J Clin Endocrinol Metab. 2022 Feb 25:dgac105. doi: 10.1210/clinem/dgac105. Online ahead of print.
ABSTRACT
CONTEXT: 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.
OBJECTIVE: Assess the efficacy, pharmacokinetics, pharmacodynamics, and safety of GLWL-01 in the treatment of PWS patients.
DESIGN: Double-blind, placebo-controlled Phase 2 crossover study with two active treatment periods of 28-days in 19 patients (16 to 65 years; body mass index (BMI) ≥28 kg/m 2) with genetically confirmed PWS.
SETTING: Seven hospital-based study centers in the US and Canada.
INTERVENTION: Patients received placebo or GLWL-01 (450 mg twice daily) orally after lead-in placebo and washout periods.
MAIN OUTCOME: The Hyperphagia Questionnaire for Clinical Trials (HQ-CT) and Caregiver Global Impression of Change (CGIC) were used to measure reductions in hyperphagia. Plasma concentrations of AG and UAG were evaluated as correlates.
RESULTS: Treatment resulted in significant differences compared to placebo in plasma AG (p=0.0002), UAG (p=0.0488), and AG/UAG (p=0.0003). GLWL-01 did not significantly reduce hyperphagia-related behavior or bring about changes in global clinical endpoints, as assessed by caregivers. Anthropometric and clinical parameters correlated with obesity did not 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.
CONCLUSIONS: GLWL-01 was 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.
PMID:35213714 | DOI:10.1210/clinem/dgac105
