of potent and highly selective small molecule candidates.
+Added: Structure Therapeutics Integrated Technology Platform from Target to IND
+Added: Oral small molecules have the potential to address the key limitations of biologic and peptide drugs, such as high cost and patient inconvenience, thereby significantly improving patient access.
+Added: We believe this is particularly important for the most prevalent chronic diseases including those involving the endocrine, cardiovascular and pulmonary systems.
+Added: We believe the strengths of our technology platform will enable us to develop oral small molecule drugs that can deliver biologic-like activity and specificity.
+Added: GPCR Target Prioritization
+Added: We start with target prioritization by focusing on validated GPCR targets that do not have attractive small molecule solutions.
+Added: We then prioritize by assessing the feasibility of a small molecule solution for these targets and market opportunities of their respective target indication.
+Added: Expertise in GPCR Structure-Based Drug Discovery
+Added: GPCRs are difficult to characterize structurally because they are composed of seven transmembrane domains, have low expression and are unstable outside of the cell membrane environment.
+Added: While structure-based approaches have been utilized for decades in soluble protein drug discovery, recent breakthrough advancements in computational chemistry, artificial intelligence, machine learning and electron microscopy are redefining the field of GPCR structure-based drug discovery.
+Added: Visualization of GPCR Structure and Binding Site Interactions
+Added: As shown above, our structure-based technology platform combines direct visualization of protein receptor binding interactions with advanced simulation of molecular motion and signal transduction.
+Added: Site 1 is considered to be the orthosteric or primary binding site for receptor activation.
+Added: Site 2 is on the surface of the receptor, often referred to as the allosteric site and may potentially regulate receptor activation signaling.
+Added: By visualizing and analyzing how different ligands bind to a particular target and specific sites and affect their conformational dynamics, we believe we are able to efficiently convert biologics and peptides into more accessible, patient-accommodating oral small molecules.
+Added: In addition, we can enhance the pharmaceutic properties of our small molecules with the aim of eliciting the desired function while maintaining superior pharmaceutical properties.
+Added: Non-biased vs Biased GPCR Agonists
+Added: Additionally, GPCR signaling can follow several pathways and molecules can be designed such that their pharmacology is selected to create “biased signaling” as illustrated above.
+Added: GPCRs are known to signal not only through G-proteins, but also through β-arrestins, intracellular proteins that “arrest” the signal and stop the receptor from becoming over-stimulated through a receptor internalization mechanism.
+Added: Using the three-dimensional structures of GPCRs and selection methods, we can potentially design highly selective “biased”
+Added: molecules that preferentially activate G-protein and not β-arrestin pathways, which could lead to enhanced clinical activity as well as an improved safety profile due to lower dosage requirements.
+Added: Robust and Integrated Medicinal Chemistry to Generate and Optimize Hits on GPCR Targets
+Added: We have extensive medicinal chemistry know-how on the discovery and development of novel molecules that target GPCRs.
+Added: When coupled with our deep understanding of GPCR biology, we have the potential to design appropriate chemotypes for each GPCR function as illustrated below.
+Added: Family Members with Determined Structures are Highlighted within the Tree, and their Binding Pockets with the Ligand
+Added: Four Character Code at End of Each Image is Protein Data Bank ID.
+Added: Further optimization of compounds powered by our excellence in medicinal chemistry led us to identify potent and selective oral small molecule product candidates.
+Added: Partnership with Schrödinger Leveraging its Cutting-Edge Computational Chemistry Capability
+Added: We have collaborations with Schrödinger on the iteration and optimization of GPCR lead compounds using various next-generation physics-based computational technologies.
+Added: Schrödinger is a scientific leader in chemical simulation, accurate physics-based methods, which includes among many technologies, FEP and in silico drug discovery.
+Added: Its’ computational platforms integrate predictive physics-based methods with machine learning to evaluate billions of compounds in silico, achieving experimental accuracy on properties such as binding affinity and solubility.
+Added: Through this iterative process, we can accelerate evaluation and optimization of molecules in silico ahead of synthesis and assay and then further optimize them through additional cycles of computation analysis.
+Added: Structure Therapeutics Integrated Platform
+Added: As shown above, our collaborations with Schrödinger in our computational and chemistry module enables us to accelerate our lead optimization drug discovery process and reduce development costs.
+Added: In our partnership with Schrödinger on GPCR drug discovery, we retain the full product rights on the compounds under development.
+Added: Safety Assays
+Added: We have proactively used cell and animal-based safety assays to better screen out unwanted side effects, such as liver, cardiovascular and central nervous system toxicity at the initial stages of lead optimization, and we have designed molecules to help minimize safety risks at every step.
+Added: Our in-depth understanding of GPCR signaling pathway provides us insights to design biased molecules when necessary to mitigate any unwanted liabilities while maintaining the desired activities.
+Added: Other Proprietary In-House Development Tools for Drug Synthesis and Screening
+Added: In addition to our robust iterative structure-based drug discovery platform shown above, Basecamp Bio is optimizing proprietary in-house drug discovery tools including DNA-Encoded Library technology and Affinity Mass Spectrometry technology to enable the synthesis and screening of vast numbers of small molecule product candidates at a scale that is not possible to achieve by traditional methods.
Intellectual Property
1 unchanged sentence
Our success also depends in part on our ability to operate without infringing the proprietary rights of others, and in part on our ability to prevent others from infringing our proprietary rights.
−Removed: A comprehensive
−Removed: discussion on risks relating to intellectual property is provided under Part I.
+Added: A comprehensive discussion on risks relating to intellectual property is provided under Part I.
“Risk Factors—Risks Related to Our Intellectual Property.”
−Removed: For our GLP-1R program, as of December 31, 2023, our wholly-owned subsidiary Gasherbrum Bio, Inc., is the sole owner of one granted U.S.
−Removed: patent and 11 pending U.S.
−Removed: patent applications, 14 Patent Cooperation Treaty (“PCT”), applications, and 94 pending foreign patent applications in Argentina, the African Regional Intellectual Property Organization (“ARIPO”), Australia, Brazil, Canada, Chile, the People’s Republic of China (“PRC”), Colombia, Costa Rica, Dominican Republic, Egypt, the Eurasian Patent Office (the “EAPO”), the European Patent Office (the “EPO”), Guatemala, Hong Kong, Indonesia, Israel, India, Japan, South Korea, Mexico, Malaysia, New Zealand, Panama, Peru, Philippines, Saudi Arabia, Singapore, Thailand, Taiwan, Ukraine, Vietnam, and South Africa.
−Removed: These patent applications, to the extent they issue (or in the case of priority applications, if issued from future non-provisional applications that we file), are expected to expire between 2041 and 2044, without accounting for potentially available patent term adjustments or extensions.
−Removed: These patent applications relate to compositions of matter of heterocyclic GLP-1 agonists, including GSBR-1290 and its analogs, solid forms and methods of treating conditions associated with GLP-1R activity.
−Removed: We intend to strengthen the patent protection of our product candidates and other discoveries, inventions, trade secrets and know-how that are critical to our business operations through additional patent application filings.
−Removed: For our oral small molecule APJR program, as of December 31, 2023, our wholly-owned subsidiary Annapurna Bio, Inc.
−Removed: is the sole owner of two granted U.S.
−Removed: patents and three pending U.S.
−Removed: patent applications, one PCT application, one granted European patent and 24 pending foreign patent applications in Argentina, Australia, Brazil, Canada, the PRC, the EAPO, the EPO, Hong Kong, Israel, India, Japan, South Korea, Mexico, New Zealand, Singapore, Taiwan, and South Africa relating to compounds and compositions of matter for treating conditions associated with Apelin receptor activity, including ANPA-0073 and its analogs, solid forms and methods of treating conditions associated with Apelin receptor activity.
−Removed: Any patents issuing from these patent applications (or in the case of priority applications, if issued from future non-provisional applications that we file) are expected to expire between 2039 and 2043, without accounting for potentially available patent term adjustments or extensions.
−Removed: For our LPA1R program, as of December 31, 2023, our wholly-owned subsidiary Lhotse Bio, Inc.
−Removed: (“Lhotse”) is the sole owner of three pending U.S.
−Removed: patent applications, four PCT applications and seven pending foreign patent applications in Argentina, the PRC, the EPO, Japan, and Taiwan relating to compounds and compositions of matter for treating conditions associated with LPA receptor activity, including LTSE-2578 and its analogs, and methods of treating conditions associated with LPA receptor activity.
−Removed: Any patents issuing from these patent applications (or in the case of priority applications, if issued from future non-provisional applications that we file) are expected to expire between 2041 and 2044, without accounting for potentially available patent term adjustments or extensions.
