Lilly’s GIP/GLP-1 Candidate Brenipatide Shows Early Clinical Promise in Substance, Psych Disorders

Eli Lilly presented early positive clinical data supporting once-weekly dosing for its GIP/GLP-1 receptor agonist candidate brenipatide in substance use, psychiatric, and immunologic disorders—and detailed the design of Phase III trials that will assess the drug in major depressive disorder (MDD) and alcohol use disorder (AUD).

Brenipatide is a dual-agonist of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors—the same modality as its blockbuster tirzepatide, marketed for type 2 diabetes in adults as Mounjaro® and for obesity as Zepbound®. The two drugs have racked up a combined $27.6 billion-plus in revenue for Lilly so far this year—$18.605 billion for Mounjaro, $9.088 billion for Zepbound—accounting for about 65% of Lilly’s total $42.773 billion in revenue between January and June 2026.

Unlike tirzepatide, brenipatide is designed to target GIP and GLP-1 receptors in central nervous system and inflammatory pathways that include receptors linked to reward and addiction in the brain.

At the Psych Congress 2026, held in New Orleans, Lilly presented “Brenipatide, a GIP/GLP-1 Receptor Agonist: Clinical Data Supporting Dose Selection for Substance Use, Psychiatric and Immunologic Disorders,” a poster detailing results from its Phase I J2S-MC-GZMD trial (NCT06606106).

The Lilly-sponsored study was designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of brenipatide in healthy, overweight, and obese participants as measured by body mass index (BMI), with the goal of determining a brenipatide dosing regimen suitable for substance use, psychiatric, and immunologic disorders.

Brenipatide showed a mean half-life ranging between 9.08 days and 12.5 days, with the longer half-life seen in participants given the highest dose of the drug at 4.5 mg. Participants treated with brenipatide received doses of 4.5 mg or lower (0.3 mg, 0.75 mg, 1.5 mg, or 3 mg).

“That allows us to have a durability of exposure that can go beyond the weekly dosing interval, which is what we’re testing benepatide in within the neuroscience space,” Robert Nicholson, PhD, associate vice president, U.S. & global neuroscience medical affairs, psychiatry & substance use disorders with Eli Lilly, told GEN.

The data, Lilly researchers concluded in the poster, “support the selection of weekly maintenance doses across a broad range of BMIs, including normal body weight, that optimize safety, tolerability, and incretin pharmacology” in substance use, psychiatric, and immunological disorders.

“Potentially a really good option”

“As we think through those living with substance use disorders, psychiatric disorders, and certainly in our Phase III trials right now within alcohol use disorder and those with recurrent major depressive disorder, that weekly dosing could be potentially a really good option for those people,” Nicholson added. “Having that longer half-life is some of the reason why we think there’s a distinct profile for brenipatide relative to currently available incretin therapies.”

The Phase I trial was an investigator- and participant-blind, multiple ascending dose study of brenipatide with an eight-week follow-up period. More than 200 people participated in the trial, a population split into three parts:

• Part A: BMIs of 27.0–45.0 kg/m2, randomized 16:2 (96 to brenipatide, 12 to placebo).
• Part B: BMIs of 22.0–26.9 kg/m2: randomized 16:2 (64 to brenipatide, 8 to placebo).
• Part C: BMIs of 22.0–26.9 kg/m2 in Japanese and Chinese participants, randomized 6:2 (24 to brenipatide, 8 to placebo).

Part A participants at the highest 4.5 mg dose showed a mean plasma concentration of the drug of just over 1,000 ng/mL on Day 78, with plasma concentration being dose-dependent—a correlation that was also seen with participants in parts B and C, Lilly said.

The Phase I trial also showed brenipatide to have met the study’s primary outcome measure of positive safety data measured by one or more adverse events, including severe and treatment-emergent, that investigators considered related to the study drug. Researchers reported no deaths or serious adverse events (SAEs), with only four participants (2.2%) discontinuing the study due to a treatment-emergent adverse event (TEAE). Brenipatide was generally well-tolerated across all doses studied in participants with a wide range of BMI and different ethnicities, Lilly said.

The most frequently reported TEAEs were gastrointestinal (GI)-related, with an overall GI TEAE frequency of 25% in both brenipatide- and placebo-treated participants. Dysesthesia-related TEAEs were reported in 15.2% of brenipatide-treated participants, but none on placebo.

