Prader-Willi syndrome (PWS) is a rare and complex endocrine disease caused by a spontaneous genetic error that is characterized by unrelenting hunger (hyperphagia), intellectual disability, short stature and incomplete sexual development. Recognized as the most common genetic cause of life-threatening childhood obesity, PWS occurs in about one in 15,000 births. While PWS patients experience a multitude of symptoms, hyperphagia, which typically begins in early childhood, is among the most serious.
Livoletide targets hyperphagia, the key concern for Prader-Willi syndrome (PWS) patients
Millendo Therapeutics is currently advancing the development of livoletide (AZP-531) for the treatment of PWS. Millendo believes that livoletide may provide a unique, first-in-class approach for the treatment of all hyperphagic PWS patients by reducing the underlying hormone dysregulation causing the disease.
Livoletide reduced hyperphagia in a Phase 2 placebo-controlled trial
Livoletide was evaluated in a randomized, double-blind, placebo-controlled Phase 2 clinical trial to study its effects in adult patients with PWS. The trial compared livoletide administered at 3 or 4 mg doses once daily for 14 days with placebo. The primary objective of the trial was to evaluate the safety and tolerability of livoletide over the course of two weeks. Food-related behaviors were assessed using the Hyperphagia Questionnaire (HQ) as reported by care providers1. In the trial, Millendo observed a decrease in the total HQ score across all patients administered livoletide as compared to placebo2. Millendo observed the largest treatment effect in a post-hoc analysis of 26 home-resident patients with baseline HQ scores of 10 or greater, which is indicative of patients with more frequent negative food-related behaviors (p=0.019). Millendo believes that these changes in HQ scores reflect clinically meaningful changes in hyperphagic behaviors that affect patient and caregiver quality of life.
*Includes patients from a hospital environment in which the HQ was completed by different persons at baseline (parents) vs day 14 (study personnel).
Potentially first-in-class mechanism of action
Livoletide, an analogue of unacylated ghrelin, has the potential to be a first-in-class treatment for PWS. Ghrelin, also known as acylated ghrelin (AG), is commonly known as the “hunger hormone” and is synthesized in the gastrointestinal tract. Ghrelin functions as a neuropeptide to stimulate feeding and food seeking behavior and serves as a ligand for the growth hormone secretagogue receptor, GHSR1a.
Livoletide has been shown to inhibit effects of ghrelin
Unacylated ghrelin (UAG), also referred to as des-acyl ghrelin (DAG), is a naturally occurring hormone with biological activities of its own separate from those of ghrelin. UAG neither activates nor inhibits the growth hormone receptor (GHSR1a) at physiological concentrations, but has been shown to inhibit ghrelin-induced food intake and other effects of ghrelin in vivo. Historically, the high total ghrelin concentrations reported in the literature have implicated ghrelin in the hyperphagia and excessive eating that is characteristic of PWS. However, recent studies indicate that the ratio of AG to UAG is elevated in PWS compared to aged-matched healthy subjects and may be more relevant to hyperphagia associated with PWS than the absolute concentrations of total ghrelin3.
Livoletide is a cyclic peptide analogue of UAG that has been shown to inhibit certain aspects of ghrelin activity and improve metabolic status in rodent models of diabetes or metabolic syndrome. In a rodent model of appetite-stimulating activity, ghrelin-induced food intake was inhibited by co-administration of both livoletide and UAG4 in separate studies. Based on clinical and preclinical data, Millendo believes that livoletide has the potential to decrease hyperphagia and negative food-related behaviors, thereby improving the lives of PWS patients and their care providers.
Millendo is planning a new clinical study of livoletide in PWS
Millendo is planning to initiate a pivotal Phase 2b/3 clinical trial of livoletide for the treatment of PWS in the first quarter of 2019, with results expected in the first half of 2020.
- Fehnel S, Brown TM, Nelson L, Chen A, Rook E, Kim DD, Dykens EM. Development of the Hyperphagia Questionnaire for Use in Prader-Willi Syndrome Clinical Trials, ISPOR Meeting 2015, Philadelphia PA, USA
- Allas S, Caixàs A, Poitou C, Coupaye M, Thuilleaux D, Lorenzini F, Diene G, Crinò A, Illouz F, Grugni G, Potvin D, Bocchini S, Delale T, Abribat T, Tauber M. AZP-531, an unacylated ghrelin analog, improves food-related behavior in patients with 3 Prader-Willi syndrome: A randomized placebo-controlled trial. In press.
- Kuppens RJ, Diène G, Bakker NE, Molinas C, Faye S, Nicolino M, Bernoux D, Delhanty PJ, van der Lely AJ, Allas S, Julien M, Delale T, Tauber M, Hokken-Koelega AC. (2015) Elevated ratio of acylated to unacylated ghrelin in children and young adults with Prader-Willi syndrome Endocrine 50:633-642.
- Inhoff T, Mönnikes H, Noetzel S, Stengel A, Goebel M, Dinh QT, Riedl A, Bannert N, Wisser AS, Wiedenmann B, Klapp BF, Taché Y, Kobelt P (2008) Desacyl ghrelin inhibits the orexigenic effect of peripherally injected ghrelin in rats Peptides 29:2159-2168.