In October 2023, the FDA granted Fast Track designation for Altimmune’s incretin mimetic, pemvidutide, in non-alcoholic steatohepatitis (NASH). Pemvidutide is a glucagon-like peptide 1 (GLP-1) glucagon receptor (GCGR) dual agonist peptide (GLP-1R/GCGR) currently in Phase IIb development for NASH (IMPACT trial) and for obesity (MOMENTUM trial). The Fast Track designation is supported by the data from the Phase Ib trial evaluating pemvidutide in patients with nonalcoholic fatty liver disease (NAFLD).  This designation will reinforce the use of GLP-1 receptor agonists (GLP-1RAs) in NASH, according to GlobalData, a leading data and analytics company.

Sravani Meka, Senior Immunology Analyst at GlobalData, comments: “The recent designation not only raises the profile of pemvidutide in NASH but also highlights the potential of incretin mimetics in NASH. Despite the recent fast-track designation, it should be noted that pemvidutide still has a long road ahead to establish its significance in NASH.”

While topline data from pemvidutide’s Phase IIb trial in NASH is still unreported, it is worth noting that results from its late-stage trial in obesity have signalled potential problems. This is due to the high level of trial discontinuations in both the treatment (24.0%) and placebo (28.2%) cohorts, despite the positive interim data from its Phase IIb MOMENTUM trial for obesity.

Sravani continues: “However, when considering that approximately 50% of the withdrawals from the treatment group were attributed to gastrointestinal (GI) adverse events (AEs) (e.g., nausea, vomiting, etc.) and most placebo discontinuations were due to withdrawal of consent, the high level of discontinuations is not so alarming.”

Additionally, there were similar dropout rates observed in Eli Lilly’s tirzepatide (Mounjaro) Phase 2 diabetes trial (NCT03131687), where 25% of the patients given the highest dose (15mg) discontinued due to adverse events (AEs). Also, pemvidutide’s trial protocol differed from that of Novo Nordisk’s semaglutide and Lilly’s tirzepatide as it did not allow for dose reduction due to intolerability nor did it consider as long of a titration period, which could have impacted both the AE and dropout rate.

Sravani adds: “Pemvidutide could prove to be a worthy competitor to semaglutide and tirzepatide among other GLP-1RAs, and earn a unique position in the market as data from its Phase Ib trial showed that it does not cause hyperglycemia, while also addressing NASH.”

Despite the promise of GLP-1RAs for NASH, questions still remain about how effective their mechanism of action can be for this indication. Though the research suggests the promising role of incretin mimetics, also known as GLP-1RAs, for the treatment of NASH, there is still much unknown about the utility of the class in NASH.

Sravani concludes: “While GLP-1RAs have proven to have positive effects on glycemic control and weight loss, which in turn decrease fat concentration in the liver, there is still limited data on whether and how they work to directly improve liver health, especially as there are no GLP-1 receptors in the liver.

“Although it is possible that NASH resolution might be attributed to the improvement of a patient’s overall metabolic health, it is speculated that the improvement of insulin sensitivity could lead to a reduction in free fatty acid (FFA) flux in the liver (an energy source that can lead to fatty liver disease). As such, while the investigation into the extent to which these drugs will be most effective in NASH is ongoing, the precise scope of their impact remains uncertain.”