ECTRIMS-ACTRIMS: Updates to safety of ocrelizumab in pregnancy still “ongoing” after new analysis

ECTRIMS-ACTRIMS: Updates to safety of ocrelizumab in pregnancy still “ongoing” after new analysis

898 599 Peter Stevenson, PhD

An update on pregnancy outcomes following ocrelizumab (OCR) treatment in patients with multiple sclerosis (MS) and other autoimmune diseases was delivered at this year’s joint ECTRIMS-ACTRIMS meeting, held 25-28 October in Paris, France.

As a poster detailing the study described,1 a large proportion of MS patients are women of reproductive age, thus it is important to understand any potential harms that OCR therapy – a humanised monoclonal antibody that selectively targets CD20+ B cells – could have on the immune systems of children born to either relapsing-remitting (RMS) or primary progressive (PPMS) MS mothers.

The primary concern is that while immunoglobulin molecules such as OCR do not cross the placenta during the first trimester, foetal CD20+ B-cell depletion could be a risk to the infant at a later stage.1 Because of this, women of reproductive age are advised to use effective contraception when receiving OCR, and for up to six months after the last infusion of the agent.

Pre-clinical study data in cynomolgus monkeys has shown that intravenous administration of OCR (loading doses of 15 or 75 mg/kg on gestation days 20, 21, and 22, followed by weekly doses of 20 or 100 mg/kg) during the foetal organogenesis period resulted in no evidence of maternal toxicity, embryotoxicity or teratogenicity, and no observed effect on abortion or embryo-foetal fatality rate.1,2 However, OCR administration did result in B-cell depletions in both mothers and offspring.

A similar study of three daily loading doses of 15 or 75 mg/kg, followed by weekly doses of 20 or 100 mg/kg in pregnant monkeys in the organogenesis period and into the neonatal period resulted in two perinatal deaths, renal toxicity, lymphoid follicle formation in the bone marrow, and severe decreases in circulating B-lymphocytes in neonates.2 However, the cause of neonatal death was not known, yet both had bacterial infections. Reduced testicular weight was also observed in neonates at the higher dose. Critically, these doses were between two and 10-times higher than the recommended human dose.

To date there have been no OCR studies performed focused on human reproduction,1 but there have been several studies focusing on other OCR outcomes for MS, as well as in the treatment of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). As such, the poster authors served up an update to the retrospective analysis that they have been performing regarding follow-up of pregnancy outcomes in patients enrolled in MS, RA and SLE OCR clinical trials (dose range 20 to 2000 mg) from 2008 to 31 January 2017. While inclusion criteria required a negative pregnancy urine test at enrolment, and use of appropriate contraceptive precautions for the entire period of B-cell depletion, any women that became pregnant during one of the studies were followed to determine outcomes.

An embryo/foetus was considered to have been exposed to OCR if the last infusion occurred within three months of conception, or during pregnancy if the date of infusion was unknown.

MS trials

There were 25 maternal exposure pregnancies in the MS trials during the study period. In total, 14 of the 25 pregnancies were considered to have had foetal OCR exposure. Of these, four pregnancies resulted in a healthy baby, six were elective determinations (including two therapeutic abortions with unreported reason), one preterm infant at 32 weeks with temperature instability, feeding difficulties, bradycardia, respiratory distress and anaemia, one stillbirth, and two pregnancies ongoing at the time of the report.

In the pregnancies not considered to have foetal exposure, 11 pregnancies included seven healthy term babies, one preterm infant at 34 weeks with benign nasopharyngeal neoplasm, jaundice, respiratory distress and low birth rate, one elective termination and two ongoing pregnancies.

RA and SLE trials

There were 33 maternal exposure pregnancies in 31 patients with RA or SLE, with 11 healthy full-term pregnancies (two for one mother) reported. One pregnancy was healthy but at unreported gestational week. Seven babies had structural malformation, function deficit, growth abnormality and/or pre-term delivery, and two elective terminations were performed. Ten pregnancies in nine women resulted in spontaneous abortion, one pregnancy resulted in foetal death at 7.5 months gestation (secondary to fatal pulmonary embolism in mother), and one pregnancy was lost to follow-up.

Conclusions

As the authors describe, drawing a conclusion from the new analysis is difficult given that the number of pregnancies included was small, but it remains that increased understanding about pregnancy outcomes after OCR treatment is paramount, thus they hope that ongoing exploration of child heath outcomes will elucidate more grounding.

In the meantime, as the authors underline, women of childbearing potential should continue to use contraception while receiving OCR treatment, and for six months after the last infusion.


References

  1. Vukusic S, et al. ‘An update on pregnancy outcomes following ocrelizumab treatment in patients with multiple sclerosis and other autoimmune diseases’, poster presentation at MSPARIS2017: The 7th Joint ECTRIMS-ACTRIMS Meeting, 25-28 October 2017, Paris, France.
  2. FDA.gov. ‘OCREVUSTM (ocrelizumab) injection Highlights of prescribing information’, http:// www.accessdata.fda.gov (accessed October 28, 2017).
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