Maternal and fetal pharmacokinetics (PK) of pegcetacoplan in paroxysmal nocturnal hemoglobinuria (PNH): A case report of use in pregnancy

Abstract Background: PNH is a rare, life-threatening hematologic disorder that poses significant risks in pregnancy. Pegcetacoplan, a first-in-class C3 inhibitor, has superior efficacy in patients with persistent anemia on eculizumab but data in pregnancy are limited. We report the first case of pegcetacoplan use in pregnancy with accompanying PK data on placental and breast milk transfer, offering novel insights into the safety and feasibility of use of pegcetacoplan in pregnancy. Methods A 24-year-old woman was diagnosed with hemolytic PNH (95% PNH neutrophil clone) 5 years prior to her first pregnancy. She experienced transfusion-dependent anemia despite eculizumab. After trials of vemircopan and iptacopan, she was transitioned to pegcetacoplan 1080 mg subcutaneous 2x/week and achieved transfusion independence (hemoglobin ~110 g/L). Unplanned pregnancy occurred while on pegcetacoplan. Given lack of safety data, she was switched to eculizumab at 4 weeks gestational age (GA). Despite increased eculizumab dosing, she redeveloped transfusion-dependent anemia (2-3 units RBC/month) due to extravascular hemolysis (EVH). Following multidisciplinary consultation and shared decision-making, pegcetacoplan was reinitiated at 28 weeks GA. Maternal hematologic parameters and complement levels/activity were monitored throughout pregnancy and postpartum. PK sampling assessed drug transfer via maternal plasma pre- and post-delivery, cord blood, and breast milk. Quantitative analysis of pegcetacoplan concentrations was performed using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Results Following reinitiation of pegcetacoplan at 28 weeks GA, the patient had rapid hematologic improvement and achieved transfusion independence (hemoglobin 92-103 g/L in third trimester) with control of EVH. At 33 weeks GA, the decision was made to preventatively increase the dose of pegcetacoplan to 1080 mg 3x/week to mitigate risk of peripartum breakthrough hemolysis (BTH). Pregnancy was complicated by maternal obesity, gestational diabetes, and fetal growth above the 95th percentile. The patient elected to undergo a scheduled caesarean delivery at 37 weeks GA. She had an uncomplicated caesarean section and delivered a healthy male infant (weight 3.74 kg) with normal Apgar scores. Daily pegcetacoplan 1080 mg was administered on postpartum days (PPD) 0-3 to prevent BTH. Postpartum course was uncomplicated, with no BTH or thrombosis. Pegcetacoplan 1080 mg 3x/week was continued for 6 weeks postpartum, before returning to 2x/week regimen. The patient initially breastfed during the birth hospitalization but elected not to continue after discharge. The infant has demonstrated normal growth and development, with no complications observed at 6-month follow-up. Maternal plasma concentrations of pegcetacoplan remained within the expected therapeutic range, consistently near or exceeding the effective concentration for maximum hemoglobin response (EC99 = 597 μg/mL) on the day of delivery and across PPD 1-3. Pegcetacoplan was undetectable in all three cord blood samples (<10 μg/mL). Similarly, pegcetacoplan was not detected in breast milk, with concentrations below the lower limit of quantification (<20 μg/mL). Discussion This case provides the first PK data on pegcetacoplan use in pregnancy, demonstrating undetectable fetal/neonatal exposure despite sustained maternal drug levels in therapeutic range. These findings are consistent with preclinical non-human animal data and pegcetacoplan's physicochemical properties—a large, pegylated, and hydrophilic cyclic peptide, expected to have limited membrane permeability. In a patient with hemolytic PNH and inadequate hematologic response to eculizumab, conception on pegcetacoplan was not associated with adverse fetal/pregnancy outcomes, and third-trimester reinitiation resulted in rapid hematologic improvement, transfusion independence, and an uncomplicated peripartum course. In conclusion, this report provides the first clinical and PK evidence suggesting that third-trimester use of pegcetacoplan may be a viable treatment option in select pregnant patients with PNH with suboptimal response to C5 inhibitors. Limitations include the single-patient nature of this report and only 6 months of pediatric follow-up. Validation in larger cohorts is essential to support this use of pegcetacoplan and address the unmet need for expanded treatment options for PNH in pregnancy.

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