Efficacy and safety of the long-acting C5 inhibitor ravulizumab in patients with atypical hemolytic uremic syndrome triggered by pregnancy: a subgroup analysis

Abstract

Background: Atypical hemolytic uremic syndrome (aHUS) triggered by pregnancy is a rare disease caused by dysregulation of the alternative complement pathway that occurs in approximately 1 in 25,000 pregnancies. The 311 phase 3 trial (NCT02949128) showed that ravulizumab, a long-acting C5 inhibitor obtained through selective modifications to eculizumab, is efficacious in inhibiting complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS. In this analysis, we report outcomes in a subgroup of patients from the 311 study who developed TMA postpartum.

Methods: This was a phase 3, multicenter trial evaluating efficacy and safety of ravulizumab in adults (≥18 years of age) with aHUS naïve to complement inhibitor treatment. The primary endpoint was complete TMA response (simultaneous platelet count normalization [≥150 × 109/L], lactate dehydrogenase normalization [≤246 U/L] and 25% improvement in serum creatinine) through the 183-day initial evaluation period. Additional efficacy endpoints included time to complete TMA response, hematologic normalization, and dialysis requirement status.

Results: Eight patients presenting with TMA postpartum (median age of 37.7 [range; 22.1-45.2] years) were diagnosed with aHUS and received ≥1 dose of ravulizumab. Five patients (63%) were on dialysis at baseline. Complete TMA response was achieved in 7/8 patients (87.5%) in a median time of 31.5 days. Hematologic normalization was observed in all patients. All patients on dialysis at baseline discontinued dialysis within 21 days after treatment with ravulizumab. All patients showed continued improvements in the estimated glomerular filtration rate from baseline to Day 183. Three possible treatment-related adverse events were observed in 2 patients (arthralgia and nasopharyngitis [both non-severe]; urinary tract infection). No deaths or meningococcal infections occurred.

Conclusions: Treatment with ravulizumab provided immediate and complete C5 inhibition, resulting in rapid clinical and laboratory improvements and complete TMA response through 183 days in patients with aHUS triggered by pregnancy. The safety profile observed in this subset of patients analysed is consistent with the 311 study investigating ravulizumab in patients with aHUS naïve to complement treatment.

Trial registration: Clinical trial identifier: NCT02949128 .

Keywords: Atypical hemolytic uremic syndrome; Pregnancy microangiopathies; Ravulizumab; Thrombotic microangiopathy.

Conflict of interest statement

Anja Gäckler: Honoraria and lecture fees from Alexion, Ablynx/Sanofi and Novartis.

Ulf Schönermarck: study fees, travel support and consultancy fees from Alexion, and study fees and consultancy fees from Ablynx.

Vladimir Dobronravov: no disclosures.

Gaetano La Manna: no disclosures.

Andrew Denker: employee of Alexion at the time of the study and owns stock in the company.

Peng Liu: employee and shareholder of Alexion.

Maria Vinogradova: no disclosures.

Sung-Soo Yoon: no disclosures.

Manuel Praga: personal fees from Otsuka, grants and personal fees from Alexion, personal fees from Retrophin.

Figures

Fig. 1

Kaplan–Meier graph depicting time to complete TMA response. BL baseline, TMA thrombotic microangiopathy

Fig. 2

Observed platelet count value over time. Data are shown as mean (error bars, 95% confidence interval). BL baseline

Fig. 3

Observed lactate dehydrogenase values over time. Data are shown as mean (error bars, 95% confidence interval). BL baseline

Fig. 4

Observed eGFR values over time. Data are shown as mean (error bars, 95% confidence interval). BL baseline, eGFR estimated glomerular filtration rate