A Growth Differentiation Factor 15 Receptor Agonist in Randomized Placebo-Controlled Trials in Healthy or Obese Persons
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Le résumé fourni par la source
BACKGROUND: Growth differentiation factor 15 (GDF15), a divergent member of the TGF-β superfamily, signals via the hindbrain glial-derived neurotrophic factor receptor alpha-like and rearranged during transfection receptor co-receptor (GFRAL-RET) complex. 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 multiple nonclinical species, and then in humans, in 2 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 phase 2, MBL949 or placebo was administered subcutaneously every other week for a total of 8 doses to obese participants (n = 126) in 5 different dose regimens predicted to be efficacious based on data from the phase 1 trial. RESULTS: In nonclinical species, MBL949 was generally safe and effective with reduced food intake and body weight in mice, rats, dogs, and monkeys. Weight loss was primarily from reduced fat, and metabolic endpoints improved. A single ascending dose study in overweight or obese healthy adults demonstrated mean terminal half-life of 18 to 22 days and evidence of weight loss at the higher doses. In the phase 2, 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.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- A Growth Differentiation Factor 15 Receptor Agonist in Randomized Placebo-Controlled Trials in Healthy or Obese Persons
- Date Crossref
- 16/08/2024
- Éditeur
- The Endocrine Society
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
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Alliance for Multispecialty Research (United States) pays non établi dans la noticeEntreprise
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Altasciences (Canada) pays non établi dans la noticeEntreprise
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Novartis (Switzerland) pays non établi dans la noticeEntreprise
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Novartis (United States) pays non établi dans la noticeEntreprise
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Tris Pharma (United States) pays non établi dans la noticeEntreprise
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Altasciences Clinical Los Angeles pays non établi dans la noticeÉtablissement de santé
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Novartis Biomedical Research pays non établi dans la noticeInstitution
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Novartis Pharmaceuticals Corporation pays non établi dans la noticeInstitution
Alliance for Multispecialty Research (United States), Altasciences (Canada) et Novartis (Switzerland), avec 5 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.