Subcutaneous zilucoplan: Evaluation of reproductive toxicology

Abstract

To further understand the safety profile of zilucoplan, reproductive toxicology studies in non-human primates (NHPs) were performed, including a male fertility study and a combined embryo–foetal development (EFD) and enhanced pre- and postnatal development (ePPND) study. Human transplacental transfer of zilucoplan was examined in an ex vivo human placental perfusion model of foetal exposure during pregnancy. By comparison with the positive control, a low transfer rate of 0.5 % was observed with a target blood zilucoplan concentration that mimics the therapeutic dose of 0.3 mg/kg used in clinical trials in patients with generalised myasthenia gravis. In each in vivo study, daily subcutaneous zilucoplan 1.0, 2.0 or 4.0 mg/kg or vehicle control were randomly assigned. Six male cynomolgus monkeys/group received treatment for 13 weeks (male fertility), 4 females/group received treatment for 80 days (EFD) and 16 females/group received treatment from gestation day 20 to delivery (∼140 days, ePPND). Developmental, reproductive and toxicokinetic effects were analysed. No zilucoplan-related reproductive effects were observed in the male fertility study. There were no effects on pregnancy outcome, number of viable foetuses or foetal development in the combined EFD/ePPND study. Overall pregnancy loss (including stillbirths and death during birth) was 25.0 % (4/16) in the control group compared with 37.5 % (6/16) in the zilucoplan-treated groups and was within the published range of pregnancy loss in cynomolgus monkeys. These reproductive toxicity studies demonstrate no adverse effect of zilucoplan on male fertility or maternal or embryo–foetal outcomes, and no pre- or postnatal toxicity in NHPs receiving daily zilucoplan. Data from the ex vivo placental transfer model and the lack of effect of FcRn-mediated transfer on zilucoplan suggest that placental transfer is low.