Structure Therapeutics Inc., a clinical stage global biopharmaceutical company, develops, and delivers novel oral therapeutics to treat a range of chronic diseases with unmet medical needs.
The company’s differentiated technology platform leverages structure-based drug discovery and computational chemistry expertise and enables it to develop oral small molecule therapeutics for the treatment of various diseases, including those impacting the metabolic, cardiovascular, and pulmonary systems. The...
Structure Therapeutics Inc., a clinical stage global biopharmaceutical company, develops, and delivers novel oral therapeutics to treat a range of chronic diseases with unmet medical needs.
The company’s differentiated technology platform leverages structure-based drug discovery and computational chemistry expertise and enables it to develop oral small molecule therapeutics for the treatment of various diseases, including those impacting the metabolic, cardiovascular, and pulmonary systems. The company’s initial focus is on G-protein coupled receptors (GPCRs) as a therapeutic target class. GPCRs regulate numerous diverse physiological and pathological processes, and approximately one in every three marketed medicines targets GPCR-associated pathways.
The company is developing GSBR-1290, its 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. The company completed its Phase 1 single ascending dose (SAD) study of GSBR-1290 in September 2022. GSBR-1290 was generally well tolerated and demonstrated dose- dependent pharmacokinetic (PK) and pharmacodynamic (PD) activity. The company 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. The company initiated the Phase 1b multiple ascending dose (MAD) study of GSBR-1290 in January 2023 and completed dosing in otherwise healthy overweight subjects in March 2023. In May 2023, it submitted a protocol amendment to the FDA and initiated dosing of the Phase 2a proof-of-concept study in T2DM and obesity. The company 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.
In December 2023, the company reported clinically meaningful topline data from its Phase 2a T2DM cohort, interim results from its Phase 2a obesity cohort and topline data from a Japanese ethno-bridging study of GSBR-1290. 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. 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. The company expects 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. The company also fully enrolled a formulation bridging and titration optimization study to evaluate capsule versus tablet PK and explore different titration regimens of GSBR-1290. It expects 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 it expects to initiate in the second half of 2024. A Phase 2 study in T2DM is also planned for the fourth quarter of 2024.
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. As such, GPCRs has emerged as the largest family of targets for approved drugs, has provided significant benefit to patients and has 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). Despite this success, there remain a number of challenges to continued innovation in this target class, including low expression levels on cell surfaces; the complexity of the multi-subunit peptide GPCR receptor; difficulties in obtaining relevant crystal structures as a basis for drug design; and non-specific signaling through multiple intracellular signaling pathways, a concept known as non-biased signaling, which can limit activity and increase side effects. The company has developed a platform designed to address these key challenges, enabling it to discover small molecule drugs to effectively target GPCRs. Further, the company’s platform has been designed to develop novel drugs against other targets where traditional drug discovery methods have not been adequate.
The company’s next generation structure-based drug discovery platform is based on techniques that its founders have evolved for over 25 years, which enables it to generate small molecule product candidates designed to overcome the historical limitations of GPCR drug development. The company designs its novel compounds by combining its knowledge of GPCR structures together with advanced physics-based computational methods, which it believes allows it to predict the binding affinity of molecules to the target site with a high degree of accuracy.
Oral small molecules can address many of the key limitations of biologic and peptide drugs, thereby significantly improving patient access. The company believes this is particularly important for the most prevalent chronic diseases, including those involving the metabolic, cardiovascular, and pulmonary systems.
The company’s 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, in Phase 2 development. There are ten marketed peptide molecules that target GLP-1R. However, there are no approved oral small molecule therapies targeting GLP-1R. In non-human primate (NHP), studies, GSBR-1290 demonstrated glucose-dependent insulin secretion and suppressed food intake, resulting in weight reduction. Given these findings and other compelling preclinical data, the company 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. To date GSBR-1290 has demonstrated generally favorable safety, tolerability, and efficacy results in clinical trials. Beyond GSBR-1290, the company is 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.