The GI tolerability could be related to brenipatide’s low peak-to-trough ratio, which Nicholson said is more narrow than for the other incretin therapies that are currently available.

MDD, AUD trial designs

Lilly is building on that early success in part by carrying out a pair of Phase III trials for brenipatide in two indications with large patient populations. During Psych Congress 2026, Lilly presented posters detailing the designs of those two trials—one assessing brenipatide in MDD, the other in alcohol use disorder AUD.

In MDD, Lilly has launched the Phase III RENEW-MDD-1 trial (NCT07412756), a multicenter, double-blind, placebo-controlled study evaluating brenipatide plus standard of care (SoC) compared to placebo plus SoC in delaying the return of major depressive symptoms.

The trial is designed to enroll approximately 1,000 participants across 14 countries. The primary endpoint is time to relapse, measured in days from randomization, while the study has numerous secondary endpoints that include MADRS Total Score, PGI-S, GAD-7 Total Score, ReQoL-20 Total Score, patient-rated symptom and disease severity, PROMIS Short Form, SDS global functional impairment score, and body weight (on and not on an atypical antipsychotic).

In AUD, Lilly has launched a pair of 56-week Phase III trials: RENEW-ALC-1, designed to assess brenipatide in participants with moderate-to-severe AUD (NCT07219966); and RENEW-ALC-2 (NCT07219953), intended to evaluate the safety and effectiveness of brenipatide compared to placebo in people with AUD and hazardous alcohol use. The two trials are designed to enroll 2,200 participants—1,100 each—in eight countries.

Primary outcome for both studies is change in drinking patterns using the Timeline Followback Method (TFBM).

Straight to Phase III

For both MDD and AUD, Lilly advanced brenipatide straight to Phase III, launching the late-stage trials directly following positive Phase I studies, rather than pursuing Phase II studies first, because of the patient populations for both conditions.

In MDD, an estimated 21 million American adults (about 8.3% of the adult population) had experienced a major depressive episode each year as of 2021, according to data last updated in 2023 by the NIH’s National Institute of Mental Health. Globally, approximately 322 million people have MDD, according to a 2023 study cited by the World Health Organization.

As for AUD, 27.9 million Americans ages 12 and older had an alcohol use disorder in the past year, according to data from the National Survey on Drug Use and Health published in 2025 by the NIH’s National Institute on Alcohol Abuse and Alcoholism (NIAAA). An estimated 400 million people, or 7% of the world’s population aged 15 years and older, lived with alcohol use disorders, according to WHO data last updated in 2024.

“When we look at AUD and MDD, both of those have existing needs that when people think about either having different or better therapies, as well as different types of outcomes, those are the needs where we think about the opportunity and why we thought it was worth going straight to Phase III in those conditions,” Nicholson explained.

FDA-approved AUD drugs

According to NIAAA, three drugs are FDA-approved for AUD: Naltrexone, designed to help reduce the urge to drink, available in several branded or generic versions; acamprosate, a pill sold in several generic versions that is designed to decrease the negative symptoms that are sometimes felt during abstinence from alcohol, making abstinence easier to maintain; and disulfiram, a pill that discourages drinking by causing unpleasant symptoms when alcohol is consumed, and is also sold in generic versions.

“The current medications themselves that are approved for alcohol use disorder assume abstinence is what you’re either supporting further or driving towards. But for some individuals, that may not be the outcome that they’re thinking about. So from an AUD perspective, having a different or potentially better treatment or treatment or an outcome that we’re aiming for could be important,” Nicholson said.

That explains, he said, why Lilly’s focus in the AUD trials is an overall change in drinking patterns: “It’s something that is a little different from thinking about abstinence being what we’re aiming for, specifically.”

The Phase III trials in AUD and MDD are among 13 Phase II and III studies in progress for brenipatide, Nicholson said. Other potential indications for the drug that are under study include Phase II studies currently going on for two substance abuse indications, tobacco use disorder and opioid use disorder; and two psychiatric indications, bipolar disorder and schizophrenia.

In the immunology space, brenipatide is being evaluated in forms of asthma, irritable bowel syndrome, and chronic obstructive pulmonary disease (COPD).

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