Pregnancy outcomes after crovalimab exposure: Analysis of animal model and clinical trial data suggest no adverse effects in paroxysmal nocturnal hemoglobinuria Free

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening, complement-mediated hematologic disorder. Pregnancy, often a complement-activating event, is associated with poor outcomes in patients with untreated PNH and other complement-mediated diseases.

Crovalimab (PiaSky®) is a next-generation C5 inhibitor with every-4-week subcutaneous maintenance dosing, with the possibility for self-administration by the patient or caregiver, after proper training. Crovalimab is indicated for the treatment of PNH and is currently being evaluated for the treatment of other complement-mediated diseases. Here we present data on the use of crovalimab during pregnancy, with the aim of characterizing pregnancy outcomes after crovalimab exposure, using both animal and clinical trial data.

As part of the non-clinical safety evaluation, an enhanced prenatal and postnatal development study assessed pregnant cynomolgus monkeys who were given an intravenous loading dose of 100 mg/kg crovalimab on Gestation Day 20 followed by weekly subcutaneous injections of up to 100 mg/kg until parturition. The dams and infants were observed untreated for 6 months. A cynomolgus monkey model was chosen for crovalimab toxicity assessment due to the high C5 sequence homology (95.9%) to human C5, leading to comparable complement binding affinity and inhibitory effects.

A retrospective review of pregnancies in patients treated with crovalimab in the Phase I–III clinical trial program for crovalimab was performed, including patients from the COMPOSER (NCT03157635), and COMMODORE 1 (NCT04432584), 2 (NCT04434092), and 3 (NCT04654468) trials (PNH), the COMMUTE-a (NCT04861259) and -p (NCT04958265) trials (atypical hemolytic uremic syndrome [aHUS]), and the CROSSWALK-a (NCT04912869) trial (sickle cell disease [SCD]).

In the cynomolgus monkey reproductive toxicity study, there were no adverse effects of crovalimab on pregnancy with doses up to 100 mg/kg. Additionally, there were no adverse effects on the viability, growth, and development of the infants. Exposures were up to 14 times the human exposure at the maximum recommended human dose, based on area under the concentration-time curve.

In the clinical trial program, there were eight pregnancies reported, which all occurred after patients started treatment with crovalimab; six in patients with PNH, one in a patient with aHUS, and one in a patient with SCD. Among these eight patients, three (all with PNH) provided consent to share data about the pregnancies.

One patient continued crovalimab throughout the pregnancy. The patient experienced a Grade 3 adverse event of pre-eclampsia at Gestational Week 31, deemed unrelated to crovalimab by the investigator. The patient gave birth by Cesarian section at Gestational Week 36; the infant was born with dysmaturity (1.96 kg at birth), which was deemed related to the mother's pre-eclampsia. The pre-eclampsia was considered resolved the same day. The infant was hospitalized for several days but was discharged after stabilizing. Crovalimab treatment was continued, with no change in treatment due to pre-eclampsia.

Elective abortions were performed for the other two pregnancies with data available, both within the first 2 months and with no reported adverse events related to crovalimab. Crovalimab treatment was continued in both cases.

Adverse outcomes, including hypertensive disorders such as pre-eclampsia, are common in complement-mediated diseases; therefore, pregnant patients being treated for such diseases should be monitored. Although data on crovalimab treatment during pregnancy are limited in patients with PNH, data from the reproductive toxicity study in pregnant animals and clinical trial data suggest no adverse effect of crovalimab treatment on pregnant mothers or fetuses, consistent with data from other C5 inhibitors. As untreated PNH in pregnancy is associated with adverse outcomes, continuation of crovalimab treatment in patients with PNH who become pregnant should be considered.