−Removed: For our oral small molecule Amylin program, as of December 31, 2023, our wholly-owned subsidiary Aconcagua Bio, Inc.
−Removed: (“Aconcagua”) is the sole owner of two PCT applications relating to compounds and compositions of matter for treating conditions associated with Amylin receptor activity and methods of treating conditions associated with Amylin receptor activity.
−Removed: Any patents issuing from these patent applications (or in the case of priority applications, if issued from future non-provisional applications that we file) are expected to expire in 2044, without accounting for potentially available patent term adjustments or extensions.
+Added: For our product candidates, we will, in general, initially pursue patent protection covering compounds, compositions of matter and methods of use.
+Added: Throughout the development of our product candidates, we seek to identify additional means of obtaining patent protection that would potentially enhance commercial success, including through additional methods of use, process of making, formulation and dosing regimen-related claims as appropriate.
+Added: In total, our patent portfolio comprises over 350 patents and patent applications, as of December 31, 2024, filed in various jurisdictions worldwide.
+Added: This includes over 95 issued patents that are owned by our wholly-owned subsidiaries.
+Added: Our patent portfolio for our product candidates is outlined below.
In addition to patent protection, we also rely on trade secrets, know-how, trademarks, other proprietary information and continuing technological innovation to develop and maintain our competitive position.
6 unchanged sentences
“Risk Factors — Risks Related to Our Intellectual Property.”
+Added: Aleniglipron (GSBR-1290):GLP-1 Receptor Program
+Added: For our GLP-1R program, our wholly-owned subsidiary Gasherbrum Bio, Inc.
+Added: is the sole owner of 24 patent families.
+Added: These include patents and patent applications directed to our lead product candidate aleniglipron and its analogs, solid forms and methods of treating conditions associated with GLP-1R activity.
+Added: These patents and patent applications, to the extent they issue (or in the case of priority applications, if issued from future non-provisional applications that we file), are expected to expire between 2041 and 2045, without accounting for potentially available patent term adjustments or extensions.
+Added: Amylin Receptor Program
+Added: For our oral small molecule Amylin program, our wholly-owned subsidiary Aconcagua Bio, Inc.
+Added: (“Aconcagua”) is the sole owner of 6 patent families.
+Added: These include patent applications relating to compounds and compositions of matter for treating conditions associated with amylin receptor activity, including ACCG-2671 and its analogs and methods of treating conditions associated with amylin receptor activity.
+Added: Any patents issuing from these patent applications (or in the case of priority applications, if issued from future non-provisional applications that we file) are expected to expire between 2044 and 2045, without accounting for potentially available patent term adjustments or extensions.
+Added: GIP and GCG Receptor Programs
+Added: For our oral small molecule GIPR program, our wholly-owned subsidiary Gimigela Bio, Inc.
+Added: is the sole owner of 3 patent families.
+Added: These include patent applications relating to compounds and compositions of matter for treating conditions associated with GIPR activity and methods of treating conditions associated with GIPR activity.
+Added: Any patents issuing from these patent applications (or in the case of priority applications, if issued from future non-provisional applications that we file) are expected to expire in 2045, without accounting for potentially available patent term adjustments or extensions.
+Added: APJ Receptor Program
+Added: For our APJ receptor program, our wholly-owned subsidiary Annapurna Bio, Inc.
+Added: is the sole owner of 5 patent families.
+Added: These include patents and patent applications directed to our lead product candidate ANPA-0073 and its analogs, solid forms and methods of treating conditions associated with APJ receptor activity.
+Added: These patents and patent applications, to the extent they issue (or in the case of priority applications, if issued from future non-provisional applications that we file), are expected to expire between 2039 and 2045, without accounting for potentially available patent term adjustments or extensions.
+Added: LPA1 Receptor Program
+Added: For our LPA1R program, our wholly-owned subsidiary Lhotse Bio, Inc.
+Added: (“Lhotse”) is the sole owner of 5 patent families.
+Added: These include patents and patent applications relating to compounds and compositions of matter for treating conditions associated with LPA1R activity, including LTSE-2578 and its analogs and methods of treating conditions associated with LPA1R activity.
+Added: These patents and patent applications, to the extent they issue (or in the case of priority applications, if issued from future non-provisional applications that we file), are expected to expire between 2041 and 2044, without accounting for potentially available patent term adjustments or extensions.
Lhotse Collaboration Agreement with Schrödinger, LLC
10 unchanged sentences
Either party may terminate the Lhotse-Schrödinger Agreement for the other party’s uncured material breach, subject to certain notice and cure periods, or for the other party’s bankruptcy or insolvency.
−Removed: Lhotse’s obligation to make milestone and royalty payments (subject to the Royalty Term) to Schrödinger continues after the expiration or termination of the Lhotse-Schrödinger Agreement.
+Added: Lhotse’s obligation to make milestone and royalty payments (subject
+Added: to the Royalty Term) to Schrödinger continues after the expiration or termination of the Lhotse-Schrödinger Agreement.
Aconcagua Collaboration Agreement with Schrödinger
3 unchanged sentences
During the term of the Aconcagua-Schrödinger Agreement or if longer, for a specified number of years after the effective date of the Aconcagua-Schrödinger Agreement, Schrödinger is obligated, subject to certain exceptions, to work exclusively with Aconcagua on the design, research, development and commercialization of compounds that inhibit the target.
−Removed: Aconcagua will solely own the research results, work product, inventions and other intellectual property
−Removed: generated under the Aconcagua-Schrödinger Agreement other than improvements to Schrödinger’s background intellectual property.
+Added: Aconcagua will solely own the research results, work product, inventions and other intellectual property generated under the Aconcagua-Schrödinger Agreement other than improvements to Schrödinger’s background intellectual property.
During the term of the Aconcagua-Schrödinger Agreement, Aconcagua is obligated to pay Schrödinger a monthly active program payment in the low six digits, which payment includes fees payable for certain Schrödinger software employed in the Collaboration, and as of December 31, 2024, we have paid to Schrödinger an aggregate of $3.3 million.
13 unchanged sentences
While we believe that our platform and our knowledge, experience and scientific resources provide us with competitive advantages, we face competition from major pharmaceutical and biotechnology companies, academic institutions, governmental agencies and public and private research institutions, among others.
−Removed: If any of our product candidates are approved for the indications for which we expect to conduct clinical trials, they will compete with the foregoing therapies and currently marketed drugs, as well as any drugs potentially in development.
+Added: If any of our product candidates are approved for the indications for which we expect to conduct clinical studies, they will compete with the foregoing therapies and currently marketed drugs, as well as any drugs potentially in development.
It is also possible that we will face competition from other pharmaceutical approaches as well as other types of therapies.
1 unchanged sentence
Despite significant biopharmaceutical industry investment, no oral small molecule therapy targeting GLP-1R has been approved for the treatment of diabetes or obesity.
−Removed: We are aware of GLP-1R small molecules in
−Removed: development by Eccogene (licensed by Astrazeneca in November 2023) Carmot Therapeutics (acquired by Roche in January 2024), Terns Pharmaceuticals, Pfizer, Eli Lilly, and Qilu Regor Therapeutics Inc.
−Removed: There are currently approved GLP-1R peptides for the Pfizer, Eli Lilly, and Qilu Regor Therapeutics Inc.
−Removed: There are currently approved GLP-1R peptides for the treatment of diabetes and obesity marketed by Novo Nordisk, Eli Lilly, AstraZeneca, and Sanofi.
−Removed: We are aware of other GLP-1R plus dual/tri incretin targeting peptides in development by Eli Lilly, Jiangsu Hansoh Pharmaceutical Group Co., Ltd., Boehringer Ingelheim, Altimmune, Inc., Carmot Therapeutics, Inc., and Sciwind Biosciences Co., Ltd.
+Added: We are aware of GLP-1R small molecules in development by Pfizer, Eli Lilly, Qilu Regor Therapeutics, AstraZeneca/Eccogene, Terns Pharmaceuticals, Jiangsu Hengrui Medicine, Huadong, Sciwind Biosciences, Ascletis, Gilead, Kallyope, MindRank, vTv Therapeutics, Carmot Therapeutics (acquired by Roche Group in January 2024), Kailera Therapeutics, formerly Hercules CM Newco (licensed HRS-7535, an oral small molecule GLP-1;
+Added: HRS-9531 a GLP-1/GIP;
+Added: and preclinical asset HRS-4729 from Jiangsu Hengrui Medicine), and Merck (licensed HS-10535, an oral small molecule GLP-1, from Hansoh Pharma).
+Added: There are currently approved GLP-1R peptides for the treatment of diabetes and obesity marketed by Novo Nordisk, Eli Lilly, AstraZeneca, Sanofi and Kailera Therapeutics, formerly Hercules CM Newco.