The company is also developing oral small molecule therapeutics targeting other GPCRs for the treatment of pulmonary and cardiovascular diseases. Specifically, it is advancing ANPA-0073, its biased agonist, targeting the apelin receptor (APJR,) a GPCR that has been implicated in idiopathic pulmonary fibrosis (IPF). In September 2022, the company completed a Phase 1 SAD and MAD study evaluating ANPA-0073 in healthy human volunteers, in which it was generally well tolerated. Additionally, the company is developing an antagonist that targets lysophosphatidic acid 1 receptor (‘LPA1R’), a GPCR implicated in responses to tissue injury and pro-fibrotic processes. It has demonstrated substantial anti-fibrotic activity of its LPA1R antagonists in mouse models of fibrotic lung disease and it selected a development candidate, LTSE-2578, in January 2023 and expect to initiate a first-in-human study in the second quarter of 2024.
The company is also dedicated to fueling its pipeline and pursuing drug discovery partnerships. Through its discovery engine, the company leverage the power of cryo-electron microscopy (cryo-EM) machine learning and X-ray crystallography, as the basis for its molecular designs. The company employ state-of-the-art small molecule hit identification, including DNA encoded library technology and affinity mass spectrometry selections for membrane proteins.
Strategy
The key elements of the company’s strategy include invest in and leverage its next generation structure-based drug discovery platform to drive innovations in GPCR targeted therapies and beyond; advance its GLP-1R franchise of metabolic focused assets, establishing a foundation for additional opportunities; pursue additional opportunities in chronic diseases; and maximize the potential of its platform and portfolio through strategic partnerships.
Pipeline and Programs
The company is building a pipeline of wholly-owned oral small molecule drugs targeting chronic diseases with unmet medical need and commercial potential. The company’s initial focus is in areas of metabolic, cardiovascular, and pulmonary diseases.
Metabolic Diseases
The company is initially advancing its GLP-1R franchise as a treatment for obesity and T2DM, conditions affecting approximately 764 million and 537 million people worldwide, respectively. The company believes its GLP-1R programs has demonstrated qualities that offer the potential to differentiate them from approved and development stage programs.
Selective GLP-1R Program: GSBR-1290 is a biased GLP-1R agonist which has demonstrated dose-dependent activation of the G-protein pathway. 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. The product candidate is designed to be orally administered, without restrictions on diet or concomitant therapy.
GLP-1R Combination: The company’s 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. The company’s APJR agonist, ANPA-0073, is being evaluated for selective or muscle-sparing weight loss. ANPA-0073, is a G-protein biased APJR agonist for which it 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.
Pulmonary and Cardiovascular Diseases
The company is evaluating its LPA1R program, LTSE-2578 for IPF and PPF.
The company’s LPA1R program, LTSE-2578, is an investigational oral small molecule LPA1R antagonist. It believes 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. The company plans to initiate a first-in-human study in the second quarter of 2024.
Platform and Approach
The company’s platform is based on techniques that it founders has been evolving for over 25 years, which has enabled them to deliver multiple marketed medicines. The company’s approach enables it to generate small molecule product candidates that are designed to overcome the historical limitations of GPCR drug development.
The company designs its novel compounds by combining its knowledge of GPCR structures together with advanced physics-based computational methods, which it believes allows it to predict the binding affinity of molecules to the target site. Oral small molecules have the potential to address the key limitations of biologic and peptide drugs, such as cost and patient inconvenience, thereby significantly improving patient access.
Partnership with Schrödinger Leveraging its Cutting-Edge Computational Chemistry Capability
The company has collaborations with Schrödinger on the iteration and optimization of GPCR lead compounds using various next-generation physics-based computational technologies. 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. 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. Through this iterative process, it 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.
In the company’s partnership with Schrödinger on GPCR drug discovery, it retains the full product rights on the compounds under development.
Safety Assays
The company has 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 it has designed molecules to help minimize safety risks at every step. The company’s in-depth understanding of GPCR signaling pathway provide it insights to design biased molecules when necessary to mitigate any unwanted liabilities while maintaining the desired activities.
Lead GPCR Programs
By leveraging the company’s unique platform capabilities, it is 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. The company is initially focusing on chronic metabolic, cardiovascular, and pulmonary diseases with unmet medical need.
