Abstract Details

Title Effect of Ofatumumab on Pregnancy, Parturition and Lactation in Cynomolgus Monkeys

Topic Multiple Sclerosis

Presentation(s) MS and CNS Inflammatory Disease Posters (7:00 AM-5:00 PM)

Poster/Presentation
Number 135

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.

Authors/Disclosures
Muriel Bellot PRESENTER	Muriel Bellot has nothing to disclose.
	No disclosure on file
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	No disclosure on file
Krishnan Ramanathan	Krishnan Ramanathan has received personal compensation for serving as an employee of Novartis.
Kerstin Hellwig (St. Josef Hospital Bochum)	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 BMS. Kerstin Hellwig has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis . Kerstin Hellwig has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Roche . Kerstin Hellwig has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck . Kerstin Hellwig has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi Genzyme . Kerstin Hellwig has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Mylan . 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 $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche . 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 $5,000-$9,999 for serving on a Speakers Bureau for Novartis . Kerstin Hellwig has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Roche . The institution of Kerstin Hellwig has received research support from Roche . The institution of Kerstin Hellwig has received research support from Merck . The institution of Kerstin Hellwig has received research support from Biogen. The institution of Kerstin Hellwig has received research support from Genzyme . The institution of Kerstin Hellwig has received research support from Novartis . The institution of Kerstin Hellwig has received research support from BMS .

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