The Efficacy, Safety, and Pharmacology of a Ghrelin O-Acyltransferase Inhibitor for the Treatment of Prader-Willi Syndrome

Acylated ghrelin (AG) stimulates appetite and is elevated compared to its unacylated (UAG) counterpart in Prader-Willi syndrome (PWS). GLWL-01 is a selective, reversible inhibitor of ghrelin O-acyltransferase (GOAT), the enzyme that converts UAG into AG. This work aimed to assess the efficacy, pharm...

Full description

Saved in:
Bibliographic Details
Published in:The journal of clinical endocrinology and metabolism 2022-05, Vol.107 (6), p.e2373-e2380
Main Authors: Miller, Jennifer L, Lacroix, André, Bird, Lynne M, Shoemaker, Ashley H, Haqq, Andrea, Deal, Cheri L, Clark, Kristie A, Ames, Michael H, Suico, Jeffrey G, de la Peña, Amparo, Fortier, Caroline
Format: Article
Language:English
Subjects:
Acyltransferases
Cross-Over Studies
Double-Blind Method
Ghrelin - therapeutic use
Humans
Hyperphagia
Online Only
Prader-Willi Syndrome - drug therapy
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Acylated ghrelin (AG) stimulates appetite and is elevated compared to its unacylated (UAG) counterpart in Prader-Willi syndrome (PWS). GLWL-01 is a selective, reversible inhibitor of ghrelin O-acyltransferase (GOAT), the enzyme that converts UAG into AG. This work aimed to assess the efficacy, pharmacokinetics, pharmacodynamics, and safety of GLWL-01 in the treatment of PWS patients. A double-blind, placebo-controlled, phase 2 crossover study was conducted with 2 active treatment periods of 28 days in 19 patients (aged 16-65 years; body mass index (BMI) ≥ 28) with genetically confirmed PWS. The study took place in 7 hospital-based study centers in the United States and Canada. Patients received placebo or GLWL-01 (450 mg twice daily) orally after lead-in placebo and washout periods. The Hyperphagia Questionnaire for Clinical Trials and Caregiver Global Impression of Change were used to measure reductions in hyperphagia. Plasma concentrations of AG and UAG were evaluated as correlates. Treatment resulted in statistically significant differences compared to placebo in plasma AG (P = .0002), UAG (P = .0488), and AG/UAG (P = .0003). GLWL-01 did not statistically significantly reduce hyperphagia-related behavior or bring about changes in global clinical end points, as assessed by caregivers. Anthropometric and clinical parameters correlated with obesity did not statistically significantly change in response to treatment. Less than half of patients reported a treatment-emergent adverse event (TEAE). No deaths, serious adverse events, or severe TEAEs were reported. GLWL-01 is safe and well tolerated. Pharmacological parameters confirmed the inhibition of GOAT following administration of GLWL-01. Patients' eating behaviors, BMI, blood glucose, and total cholesterol, among other similar measures, were not modified.
ISSN:0021-972X
1945-7197
DOI:10.1210/clinem/dgac105