+Added: We are aware of other GLP-1R plus dual/tri incretin targeting peptides in development by Eli Lilly, Jiangsu Hansoh Pharmaceutical Group, Boehringer Ingelheim, Altimmune, Carmot Therapeutics, Sciwind Biosciences, Novo Nordisk, Viking Therapeutics, Amgen, Merck, Zealand Pharma, D&D Pharmatech, GMAX Biopharma, Jiangsu Hengrui Medicine, BrightGene, Innovent Biologics, PegBio, NeuroBo Pharmaceuticals, Hanmi Phamaceuticals, Progen Holdings, Pep2Tango, Metsera, QL Biopharma, Lexaria Bioscience, Sun Pharmaceutical, Gan & Lee, Innogen Biomed Industries and Verdiva Bio.
In addition, there are a number of companies developing product candidates for diabetes and obesity utilizing approaches with different mechanisms of action, including but not limited to sodium-glucose cotransporter-2 inhibitors.
−Removed: We are aware of APJR targeted product candidates in development for COVID-19 acute respiratory distress syndrome by CohBar, Inc.;
−Removed: IPF, systemic sclerosis interstitial lung disease, and kidney nephrotic syndrome by Apie Therapeutics;
−Removed: and muscle atrophy by BioAge Labs, Inc.
−Removed: Both Amgen and Bristol Myers Squibb (“BMS”) have APJR targeted product candidates for heart failure.
−Removed: In addition, there are a number of companies developing product candidates for PAH utilizing approaches with different mechanisms of action, including but not limited to FibroGen, Inc., Galapagos NV, Galecto, Inc., Pliant Therapeutics, Inc., Gilead Sciences, Inc., Roche Holding AG and Boehringer Ingelheim.
−Removed: We are aware of LPA1R targeted product candidates in development for IPF by BMS, Horizon Therapeutics plc (acquired by Amgen in October 2023), and DJS Antibodies Ltd;
+Added: We are aware of APJ receptor targeted product candidates in development for IPF and systemic sclerosis interstitial lung disease by Apie Therapeutics.
+Added: Both Amgen and Bristol Myers Squibb (“BMS”) have APJ receptor targeted product candidates for heart failure.
+Added: We are aware of LPA1R targeted product candidates in development for IPF by BMS, Horizon Therapeutics (acquired by Amgen in October 2023) and DJS Antibodies;
and myelin restoration and neuroinflammation by Pipeline Therapeutics.
In addition, there are a number of companies developing product candidates for IPF utilizing approaches with different mechanisms of action, including Roche Holding AG and Boehringer Ingelheim.
−Removed: Many of our current or potential competitors, either alone or with their collaboration partners, have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals, and marketing approved products than we do.
−Removed: These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.
+Added: Many of our current or potential competitors, either alone or with their collaboration partners, have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical studies, obtaining regulatory approvals, and marketing approved products than we do.
+Added: These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient registration for clinical studies, as well as in acquiring technologies complementary to, or necessary for, our programs.
Mergers and acquisitions in the biopharmaceutical industries may result in even more resources being concentrated among a smaller number of our competitors.
7 unchanged sentences
Numerous state, federal and foreign laws, regulations and standards govern the collection, use, access to, confidentiality and security of health-related and other personal or sensitive information, and could apply now or in the future to our operations or the operations of our partners.
−Removed: In the United States, numerous federal and state laws and regulations, including data breach notification laws, health information privacy and security laws and consumer protection laws and regulations govern the collection, use, disclosure, and protection of health-related and other personal information.
+Added: In the United States, numerous federal and state laws and regulations, including data breach notification laws, health information privacy and security laws and consumer protection laws and regulations have been enacted or proposed that govern the collection, use, disclosure, and protection of health-related and other personal information.
+Added: For example, California passed the California Consumer Privacy Act of 2018 (“CCPA”) as amended by the Consumer Privacy Rights Act of 2020 (“CPRA”), Virginia passed the Consumer Data Protection Act, and Colorado passed the Colorado Privacy Act.
In addition, certain foreign laws govern the privacy and security of personal data, including health-related data.
−Removed: For example, the European Union General Data Protection Regulation (“EU GDPR”) imposes strict requirements for processing the personal data of individuals within
−Removed: the European Economic Area (“EEA”).
+Added: For example, the European Union General Data Protection Regulation (“EU GDPR”) imposes strict requirements for processing the personal data of individuals within the European Economic Area (“EEA”).
Companies that must comply with the EU GDPR face increased compliance obligations and risk, including more robust regulatory enforcement of data protection requirements and potential fines for noncompliance of up to €20 million or 4% of the annual global revenues of the noncompliant company, whichever is greater.
1 unchanged sentence
The UK GDPR mirrors the fines under the GDPR relating to fines up to the greater of £17.5 million or 4% of global turnover.
+Added: The CCPA and EU GDPR are examples of the increasingly stringent and evolving regulatory frameworks related to personal data processing that may increase our compliance obligations and exposure for any noncompliance.
+Added: For example, the CCPA imposes obligations on covered businesses to provide specific disclosures related to a business’s collecting, using, and disclosing personal data and to respond to certain requests from California residents related to their personal data (for example, requests to know of the business’s personal data processing activities, to delete the individual’s personal data, and to opt out of certain personal data disclosures).
+Added: Also, the CCPA provides for civil penalties and a private right of action for data breaches which may include an award of statutory damages.
+Added: In addition, the California Privacy Rights Act of 2020 (“CPRA”), effective January 1, 2023, will expand the CCPA.
+Added: The CPRA will, among other things, give California residents the ability to limit use of certain sensitive personal data, establish restrictions on personal data retention, expand the types of data breaches that are subject to the CCPA’s private right of action, and establish a new California Privacy Protection Agency to implement and enforce the new law.
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.
7 unchanged sentences
● completion of extensive preclinical laboratory tests, preclinical animal studies and formulation studies all performed in compliance with applicable regulations, including the FDA’s good laboratory practices (“GLP”) regulations;
−Removed: ● submission to the FDA of an Investigational IND which must become effective before human clinical trials may begin;
+Added: ● submission to the FDA of an Investigational IND which must become effective before human clinical studies may begin;
● approval by an institutional review board (“IRB”) or ethics committee representing each clinical site before each clinical trial may be initiated;
−Removed: ● performance of adequate and well-controlled human clinical trials in accordance with applicable good clinical practices (“GCPs”) and other clinical trial-related regulations, to establish the safety and efficacy of the proposed drug product for its proposed indication;
+Added: ● performance of adequate and well-controlled human clinical studies in accordance with applicable good clinical practices (“GCPs”) and other clinical trial-related regulations, to establish the safety and efficacy of the proposed drug product for its proposed indication;
● preparation and submission to the FDA of an NDA together with payment of user fees;
4 unchanged sentences
● FDA review and approval of the NDA prior to any commercial marketing or sale of the drug in the United States.
−Removed: Preclinical Studies and Clinical Trials
−Removed: The preclinical development stage generally involves synthesizing the active component, developing the formulation and determining the manufacturing process, evaluating purity and stability, as well as carrying out
−Removed: non-human toxicology, pharmacology and drug metabolism studies in the laboratory, which support subsequent clinical testing.
+Added: Preclinical Studies and Clinical Studies
+Added: The preclinical development stage generally involves synthesizing the active component, developing the formulation and determining the manufacturing process, evaluating purity and stability, as well as carrying out non-human toxicology, pharmacology and drug metabolism studies in the laboratory, which support subsequent clinical testing.
The conduct of the preclinical tests must comply with federal regulations, including GLPs where applicable.
1 unchanged sentence
An IND is a request for authorization from the FDA to administer an investigational drug product to humans.
−Removed: The central focus of an IND submission is on the general investigational plan and the protocol(s) for human trials.
−Removed: The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA raises concerns or questions regarding the proposed clinical trials and places the IND on clinical hold within that 30-day time period.
+Added: The central focus of an IND submission is on the general investigational plan and the protocol(s) for human studies.
+Added: The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA raises concerns or questions regarding the proposed clinical studies and places the IND on clinical hold within that 30-day time period.
In such a case, the IND sponsor and the FDA must resolve any outstanding concerns or questions before the clinical trial can begin.
−Removed: Some long-term preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity, may continue after the IND is submitted.
−Removed: The FDA may also impose clinical holds on a drug candidate at any time before or during clinical trials due to safety concerns or non-compliance.
−Removed: Accordingly, submission of an IND does not guarantee the FDA will allow clinical trials to begin, or that, once begun, issues will not arise that could cause the trial to be suspended or terminated.
