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

Background

Glucagon-like peptide-1 (GLP-1) therapies, originally developed for diabetes and obesity, may address underlying pathways implicated in substance use disorders (SUDs). Preclinical data show that activating GLP-1 receptors suppresses drug seeking and reward, mainly through interactions with dopaminergic pathways. However, larger controlled clinical trials are needed to determine the efficacy and safety of GLP-1 therapies for SUDs. Brenipatide is a novel dual agonist of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors, being investigated as a potential treatment for alcohol, opioid, and tobacco use disorders (AUD, OUD, and TUD, respectively), and for other neuropsychiatric and immunologic indications.

Methods

Four multicenter, randomized, double-blind, placebo-controlled trials were designed to investigate the safety and efficacy of subcutaneous brenipatide across three SUD indications: AUD, OUD, and TUD. RENEW-ALC-1 (NCT07219966; phase 3, planned n = 1100; 8 countries) and RENEW-ALC-2 (NCT07219953; phase 3, planned n = 1100; 8 countries) both have a primary outcome of change in alcohol drinking patterns up to 56 weeks, assessed by daily self-report using the timeline followback method (TLFB). Secondary outcomes include change in daily alcohol consumption, alcohol craving, alcohol use disorders identification test (AUDIT) score, body weight, and patient-reported outcomes, among others. RENEW-OP-1 (NCT07420283; phase 2; planned n = 465, 3 countries) has a primary outcome of weeks of abstinence from opioid use per TLFB and urine drug screen, assessed over 13–24 weeks. Secondary outcomes include adherence to buprenorphine, 100% abstinence, opioid overdose(s), craving, reduction of OUD diagnosis severity per DSM-5, patient-reported outcomes, and body weight, among others. RENEW-Smk-1 (NCT07223840; phase 2; planned n = 222; 3 countries) has a primary outcome of carbon monoxide-confirmed self-report of no relapse (with allowed slips) to cigarette smoking through 24 weeks of treatment in people who have recently quit smoking. Secondary outcomes include continuous abstinence from cigarette smoking (without slips) and body weight, among others. All four trials enroll adults who are treatment-seeking and motivated to stop or reduce the use of the target substance. Common exclusion criteria include most other SUDs, active or significant suicide risk, and recent participation in a clinical study with active treatment. Other exclusion criteria include a history of advanced liver disease for AUD and OUD trials and chronic obstructive pulmonary disease, or any other clinically severe respiratory condition, for TUD. The trials combined span North America, Europe, and Asia.

Results

All four RCTs have been launched and are currently recruiting participants. Together, they represent a combined planned enrollment of approximately 2,887 participants across 9 countries.

Conclusions

Brenipatide represents the first GLP-1/GIP receptor agonist to be investigated globally across multiple SUDs. This incretin-based approach has the potential to meaningfully expand pharmacotherapeutic options for AUD, OUD, and TUD.

In text abbreviations include DSM-5, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition and TLFB, Timeline Followback.

References

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