GLP-1R Focused Franchise for Metabolic Disorders
To unlock the full potential of the company’s drug discovery platform across a broad range of metabolic indications, it intends to build out its franchise approach for GLP-1R. The company’s franchise approach involves developing next generation GLP-1R candidates, with each exhibiting customized properties to achieve additional benefit. The company’s lead GLP-1R product candidate, GSBR-1290, has the potential to be a differentiated treatment for T2DM and obesity based on preclinical data.
GSBR-1290 is an oral and biased agonist of the GLP-1R, a validated GPCR drug target involved in a variety of metabolic conditions. The company completed a Phase 1 SAD study for GSBR-1290 in healthy volunteers in September 2022. It initiated the Phase 1b MAD study in January 2023 and completed dosing in otherwise healthy overweight subjects in March 2023. In May 2023, the company submitted a protocol amendment to the FDA and initiated dosing of the Phase 2a proof-of-concept study in T2DM and obesity. The company 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. In December 2023, it reported clinically meaningful topline data from its Phase 2a T2DM cohort, interim results from its Phase 2a obesity cohort and topline data from its Japanese ethno-bridging study of GSBR-1290. 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.
GSBR-1290 also showed significant reduction in weight in the obesity cohort, and significant reductions in HbA1c and weight in the T2DM cohort. The company expects 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. The company also fully enrolled a formulation bridging and titration optimization study to evaluate capsule versus tablet PK and explore different titration regimens of GSBR-1290. 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 it expects to initiate in the fourth quarter of 2024. A Phase 2 study in T2DM is also planned for the second half of 2024. Based on its preclinical and clinical data, the company believes that GSBR-1290 and its next-generation product candidates has the potential to have highly differentiated profiles versus approved therapies and those in development.
Solution: Small Molecule GLP-1R Agonist
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. The company is taking a franchise approach to its GLP-1R programs by developing next generation GLP-1 agonists and potential GIPR modulators. Leveraging the depth of the company’s GLP-1R/GIPR structure platform, proprietary compound library and deep biology and disease insights, it is advancing multiple generations of structurally distinct GLP-1R agonist molecules through lead optimization. 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 its in-house platform.
GSBR-1290 Selective GLP-1R Agonist Program
The company is developing GSBR-1290, a biased orally-available small molecule GLP-1R agonist, initially as a treatment for T2DM and obesity. Due to its significant preclinical activity and oral availability, it believes that GSBR-1290 has the potential to be a differentiated treatment with no restrictions on diet or concomitant therapies.
GSBR-1290 was designed through its internal structure-based drug discovery platform. As shown above, multiple small molecules bound to GLP-1R structures has been generated to guide iterative chemistry design efforts. GSBR-1290 is also designed to be a biased GPCR agonist, which only activates the G-protein pathway without ß-arrestin signaling at therapeutic doses, thereby avoiding receptor internalization and de-sensitization. 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. 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.
GSBR-1290 Preclinical Data, Pharmacology, and Biomarker Data
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). Plasma samples were taken at indicated timepoints to evaluate insulin and glucose levels. 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.
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. Food intake was measured each day over the first six days of the study and reported as an average of these measurements. ivGTT and body weight were performed before dosing and on the sixth day (body weight) or seventh day (ivGTT) of post-dosing. At all doses of GSBR-1290, glucose reduction was shown to be statistically significantly different versus vehicle and comparable to liraglutide. 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. 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. At 10 mg/kg of GSBR-1290, the average food intake from Day 1 to Day 6 was only 59% relative to liraglutide group. 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.
In addition, the company conducted a preclinical comparison study of GSBR-1290 and PF-06882961, a clinical stage compound in development by Pfizer. Unlike GSBR-1290, PF-06882961 is a partially biased GLP-1R agonist, which could lead to de-sensitization of the receptor in vivo. In an experiment conducted in-house, GSBR-1290 demonstrated comparable in vivo activity to PF-06882961 at a lower exposure. 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). This suggests that the concentration needed to achieve full activity for GSBR-1290 is at a level much lower than that for PF-06882961. 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.