−Removed: The clinical stage of development involves the administration of the drug product to human subjects or patients under the supervision of qualified investigators, generally physicians not employed by or under the trial sponsor’s control, in accordance with GCPs, which establish standards for conducting, recording data from, and reporting the results of clinical trials, and are intended to assure that the rights, safety, and well-being of study participants are protected.
+Added: Some long-term preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity, may continue
+Added: after the IND is submitted.
+Added: The FDA may also impose clinical holds on a drug candidate at any time before or during clinical studies due to safety concerns or non-compliance.
+Added: Accordingly, submission of an IND does not guarantee the FDA will allow clinical studies to begin, or that, once begun, issues will not arise that could cause the trial to be suspended or terminated.
+Added: The clinical stage of development involves the administration of the drug product to human subjects or patients under the supervision of qualified investigators, generally physicians not employed by or under the trial sponsor’s control, in accordance with GCPs, which establish standards for conducting, recording data from, and reporting the results of clinical studies, and are intended to assure that the rights, safety, and well-being of study participants are protected.
GCPs also include the requirement that all research subjects provide their informed consent in writing for their participation in any clinical trial.
−Removed: Clinical trials are conducted under written study protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria, and the parameters to be used to monitor subject safety and assess efficacy.
+Added: Clinical studies are conducted under written study protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria, and the parameters to be used to monitor subject safety and assess efficacy.
Each protocol, and any subsequent amendments to the protocol, must be submitted to the FDA as part of the IND.
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: While the IND is active and before approval, progress reports summarizing the results of the clinical trials and nonclinical studies performed since the last progress report must be submitted at least annually to the FDA, and written IND safety reports must be submitted to the FDA and investigators for serious and unexpected suspected adverse events, findings from other studies suggesting a significant risk to humans exposed to the same or similar drugs, findings from animal or in vitro testing suggesting a significant risk to humans, and any clinically important increased incidence of a serious suspected adverse reaction compared to that listed in the protocol or investigator brochure.
+Added: While the IND is active and before approval, progress reports summarizing the results of the clinical studies and nonclinical studies performed since the last progress report must be submitted at least annually to the FDA, and written IND safety reports must be submitted to the FDA and investigators for serious and unexpected suspected adverse events, findings from other studies suggesting a significant risk to humans exposed to the same or similar drugs, findings from animal or in vitro testing suggesting a significant risk to humans, and any clinically important increased incidence of a serious suspected adverse reaction compared to that listed in the protocol or investigator brochure.
Further, each clinical trial must be reviewed and approved by each institution at which the clinical trial will be conducted.
−Removed: An IRB is charged with protecting the welfare and rights of trial participants and considers such items as whether the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits.
+Added: An IRB is charged with protecting the welfare and rights of trial participants and considers such items as whether the risks to individuals participating in the clinical studies are minimized and are reasonable in relation to anticipated benefits.
The IRB also reviews and approves the informed consent form that must be provided to each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed.
1 unchanged sentence
Depending on its charter, this group may determine whether a trial may move forward at designated check points based on access to certain data from the trial.
−Removed: There are also requirements governing the reporting of ongoing clinical trials and completed clinical trial results to public registries.
−Removed: Clinical trials are generally conducted in three sequential phases that may overlap or be combined, known as Phase I, Phase II and Phase III clinical trials.
−Removed: The drug is initially introduced into a small number of healthy volunteers or patients with the target disease or condition who are initially exposed to a single dose and then multiple doses of
−Removed: the drug candidate.
+Added: There are also requirements governing the reporting of ongoing clinical studies and completed clinical trial results to public registries.
+Added: Clinical studies are generally conducted in three sequential phases that may overlap or be combined, known as Phase I, Phase II and Phase III clinical studies.
+Added: The drug is initially introduced into a small number of healthy volunteers or patients with the target disease or condition who are initially exposed to a single dose and then multiple doses of the drug candidate.
These studies are designed to assess the metabolism, pharmacologic action, dosage tolerance, side effects associated with increasing doses, and safety of the drug, and if possible, to gain early evidence on effectiveness.
1 unchanged sentence
At the same time, safety and further PK and PD information is collected, as well as identification of possible adverse effects and safety risks and preliminary evaluation of efficacy.
−Removed: The drug is administered to an expanded number of patients, generally at multiple sites that are geographically dispersed, in well-controlled clinical trials to generate enough data to demonstrate the efficacy of the drug for its intended use, its safety profile, and to establish the overall benefit/risk profile of the drug and provide an adequate basis for drug approval and labeling of the drug product.
−Removed: Post-approval trials, sometimes referred to as Phase IV clinical trials, may be conducted after initial marketing approval.
−Removed: These trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication.
−Removed: In certain instances, the FDA may mandate the performance of Phase IV clinical trials as a condition of NDA approval.
+Added: The drug is administered to an expanded number of patients, generally at multiple sites that are geographically dispersed, in well-controlled clinical studies to generate enough data to demonstrate the efficacy of the drug for its intended use, its safety profile, and to establish the overall
+Added: benefit/risk profile of the drug and provide an adequate basis for drug approval and labeling of the drug product.
+Added: Post-approval studies, sometimes referred to as Phase IV clinical studies, may be conducted after initial marketing approval.
+Added: These studies are used to gain additional experience from the treatment of patients in the intended therapeutic indication.
+Added: In certain instances, the FDA may mandate the performance of Phase IV clinical studies as a condition of NDA approval.
The FDA, the IRB, or the clinical trial sponsor may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research subjects or patients are being exposed to an unacceptable health risk.
Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution, or an institution it represents, if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the drug has been associated with unexpected serious harm to patients.
−Removed: Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the drug as well as finalize a process for manufacturing the drug in commercial quantities in accordance with cGMP requirements.
+Added: Concurrent with clinical studies, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the drug as well as finalize a process for manufacturing the drug in commercial quantities in accordance with cGMP requirements.
The manufacturing process must be capable of consistently producing quality batches of the drug candidate and, among other things, cGMPs impose extensive procedural, substantive and recordkeeping requirements to ensure and preserve the long-term stability and quality of the final drug product.
1 unchanged sentence
NDA Submission and FDA Review Process
−Removed: Assuming successful completion of all required testing in accordance with all applicable regulatory requirements, the results of non-clinical studies and of the clinical trials, together with other detailed information, including extensive manufacturing information and information on the composition of the drug and proposed labeling, are submitted to the FDA in the form of an NDA requesting approval to market the drug for one or more specified indications.
+Added: Assuming successful completion of all required testing in accordance with all applicable regulatory requirements, the results of non-clinical studies and of the clinical studies, together with other detailed information, including extensive manufacturing information and information on the composition of the drug and proposed labeling, are submitted to the FDA in the form of an NDA requesting approval to market the drug for one or more specified indications.
Data can come from company-sponsored clinical studies intended to test the safety and effectiveness of a use of the product, or from a number of alternative sources, including studies initiated by independent investigators.
8 unchanged sentences
Once filed, the FDA has a goal of ten months from the filing date to complete a standard review of an NDA for a drug that is a new molecular entity.
−Removed: This review typically takes twelve months from the date the NDA is submitted to FDA because the FDA has approximately two months to make a “filing”
−Removed: decision after it the application is submitted.
+Added: This review typically takes twelve months from the date the NDA is submitted to FDA because the FDA has approximately two months to make a “filing” decision after it the application is submitted.
The FDA reviews the NDA to determine, among other things, whether the proposed drug is safe and effective for its intended use, and whether the drug is being manufactured in accordance with cGMP to assure and preserve the drug’s identity, strength, quality and purity.
3 unchanged sentences
The FDA will not approve the drug unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the drug within required specifications.
−Removed: In addition, before approving an NDA, the FDA may re-analyze clinical trial data and may also audit data from clinical trials to ensure compliance with GCP requirements.
+Added: In addition, before approving an NDA, the FDA may re-analyze clinical trial data and may also audit data from clinical studies to ensure compliance with GCP requirements.
After the FDA evaluates the application, manufacturing process and manufacturing facilities where the drug product and/or its API will be produced, it may issue an approval letter or a Complete Response Letter (“CRL”) An approval letter authorizes commercial marketing of the drug with specific prescribing information for specific indications.
1 unchanged sentence
A CRL usually describes all of the specific deficiencies in the NDA identified by the FDA.
−Removed: The CRL may require additional clinical data and/or an additional pivotal clinical trial(s), and/or other significant, expensive and time-consuming requirements related to clinical trials, preclinical studies or manufacturing.
+Added: The CRL may require additional clinical data and/or an additional pivotal clinical trial(s), and/or other significant, expensive and time-consuming requirements related to clinical studies, preclinical studies or manufacturing.
If a CRL is issued, the applicant may either resubmit the NDA, addressing all of the deficiencies identified in the letter, or withdraw the application.
