One-year efficacy and safety of ravulizumab in adults with paroxysmal nocturnal hemoglobinuria naïve to complement inhibitor therapy: open-label extension of a randomized study

Abstract

Background: Ravulizumab, the only long-acting complement C5 inhibitor for adults with paroxysmal nocturnal hemoglobinuria (PNH), demonstrated non-inferiority to eculizumab after 26 weeks of treatment in complement inhibitor-naïve patients during a phase III randomized controlled trial. We present open-label extension results with up to 52 weeks of treatment.

Methods: Patients assigned to ravulizumab every 8 weeks (q8w) or eculizumab every 2 weeks during the randomized primary evaluation period received ravulizumab q8w during the 26-week extension. Efficacy endpoints were lactate dehydrogenase (LDH) normalization, transfusion avoidance, breakthrough hemolysis (BTH), LDH levels, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, and stabilized hemoglobin. Serum free C5 levels and safety were assessed. Outcomes as of the data cut-off (4 September 2018) were summarized using descriptive statistics.

Results: Overall, 124 patients continued ravulizumab, and 119 switched from eculizumab to ravulizumab. During the extension, 43.5% and 40.3% of patients in the ravulizumab-ravulizumab and eculizumab-ravulizumab arms, respectively, achieved LDH normalization; 76.6% and 67.2% avoided transfusion. BTH decreased in the eculizumab-ravulizumab arm; no events were associated with free C5 ⩾0.5 μg/mL while receiving ravulizumab. Overall, 73.4% and 65.5% of patients in the ravulizumab-ravulizumab and eculizumab-ravulizumab arms, respectively, achieved stabilized hemoglobin. Similar proportions of patients achieved ⩾3-point improvement in FACIT-Fatigue at week 52 (ravulizumab-ravulizumab, 64.5%; eculizumab-ravulizumab, 57.1%). All patients maintained free C5 <0.5 μg/mL during the ravulizumab extension, including those who experienced C5 excursions ⩾0.5 μg/mL while receiving eculizumab during the primary evaluation period. Adverse events were comparable between groups and decreased over time.

Conclusion: In adult, complement inhibitor-naïve patients with PNH, ravulizumab q8w for up to 52 weeks demonstrated durable efficacy and was well tolerated, with complete and sustained free C5 inhibition and a decreased incidence of BTH with no events associated with loss of free C5 control.

Trial registration: ClinicalTrials.gov identifier, NCT02946463.

Keywords: breakthrough hemolysis; complement inhibitor; eculizumab; high disease activity; lactate dehydrogenase; paroxysmal nocturnal hemoglobinuria; ravulizumab; transfusion.

Conflict of interest statement

Conflict of interest statement: Hubert Schrezenmeier: Honoraria and grants (to the University Hospital of Ulm) from Alexion Pharmaceuticals, Inc.; grants (to the University Hospital of Ulm) from Apellis, Ra Pharmaceuticals, and Sanofi; grants and other support (to the University Hospital of Ulm) from Roche; patent pending (PCT/EP2017/065979). Austin Kulasekararaj: Travel grants from Achillion, Alexion Pharmaceuticals, Inc., Celgene, and Ra Pharmaceuticals; advisory board fees (honoraria) from Alexion Pharmaceuticals, Inc., Celgene, Novartis, Ra Pharmaceuticals, and Regeneron. Lindsay Mitchell: Honoraria from Alexion Pharmaceuticals, Inc. Flore Sicre de Fontbrune: Honoraria and grants (to St. Louis Hospital) from Alexion Pharmaceuticals, Inc. Timothy Devos: Consulting fees from Novartis, Alexion Pharmaceuticals, Inc., and Celgene. Shinichiro Okamoto: Grants and personal fees from Alexion Pharmaceuticals, Inc., Astellas, Chugai, Daiichi Sankyo, JCR Pharma, Mochida, Novartis, Pfizer, and Takeda; grants from Asahi Kasei Pharma, Dainihon Sumitomo, Shionogi, and Teijin Pharma; and personal fees from Bristol-Meyers Squibb and Nihon Shinyaku. Richard Wells: Honoraria and consulting fees from Alexion Pharmaceuticals, Inc. Scott T. Rottinghaus: Employee and stockholder of Alexion Pharmaceuticals, Inc.; patent for “Dosage and administration of anti-c5 antibodies for treatment of paroxysmal nocturnal hemoglobinuria (pnh) and atypical hemolytic uremic syndrome (ahus).” Peng Liu, Stephan Ortiz: Employees and stockholders of Alexion Pharmaceuticals, Inc. Jong Wook Lee: Honoraria, consulting fees, and grants (to Seoul St. Mary’s Hospital) from Alexion Pharmaceuticals, Inc. Gérard Socié: Speaker fees and grants from, and a consultant for, Alexion Pharmaceuticals, Inc.

© The Author(s), 2020.

Figures

Figure 1.

Patient disposition. *Patients may be counted in more than one category.

Figure 2.

Proportion of patients achieving LDH normalization during the primary evaluation (weeks 1–26) and extension (weeks 27–52) periods. *Number of patients may be lower than number enrolled at time point because of exclusion of samples having serum potassium ⩾6 mmol/L and LDH ⩾2× ULN, missing samples (because of site error or for any other reason), or patient discontinuations during the extension. †LDH levels were not measured for patients in the ravulizumab–ravulizumab group on days 197 and 225. BL, baseline; LDH, lactate dehydrogenase; ULN, upper limit of normal.

Figure 3.

Mean lactate dehydrogenase (LDH) levels during the primary evaluation (weeks 1–26) and extension (weeks 27–52) periods. Dashed horizontal line indicates 1× upper limit of normal (ULN), and the dotted horizontal line represents 1.5× ULN. *Number of patients may be lower than number enrolled at time point because of exclusion of samples having serum potassium ⩾6 mmol/L and LDH ⩾2× ULN, missing samples (because of site error or for any other reason), or patient discontinuations during the extension. †LDH levels were not measured for patients in the ravulizumab–ravulizumab group on days 197 and 225. BL, baseline.

Figure 4.

Mean (95% confidence interval) change from baseline to end of extension period in FACIT-Fatigue scale. FACIT scores range from 0 to 52, with a higher score indicating less fatigue. Dashed horizontal line indicates threshold that delineates clinically meaningful improvement (>3 points). BL, baseline; FACIT, Functional Assessment of Chronic Illness Therapy.

Figure 5.

Proportions of patients maintaining ⩾10-point improvement in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 Scale: (A) Global Health Status, (B) Physical Functioning, and (C) Fatigue subscales. BL, baseline.

Figure 6.

Free C5 levels through 52 weeks in patients in the (A) ravulizumab–ravulizumab arm and (B) eculizumab–ravulizumab arm. The horizontal line in the middle of each box indicates the median, and a diamond indicates the mean. The top and bottom borders of the box represent the 75th and 25th percentiles, respectively, and the whiskers represent the 1.5 interquartile range of the lower and upper quartile. Asterisks represent values outside the interquartile range. Dashed horizontal lines indicate serum free C5 concentration of 0.5 μg/mL. BL, baseline; EOI, end of infusion.