In-house data showed that PF-06882961 was positive in a glutathione trapping assay. GSBR-1290 was inactive in this assay, suggesting reduced risks with long-term use. In addition, GSBR-1290 also did not show activity as a time dependent inhibitor (TDI) for cytochrome P450 3A4 (CYP3A4). 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.
GSBR-1290 Phase 1 Healthy Volunteer Trial
In September 2022, the company completed a first-in-human Phase 1 SAD study for GSBR-1290 in 48 healthy adult volunteers between the ages of 18 and 55. The objective was to assess drug safety, tolerability, and PK. The study enrolled six cohorts of eight participants assigned to receive a single dose of GSBR-1290 or placebo in a 3:1 ratio. Doses ranged from 1 mg to 90 mg across the six cohorts. 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. GSBR-1290 was shown to be generally well tolerated at all dose levels administrated in this Phase 1 SAD study.
In summary, GSBR-1290 was shown to be generally well tolerated when administered as a single dose of up to 90 mg. 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. There were no treatment-related AEs reported in patients who received placebo.
GSBR-1290 Phase 1b MAD study
The Phase 1b MAD study focused on the safety and tolerability of GSBR-1290 in 24 healthy overweight or obese individuals. Participants were randomized 3:1 to GSBR-1290 or placebo across three dose cohorts with target doses of 30mg, 60mg or 90mg. GSBR-1290 demonstrated reductions in mean body weight ranging up to 4.9 kg compared to baseline, and up to 4.9% placebo-adjusted.
GSBR-1290 Phase 2a study in diabetes and obesity
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. 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. The obesity cohort initially enrolled 40 participants randomized to GSBR-1290 at 120 mg (n=24) or placebo (n=16), dosed once-daily. 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. These replacement participants have also been randomized 3:2 to GSBR-1290 or placebo.
The primary endpoints of the Phase 2a study are safety and tolerability of GSBR-1290. Key secondary endpoints include reduction in weight for both obesity and T2DM cohorts, as well as reduction in HbA1c for the T2DM cohort. 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.
GSBR-1290 Phase 1 Japanese Bridging Study
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). 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. These data will be used for regulatory interactions in Japan in preparation for potential future global studies of GSBR-1290.
GSBR-1290 Six- and Nine-Month Toxicology Studies
In preparation for Phase 2b development with longer durations of treatment, the company has completed six-month (rodent) and nine-month (non-human primate) toxicology studies to evaluate the safety of GSBR-1290. 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.
Amylin Receptor Agonist - Combination GLP-1R Program
Amylin is co-secreted with insulin from ß 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 glucagon responses to meals. Therefore, new pharmacological amylin analogues can be used as potential anti-obesity medications in individuals who are overweight or obese.
In collaboration with Schrödinger, the company is 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. It has identified two novel lead series with promising potency and PK profiles. The company has obtained multiple high quality Cryo-EM structures and established in-house in vivo animal models, which enable it to advance its lead optimization effort with high efficiency. In an in-house proof-of-concept study in rats, its small molecule amylin tool compound (ACCG-0184) showed additional beneficial effects when used as an add-on treatment to a GLP-1R agonist. The company is planning to select a development candidate in the second half of 2024.
GenerationGIPR Modulator - Combination GLP-1R Program
In the company’s GIPR program, it has identified multiple GIPR agonist, dual GLP-1R/GIRP agonist and GIPR antagonist hits for small molecule GIPR modulation. It believes GLP-1R/GIPR modulation has the potential to provide a differentiated treatment in diabetes and obesity.
Recent third-party clinical data showed tirzepatide, a GLP-1R/GIPR modulator, was superior to semaglutide with respect to glycemic control. The glycated hemoglobin level target of less than 5.7% (normoglycemia) was met in 27 to 46% of the T2DM patients who received tirzepatide compared to 19% of those who received semaglutide. The body weight reduction and gastrointestinal related side effects were similar to the GLP-1R agonists. In addition, many patients who received tirzepatide were noted to has improved biomarkers of insulin sensitivity. The company has obtained both GIP and tirzepatide bound GIPR structures along with GLP-1R structures to guide its small molecular design.
