Exploring novel treatment options for patients with psychiatric disorders: brenipatide clinical trials

Background

Glucagon-like peptide-1 (GLP-1) therapies, originally developed for diabetes and obesity, may address underlying pathways implicated in psychiatric disorders. Preclinical data show that GLP-1 receptor agonists exert effects in the central nervous system relevant to psychiatric pathophysiology, including the promotion of neurogenesis, attenuation of neuroinflammation, and modulation of key neurotransmitter systems, alongside well-established metabolic and anti-inflammatory actions. However, larger controlled clinical trials are needed to determine the efficacy and safety of GLP-1 therapies for psychiatric indications. Brenipatide is a novel dual agonist of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors, being investigated as a potential adjunctive treatment for major depressive disorder (MDD), bipolar disorder, and schizophrenia, and for other neuropsychiatric and immunologic indications.

Methods

Three multicenter, randomized, double-blind, placebo-controlled trials were designed to investigate the safety and efficacy of subcutaneous brenipatide as an adjunctive treatment to standard-of-care medications across three psychiatric indications: MDD, bipolar disorder, and schizophrenia. RENEW-MDD-1 (NCT07412756; phase 3; planned n = 1000; 14 countries) and RENEW-Bipolar-1 (NCT07286175; phase 2; planned n = 400; 7 countries) both have a primary outcome of time to relapse, with minimum treatment durations of 12 and 6 months, respectively. Secondary outcomes across both trials include changes from baseline in depressive symptom severity (MADRS total score), manic symptom severity (YMRS total score; bipolar study only), functional impairment (SDS), quality of life (ReQoL-20 total score), patient-reported global severity (PGI-S), and body weight-related measures. RENEW-Scz-1 (NCT07410507; phase 2; planned n = 450; 7 countries) has a primary outcome of percent change from baseline in body weight among participants with baseline BMI ≥25 kg/m² over 12 months. Secondary outcomes for RENEW-Scz-1 include change from baseline in neurocognitive battery composite score, time to relapse, symptom severity (PANSS total score, CGI-S-SCH and PGI-S), and other cognitive measures (VRFCAT and SCoRS). All three trials enroll adults meeting the diagnostic criteria for the respective indications. Some common exclusion criteria include a history of select psychotic disorders, borderline personality disorder, any eating disorder, moderate-to-severe substance or alcohol use disorder, and active or significant suicidal risk. The trials combined span North America, South America, Europe, Asia, and Australia.

Results

All three RCTs have been launched and are currently recruiting participants. Together, they represent a combined planned enrollment of approximately 1,850 participants across 16 countries.

Conclusions

Brenipatide represents the first GLP-1/GIP receptor agonist to be investigated globally across multiple psychiatric disorders. This incretin-based approach has the potential to meaningfully expand pharmacotherapeutic options for MDD, bipolar disorder, and schizophrenia.

In text abbreviations include: CGI-S-SCH, Clinical Global Impression - Severity – Schizophrenia; MADRS, Montgomery-Åsberg Depression Rating Scale; PANSS, Positive and Negative Syndrome Scale; SCoRS, Schizophrenia Cognition Rating Scale; SDS, Sheehan Disability Scale; ReQoL-20, Recovering Quality of Life - 20 Items; YMRS, Young Mania Rating Scale; VRFCAT, Virtual Reality Functional Capacity Assessment Tool

References

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