1 unchanged sentence
If a drug receives marketing approval, such approval will be granted for particular indications and may be significantly limited to specific diseases, dosages, or patient populations.
−Removed: Further, the FDA may require that certain contraindications, warnings or precautions be included in the drug labeling or may condition the approval of the NDA on other changes to the proposed labeling, development of adequate controls and specifications, or a commitment to conduct post-market testing or clinical trials and surveillance to monitor the effects of approved drugs.
−Removed: For example, the FDA may require so-called Phase IV testing which involves clinical trials designed to further assess a drug’s safety and effectiveness and may require testing and surveillance programs to monitor the safety of approved drugs that have been commercialized.
+Added: Further, the FDA may require that certain contraindications, warnings or precautions be included in the drug labeling or may condition the approval of the NDA on other changes to the proposed labeling, development of adequate controls and specifications, or a commitment to conduct post-market testing or clinical studies and surveillance to monitor the effects of approved drugs.
+Added: For example, the FDA may require so-called Phase IV testing which involves clinical studies designed to further assess a drug’s safety and effectiveness and may require testing and surveillance programs to monitor the safety of approved drugs that have been commercialized.
The FDA may also place other conditions on approvals including the requirement for a Risk Evaluation and Mitigation Strategy (“REMS”) to ensure that the benefits of a drug or biological product outweigh its risks.
2 unchanged sentences
Drug approvals may be withdrawn for non-compliance with regulatory standards or if problems occur following initial marketing.
−Removed: Pediatric Trials
+Added: Pediatric Studies
Under the Pediatric Research Equity Act, an NDA or supplement thereto must contain data that are adequate to assess the safety and effectiveness of the drug product 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: A sponsor who is planning to submit a marketing application for a drug that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration must also submit an initial Pediatric Study Plan (“PSP”) within sixty days of an end-of-Phase II
−Removed: meeting or as may be agreed between the sponsor and the FDA.
+Added: A sponsor who is planning to submit a marketing application for a drug that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration must also submit an initial Pediatric Study Plan (“PSP”) within sixty days of an end-of-Phase II meeting or as may be agreed between the sponsor and the FDA.
The initial PSP must include an outline of the pediatric study or studies that the sponsor plans to conduct, including study objectives and design, age groups, relevant endpoints and statistical approach, or a justification for not including such detailed information, and any request for a deferral of pediatric assessments or a full or partial waiver of the requirement to provide data from pediatric studies along with supporting information.
The FDA and the sponsor must reach agreement on the PSP.
−Removed: A sponsor can submit amendments to an agreed-upon initial PSP at any time if changes to the pediatric plan need to be considered based on data collected from preclinical studies, early phase clinical trials, and/or other clinical development programs.
+Added: A sponsor can submit amendments to an agreed-upon initial PSP at any time if changes to the pediatric plan need to be considered based on data collected from preclinical studies, early phase clinical studies, and/or other clinical development programs.
Orphan Drug Designation and Exclusivity
13 unchanged sentences
NDA holders using contract manufacturers, laboratories or packagers are responsible for the selection and monitoring of qualified firms, and, in certain circumstances, qualified suppliers to these firms.
−Removed: These manufacturers must comply with cGMP regulations that require, among other things, quality control and quality assurance as well as the corresponding maintenance of records and documentation and the obligation to investigate and correct any
−Removed: deviations from cGMP.
+Added: These manufacturers must comply with cGMP regulations that require, among other things, quality control and quality assurance as well as the corresponding maintenance of records and documentation and the obligation to investigate and correct any deviations from cGMP.
Drug manufacturers and other entities involved in the manufacture and distribution of approved drugs are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP and other laws.
1 unchanged sentence
The FDA may withdraw approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market.
−Removed: Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information;
−Removed: imposition of post-market studies or clinical trials to assess new safety risks;
+Added: Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing
+Added: processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information;
+Added: imposition of post-market studies or clinical studies to assess new safety risks;
or imposition of distribution restrictions or other restrictions under a REMS program.
2 unchanged sentences
● fines, warning letters, or untitled letters;
−Removed: ● clinical holds on clinical trials;
+Added: ● clinical holds on clinical studies;
● refusal of the FDA to approve pending applications or supplements to approved applications, or suspension or revocation of product approvals;
17 unchanged sentences
A drug is a new chemical entity if the FDA has not previously approved any other new drug containing the same active moiety, which is the molecule or ion responsible for the action of the drug substance.
−Removed: During the exclusivity period, the FDA may not accept for review an abbreviated new drug application (“ANDA”), or
−Removed: an NDA submitted under Section 505(b)(2), or 505(b)(2) NDA, submitted by another company for another drug based on the same active moiety, regardless of whether the drug is intended for the same indication as the original reference drug or for another indication, where the applicant does not own or have a legal right of reference to all the data required for approval.
+Added: During the exclusivity period, the FDA may not accept for review an abbreviated new drug application (“ANDA”), or an NDA submitted under Section 505(b)(2), or 505(b)(2) NDA, submitted by another company for another drug based on the same active moiety, regardless of whether the drug is intended for the same indication as the original reference drug or for another indication, where the applicant does not own or have a legal right of reference to all the data required for approval.
However, an application may be accepted for review after four years if it contains a certification of patent invalidity or non-infringement to one of the patents listed with the FDA for the reference drug.
−Removed: The FDCA alternatively provides three years of marketing exclusivity for an NDA, or supplement to an existing NDA if new clinical investigations, other than bioavailability studies, that were conducted or sponsored by the applicant are deemed by the FDA to be essential to the approval of the application, such as new indications, dosages or strengths of an existing drug.
+Added: The FDCA alternatively provides three years of marketing exclusivity for an NDA, or supplement to an existing NDA if new clinical investigations, other than bioavailability studies, that were conducted or
+Added: sponsored by the applicant are deemed by the FDA to be essential to the approval of the application, such as new indications, dosages or strengths of an existing drug.
This three-year exclusivity covers only the modification for which the drug received approval on the basis of the new clinical investigations and does not prohibit the FDA from approving abbreviated NDAs or 505(b)(2) NDAs for drugs containing the active agent for the original indication or condition of use.
Five-year and three-year exclusivity will not delay the submission or approval of a full NDA.
−Removed: However, an applicant submitting a full NDA would be required to conduct or obtain a right of reference to any preclinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.
+Added: However, an applicant submitting a full NDA would be required to conduct or obtain a right of reference to any preclinical studies and adequate and well-controlled clinical studies necessary to demonstrate safety and effectiveness.
Pediatric exclusivity is another type of marketing exclusivity available in the United States.
−Removed: Pediatric exclusivity provides for an additional six months of marketing exclusivity attached to another period of exclusivity if a sponsor conducts clinical trials in children in response to a written request from the FDA.
−Removed: The issuance of a written request does not require the sponsor to undertake the described clinical trials.
+Added: Pediatric exclusivity provides for an additional six months of marketing exclusivity attached to another period of exclusivity if a sponsor conducts clinical studies in children in response to a written request from the FDA.
+Added: The issuance of a written request does not require the sponsor to undertake the described clinical studies.
Regulatory Matters
12 unchanged sentences
Depending on the circumstances, failure to meet applicable regulatory requirements can result in criminal prosecution, fines, civil monetary or other penalties, injunctions, recall or seizure of drugs, total or partial suspension of production, denial or withdrawal of product approvals, additional regulatory oversight and integrity monitoring, exclusion from participation in government healthcare programs or refusal to allow a firm to enter into supply contracts, including government contracts.
−Removed: In addition, even if a firm complies with
−Removed: FDA and other requirements, new information regarding the safety or efficacy of a product could lead the FDA to modify or withdraw product approval.
+Added: In addition, even if a firm complies with FDA and other requirements, new information regarding the safety or efficacy of a product could lead the FDA to modify or withdraw product approval.
Prohibitions or restrictions on sales or withdrawal of future products marketed by us could materially affect our business in an adverse way.
9 unchanged sentences
Rest of the World Regulation of Pharmaceutical Product Development and Approval
−Removed: For other countries outside of Asia and the United States, such as countries in Europe, Latin America or other parts of Asia, the requirements governing the conduct of clinical trials, drug licensing, pricing and reimbursement vary from country to country.
−Removed: In all cases the clinical trials must be conducted in accordance with applicable GCP requirements and the applicable regulatory requirements and ethical principles.
+Added: For other countries outside of Asia and the United States, such as countries in Europe, Latin America or other parts of Asia, the requirements governing the conduct of clinical studies, drug licensing, pricing and reimbursement vary from country to country.
+Added: In all cases the clinical studies must be conducted in accordance with applicable GCP requirements and the applicable regulatory requirements and ethical principles.
