Advancements in MASH Treatment: Pemvidutide and a Dual-Action Approach

Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), is a serious and increasingly prevalent liver disease impacting an estimated 22 million people in the United States.¹ It’s a leading cause of liver transplantation^1,2 and is frequently associated with obesity, with over 80% of patients also being overweight or obese.^4,5 Current treatments often target either the metabolic or liver-specific causes of MASH, leaving a gap for therapies that address the disease’s complexity and support long-term adherence.

Understanding the Multifaceted Nature of MASH

MASH arises from the intersection of metabolic and hepatic dysfunction, creating a complex clinical picture. Therapies focused solely on metabolic improvements, such as weight loss, may not directly impact liver inflammation and fibrosis. Conversely, liver-directed agents might address liver dysfunction without tackling the underlying metabolic drivers. A comprehensive approach is needed to effectively treat MASH.

Pemvidutide: A Potential Dual-Action Therapy

Altimmune is developing pemvidutide, a product candidate designed to address both the metabolic and liver-related causes of MASH. Pemvidutide is a glucagon/GLP-1 dual receptor agonist, uniquely formulated with a balanced one-to-one ratio of these two activities. It also incorporates EuPort, a proprietary structure designed for weekly dosing and potentially improved tolerability.

Glucagon drives liver-directed effects, reducing liver fat, inflammation, and fibrosis. GLP-1 receptor agonists address metabolic dysfunction through appetite suppression and weight loss, and may also have anti-inflammatory properties. Combining these mechanisms could offer a synergistic effect, functioning as a combination therapy within a single molecule.

Promising Results from the IMPACT Phase 2b Trial

Data from Altimmune’s IMPACT Phase 2b trial of pemvidutide demonstrated early MASH resolution, anti-inflammatory, and antifibrotic activity, alongside weight loss and other metabolic improvements. Importantly, discontinuation rates due to adverse events were lower than placebo, suggesting a favorable tolerability profile.

Looking Ahead: Phase 3 Development and Potential Benefits

Altimmune is designing a Phase 3 MASH program with the goal of demonstrating:

• Early reductions in liver fat and inflammation
• Clinically relevant fibrosis improvements
• Quality weight loss that preserves lean muscle mass
• A favorable tolerability profile for chronic treatment

The FDA has granted pemvidutide Breakthrough Therapy Designation, recognizing its potential to offer improvement over existing therapies. Altimmune plans to initiate the Phase 3 MASH program in 2026.

Beyond MASH: Potential Applications in AUD and ALD

Pemvidutide may also hold promise for treating alcohol use disorder (AUD) and alcohol-associated liver disease (ALD), conditions sharing similar pathophysiology with MASH, including hepatic fat accumulation, inflammation, and fibrosis. Preclinical research suggests pemvidutide can rapidly decrease drinking behavior, and clinical trials are underway to evaluate its efficacy in AUD and ALD.

The potential benefits of glucagon acting directly on the liver could improve hepatic damage resulting from sustained alcohol use. A single therapeutic approach addressing both behavioral and hepatic aspects of these diseases could represent a significant advancement.

Commitment to Innovation and Patient Needs

Altimmune is focused on advancing pemvidutide through clinical development and strengthening its organizational foundation to address substantial unmet needs across multiple serious liver diseases. The company is committed to developing therapies that consider long-term patient needs, mechanistic innovation, and rigorous clinical trials.

Learn more at Altimmune.com.

References:

1. Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, et al. AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023. 77(5):1797-1835. Doi:10.1097/HEP.0000000000000323.
2. Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018;67(1):123-133. Doi:10.1002/hep.29466.
3. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease–meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73-84. Doi:10.1002/hep.2843.
4. Milic S, Lulic D, Stimac D. Non-alcoholic fatty liver disease and obesity: biochemical, metabolic and clinical presentations. World J Gastroenterol. (2014) 20:9330–7. Doi: 10.3748/wjg.v20.i28.9330
5. Younossi ZM. The epidemiology of nonalcoholic steatohepatitis. Clin Liver Dis. (2018) 11:92–4. Doi: 10.1002/cld.710.