Multiple approaches were applied for hit identification, including a screen of its proprietary incretin compound library. Weak antagonists and agonists were identified. After several rounds of structure activity relationship evolution, a full potential GLP-1R/GIPR antagonist and initial dual GLP-1R/GIPR agonist hit leading to the discovery of an optimized dual GLP-1R/GIPR agonist hit. While displaying different GIPR activity, both compounds still maintained certain levels of GLP-1R activities. The company is planning to select a development candidate in the first half of 2025.
LPA1R and APJR Program for the Treatment of IPF
The company is developing LTSE-2578, an investigational oral small molecule LPA1R antagonist for the treatment of IPF. It believes 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. The company has completed IND-enabling studies, including 28-day GLP-toxicology studies in dogs and rats. The company is planning to initiate a first-in-human Phase 1 single and multiple ascending dose study in healthy volunteers in the second quarter of 2024.
In addition, the company is developing ANPA-0073, an investigational oral small molecule APJR agonist, for the treatment of IPF. When compared to a non-biased APJR agonist (Apelin-12) in a preclinical study, ANPA-0073 avoided hypotension. In September 2022, it completed a Phase 1 SAD and MAD study evaluating ANPA-0073, in which it was generally well tolerated in healthy human volunteers. The company expects to conduct additional preclinical studies and are evaluating plans to initiate a Phase 2 study in IPF.
LTSE-2578 Preclinical Data
In an in vivo PK and PD study, mice were orally dosed with LTSE-2578 and challenged by LPA at one hour and at 12 hours after dosing. Plasma was collected at two minutes post-LPA challenge and histamine level was measured as a pharmacodynamics biomarker. As shown below, LTSE-2578 demonstrated reductions in histamine release at doses = 0.06 mg/kg, as compared to approximately 45 ng/mL and approximately 201 ng/mL for BMS’s first generation (BMS-986020) and second generation (BMS-986278) LPA1R antagonists, respectively.
One month GLP toxicity studies of LTSE-2578 in rats and dogs has been completed to enable the upcoming first time in human study.
APJR Program for the Treatment of Obesity
APJ is expressed in human and murine skeletal muscles. Apelin and APJ are widely distributed in the body and are involved in various physiological functions as blood pressure regulation. 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. Activation of these pathways would result in worthwhile increases in the protein content of skeletal muscles. Apelin has in fact proved beneficial in maintaining muscle and could potentially counteract age-associated atrophy.
The company is evaluating ANPA-0073 which is Phase 2 ready, to be used in combination with weight loss medicines for selective or muscle-sparing weight loss.
ANPA-0073
The company is also developing ANPA-0073, an investigational, oral, small molecule APJR agonist, for the treatment of IPF. ANPA-0073 is designed to suppress cAMP production through activation of a G-protein-mediated signaling without significant activation of the ß-arrestin pathway in order to avoid APJ internalization, and thereby potentially avoid any desensitization effects of an unbiased APJR agonist. The company conducted preclinical in vitro studies on its compounds and third-party compounds to assess arrestin signaling and internalization. Apelin peptide and clinically tested competitor compounds, including AMG-986 and BMS-986224 are all non-biased APJR agonists in these in vitro studies, with low ß-arrestin/cAMP and internalization/cAMP ratios. The company’s molecules, such as ANPA-0073 and ANPA-137, are designed to be biased with much higher ß-arrestin/cAMP and internalization/cAMP ratios than apelin peptide and the competitor compounds shown below.
ANPA-0073 Preclinical Data
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 ß-arrestin pathway and APJR internalization respectively. These data suggest ANPA-0073 is highly biased. The G-protein agonist potency of ANPA-0073 was similar across different species (rat, dog, and monkey).
Anti-fibrosis effect of an APJ agonist ANPA-0137 was evaluated in bleomycin induced lung fibrosis model. Seven days after bleomycin challenges, mice received oral ANPA-137 for two weeks. ANPA-137 significantly reduced lung fibrosis Ashcroft scores and inflammatory cells infiltration into lung as quantified by inflammatory.
ANPA-0073 Phase 1 Healthy Volunteer Trial Design
In September 2022, the company 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. The objective was to assess drug safety and PK. 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. Doses from 2 mg to 600 mg across the eight cohorts were evaluated. 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. ANPA-0073 was generally well tolerated at all dose levels administrated in the SAD and MAD parts of this Phase 1 study.
