Dual Incretin Cuts Heavy Drinking With Biomarker Backing But No AUD Precedent

Altimmune Prepares for FDA Meeting on Pivotal AUD Trial

Altimmune is preparing for an end-of-Phase 2 meeting with the FDA in December to discuss the design of a pivotal Phase 3 program for its glucagon/GLP-1 dual receptor agonist, pemvidutide, in alcohol use disorder (AUD). This follows positive topline results from the Phase 2 RECLAIM trial, where pemvidutide demonstrated a "highly statistically significant" treatment effect. Patients on pemvidutide experienced 4.2 fewer heavy-drinking days per week during weeks 21-24, compared to 2.75 fewer for placebo. The trial also showed a robust 38% reduction in serum phosphatidylethanol (PEth), a direct biomarker for alcohol consumption, versus a 5.9% increase with placebo, providing strong validation for the drug's efficacy.

• Significant Reduction in Heavy Drinking Days: The Phase 2 RECLAIM trial successfully met its primary endpoint, showing that pemvidutide significantly reduced heavy-drinking days in patients with alcohol use disorder. Participants treated with pemvidutide experienced an average of 4.2 fewer heavy-drinking days per week from baseline during weeks 21 to 24, a "highly statistically significant" improvement compared to the 2.75-day reduction observed in the placebo group. This outcome forms the basis for advancing the drug.
• Objective Biomarker Validation: Beyond patient-reported outcomes, pemvidutide demonstrated strong objective evidence of efficacy through a 38% reduction in serum phosphatidylethanol (PEth), a direct and reliable biomarker for alcohol consumption. In contrast, the placebo group showed a 5.9% increase in PEth levels. This robust biomarker data provides crucial validation for pemvidutide's therapeutic activity and differentiates its profile.
• Pathway to Phase 3 and Market Context: Altimmune has scheduled a critical end-of-Phase 2 meeting with the FDA for December to finalize the design of its registrational Phase 3 program for AUD. This strategic step positions pemvidutide for potential market entry. However, the competitive landscape, including Eli Lilly's ongoing large-scale Phase 3 trials for brenipatide, suggests Altimmune may need additional capital to fund its extensive pivotal program.

Defining Success: Key Endpoints for Pemvidutide's Pivotal AUD Trials

Abstinence and reduced heavy drinking anchor efficacy evaluation in alcohol use disorder trials, often assessed over extended follow-up to demonstrate stability. Trials complement these drinking outcomes with measures of craving, withdrawal, and functional impact.

• Abstinence outcomes: percent days abstinent (PDA), percentage of days abstinent, rates of complete abstinence, continuous abstinence, abstinence rate, and longest period of abstinence (LPA), including continuous abstinence over 6-months and at 12 months, 24 and 36 months.

• Heavy drinking outcomes: percent heavy drinking days, percentage days heavy drinking (PDHD), no heavy drinking days (with a heavy drinking day defined as more than 3 drinks per day for women and more than 4 drinks per day for men [>3/>4 cutoff]), no heavy drinking between weeks 4 and 12 of the study, and drinking days per week.

• Consumption quantity and pattern: quantity and duration of alcohol consumption, reduction of alcohol consumption, reduction in drinking frequency and reduction in drinking intensity, drinks per drinking day (DDD), mean and peak breath alcohol concentrations (BrAC), and time to relapse.

• Craving, withdrawal and relapse-related symptoms: alcohol craving including cue-induced alcohol cravings assessed with Visual Analog Scale and Alcohol Urge Questionnaire, change from baseline to the end of treatment using the Obsessive Compulsive Drinking Scale (OCDS-G), Obsessive and Compulsive Drinking Scale (OCDS), craving [visual analogue scale (VAS); Obsessive and Compulsive Drinking Scale (OCDS)], withdrawal (CIWA-Ar), and changes in mood, sleep, and craving including insomnia, dysphoria, anxiety, depression and post-traumatic stress disorder (PTSD).

