Prader-Willi syndrome (PWS) is a rare complex endocrine disease characterized by hyperphagia and abnormal food-related behaviors that contribute to severe morbidity and early mortality and to a significant burden on patients and caregivers. There are no approved treatments for hyperphagia in PWS. Patients with PWS have increased circulating levels of the orexigenic hormone acylated ghrelin (AG) with a relative deficit of unacylated ghrelin (UAG). These abnormalities in AG and UAG levels may be involved in the underlying mechanisms of hyperphagia. UAG is a 28-amino-acid peptide that does not bind the growth hormone secretagogue receptor (GHSR), unlike AG. UAG has intrinsic central and peripheral effects that counteract the effects of AG and are exerted through a GHSR-independent mechanism. Livoletide is a cyclic 8-amino-acid analog of UAG with improved plasma stability and pharmacokinetics. The objective of this nonclinical development program was to support the clinical development of livoletide, which includes a pivotal Phase 2b/3 clinical trial in patients with PWS initiated in early 2019. The program was designed to define the safety pharmacology and the chronic toxicologic and toxicokinetic profile of livoletide and to identify parameters for clinical monitoring of potential adverse effects. Genotoxicity, safety pharmacology, reproductive toxicity, and repeat-dose 13-week toxicology studies were all completed. In the in vivo studies, livoletide was administered subcutaneously consistent with the clinical route of delivery. Livoletide was not found cytotoxic or genotoxic. Safety pharmacology studies indicated no treatment-related effects on major physiological systems. Results from preliminary embryo-fetal developmental toxicity studies in rat and rabbit indicated that livoletide at high multiples of the anticipated human exposure was not associated with adverse maternal toxicity, embryo-fetal toxicity or teratogenic potential when administered throughout the period of organogenesis. Repeat-dose toxicity studies of up to 26 and 39 weeks duration in rats and dogs demonstrated that livoletide was very well tolerated, with no evidence of systemic toxicity. Cumulative data indicated that livoletide has a wide safety margin relative to planned clinical exposures. The highest chronic doses tested were 45 mg/kg in rat and 30 mg/kg in dog; these were considered to be the NOAELs. These dose levels provided AUC values of ≥50-fold the intended clinical systemic exposure (~1200 ng·h/ml). No anti-livoletide antibodies were detected in any of the toxicology studies. These results confirm the favorable long-term safety profile of livoletide and support the subcutaneous administration of the highest anticipated human clinical dose in the Phase 2b/3 study.
18 May 2019 - 21 May 2019