Effect of Ofatumumab on Pregnancy, Parturition and Lactation in Cynomolgus Monkeys (2265)

Objective: To understand the effect of ofatumumab intravenous infusion on pregnancy, parturition, lactation, and pre/postnatal development in offspring of cynomolgus monkeys. Background: Anti-CD20 therapy exposure during gestation may result in transient B-cell depletion in offspring. Ofatumumab 20mg subcutaneous, is a fully-human anti-CD20 monoclonal antibody approved by the FDA for treatment of adults with relapsing multiple sclerosis. Design/Methods: This preclinical, enhanced pre/postnatal development study was conducted in 42 pregnant cynomolgus monkeys (Asian origin; age [5–6 years]; weight [2.8–4.9 kg]). Ofatumumab or control was administered intravenously from gestation day (GD) 20 until parturition. An initial dose (0, 10, 100 mg/kg) was given once weekly for 5 weeks, followed by a maintenance dose (0, 3, 20 mg/kg) once every 2 weeks from GD 62 onwards. Ofatumumab was discontinued after parturition and maternal monkeys and infants were observed for 6 months prior to necropsy on lactation day/postnatal day 180±1. Results: Exposure to intravenous ofatumumab (10/3 mg/kg or 100/20 mg/kg) during gestation led to B-cell depletion in maternal monkeys and their infants at both dose levels. At 100/20 mg/kg but not at 10/3 mg/kg, the transient reduction in the humoral immune function of infants was, in a few cases, associated with secondary infection leading to perinatal death. These findings were observed at a dose 160-fold higher than the therapeutic dose of 20 mg in terms of area under the curve (AUC). The humoral immune function of infants returned to normal when B cells replenished. The no-observed-adverse-effect-level in infants was defined at 100/20 mg/kg for pre/postnatal development and at 10/3 mg/kg for pharmacological effects corresponding to safety margins of 160-fold and 22-fold, respectively, compared with the therapeutic dose of 20 mg in terms of AUC. Conclusions: Ofatumumab did not affect the pre/postnatal development and had high safety margins owing to the low therapeutic dose of 20 mg. Disclosure: Muriel Bellot has nothing to disclose. Morten Bagger has received personal compensation for serving as an employee of Novartis. Morten Bagger has received stock or an ownership interest from Novartis. Courtney Horvath has nothing to disclose. Esther Sutter has received personal compensation for serving as an employee of Novartis Pharma AG. Esther Sutter has received stock or an ownership interest from Novartis Pharma AG. Anthony DeLise has received personal compensation for serving as an employee of Novartis. Anthony DeLise has received stock or an ownership interest from Novartis Pharmaceuticals. Dominique Brees has received personal compensation for serving as an employee of novartis. Jose M Carballido has received stock or an ownership interest from Novartis. Jose M Carballido has received personal compensation in the range of $100,000-$499,999 for serving as a Employee with Novartis. Ratnakar Pingili has received personal compensation for serving as an employee of Novartis. Krishnan Ramanathan has received personal compensation for serving as an employee of Novartis. Kerstin Hellwig has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Teva . Kerstin Hellwig has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen . Kerstin Hellwig has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for INC research . Kerstin Hellwig has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis . Kerstin Hellwig has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Merck . Kerstin Hellwig has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen . Kerstin Hellwig has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer .