Pemvidutide

Pemvidutide (ALT-801; CAS 2538014-94-5; UNII A35F525WBG; molecular formula C182H275N39O54; molecular weight 3873.42 g/mol) is a synthetic 29-amino-acid peptide that functions as a balanced (1:1) dual agonist of the glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR), developed by Altimmune, Inc. (Gaithersburg, Maryland) for the treatment of metabolic dysfunction-associated steatohepatitis (MASH), obesity, alcohol use disorder (AUD), and alcohol-associated liver disease (ALD). The compound incorporates sequence elements derived from both GLP-1 and glucagon and is conjugated to an 18-carbon diacid alkyl chain through a proprietary glycosidic linkage (designated EuPort), which provides near-quantitative but transient binding to serum albumin and extends the plasma half-life to a duration consistent with once-weekly subcutaneous administration without dose titration [1, 2]. The dual receptor mechanism differentiates pemvidutide from selective GLP-1 receptor agonists such as semaglutide and liraglutide: GLP-1R activation suppresses appetite through hypothalamic and brainstem satiety circuits, delays gastric emptying, and improves glycemic control, while GCGR activation directly stimulates hepatic fatty acid beta-oxidation, suppresses de novo lipogenesis, and increases energy expenditure through thermogenic pathways, producing a composite antisteatotic and weight-reducing pharmacology that is mechanistically suited to liver-predominant metabolic disease [3, 4, 5]. In the translational AMLN diet-induced obese mouse model of NASH, pemvidutide at 10 nmol/kg subcutaneous produced approximately 25 percent body weight reduction, significant reductions in liver triglycerides, galectin-3, collagen type 1 alpha 1, and NAFLD Activity Score, with efficacy exceeding that of semaglutide and elafibranor at equimolar doses on composite histological endpoints [6]. Clinical development has advanced through Phase 1 studies (NCT04561245, 100 subjects), Phase 1b/2a studies in MASLD (NCT05006885, 95 subjects; NCT05292911, 64 subjects), the Phase 2 MOMENTUM obesity trial (391 subjects, 48 weeks), and the Phase 2b IMPACT trial in biopsy-confirmed MASH (NCT05989711, 212 subjects) [1, 7, 8, 9, 10]. In the Phase 1b/2a MASLD study (Harrison et al. 2025), 12 weeks of pemvidutide at 1.8 mg weekly produced a 68.5 percent relative reduction in liver fat content by MRI-proton density fat fraction versus 4.4 percent for placebo (p < 0.001), with 55.6 percent of treated subjects achieving liver fat normalization to 5 percent or below [8]. Extension to 24 weeks produced 75.2 percent liver fat reduction at 1.8 mg and 6.2 percent body weight reduction versus placebo [7]. In the MOMENTUM trial, pemvidutide at 2.4 mg weekly for 48 weeks produced mean weight loss of 15.6 percent versus 2.2 percent on placebo, with body composition analysis demonstrating 78.1 percent of weight loss attributable to fat mass and 21.9 percent to lean mass [9, 10]. In the Phase 2b IMPACT trial (Noureddin et al. 2025) in 212 patients with biopsy-confirmed MASH and fibrosis stages F2 or F3, pemvidutide met the primary endpoint of MASH resolution without fibrosis worsening: 59.1 percent at 1.2 mg and 52.1 percent at 1.8 mg versus 19.1 percent for placebo (p < 0.0001 for both comparisons) [11]. Topline 48-week data demonstrated continued antifibrotic activity with statistically significant improvements in Enhanced Liver Fibrosis score and liver stiffness measurement versus placebo [12]. The United States Food and Drug Administration has granted Breakthrough Therapy Designation for pemvidutide in MASH (January 2026) and Fast Track designations for both MASH and AUD [13, 14]. Phase 3 registrational programs for MASH and the VELOCITY Phase 3 program for obesity are in planning as of May 2026. Safety across completed trials has been favorable; adverse events are predominantly gastrointestinal (nausea, diarrhea, decreased appetite), mild to moderate in severity, and concentrated in the first 16 weeks of treatment. No imbalances in cardiac events, arrhythmias, or clinically meaningful heart rate increases have been observed. This monograph reviews the compound identification, structural pharmacology, mechanism of action, pharmacokinetics, preclinical and clinical evidence base, sourcing and quality verification, reconstitution and handling, stack interactions, adverse events, and a comparative assessment of five alternative agents (survodutide, semaglutide, tirzepatide, cotadutide, resmetirom) against pemvidutide on five competency standards.