• Functional and broader clinical outcomes: reduced alcohol-related consequences, alcohol addiction severity, quality of life, depressive symptoms, anxiety, patient-reported outcomes, retention in treatment, healthcare cost offsets, treatment safety, and women with any adverse event.

Pemvidutide's Promising Phase 2 RECLAIM Data in AUD

In a multicenter, open-label, randomized controlled trial registered as jRCT2032220560, participants with alcohol dependence at high or very high drinking risk levels were randomized to psychosocial intervention enhanced by the digital therapeutic ALM-003 or psychosocial intervention with a basic drinking diary app for 24 weeks. Baseline heavy drinking days were 19.4 and 19.1 days/28 days in the intervention and control groups, respectively. At Week 12, the intervention and control groups showed a reduction in HDDs of -12.2 and -9.5 days from baseline, with a between-group difference of -2.79 days/28 days (95% confidence interval: -4.67 to -0.90; P = 0.004). Adverse events occurred in 32.9% of participants in the intervention group and 33.6% in the control group, with no adverse events attributed to app use. In a separate randomized comparison registered as KCT0010289, 30 outpatients were assigned to a 12-week mobile application-based CBT program including 84 video-based CBT sessions or an 8-session standardized face-to-face CBT program, with data from 28 participants analyzed. The primary outcome, abstinence rate during weeks 9-12, was significantly higher in the digital intervention group (73.3%) compared to the control group (30.8%), with significantly greater reductions in risky drinking, craving, and anxiety levels in the digital group.

A single-center unblinded prospective pilot randomized controlled trial registered as NCT06471686 evaluated acamprosate (666 mg dose 3 times daily) versus standard of care over 14 weeks in adults with liver transplant for alcohol-associated liver disease enrolled between 2021 and 2023. Of 78 participants approached, 30 enrolled (19 acamprosate and 11 SOC), with 8 withdrawals (6 acamprosate before medication administration and 2 SOC). Adverse events were similar between acamprosate and SOC groups (92.3% vs. 90.0%, p > 0.99), including grade 3 AEs (53.9% vs. 60.0%, p > 0.99) with no reported grade 4/5 AEs. Survey response rates were 61.0% vs. 76.0% (p = 0.19), and 69.0% were acamprosate adherents. Baseline Penn Alcohol Craving Scale values were low with no difference in median absolute change for intention-to-treat (0, IQR: -4 to 0 vs. 0, IQR: 0-0, p = 0.32) and per-protocol analyses (-1, IQR: -6 to 0 vs. 0, IQR: -0 to 0, p = 0.36), and there was no reported or biochemical evidence of alcohol relapse defined by blood phosphatidylethanol (≥20 ng/mL/reported alcohol use).

A single-arm, mixed methods pilot clinical trial registered as NCT05778734 assessed feasibility and acceptability of an integrated behaviour therapy of contingency management and problem-solving therapy (CM-PST) in a fully remote format for young adults with AUD. Twenty young adults aged 18-24 with mild, moderate or severe AUD received 8 sessions over 12 weeks focusing on problem-solving skills, goal setting, stress management and behaviour change, with twice-daily breathalyser tests for incentives. The mean age was 21.35 (SD=2.18) and 55% of participants were women. Adherence to the PST sessions, defined as attendance and remaining for the full duration of each session, was 100.0%, while the benchmark of 85% expected retention rate was unmet. Participant feedback highlighted the influence of CM on behaviour and decision-making and the effectiveness of PST in addressing life challenges, with acceptability assessed by participant feedback of ≥3 on Client Counselling Satisfaction Scale.

Navigating the Emerging GLP-1 Landscape for Alcohol Use Disorder

Pemvidutide is a glucagon-like peptide-1 (GLP-1)/glucagon dual receptor agonist evaluated for liver fat content reduction in metabolic dysfunction-associated steatotic liver disease (MASLD). Other GLP-1/glucagon receptor dual agonists with trial data in MASLD and metabolic dysfunction-associated steatohepatitis (MASH) include survodutide, cotadutide and mazdutide. Their intervention models are randomized, placebo-controlled evaluations with imaging and histologic endpoints.