If we fail to comply with applicable foreign regulatory requirements, we may be subject to, among other things, fines, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions and criminal prosecution.
13 unchanged sentences
● federal laws that require pharmaceutical manufacturers to report certain calculated product prices to the government or provide certain discounts or rebates to government authorities or private entities, often as a condition of reimbursement under government healthcare programs;
−Removed: ● the federal Physician Payments Sunshine Act, which 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 certain exceptions) to report annually to the CMS, information related to payments or other transfers of value made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), other healthcare professionals (such as physician assistants and nurse practitioners) and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members;
+Added: ● the federal Physician Payments Sunshine Act, which 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 certain exceptions) to report annually to CMS, information related to payments or other transfers of value made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), other healthcare professionals (such as physician assistants and nurse practitioners) and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members;
● HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act (“HITECH”), and their implementing regulations, imposes obligations, including mandatory contractual terms, on “covered entities,” including certain healthcare providers, health plans, healthcare clearinghouses, and their respective “business associates,” and their subcontractors that create, receive, maintain or transmit individually identifiable health information for or on behalf of a covered entity, with respect to safeguarding the privacy, security and transmission of individually identifiable health information;
10 unchanged sentences
Patients who are provided with prescriptions as part of their medical treatment generally rely on such third-party payors to reimburse all or part of the costs associated with their prescriptions and therefore adequate coverage and reimbursement from such third-party payors are critical to new and ongoing product acceptance.
−Removed: Coverage and reimbursement policies for drug products can differ significantly from payor to payor as there is no uniform policy of coverage and reimbursement for drug products among third-party payors in the United States.
+Added: Coverage and reimbursement policies for drug products can differ significantly from payor to payor as there is no uniform policy of coverage and reimbursement for drug
+Added: products among third-party payors in the United States.
There may be significant delays in obtaining coverage and reimbursement as the process of determining coverage and reimbursement is often time consuming and costly.
Further, third-party payors are increasingly reducing reimbursements for medical drugs and services and implementing measures to control utilization of drugs (such as requiring prior authorization for coverage).
+Added: Further, coverage policies and third-party payor reimbursement rates may change at any time.
+Added: Therefore, even if favorable coverage and reimbursement status is attained for one or more products for which we receive marketing approval, less favorable coverage policies and reimbursement rates may be implemented in the future.
Additionally, the containment of healthcare costs has become a priority of federal and state governments, and the prices of drugs have been a focus in this effort.
9 unchanged sentences
The ACA contains provisions that may reduce the profitability of drug products through increased rebates for drugs reimbursed by Medicaid programs, extension of Medicaid rebates to Medicaid managed care plans, mandatory discounts for certain Medicare Part D beneficiaries and annual fees based on pharmaceutical companies’ share of sales to federal health care programs.
−Removed: There have been judicial, Congressional and executive branch challenges to certain aspects of the ACA, including efforts to repeal or replace certain aspects of the ACA.
−Removed: For example, on June 17, 2021 the U.S.
−Removed: Supreme Court dismissed a challenge on procedural grounds that argued the ACA is unconstitutional in its entirety because the individual mandate was repealed by Congress.
−Removed: In addition, on August 16, 2022, President Biden signed the Inflation Reduction Act of 2022 (“IRA”) into law, which among other things, extends enhanced subsidies for individuals purchasing health insurance coverage in ACA marketplaces through plan year 2025.
+Added: There have been judicial, Congressional and executive branch challenges and amendments to certain aspects of the ACA, including efforts to repeal or replace certain aspects of the ACA.
+Added: For example, on August 16, 2022, the Inflation Reduction Act of 2022 (“IRA”) was signed into law, which among other things, extends enhanced subsidies for individuals purchasing health insurance coverage in ACA marketplaces through plan year 2025.
The IRA also eliminates the “donut hole” under the Medicare Part D program beginning in 2025 by significantly lowering the beneficiary maximum out-of-pocket cost and through a newly established manufacturer discount program.
Additionally, there has been heightened governmental scrutiny in the United States of pharmaceutical pricing practices in light of the rising cost of prescription drugs and biologics.
−Removed: Such scrutiny has resulted in several recent Congressional inquiries, presidential executive orders and proposed and enacted federal and state
−Removed: legislation designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for products.
−Removed: For example, in July 2021, the Biden administration released an executive order with multiple provisions aimed at prescription drugs.
−Removed: In response to Biden’s executive order, on September 9, 2021, the U.S.
−Removed: Department of Health and Human Services (“HHS”) released a Comprehensive Plan for Addressing High Drug Prices that outlines principles for drug pricing reform and sets out a variety of potential legislative policies that Congress could pursue to advance these principles.
−Removed: In addition, the IRA, among other things, (1) directs the HHS to negotiate the price of certain single-source drugs and biologics covered under Medicare and (2) imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation.
−Removed: These provisions will take effect progressively starting in fiscal year 2023.
−Removed: On August 29, 2023, HHS announced the list of the first ten drugs that will be subject to price negotiations, although the Medicare drug price negotiation program is currently subject to legal challenges.
−Removed: 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.
−Removed: It is unclear whether the models will be utilized in any health reform measures in the future.
−Removed: Further, on December 7, 2023, the Biden administration announced an initiative to control the price of prescription drugs through the use of march-in rights under the Bayh-Dole Act.
+Added: Such scrutiny has resulted in several recent Congressional inquiries, presidential executive orders and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for products.
+Added: For example, the IRA, among other things, (1) directs the U.S.
+Added: Department of Health and Human Services (“HHS”) to negotiate the price of certain high-expenditure, single-source drugs covered under Medicare that have been on the market for at least 7 years (the “Medicare Drug Price Negotiation Program”) and (2) imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation.
+Added: These provisions began to take effect progressively in fiscal year 2023.
+Added: On August 15, 2024, HHS announced the agreed-upon price of the first ten drugs that were subject to price negotiations, although the Medicare Drug Price Negotiation Program is currently subject to legal challenges.
+Added: HHS will select up to fifteen additional drugs covered under Part D for price negotiation in 2025.
+Added: thereafter more Part B and Part D products will become subject to the Medicare Drug Price Negotiation Program.
+Added: Further, on December 7, 2023, an initiative to control the price of prescription drugs through the use of march-in rights under the Bayh-Dole Act was announced.
On December 8, 2023, the National Institute of Standards and Technology published for comment a Draft Interagency Guidance Framework for Considering the Exercise of March-In Rights which for the first time includes the price of a product as one factor an agency can use when deciding to exercise march-in rights.
While march-in rights have not previously been exercised, it is uncertain if that will continue under the new framework.
+Added: Additional healthcare reform initiatives may be adopted in the future, particularly in light of the upcoming recent U.S.
+Added: presidential and Congressional elections.
Other Significant Chinese Regulation Affecting Our Business Activities in China
4 unchanged sentences
The PRC Company Law also applies to foreign-invested limited liability companies.
−Removed: Pursuant to the PRC Company Law, where laws on foreign investment have other stipulations, such stipulations shall prevail.
−Removed: The most recent amendment of the PRC Company Law was adopted in December 2023 and will come into effect on July 1, 2024, which introduced multiple updates to the current PRC Company Law with regard to, among others, the capital contribution liability, corporate governance structure and responsibilities of directors, supervisors, senior managers, controlling shareholders and actual controllers.
−Removed: Investment activities in China by foreign investors are governed by the Guiding Foreign Investment Direction, which was promulgated by the State Council on February 11, 2002 and came into effect on April 1, 2002, and the latest Special Administrative Measures (Negative List) for Foreign Investment Access (2021) (the “Negative List”), which was promulgated by the Ministry of Commerce of the People’s Republic of China (“MOFCOM”), and National Development and Reform Commission (“NDRC”), on December 27, 2021 and took effect on January 1, 2022.
+Added: The most recent amendment of the PRC Company Law was adopted in December 2023 and came into effect on July 1, 2024, which introduced multiple updates to the current PRC Company Law with regard to, among others, the capital contribution liability, corporate governance structure and responsibilities of directors, supervisors, senior managers, controlling shareholders and actual controllers.
+Added: Investment activities in China by foreign investors are governed by the Guiding Foreign Investment Direction, which was promulgated by the State Council on February 11, 2002 and came into effect on April 1, 2002, and the latest Special Administrative Measures (Negative List) for Foreign Investment Access (2024) (the “Negative List”), which was promulgated by the Ministry of Commerce of the People’s Republic of China (“MOFCOM”), and National Development and Reform Commission (“NDRC”), on September 26, 2024 and took effect on November 1, 2024.
The Negative List set out in a unified manner the restrictive measures, such as the requirements on shareholding percentages and management, for the access of foreign investments, and the industries that are prohibited for foreign investment.
