Schofield, Jul, Kagan, Mark, Kompa, Jill, He, YanLing, Jamontt, Joanna, Schwartzkopf, Chad, Layne Jr, Joseph, O'Donnell, Chris, Heldwein, Kurt, Streeper, Ryan and Goldfine, Allison (2024) MBL949, a long acting GDF15 receptor agonist, in preclinical and Phase 1 and Phase 2 randomized placebo controlled parallel design clinical trials in healthy volunteers and patients with obesity. Journal of Clinical Endocrinology and Metabolism. ISSN PMID: 39148430

Abstract

Background: Growth Differentiation Factor 15 (GDF15) is a divergent member of the TGF- superfamily which signals via the hindbrain glial-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL)-rearranged during transfection (RET) (GFRAL-RET) receptor. In nonclinical species, GDF15 is a potent anorexigen leading to substantial weight loss. MBL949 is a half-life extended recombinant human GDF15 dimer.

Methods: MBL949 was evaluated in nonclinical species and in humans in two randomized and placebo-controlled clinical trials. In the Phase 1 first-in-human, single ascending dose trial MBL949 or placebo was injected subcutaneously to overweight and obese healthy volunteers (n=65) at doses ranging from 0.03 to 20 mg. In the Phase 2 clinical trial, MBL949 or placebo was administered to obese participants (n=126) in five different dose regimens predicted to be efficacious from the Phase 1 trial or placebo, with investigational drug administered subcutaneously every other week for a total of 8 doses.

Results: In nonclinical species, MBL949 was generally safe and effective with reduced food intake and body weight.
observed in mice, rats, dogs, and monkeys. Weight loss was primarily from reduction in fat, and metabolic endpoints were improved. In humans, a single ascending dose study in overweight or obese healthy adults demonstrated mean terminal half-life of 18-22 days, and evidence of weight loss at the higher doses. In the Phase 2 trial, weight loss was minimal following biweekly dosing of MBL949 for 14 weeks. MBL949 was safe and generally tolerated in humans over the dose range tested, adverse events of the gastrointestinal system were the most frequent observed.

Conclusion: The prolonged half-life of MBL949 supports biweekly dosing in patients. MBL949 had an acceptable safety profile. The robust weight loss observed in nonclinical species did not translate to weight loss efficacy in humans.

Item Type:	Article
Date Deposited:	10 Dec 2024 00:45
Last Modified:	10 Dec 2024 00:45
URI:	https://oak.novartis.com/id/eprint/53811