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Livoletide for Prader-Willi syndrome

Our team at Millendo is currently advancing the development of livoletide (AZP-531) for the treatment of Prader-Willi syndrome (PWS). We believe that livoletide may provide a unique, first-in-class approach for the treatment of hyperphagic PWS patients by reducing the underlying hormone dysregulation causing the disease, thereby alleviating a key root cause of early morbidity and mortality in PWS patients.

Livoletide targets hyperphagia, the key concern for Prader-Willi syndrome (PWS) patients and caregivers

Prader-Willi syndrome (PWS) is a rare and complex genetic endocrine disease 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. There currently is no treatment for hyperphagia.

ZEPHYR, a pivotal Phase 2b/3 clinical study of livoletide in patients with PWS, was initiated in March 2019

We are currently conducting a human clinical study of livoletide in patients with PWS. For more information about the ZEPHYR clinical study, please go to Our Patients.

What is the ZEPHYR Study?

Livoletide reduced hyperphagia in a Phase 2a placebo-controlled trial

Livoletide was evaluated in a randomized, double-blind, placebo-controlled Phase 2a clinical trial to study its effects in 47 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, we observed a decrease in the total HQ score across all patients administered livoletide as compared to placebo2. We believe that these changes in HQ scores reflect potentially clinically meaningful changes in hyperphagic behaviors that affect patient and caregiver quality of life and warrant further study.

Patients on livoletide showed improvement as early as one week, and 65% of patients showed a reduction of at least 4-points or greater over the two week treatment period. Finally, there were clinically meaningful improvements across all behavioral dimensions that were part of the survey tool used:

Potentially first-in-class mechanism of action

Livoletide, a functional analogue of unacylated ghrelin (UAG), has the potential to be a first-in-class treatment for PWS. It is a cyclic peptide analogue of UAG and serves to replace the relative deficit of UAG that is observed in hyperphagic PWS patients.

Livoletide has been shown to inhibit effects of ghrelin

Livoletide, a cyclic peptide analogue of UAG, has been shown to inhibit certain aspects of ghrelin activity and improve metabolic status in rodent models of diabetes or metabolic syndrome3. Based on clinical and preclinical data, we believe that livoletide has the potential to decrease hyperphagia and negative food-related behaviors, thereby improving the lives of PWS patients, families and caregivers.

Ghrelin, also known as acylated ghrelin (AG), is commonly known as the “hunger hormone” and is synthesized in the gastrointestinal tract. Ghrelin stimulates 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 separate from those of ghrelin. UAG neither activates nor inhibits 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 ghrelin4.

For more information about the PWS Clinical Trial Webinar visit https://clinicaltrials.gov/ct2/show/NCT03790865.

  1. 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
  2. Allas S, Caixàs, A, Poitou C, Coupaye M, ThuilleauxD, LorenziniF, et al. (2018) AZP-531, an unacylated ghrelin analog, improves food-related behavior in patients with Prader-Willi syndrome: A randomized placebo-controlled trial. PLoS ONE 13 (1): e0190849. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0190849
  3. 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.
  4. 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.

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