1 unchanged sentence
The Foreign Investment Law of the People’s Republic of China (the “Foreign Investment Law”) was promulgated by the National People’s Congress (“NPC”) in March 2019 and became effective in January 2020.
−Removed: After the Foreign Investment Law came into force, the Law on Wholly Foreign-Owned Enterprises of the People’s Republic of China, the Law on Sino-foreign Equity Joint Ventures of the People’s Republic of China and the Law on Sino-foreign Contractual Joint Ventures of the People’s Republic of China
−Removed: have been repealed simultaneously.
+Added: After the Foreign Investment Law came into force, the Law on Wholly Foreign-Owned Enterprises of the People’s Republic of China, the Law on Sino-foreign Equity Joint Ventures of the People’s Republic of China and the Law on Sino-foreign Contractual Joint Ventures of the People’s Republic of China have been repealed simultaneously.
The investment activities of foreign natural persons, enterprises or other organizations (hereinafter referred to as foreign investors) directly or indirectly within the territory of China shall comply with and be governed by the Foreign Investment Law, including:
28 unchanged sentences
Under the amendment on October 25, 2013, all business operators shall pay high attention to protect the customers’ privacy and strictly keep confidential any consumer information they obtain during the business operation.
−Removed: In addition, in extreme situations, pharmaceutical product manufacturers and operators may be subject to criminal liability if their goods or services lead to the death or injuries of customers or other third parties.
+Added: In addition, in extreme situations, pharmaceutical product manufacturers and operators
+Added: may be subject to criminal liability if their goods or services lead to the death or injuries of customers or other third parties.
Chinese Tort Law
17 unchanged sentences
In China, a patent must have novelty, creativity and practical applicability.
−Removed: Under the PRC Patent Law, novelty means that before a patent application is filed, no
−Removed: identical invention or utility model has been publicly disclosed in any publication in China or overseas or has been publicly used or made known to the public by any other means, whether in or outside of China, nor has any other person filed with the patent authority an application that describes an identical invention or utility model and is recorded in patent application documents or patent documents published after the filing date.
+Added: Under the PRC Patent Law, novelty means that before a patent application is filed, no identical invention or utility model has been publicly disclosed in any publication in China or overseas or has been publicly used or made known to the public by any other means, whether in or outside of China, nor has any other person filed with the patent authority an application that describes an identical invention or utility model and is recorded in patent application documents or patent documents published after the filing date.
Creativity means that, compared with existing technology, an invention has prominent substantial features and represents notable progress, and a utility model has substantial features and represents any progress.
3 unchanged sentences
The applicant must apply to the CNIPA for a substantive examination within three years from the date of application.
−Removed: Article 19 of the PRC Patent Law provides that, for an invention or utility model completed in China, any applicant (not just Chinese companies and individuals), before filing a patent application outside of China, must first submit it to the CNIPA for a confidential examination.
+Added: Article 19 of the PRC Patent Law provides that, for an invention or utility model completed in China, any applicant (not just Chinese companies and individuals), before filing a patent application outside of China,
+Added: must first submit it to the CNIPA for a confidential examination.
Failure to comply with this requirement will result in the denial of any Chinese patent for the relevant invention.
44 unchanged sentences
Chinese Regulation of Labor Protection
−Removed: Under the Labor Law of the People’s Republic of China, effective on January 1, 1995 and subsequently amended on August 27, 2009 and December 29, 2018, the Employment Contract Law of the People’s Republic of China, effective on January 1, 2008 and subsequently amended on December 28, 2012 and the Implementing Regulations of the Employment Contract Law, effective on September 18, 2008, employers must establish a comprehensive management system to protect the rights of their employees, including a system governing occupational health and safety to provide employees with occupational training to prevent occupational injury, and employers are required to truthfully inform prospective employees of the job description, working conditions, location, occupational hazards and status of safe production as well as remuneration and other conditions as requested by the Labor Contract Law of the People’s Republic of China.
+Added: On July 10, 2021, the Cybersecurity Administration of China (the “CAC”) published a draft revision to the existing Cybersecurity Review Measures for public comment (the “Revised Draft CAC Measures”).
+Added: On January 4, 2022, together with 12 other Chinese regulatory authorities, the CAC released the final version of the Revised Draft CAC Measures (the “Revised CAC Measures”), which came into effect on February 15, 2022.
+Added: Pursuant to the Revised CAC Measures, critical information infrastructure operators procuring network products and services, and online platform operators (as opposed to “data processors” in the Revised Draft CAC Measures) carrying out data processing activities which affect or may affect national security, shall conduct a cybersecurity review pursuant to the provisions therein.
+Added: In addition, online platform operators possessing personal information of more than one million users seeking to be listed on foreign stock markets must apply for a cybersecurity review.
+Added: On November 14, 2021, the CAC further published the Regulations on Network Data Security Management (Draft for Comment) for public comment.
+Added: On September 24, 2024, the State Council released the final version of the Draft Management Regulations (the “Management Regulations”), which came into effect on January 1, 2025.
+Added: Under the Management Regulations, online data processors refer to individuals and organizations who determine the data processing activities in terms of the purpose and methods at their discretion.
+Added: The Management Regulations reiterate that online data processors shall be subject to national security review pursuant to relevant provisions if they carry out data processing activities which affect or may affect national security.
+Added: As of the date of this Annual Report, we have not received any notice from any Chinese regulatory authority identifying us as a “critical information infrastructure operator,” “online platform operator”, “online platform service provider” or “online data processor,” or requiring us to go through the cybersecurity review procedures pursuant to the Revised CAC Measures and the Management Regulations.
+Added: Based on our understanding of the Revised CAC Measures and the Management Regulations, we do not expect to become subject to cybersecurity review by the CAC for issuing securities to foreign investors because:
+Added: (i) the clinical and preclinical data we handle in our business operations, either by its nature or in scale, do not normally trigger significant concerns over Chinese national security;
+Added: and (ii) we have not processed, and do not anticipate to process in the foreseeable future, personal information for more than one million users or persons.
+Added: However, there remains uncertainty as to how the Revised CAC Measures and the Management Regulations will be interpreted or implemented.
+Added: For example, neither the Revised CAC Measures nor the Management Regulations provides further clarification or interpretation on the criteria for determining those activities that “affect or may affect national security” and relevant Chinese regulatory authorities may interpret it broadly.
+Added: Furthermore, there remains uncertainty as to whether the Chinese regulatory authorities may adopt new laws, regulations, rules, or detailed implementation and interpretation in relation, or in addition, to the Revised CAC Measures and the Management Regulations.
+Added: While we intend to closely monitor the evolving laws and regulations in this area and take all reasonable measures to mitigate compliance risks, we cannot guarantee that our business and operations will not be adversely affected by the potential impact of the Revised CAC Measures, the Management Regulations or other laws and regulations related to privacy, data protection and information security.
+Added: For additional information, see the sections titled “Risk Factors — Risks Related to Doing Business in China and Our International Operations — Compliance with China’s new Data Security Law, Cybersecurity Review Measures, Personal Information Protection Law, regulations and guidelines relating to the multi-level protection scheme on cyber security and any other future laws and regulations may entail significant expenses and could affect our business” and “Risk Factors — Risks Related to Doing Business in China and Our International Operations — The approval of, filing or other procedures with the CSRC or other Chinese regulatory agencies may be required in connection with issuing securities to foreign investors under Chinese law, and, if required, we cannot predict whether we will be able, or how long it will take us, to obtain such approval or complete such filing or other procedures” in this Annual Report.
+Added: Chinese Regulation of Labor Protection
+Added: Under the Labor Law of the People’s Republic of China, effective on January 1, 1995 and subsequently amended on August 27, 2009 and December 29, 2018, the Employment Contract Law of the People’s Republic of China, effective on January 1, 2008 and subsequently amended on December 28, 2012 and the Implementing Regulations of the Employment Contract Law, effective on September 18, 2008, employers
+Added: must establish a comprehensive management system to protect the rights of their employees, including a system governing occupational health and safety to provide employees with occupational training to prevent occupational injury, and employers are required to truthfully inform prospective employees of the job description, working conditions, location, occupational hazards and status of safe production as well as remuneration and other conditions as requested by the Labor Contract Law of the People’s Republic of China.
Pursuant to the Law of Manufacturing Safety of the People’s Republic of China effective on November 1, 2002 and amended on August 27, 2009, August 31, 2014 and June 10, 2021, manufacturers must establish a comprehensive management system to ensure manufacturing safety in accordance with applicable laws, regulations, national standards, and industrial standards.
6 unchanged sentences
In July 2014, the State Administration of Foreign Exchange (“SAFE”), issued SAFE Circular 37 and its implementation guidelines.
