Structure Therapeutics (GPCR) Provides GSBR-1290 Program Update

Structure Therapeutics Inc. (NASDAQ: GPCR), a clinical-stage global biopharmaceutical company developing novel oral small molecule therapeutics for metabolic and cardiopulmonary diseases, today provided a comprehensive development program update for its highly selective oral GLP-1 receptor agonist, GSBR-1290.

“We are pleased that we have achieved the objectives of our first Phase 2a clinical trial of GSBR-1290 in T2DM patients which were to demonstrate favorable safety, tolerability and efficacy results and guide our plans to further optimize the already encouraging performance of GSBR-1290,” said Raymond Stevens, Ph.D., Founder and CEO of Structure. “Our data demonstrated that once-daily GSBR-1290 has the potential to be a best-in-class compound and a backbone for future combinations that could address large cardiometabolic indications.”

“GSBR-1290 has demonstrated proof of concept in individuals with both obesity and T2DM, with clear effects on both weight loss and HbA1c that has the potential to increase with longer duration of treatment,” said David D’Alessio, M.D., Chief of the Division of Endocrinology and Metabolism at Duke University. “The unmet medical need for both T2DM and chronic weight management continues to be very large, and the GLP-1 receptor is a target with considerable potential. Safe and effective oral small molecule GLP-1 receptor agonists would be a significant advance in that they could expand access for many patients for whom this is not now possible.”

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 45 mg (n=10) or 90 mg (n=26), or placebo (n=18), dosed once daily. The obesity cohort initially enrolled 40 individuals randomized to GSBR-1290 120 mg (n=24) or placebo (n=16), once-daily. An additional 24 participants are currently being enrolled in the obesity arm as previously announced and will also be randomized 3:2 to GSBR-1290 or placebo.

The primary endpoint of the Phase 2a study is safety and tolerability of GSBR-1290. Key secondary endpoints include reduction in weight for both cohorts, as well as reduction in HbA1c for the T2DM cohort.

Safety and Tolerability Results

GSBR-1290 demonstrated encouraging safety and tolerability following repeated, daily dosing for all doses studied (up to 120 mg) in the obesity and T2DM cohorts.

• The majority (88 to 96%, depending on study arm) of adverse events (AEs) reported were mild to moderate.
• There were no serious adverse events (SAEs) related to study drug.
• As expected for this mechanism of action, leading AEs were gastrointestinal-related. The two most common AEs were nausea and vomiting.
• There were no cases of elevated liver enzymes in the obesity cohort. One participant in the T2DM treatment group experienced an event of elevated liver enzymes without an increase in bilirubin initially at day 8 while receiving 5 mg of study drug. This participant was diagnosed with fatty liver disease while in the study.
• 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).

Table 1: Summary of Treatment Emergent Adverse Events (TEAEs)

Efficacy Results

GSBR-1290 demonstrated clinically meaningful activity in both T2DM and obesity cohorts.

• In the T2DM cohort, there was a statistically significant HbA1c reduction (- 1.01 to -1.02%, placebo-adjusted) at Week 12 (Table 2). The study demonstrated a statistically significant and clinically meaningful reduction in weight at Week 12 (-3.26% to -3.51%, placebo-adjusted) (Table 3). Weight loss continued to decrease through Week 12.
• 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 4). Weight loss continued to decrease throughout the eight weeks of treatment.

Table 2: Diabetes cohort least square means difference (LSM) change in HbA1C from baseline to 12 weeks (%)

* LSM, CI and p value from Mixed Model for Repeated Measures

Table 3: Diabetes cohort LSM change in weight from baseline (%)

* LSM, CI and p value from Mixed Model for Repeated Measures

Table 4: Obesity Cohort LSM change in weight from baseline (%) 8-week interim results

* LSM, CI and p value from Mixed Model for Repeated Measures

Results from 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.

Results from 6- and 9-Month Toxicology Studies

In preparation for Phase 2b development with longer durations of treatment, Structure has completed 6-month (rodent) and 9-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 >100 fold safety window at the 120 mg therapeutic dose.

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