Ocrelizumab during pregnancy and lactation: Rationale and design of the MINORE and SOPRANINO studies in women with MS and their infants

Abstract

Background: Most disease-modifying therapies (DMTs) approved for the treatment of multiple sclerosis (MS) are not recommended during pregnancy, and discouraged while breastfeeding. However, discontinuation of some DMTs before pregnancy can leave women vulnerable to MS relapses. Although available data on ocrelizumab suggest no increased risk in terms of pregnancy or neonatal outcomes, it is unknown whether ocrelizumab transfers across the placenta or is absorbed through breastmilk; and if so, whether infant B cell development, immune responses or growth and development are affected. This manuscript describes two studies designed to address these uncertainties.

Methods/design: MINORE and SOPRANINO are multicentre open-label studies. MINORE, which addresses placental transfer, will recruit 44 women with MS or clinically isolated syndrome (CIS) exposed to ocrelizumab between 6 months before the last menstrual period (LMP) to the end of the first trimester. It will evaluate pharmacodynamic effects of potential in utero exposure through the proportion of infants with B cell numbers below lower limit of normal (LLN) at week 6 of life (primary endpoint); as well as through vaccine-induced antibody responses (reflecting B cell function) during the first year of life. Placental transfer will be assessed through measurement of ocrelizumab concentrations in paired samples at delivery (maternal blood as well as umbilical cord blood), and infant serum at week 6 of life. SOPRANINO, which evaluates breastmilk transfer, will recruit 20 women with MS or CIS who resume or initiate ocrelizumab treatment while breastfeeding. The effect of potential exposure through breastmilk will be assessed through the proportion of infants with B cell levels below LLN at 30 days after the mother's first post-partum ocrelizumab infusion (co-primary endpoint). Infant exposure via breastmilk will be assessed through ocrelizumab average daily infant dose in breastmilk over 60 days after the same infusion (co-primary endpoint). Vaccine-induced responses will be measured as in MINORE. Both studies will also measure infant growth and development over the first year of life and safety outcomes in both mothers and infants. All analyses will be descriptive, under an estimand framework.

Discussion: Both studies are designed to mimic real-world clinical practice. Treatment decisions for ocrelizumab are independent from study participation; as such, these studies will recruit women who decide, along with their physicians, to continue their pregnancies despite potential in utero exposure (for MINORE); or to breastfeed while under ocrelizumab treatment (for SOPRANINO). MINORE is the first prospective study to measure placental transfer of any DMT in MS, and to perform comprehensive assessments in infants and mothers. Results may inform the optimal contraception period for women treated with ocrelizumab who are planning a pregnancy. Similarly, SOPRANINO is the first prospective study to measure pharmacodynamic effects of ocrelizumab in breastfed infants in addition to pharmacokinetic parameters in breastmilk. SOPRANINO may establish whether breastfeeding is safe for infants whose mothers received treatment with ocrelizumab.

Conclusion: By collecting detailed pharmacokinetic, pharmacodynamic and safety information, MINORE and SOPRANINO will contribute to understanding the risk/benefit of ocrelizumab in pregnant and lactating women with MS.

Keywords: Breastfeeding; Disease-modifying therapy; Infant outcome; Lactation; Multiple sclerosis; Ocrelizumab; Pregnancy.