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

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: This work aimed to assess the efficacy, pharmacokinetics, pharmacodynamics, and safety of GLWL-01 in the treatment of PWS patients.

Methods: 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.

Results: 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.

Conclusion: 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.

Trial registration: ClinicalTrials.gov NCT03274856.

Keywords: GLWL-01; Prader-Willi syndrome (PWS); acylated ghrelin (AG); ghrelin; ghrelin O-acyltransferase (GOAT).

© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Plot of mean (SD) acylated ghrelin (AG) and unacylated ghrelin (UAG) values over time. For visual acuity, all plotted lines are slightly offset from day 0 and 28. AG was reduced by an order of magnitude by treatment with GLWL-01. Scheduled day refers to scheduled treatment day.

Figure 2.

Mean plasma GLWL-01 concentrations vs time following single (day 1) and multiple (day 28) dosing. GLWL-01 concentration data were plotted both on A, a linear scale, and B, semi-log scale on the Y axis. The concentration-time profiles demonstrate that the study drug was absorbed rapidly and declined in a monophasic manner. Error bars represent 1 SD from the mean.