The company will initiate the 26-week chronic GLP-toxicology studies in rats and 39-week studies in dogs that it believes will be required by regulatory agencies to continue dosing beyond 13 weeks in Phase 2. The company is also evaluating ANPA-0073 for selective or muscle-sparing weight loss.
Intellectual Property
For the company’s GLP-1R program, as of December 31, 2023, its wholly-owned subsidiary Gasherbrum Bio, Inc., is the sole owner of one granted U.S. patent and 11 pending U.S. 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. These patent applications, to the extent they issue (or in the case of priority applications, if issued from future non-provisional applications that the company files), are expected to expire between 2041 and 2044, without accounting for potentially available patent term adjustments or extensions. 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.
For the company’s oral small molecule APJR program, as of December 31, 2023, its wholly-owned subsidiary Annapurna Bio, Inc. is the sole owner of two granted U.S. patents and three pending U.S. 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. Any patents issuing from these patent applications (or in the case of priority applications, if issued from future non-provisional applications that it files) are expected to expire between 2039 and 2043, without accounting for potentially available patent term adjustments or extensions.
For the company’s LPA1R program, as of December 31, 2023, its wholly-owned subsidiary Lhotse Bio, Inc. (‘Lhotse’) is the sole owner of three pending U.S. 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. Any patents issuing from these patent applications (or in the case of priority applications, if issued from future non-provisional applications that it files) are expected to expire between 2041 and 2044, without accounting for potentially available patent term adjustments or extensions.
For the company’s oral small molecule Amylin program, as of December 31, 2023, its wholly-owned subsidiary Aconcagua Bio, Inc. (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. Any patents issuing from these patent applications (or in the case of priority applications, if issued from future non-provisional applications that it files) are expected to expire in 2044, without accounting for potentially available patent term adjustments or extensions.
Lhotse Collaboration Agreement with Schrödinger, LLC
In October 2020, Lhotse, its wholly-owned subsidiary, entered into a collaboration agreement with Schrödinger (the ‘Lhotse-Schrödinger Agreement’) to discover and develop novel, orally bioavailable, small molecule inhibitors of LPA1R. Under the Lhotse-Schrödinger Agreement, Schrödinger is obligated to provide computational modeling and design support, including by using its technology platform to perform virtual screens, and Lhotse is obligated to provide day-to-day chemistry and biology support. Pursuant to the Lhotse-Schrödinger Agreement, a joint steering committee comprising representatives from both parties oversees the research performed under the agreement. During the term of the Lhotse-Schrödinger Agreement and for a specified period thereafter while Lhotse is engaged in active development of any compound having activity against LPA1R that is discovered or developed under the Lhotse-Schrödinger Agreement, Schrödinger is obligated to work exclusively with Lhotse on the design, research, development and commercialization of compounds that inhibit LPA1R. Lhotse will solely own the research results, work product, inventions and other intellectual property generated under the Lhotse-Schrödinger Agreement that are directed to LPA1R.
Aconcagua Collaboration Agreement with Schrödinger
In November 2023, Aconcagua, its wholly-owned subsidiary, entered into a collaboration agreement (the ‘Aconcagua-Schrödinger Agreement’) with Schrödinger to discover and develop novel, small molecule modulators of a specific target. Under the Aconcagua-Schrödinger Agreement, Schrödinger is obligated to provide computational modeling and design support, including by using its technology platform to perform virtual screens, and Aconcagua is obligated to provide day-to-day chemistry and biology support. Pursuant to the Aconcagua-Schrödinger Agreement, a joint steering committee comprising representatives from both parties oversees the research performed under the agreement. 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. 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.
Research and Development
The company's research and development expenses were $70.1 million for the year ended December 31, 2023.
Regulations
The company’s drug candidates must be approved by the U.S. Food and Drug Administration (FDA) through the NDA process before they be legally marketed in the United States.
History
Structure Therapeutics Inc. was founded in 2016. The company was incorporated in the Cayman Islands in 2016. The company was formerly known as ShouTi Inc.
