Livoletide targets hyperphagia, the key concern for Prader-Willi Syndrome patients
Millendo Therapeutics is currently advancing the development of livoletide (AZP-531) for the treatment of Prader-Willi Syndrome (PWS), a severe genetic disease in which patients have unrelenting hunger (hyperphagia). Millendo believes that administering livoletide will reduce the hyperphagic drive in PWS patients.
Livoletide reduced hyperphagia in a Phase 2 placebo-controlled trial
Livoletide was evaluated in a multi-center, randomized, double-blind, placebo-controlled Phase 2 clinical trial to study its effects in adults with PWS. The study tested livoletide administered at 4 mg daily for 14 days versus placebo. The study assessed food-related behaviors using the Hyperphagia Questionnaire was used to capture food-related behaviors in PWS as reported by care providers1. Livoletide demonstrated a statistically-significant and clinically meaningful decrease in the total HQ score for livoletide as compared to placebo2. This finding was even more pronounced in home-resident patients and in patients with higher baseline HQ scores which is indicative of patients with more frequent negative food-related behaviors (p=0.019).
*Includes patients from a hospital environment in which the HQ was completed by different persons at baseline (parents) vs day 14 (study personnel). A 1 to 5 scale was used for each question.
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”. 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. 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.
Livoletide has been shown to inhibit effects 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 the clinical and preclinical data, we believe that livoletide will 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 plans to announce details of additional clinical development of livoletide in 2018.
- 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.