Results of Preclinical Animal Studies to Evaluate the Effect of Iptacopan on Pregnancy-Related Outcomes

Introduction: Iptacopan is a first-in-class, oral, selective inhibitor of factor B, a key component of the complement system alternative pathway. Inhibition of the complement system represents a potential mechanism for treatment of several complement-driven diseases including paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Here, we report results from the preclinical GLP toxicology studies of iptacopan on embryo-fetal development in rats and rabbits and pre- and postnatal development in rats. Methods: In the definitive embryo-fetal development studies,iptacopan was dosed orally via gavage to pregnant rats at 0, 100, 300, and 1000 mg/kg/day (N=24/group) and to pregnant rabbits at doses of 0, 100, 250, and 450 mg/kg/day (N=20/group) during the period of organogenesis (Gestation Day [GD] 6 to 17 and GD7 to 20, respectively). The progress and outcome of pregnancy were evaluated and fetuses were examined for external, visceral, and skeletal abnormalities. In a pre- and postnatal developmental toxicity study in pregnant rats, iptacopan was dosed orally via gavage at 0, 100, 300, and 1000 mg/kg/day (N=22/group) from GD6 to Lactation Day (LD) 21. The untreated offspring were allowed to mature and the effects on development, behavior, and reproductive performance were assessed. Results: In the rat embryo-fetal development study, maternal administration of iptacopan resulted in no adverse clinical observations, no effects on maternal body weights, and no adverse fetal findings. Non-adverse fetal variations of delayed ossification were observed in the skull. Two fetuses in one out of 22 litters at 1000 mg/kg/day had benign cysts on the left side of the parietal region of the head, with no impact on skeletal (skull), CNS (brain), or any other head-based structure. The no observed adverse effect level (NOAEL) for maternal toxicity and embryo-fetal development was 1000 mg/kg/day. In the definitive rabbit embryo-fetal development study, administration of iptacopan caused reduced maternal body weight gain and food consumption at 450 mg/kg/day. There were no treatment-related fetal malformations or variations. The NOAEL was 250 mg/kg/day for maternal toxicity and 450 mg/kg/day for embryo-fetal development. In the pre- and postnatal development study, no adverse findings were observed in the mated female rats during gestation, parturition, and lactation and there were no adverse effects on development of their offspring, including survival, physi