Ravulizumab in Pregnant Women with Paroxysmal Nocturnal Hemoglobinuria (PNH) - Favourable Experience from a Retrospective Case Series

Background:

The terminal complement component 5 inhibitor (C5i) eculizumab (Ecu) is the standard of care (SoC) for pregnant PNH patients (pts). As the C5i ravulizumab (Ravu) is increasingly used as SoC for PNH treatment and family planning is important for the quality of life and social participation of PNH pts., the question arises whether treatment with Ravu during pregnancy is safe and efficacious. The Summary of Product Characteristics (SPC) and the US Prescribing Information (USPI) indicate that there are no clinical data and non-clinical reproductive toxicology studies for the use of ravulizumab in pregnant women. The recommendation is therefore that treatment with ravulizumabin women of childbearing age should only be considered in combination with effective contraceptive methods and in pregnant pts. only after an individual risk-benefit assessment. It is important to report real-world data.

Methods:

This retrospective case series includes 12 pregnancies in 5 women with PNH and C5i exposure during pregnancy. 4/5 of the pts. had at least one pregnancy with Ecu exposure (“Ecu pregnancies”) and at least one with Ravu exposure (“Ravu pregnancies”), allowing for intraindividual comparison. Of the 4 pts. with Ecu exposure, 2 pts. had 2 pregnancies and 2 had one pregnancy. Of the 5 pts. with Ravu exposure during pregnancy, one had 2 pregnancies and 4 had one pregnancy, thus a total of 6 Ecu and 6 Ravu pregnancies were retrospectively analyzed.

Results:

In the 6 Ecu pregnancies, two miscarriages occurred in the 7^th and 8^th week (wk) of pregnancy. One pregnancy was terminated at 25 wks' gestation due to persistent intravascular hemolysis, massive fetal growth retardation and dopplersonographic evidence of inadequate fetal blood supply. The child was not viable (birth weight 310 g). Three surviving children were delivered in wk 30, 34 and 41 (birth weights 1930 g, 2576 g and 3650 g). They showed no constitutional anomalies and survived without developmental delay with a follow-up period of 35, 49 and 73 months (mo).

The median age of the pts. at the onset of the Ravu pregnancies was 35 years (min. 31 - max. 37). In all cases, Ravu had been started prior to pregnancy. The median interval from start of Ravu to pregnancy was 15 mo. Six healthy, surviving children were born from the 6 Ravu pregnancies. One child was delivered prematurely at 35 wks, the others were born between 38 and 42 wks. (median birth weight 2710 g (min. 2120, max. 3350) Four women were breastfeeding after the Ravu pregnancies. During a median follow-up period of 13 mo (min. 6, max. 36), no developmental or constitutional abnormalities were detected in any of the 6 children born from Ravu pregnancies. Escalation of C5i inhibition (dose increase or shortening of the interval or both) was required in 3/6 Ecu pregnancies and 3/6 Ravu pregnancies. Regardless of C5i type, prophylactic heparin was routinely administered once pregnancy was detected.

All treatment decisions were made after intensive patient counseling about the risk of maternal and fetal PNH complications, the available evidence on Ecu during pregnancy, and the lack of experience with Ravu exposure during pregnancy. These women began pregnancy while receiving Ravu as standard treatment and strongly preferred to continue treatment with Ravu, especially pts. with complications during previous Ecu pregnancies. The continuation of treatment with Ravu was supported by the observation that control of hemolysis was maintained with Ravu despite the occurrence of pregnancy as a new complement-activating condition. The pregnancies were closely monitored.

Conclusion:

This is the first report of a series of 5 PNH pts. with Ravu exposure throughout 6 pregnancies. All but one of the pts. in our series had previous ecu pregnancies. The limited number of pts. and the retrospective nature of this analysis do not allow a formal comparison of the outcomes of Ecu and Ravu pregnancies. However, it is noteworthy that 6/6 Ravu pregnancies resulted in the birth of healthy children with normal development to date. In particular, in the two women with two miscarriages and premature termination with subsequent death during 3 previous Ecu pregnancies, the Ravu pregnancies went without complications. Like Ecu, Ravu may be safe in pregnancy and should at least be considered as an option for women with previous pregnancy complications during treatment with Ecu. Gathering more information on Ravu pregnancies is urgently needed.

Hoechsmann:Novartis: Honoraria; Sobi: Honoraria; Roche: Honoraria; Omeros: Honoraria; Pfizer: Honoraria; Alexion: Honoraria. Leopold:Novartis Pharma: Honoraria, Research Funding; Alexion Pharma: Research Funding; Roche Pharma: Research Funding; Sobi GmbH: Research Funding; Ispen Pharma: Research Funding; Astra Zeneca: Honoraria; Servier Deutschland GmbH: Honoraria; Janssen-Cilag GmbH: Honoraria. Koerper:Alexion: Honoraria. Schrezenmeier:Alexion, AstraZeneca Rare Disease: Other: Fees and travel support, Research Funding; Novartis: Other: Fees and travel support, Research Funding; Sobi: Other: Fees and travel support, Research Funding; Amgen: Other: Fees; Apellis: Other: Fees; F. Hoffmann-La Roche: Other: Fees; Omeros: Other: Fees; Sanofi: Other: Fees.