Abstract
Prader-Willi syndrome (PWS) is a rare and 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. Hyperghrelinemia may be involved in the underlying mechanisms of hyperphagia. While ghrelin, the most potent appetite-stimulating hormone, is present at higher concentrations in the plasma of PWS patients compared to age-matched controls, detailed studies of ghrelin and unacylated ghrelin (UAG) reveal a relative deficit of UAG in hyperphagic individuals. UAG is a 28-amino-acid peptide that does not bind the growth hormone secretagogue receptor (GHSR), in contrast to acylated ghrelin. UAG has intrinsic activities that often counteract effects of ghrelin, and exerts its actions through a GHSR-independent mechanism. Livoletide is a cyclic 8-amino-acid analogue of UAG with improved plasma stability and pharmacokinetics. The objective of this nonclinical safety program was to support the clinical development of livoletide including a pivotal Phase 2b/3 clinical trial in patients with PWS. The program was designed to define the safety pharmacology and the chronic toxicologic and toxicokinetic profile, and 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 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 is 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 13 weeks’ duration in rats and dogs demonstrated that livoletide is 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 75 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.