Brenipatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor agonist: clinical data supporting dose selection for neuropsychiatric and immunological indications

Introduction

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are incretin hormones that play complementary roles in metabolic regulation. GLP-1 and GIP receptors are located throughout the body, including in the pancreas, gastrointestinal tract, heart, lungs, kidneys, liver, adipose tissue, and brain, thus, GLP-1 and GIP receptor agonists may show utility both centrally and peripherally for several indications. Brenipatide, a novel long-acting dual agonist of GLP-1 and GIP receptors, is being investigated as a potential treatment for neuropsychiatric and immunologic indications.

Aims

Evaluate safety, pharmacokinetics (PK), and pharmacodynamics (PD) across a broad range of BMI to determine brenipatide dosing regimen for neuropsychiatric and immunological disorders.

Methods

This 12-week phase 1, investigator- and participant-blind, multiple ascending dose study with an 8-week follow-up period (NCT06606106), enrolled participants of different ethnicities with body mass indices (BMIs) ranging from 22.0-45.0 kg/m². Participants were randomized to receive weekly subcutaneous injections of brenipatide or placebo. Brenipatide weekly maintenance doses of 0.3 mg, 0.75 mg, 1.5 mg, 3 mg, and 4.5 mg were evaluated. Doses above 0.75 mg were attained via dose-escalation, with a starting dose of 0.75 mg. Primary safety endpoints included number and incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). Secondary endpoints included PK and PD parameters.

Results

184 participants received brenipatide and 28 received placebo. Brenipatide was generally well tolerated across all doses studied, with the majority of TEAEs being mild in severity. The most frequently reported TEAEs were gastrointestinal-related (nausea, diarrhea, dyspepsia, and vomiting), with an overall gastrointestinal frequency of 25% in both brenipatide- and placebo-treated participants. Dysesthesia-related TEAEs were reported in 15.2% of brenipatide-treated participants and none on placebo; all were mild except for one moderate event, and all resolved. Gastrointestinal and dysesthesia TEAEs were dose-dependent. Four brenipatide-treated participants (2.2%) discontinued treatment due to TEAEs. No SAEs or deaths were reported. Brenipatide displayed dose-proportional PK with a prolonged mean half-life ranging between 9.1-11.4 days, with peak-to-trough ratio of approximately 1.5 observed across cohorts. Brenipatide treatment showed dose-dependent reductions in body weight. The percentage change in body weight from baseline to week 12 across dosing cohorts ranged from -2.1% to -11.5% in participants with higher BMIs (27.0-45.0 kg/m²) and -3.9% to -12.2% in participants with BMIs of 22.0-26.9 kg/m². No clinically meaningful differences were observed across ethnic groups.

Conclusions

Brenipatide demonstrated a differentiated safety, tolerability, and pharmacokinetic profile compared with published profiles of other weekly incretin therapies. The half-life of brenipatide and sustained exposure observed across the dosing interval result in a favorable peak-to-trough ratio, supporting once-weekly dosing, which may lead to sustained pharmacological effect and provide favorable gastrointestinal tolerability as observed in this study. These data support selection of weekly maintenance doses intended to optimize safety/tolerability, incretin pharmacology, and weight reduction across broad BMIs in neuropsychiatric and immunological indications.

References

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