SUN-608 Juvenile Toxicity Study of Livoletide: A Peptide Analogue of Unacylated Ghrelin for the Treatment of Hyperphagia in Prader-Willi Syndrome

Background: Prader-Willi syndrome (PWS) is a rare endocrine disorder characterized by hyperphagia and abnormal food-related behaviors that contribute to severe morbidity, early mortality, and significant burdens for patients and caregivers. Dysregulation of acylated ghrelin (AG) and unacylated ghrelin (UAG) in people with PWS and hyperphagia has led to the hypothesis that replacing the relative deficit of UAG observed in this population will reduce hyperphagia. Livoletide is a cyclic, 8 amino acid analogue of UAG being developed as a potential treatment for hyperphagia and food-related behaviors associated with PWS. In a previous Phase 2a study (n=47) in people with PWS, livoletide improved food-related behaviors and hyperphagia scores relative to placebo. An extensive nonclinical safety program to support clinical development of livoletide has been conducted. Here we report the results of study of livoletide in juvenile rats. Methods: Male and female juvenile Wistar rats were administered livoletide (10, 25, or 75 mg/kg/day, subcutaneous) once daily from the age of weaning (postnatal day 21) until 12 weeks of age (n=32/sex/group). Subgroups were sacrificed at the end of the dosing period or after a recovery period. Toxicity was assessed based on local tolerance, clinical observations, body weights, food consumption, tibia length, bone densitometry, behavioral tests, IGF1 (insulin-like growth factor-1), LH (luteinizing hormone), and other endpoints. Macroscopic (necropsy), microscopic/histopathological, and caesarean examinations were also performed. Toxicokinetic (TK) evaluations were performed at various time-points after dosing to assess exposure. Results: Livoletide was not associated with treatment-related clinical signs or any relevant changes in hematological, coagulation, clinical chemistry parameters or urine analysis. Body weight and food consumption were unaffected. Livoletide did not affect systemic concentrations of IGF-1 or LH. No adverse effects of livoletide on bone growth, mating performance, or fertility were observed. Pups delivered by caesarian section did not exhibit abnormalities. Results were consistent with a lack of effect of livoletide on growth hormone signaling. Histological changes were limited to minimal local reversible reactions at injection sites that were non-adverse and observed at low incidence and severity. Conclusions: Livoletide was well-tolerated and not associated with evidence of overt systemic toxicity. The no observed adverse effect level (NOAEL) of 75 mg/kg/day was associated with C(max) and AUC(0-24h) values of 72.6/83.2 μg/mL and 169/144 μg.h/mL (males/females), respectively. These exposures are >100-fold above the anticipated clinical exposures in the Phase 2b/3 ZEPHYR study, which is enrolling people ages 4 to 65 with PWS.