Maritide

Maridebart cafraglutide (MariTide; development code AMG 133) is a first-in-class bispecific peptide-antibody conjugate engineered at Amgen by covalent attachment of two glucagon-like peptide 1 (GLP-1) receptor agonist peptide analogues to a fully human immunoglobulin G2 (IgG2) monoclonal antibody that functions as a potent antagonist of the glucose-dependent insulinotropic polypeptide receptor (GIPR). The molecule was designed to exploit the additive weight-loss pharmacology of simultaneous GLP-1 receptor (GLP-1R) activation and GIP receptor blockade, a mechanistic combination that in preclinical diet-induced obese mouse and cynomolgus monkey models produced greater body-weight reduction than either moiety alone. In cell-based functional assays the compound demonstrates GLP-1R agonist activity with EC50 values of 24.4 picomolar (human), 5.7 picomolar (cynomolgus monkey), 2.4 picomolar (rat), and 123 picomolar (mouse), and GIPR antagonist activity with IC50 values of 46.4 nanomolar (human), 26.5 nanomolar (cynomolgus monkey), and 822.3 nanomolar (rat) [1, 2]. The antibody scaffold confers a terminal elimination half-life of approximately 21 days in humans after subcutaneous administration, approximately three-fold longer than the longest-acting approved once-weekly GLP-1 receptor agonists, and supports once-monthly or less frequent dosing [1]. In a Phase 1 randomized, double-blind, placebo-controlled single- and multiple-ascending-dose study (NCT04478708) in 163 adults with obesity, maridebart cafraglutide produced dose-dependent weight loss of up to 14.5 percent at 12 weeks with weight loss maintained for up to 150 days after the final dose, accompanied by an acceptable safety and tolerability profile in which gastrointestinal adverse events (nausea, vomiting) were predominantly mild and transient [1]. A Phase 2 dose-ranging study (NCT05669599) in 592 adults with obesity with or without type 2 diabetes randomized to subcutaneous maridebart cafraglutide at 140, 280, or 420 mg every four weeks or 420 mg every eight weeks versus placebo for 52 weeks demonstrated mean weight loss of 12.3 to 20 percent in participants without type 2 diabetes and 8.4 to 17 percent in participants with type 2 diabetes, with HbA1c reductions of up to 2.2 percentage points, without evidence of a weight-loss plateau at 52 weeks [3, 4]. The Phase 2 study further reported no clinically significant changes in bone mineral density and body-composition data indicating that the majority of weight lost was fat mass rather than lean tissue. Gastrointestinal adverse events were the most common treatment-emergent events and were mitigated by dose escalation from a lower starting dose; discontinuation rates due to gastrointestinal events were approximately 8 percent with dose escalation compared with 12 to 27 percent without [3, 4]. Amgen initiated the Phase 3 MARITIME program in 2025, comprising chronic weight management trials (MARITIME-1 in obesity without type 2 diabetes, MARITIME-2 in obesity with type 2 diabetes) with planned 72-week treatment duration and primary readouts expected in early 2027, as well as planned Phase 3 cardiovascular outcomes, heart failure, and obstructive sleep apnea studies [5, 6]. The compound is not approved by any regulatory authority as of the monograph date. This monograph documents the molecular design and structural biology of the peptide-antibody conjugate; the dual-receptor pharmacology at GLP-1R and GIPR in molecular and cellular detail; the preclinical pharmacology in rodent and primate models; the comprehensive human pharmacokinetic record; the clinical evidence base across Phase 1 and Phase 2 obesity and type 2 diabetes endpoints; sourcing and handling considerations; stack-interaction implications; adverse-event profile; and a comparative assessment of five incretin-class obesity therapeutics against maridebart cafraglutide on five competency standards.