Novel Weight Loss Entrant from Amgen Challenges Duration of Effect and Dosing with Wegovy, Zepbound

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Amgen’s novel weight loss drug candidate maridebart cafraglutide (MariTide) showed significant promise in a Phase I trial (NCT04478708), with data suggesting longer lasting and durable reductions in body weight compared with the popular glucagon-like peptide (GLP)-1 agonists currently on the market—Novo Nordisk’s Wegovy (semaglutide) and Eli Lilly’s Zepbound (tirzepatide).1

The results of the study, published in Nature Metabolism, indicate MariTide, formerly known as AMG 133, promotes significant weight loss with an acceptable safety profile across different doses, from 21 mg to 840 mg. Patients enrolled in the trial were obese, but did not have additional underlying health conditions, such as diabetes.1

Previously published data from a Phase I trial (NCT04478708) of the drug found that among those with obesity but without diabetes, the highest dose of MariTide produced 14.5% body weight loss by day 85 compared to 1.5% body weight loss in those administered a placebo. The lowest dose of MariTide produced 7.4% body weight loss after three doses.2

For comparison, participants in clinical trials of Wegovy and Zepbound experienced 15% to 21% body weight loss after taking the drugs for a year.3,4 However, recent research has shown that patients who lose a significant amount of weight with the GLP-1 agonists may experience a sharp rebound in weight gain if they stop taking the drugs.

A study published by Diabetes, Obesity and Metabolism found that at one year after stopping use of once-weekly Wegovy, participants regained two-thirds of their prior weight loss, with similar changes in cardiometabolic variables.5 A study published by JAMA found that patients who were obese and without diabetes experienced 14% weight regain approximately one year after switching to a placebo from an eight-month course of Zepbound.6

“In participants with obesity or overweight, withdrawing [Zepbound] led to substantial regain of lost weight, whereas continued treatment maintained and augmented initial weight reduction,” the study authors wrote.6

Where Amgen’s MariTide may separate itself from the blockbuster drugs is in terms of durability and administration frequent. The early data suggest that dosing of MariTide may be effectively tapered down and taken less frequently over time, according to the study authors.1

MariTide is a bispecific molecule produced by conjugating a fully human monoclonal anti-human GIPR antagonist antibody to 2 GLP-1 analogue agonist peptides using amino acid linkers. The Phase I, randomized, double-blind, placebo-controlled trial found that MariTide produced an acceptable safety and tolerability profile, as well as pronounced dose-dependent weight loss. Results from the multiple ascending dose cohorts found that weight loss was maintained for up to 150 days following the last dose of MariTide and maximum weight loss was maintained for two months after the last dose, which investigators said support continued clinical evaluation.

A Phase II trial (NCT05669599) is currently assessing the efficacy of a less intensive dosing regimen for MariTide, with results of the trial expected later this year.

“The overall changes observed in weight and metabolic parameters for both preclinical and clinical studies suggest strong incretin-related effects,” the study authors wrote.1 “Further investigation is still needed to optimize the dosing regimen of [MariTide] for weight loss and other metabolic effects.

“In conclusion, the safety and tolerability profiles, the longer half-life of [MariTide] allowing for extended dosing intervals and the magnitude and durability of weight loss support continued evaluation of [MariTide] in a phase 2 setting.”

This review originally appeared on partner site Pharmaceutical Executive.


References
1. Véniant MM, Lu SC, Atangan L, et al. A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings. Nat Metab. Published online February 5, 2024. doi:10.1038/s42255-023-00966-w
2. Amgen presents new AMG 133 phase 1 Presents New AMG 133 Phase 1 Clinical Data At WCIRDC 2022. News release. Amgen. December 1, 2022. Accessed February 6, 2024. https://www.amgen.com/newsroom/press-releases/2022/12/amgen-presents-new-amg-133-phase-1-clinical-data-at-wcirdc-2022
3. Aronne LJ, Sattar N, Horn DB, et al. Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: the SURMOUNT-4 randomized clinical trial. JAMA. 2024;331(1):38–48. doi:10.1001/jama.2023.24945
4. Wilding, J, Batterham R, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384:989-1002. doi: 10.1056/NEJMoa2032183
5. Wilding JPH, Batterham RL, Davies M, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes Obes Metab. 2022; 24(8):1553-1564. doi:10.1111/dom.14725

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