Structure Therapeutics Inc. provided a comprehensive development program update for its highly selective oral GLP-1 receptor antagonist, 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 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). 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. 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.

GSBR-1290 Next Steps: Full 12-week results from the Phase 2a obesity cohort (n=64), including data from the additional 24 participants currently being enrolled, are expected in the second quarter of 2024. Structure plans to initiate a Phase 2b obesity study of GSBR-1290 in the second half of 2024. The study is planned to include at least 275 individuals across the United States and Europe and will include multiple modified dose titration regimens to optimize efficacy and tolerability.

An additional Phase 2 study in T2DM is also planned for the second half of 2024 to optimize the efficacy and tolerability of GSBR-1290 in this patient population. The ongoing formulation bridging and titration optimization study is evaluating capsule versus tablet pharmacokinetics (PK) and exploring different titration regimens. This study has completed enrollment (n=54), and data are expected in the second quarter of 2024.

Pending supportive data from this bridging study, the tablet formulation would be used in future GSBR-1290 studies starting with the Phase 2b studies.