−Removed: Pursuant to SAFE Circular 37 and its implementation guidelines, residents of
−Removed: China (including Chinese institutions and individuals) must register with local branches of SAFE in connection with their direct or indirect offshore investment in an overseas special purpose vehicle (“SPV”), directly established or indirectly controlled by Chinese residents for the purposes of offshore investment and financing with their legally owned assets or interests in domestic enterprises, or their legally owned offshore assets or interests.
+Added: Pursuant to SAFE Circular 37 and its implementation guidelines, residents of China (including Chinese institutions and individuals) must register with local branches of SAFE in connection with their direct or indirect offshore investment in an overseas special purpose vehicle (“SPV”), directly established or indirectly controlled by Chinese residents for the purposes of offshore investment and financing with their legally owned assets or interests in domestic enterprises, or their legally owned offshore assets or interests.
Such Chinese residents are also required to amend their registrations with SAFE when there is a change to the basic information of the SPV, such as changes of a Chinese resident individual shareholder, the name or operating period of the SPV, or when there is a significant change to the SPV, such as changes of the Chinese individual resident’s increase or decrease of its capital contribution in the SPV, or any share transfer or exchange, merger, division of the SPV.
1 unchanged sentence
Regulations Relating to Employee Stock Incentive Plan
−Removed: In February 2012, SAFE promulgated the Notices on Issues Concerning the Foreign Exchange Administration for Domestic Individuals Participating in Stock Incentive Plans of Overseas Publicly Listed Companies (the “Stock Option Rules”).
+Added: In February 2012, SAFE promulgated the Notices on Issues Concerning the Foreign Exchange Administration for Domestic Individuals Participating in Stock Incentive Plans of Overseas Publicly Listed Companies (the
+Added: “Stock Option Rules”).
In accordance with the Stock Option Rules and relevant rules and regulations, Chinese citizens or non-Chinese citizens residing in China for a continuous period of not less than one year, who participate in any stock incentive plan of an overseas publicly listed company, subject to a few exceptions, are required to register with SAFE through a domestic qualified agent, which could be a Chinese subsidiary of such overseas listed company, and complete certain procedures.
18 unchanged sentences
The use of such RMB capital may not be changed without SAFE’s approval, and such RMB capital may not in any case be used to repay RMB loans if the proceeds of such loans have not been used.
−Removed: In March 2015, SAFE issued the Circular of the State Administration of Foreign Exchange on Reforming the Management Approach regarding the Settlement of Foreign Exchange Capital of Foreign-invested Enterprises (“SAFE Circular 19”), which became effective and replaced SAFE Circular 142 on June 1, 2015.
+Added: In March 2015, SAFE issued the Circular of the State Administration of Foreign Exchange on Reforming the
+Added: Management Approach regarding the Settlement of Foreign Exchange Capital of Foreign-invested Enterprises (“SAFE Circular 19”), which became effective and replaced SAFE Circular 142 on June 1, 2015.
Although SAFE Circular 19 allows for the use of RMB converted from the foreign currency- denominated capital for equity investments in China, the restrictions continue to apply as to foreign-invested enterprises’ use of the converted RMB for purposes beyond the business scope, for entrusted loans or for inter-company RMB loans.
7 unchanged sentences
In addition, SAFE promulgated the Circular on Printing and Distributing the Provisions on Foreign Exchange Administration over Domestic Direct Investment by Foreign Investors and the Supporting Documents in May 2013, which specifies that the administration by SAFE or its local branches over direct investment by foreign investors in China shall be conducted by way of registration and banks shall process foreign exchange business relating to the direct investment in China based on the registration information provided by SAFE and its branches.
−Removed: In February 2015, SAFE promulgated the Circular on Further Simplifying and Improving the Policies Concerning Foreign Exchange Control on Direct Investment (“SAFE Circular 13”), which took effect on
−Removed: June 1, 2015.
+Added: In February 2015, SAFE promulgated the Circular on Further Simplifying and Improving the Policies Concerning Foreign Exchange Control on Direct Investment (“SAFE Circular 13”), which took effect on June 1, 2015.
SAFE Circular 13 delegates the authority to enforce the foreign exchange registration in connection with the inbound and outbound direct investment under relevant SAFE rules to certain banks and therefore further simplifies the foreign exchange registration procedures for inbound and outbound direct investment.
Regulations on Securities Offering and Listing Outside of China
−Removed: On February 17, 2023, the CSRC promulgated a new set of regulations consisting of the Trial Administrative Measures of Overseas Securities Offering and Listing by Domestic Companies (the “Trial Measures”) and five supporting guidelines which came into effect on March 31, 2023 to regulate overseas securities offering and listing activities by domestic companies either in direct or indirect form.
+Added: On July 6, 2021, the General Office of the Communist Party of China Central Committee and the General Office of the State Council jointly issued the Opinions on Strictly Cracking Down Illegal Securities Activities in Accordance with the Law.
+Added: These opinions call for strengthened regulation over illegal securities activities and increased supervision of overseas listings by China-based companies, and propose to take effective measures, such as promoting the construction of relevant regulatory systems to regulate the risks and incidents faced by China-based overseas-listed companies.
+Added: On February 17, 2023, the China Securities Regulatory Commission (“CSRC”) promulgated a new set of regulations consisting of the Trial Administrative Measures of Overseas Securities Offering and Listing by Domestic Companies (the “Trial Measures”) and five supporting guidelines which came into effect on March 31, 2023 to regulate overseas securities offering and listing activities by domestic companies either in direct or indirect form.
The Trial Measures and supporting guidelines apply to overseas offerings by domestic companies of equity shares, depositary receipts, convertible corporate bonds, or other equity-like securities, and overseas listing of the securities for trading.
13 unchanged sentences
If domestic companies fail to fulfill the above-mentioned filing procedures or offer and list in an overseas market against the prohibited circumstances, they would be warned and fined up to RMB 10 million.
−Removed: The controlling shareholders and actual controllers of such domestic companies that organize or instruct the
−Removed: aforementioned violations would be fined up to RMB10 million and directly liable persons-in-charge and other directly liable persons would be each fined up to RMB 5 million.
+Added: The controlling shareholders and actual controllers of such domestic companies that organize or instruct the aforementioned violations would be fined up to RMB10 million and directly liable persons-in-charge and other directly liable persons would be each fined up to RMB 5 million.
Other Chinese National- and Provincial-Level Laws and Regulations
5 unchanged sentences
Of these 163 employees, 119 were engaged in research and development activities and 44 were engaged in business development, finance, information systems, facilities, human resources or administrative support.
−Removed: Four of the non-research and development-based employees were based in Shanghai, China and one based in the UK, while the other 22 resided in the United States.
+Added: Seven of the non-research and development-based employees were based in Shanghai, China and one based in the UK, while the other 36 resided in the United States.
None of our employees are represented by labor unions or covered by collective bargaining agreements.
4 unchanged sentences
We are a Cayman Islands exempted company incorporated with limited liability.
−Removed: We were initially formed as a Delaware corporation in 2016 under the name ShouTi Inc., and reorganized as a Cayman Islands exempted company in 2019.
−Removed: We completed our IPO on February 7, 2023, and our ADS began trading on the Nasdaq Global Market on February 3, 2023.
+Added: We were initially formed as a Delaware limited liability company in 2016 under the name ShouTi Inc., and reorganized as a Cayman Islands exempted company in February 2019.
Our principal executive office is located at 601 Gateway Blvd., Suite 900, South San Francisco, California 94080 and our telephone number is (650) 457-1978.
1 unchanged sentence
Our telephone number at this address is 86 21 61215839.
−Removed: Our current registered office in the Cayman Islands is located at the offices of International Corporation Services Ltd., P.O, Box 472, 2nd Floor, Harbour Place, 103 South Church Street, George Town, Grand Cayman KY1-1106, Cayman Islands.
+Added: Our current registered office in the Cayman Islands is located at the offices of International Corporation Services Ltd., P.O.
+Added: Box 472, 2nd Floor, Harbour Place, 103 South Church Street, George Town, Grand Cayman KY1-1106, Cayman Islands.
Our website is www.structuretx.com.
4 unchanged sentences
The SEC maintains a website at www.sec.gov that contains reports, proxy and information statements, and other information that we file with the SEC electronically.
+Added: We intend to announce material information to the public through filings with the SEC, the investor relations page on our website, which is located at ir.structuretx.com, press releases, public conference calls, and public webcasts.
+Added: The information disclosed through the foregoing channels could be deemed to be material information.
+Added: As such, we encourage investors, the media, and others to follow the channels listed above and to review the information disclosed through such channels.
+Added: The information we post through these channels is not a part of this Annual Report.
+Added: Any updates to the list of disclosure channels through which we will announce information will be posted on the investor relations page on our website.
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.