VK-2735

VK-2735 is a synthetic, acylated 39-amino-acid peptide dual agonist of the glucagon-like peptide 1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR), developed by Viking Therapeutics, Inc. (San Diego, California) as a candidate therapeutic for chronic weight management and metabolic disease. The compound binds both incretin receptors with high affinity (GLP-1R IC50 188 nM; GIPR IC50 325 nM) and activates the canonical Gs-coupled adenylate cyclase/cAMP signaling cascades that underlie glucose-dependent insulin secretion, appetite suppression, delayed gastric emptying, and enhanced lipid metabolism [1]. The dual-agonist mechanism places VK-2735 in the same pharmacological class as tirzepatide (Eli Lilly), the first dual GLP-1/GIP receptor agonist approved for the treatment of obesity and type 2 diabetes, and distinguishes it from the selective GLP-1 receptor agonists semaglutide and liraglutide by the addition of GIP receptor-mediated activity on adipose tissue, pancreatic beta cells, and central appetite circuits. VK-2735 was selected from an internally developed series of dual-agonist peptides characterized at ObesityWeek 2021 in diet-induced obese mouse models, in which the Viking compounds produced weight loss, glucose normalization, insulin sensitization, and hepatic fat reduction that exceeded the effects of equimolar semaglutide and were broadly comparable to tirzepatide [2]. The compound has been formulated for both subcutaneous injection (weekly dosing) and oral tablet administration (daily dosing), a dual-formulation strategy that is unusual in the incretin peptide class and that, if successful in registration, would provide the first oral dual GLP-1/GIP receptor agonist approved for human use. In the Phase 1 subcutaneous trial (NCT05203237), single and multiple ascending doses in healthy adults with elevated body mass index demonstrated a plasma elimination half-life of approximately 170 to 250 hours, a time to maximum plasma concentration of approximately 75 to 90 hours, predictable dose-proportional pharmacokinetics, and mean placebo-adjusted body weight reductions of up to 6.0 percent after 28 days of weekly dosing, with 98 percent of adverse events classified as mild or moderate [3, 4]. In the Phase 2 VENTURE trial (NCT06068946), 176 adults with obesity or overweight with at least one weight-related comorbidity were randomized to weekly subcutaneous VK-2735 at 2.5, 5.0, 10, or 15 mg or placebo for 13 weeks; the primary endpoint of percent change in body weight from baseline was met at all dose levels, with least-squares mean reductions of 9.1, 10.9, 12.9, and 14.7 percent, respectively, versus 1.7 percent on placebo (all p<0.0001), with 100 percent of participants in the 15 mg arm achieving at least 5 percent weight loss and 89.1 percent achieving at least 10 percent weight loss [1]. Weight loss trajectories showed no plateau at 13 weeks. Of 74 participants with prediabetes at baseline, 78 percent shifted to normoglycemic status across the active treatment arms with no new cases of diabetes. The Phase 1 oral tablet trial demonstrated dose-dependent weight loss of up to 5.3 percent from baseline at 40 mg daily over 28 days, with a gastrointestinal adverse-event profile that was notably mild relative to the subcutaneous formulation and included no vomiting events [5]. The Phase 2 VENTURE-Oral trial in 280 adults with obesity randomized across six dose arms (15, 30, 60, 90, 120 mg daily, and a maintenance cohort) or placebo for 13 weeks demonstrated up to 12.2 percent mean weight loss at the 120 mg dose, with up to 97 percent of participants achieving at least 5 percent weight loss [6]. The principal adverse events across all formulations and trials are gastrointestinal: nausea, vomiting, constipation, and diarrhea, consistent with the incretin agonist class and generally mild to moderate in severity, with decreasing frequency upon continued dosing. VK-2735 is currently in Phase 3 evaluation in two large registration trials (VANQUISH-1, approximately 4,650 participants, and VANQUISH-2, approximately 1,000 participants with type 2 diabetes) evaluating subcutaneous weekly dosing for 78 weeks with a 52-week extension, and Viking has announced plans to advance the oral formulation to Phase 3 in the third quarter of 2026 [7, 8]. The compound is not approved by any regulatory authority. It is available only through clinical trial enrollment or as a research-grade preparation from chemical suppliers. This monograph reviews the chemistry and peptide structure, the dual-receptor pharmacology in molecular detail, the comprehensive pharmacokinetic record across subcutaneous and oral formulations, the preclinical and clinical evidence base, reconstitution and handling, stack-interaction considerations, the adverse-event and safety signal, and a comparative assessment of five alternative obesity pharmacotherapies against VK-2735 on five competency standards.