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Pemvidutide Cuts NAFLD Liver Fat and Weight Through 24 Weeks
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EASL Congress 2023, June 21-24, Vienna
Mark Mascolini
Pemvidutide, a novel multiactive agent being developed for obesity and nonalcoholic steatohepatitis (NASH), promoted quick and large drops in liver fat content (LFC), weight, and liver enzymes after 12 and 24 weeks in a 94-person placebo-controlled trial [1]. Relative reduction in LFC averaged more than 75% at 24 weeks with the 2 higher doses of pemvidutide.
A balanced glucagon-like peptide (GLP)-1/glucagon dual receptor agonist, pemvidutide is a subcutaneously administered agent that may have applications in people with obesity, nonalcoholic fatty liver disease (NAFLD), NASH, and type 2 diabetes [2]. Its compelling mechanism of action involves activation of GLP-1 and glucagon receptors, thereby mimicking the weight-lowering impact of combined diet (GLP-1 suppresses appetite) and exercise (glucagon boosts energy expenditure) [3]. Activating glucagon receptors also promotes lipolysis (breakdown of triaglycerols into glycerol and free fatty acids) and fat mobilization (release of fatty acids from adipose cells). Activating GLP-1 receptors also quells inflammation and slows gastric emptying.
This multicenter, double-blind, placebo-controlled trial enrolled people with NAFLD with liver fat content at or above 10% by MRI-PDFF, a FibroScan liver stiffness measure below 10 kPa, alanine aminotransferase (ALT) at or below 75 IU/L, and no diabetes or non-insulin-dependent diabetes with A1C below 9.5%. Researchers randomized participants in a 1-to-1-to-1-to-1 ratio to weekly subcutaneous injections of 1.2 mg, 1.8 mg, or 2.4 mg of pemvidutide or to placebo for 12 weeks. Participants who completed the first 12 weeks could continue for another 12 weeks if they wanted to. The investigators increased the pemvidutide dose gradually over the first 4 weeks to reach the 2.4-mg dose. The 1.2- and 1.8-mg doses started at full dose.
The trial randomized and dosed 94 people for the first 12 weeks of study; 64 people continued pemvidutide for another 12 weeks. In the 12-week extension phase, age averaged about 49 across the 4 study arms, slightly more than half of participants were women, and 47 (73%) were Hispanic.
Starting body mass index in the extension phase averaged about 37 kg/m2 (well into the obese range). LFC measured by MRI-PDFF averaged 22.1%and ALT 34.6 IU/L. Seventeen people (27%) had type 2 diabetes.
All participants receiving pemvidutide attained the primary endpoint-a drop in LFC at weeks 12 and 24. At week 12 people assigned to placebo or 1.2, 1.8, or 2.4 mg of pemvidutide had absolute LFC reductions of 0.2%, 8.9%, 14.7%, and 11.3%. Respective declines at week 24 were 1.6%, 11.2%, 17.0%, and 15.6%. Relative reductions in LFC at week 24 measured 14.0%, 56.3%, 75.2%, and 76.4%. Proportions of people with at least a 50% drop in LFC at week 24 in the placebo group and the 1.2-, 1.8-, and 2.4-mg pemvidutide groups were 0.0%, 61.5%, 84.6%, and 72.7%. Respective proportions who reached a normal LFC (defined as 5% or less) at week 24 were 0.0%, 30.8%, 53.8%, and 45.5%.
For the groups randomized to placebo, 1.2 mg of pemvidutide, 1.8 mg, and 2.4 mg,, week-24 absolute reduction in liver volume, which is linked to overall mortality, was 3.3%, 12.6%, 19.1%, and 18.0%. At week 24 weight loss in those 4 arms averaged 1.4%, 5.1%, 8.2%, and 5.2%. Overall weight loss averaged 6.2% at week 24 and continued through the end of treatment.
ALT change at week 24 averaged -2.2 IU/L, -13.3 IU/L, -13.7 IU/L, and -15.2 IU/L in the placebo, 1.2-mg, 1.8-mg, and 2.4-mg arms. cT1, or corrected T1, uses MRI to assess a composite of liver inflammation and fibrosis and may thereby distinguished between NAFLD and NASH [4]. Defining a cTI responder as someone with at least an 80 ms drop from baseline to week 24, the researchers found response rates of 0% in the placebo group, 85.7% with 1.2 mg of pemvidutide, 75.0% with 1.8 mg, and 100% with 2.4 mg.
The investigators recorded "cardioprotective" drops in blood pressure with pemvidutide and no clinically meaningful jumps in heart rate. Fasting glucose and A1C tended to improve in people with diabetes and remained in control in those without diabetes.
In the 12-week extension trial, the researchers recorded no serious or severe adverse events related to pemvidutide in any study arm. Adverse events leading people to stop pemvidutide occurred in 2 people (12.5%) taking 1.2 mg, 1 (6.7%) taking 1.3 mg, and none taking 2.4 mg.
The investigators believe their results indicate "a high likelihood" of histologic improvement in people with NASH who participate in a planned paired liver biopsy study.
In a separate report, NATAP reviewed results of a 24-week randomized trial that found greater liver fat reduction with the GLP-1/glucagon dual receptor agonist efinopegdutide than with the GLP-1 receptor agonist semaglutide [5].
References
1. Harrison S, Tomah S, Suschak J, et al. Pemvidutide, a GLP-1/glucagon dual receptor agonist, significantly reduces liver fat, fibro-inflammation, and body weight in patients with non-alcoholic fatty liver disease: a 24-week multicenter, randomized, double-blind, placebo-controlled trial. EASL Congress 2023, June 21-24, Vienna. Abstract OS-063.
2. Pemvidutide by Altimmune for obesity: likelihood of approval. Pharmaceutical Technology. Updated May 31, 2023. https://www.pharmaceutical-technology.com/data-insights/pemvidutide-altimmune-obesity-likelihood-of-approval/
3. Altimmune announces FDA clearance of pemvidutide (ALT-801) IND for obesity. Drug Development & Delivery. https://drug-dev.com/altimmune-announces-fda-clearance-of-pemvidutide-alt-801-ind-for-obesity/
4. Mojtahed A, Kelly J, Herlihy AH, et al. Reference range of liver corrected T1 values in a population at low risk for fatty liver disease-a UK Biobank sub-study, with an appendix of interesting cases. Abdom Radiol (NY). 2019;44:72-84. doi: 10.1007/s00261-018-1701-2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348264/
5. Romero Gomez M, Lawitz E, Shankar RR, et al. A phase 2a, randomized, active-comparator-controlled, open-label study to evaluate the efficacy and safety of efinopegdutide in individuals with non-alcoholic fatty liver disease. EASL Congress 2023, June 21-24, Vienna. Abstract OS-060.
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