Ravulizumab (ALXN1210) in patients with paroxysmal nocturnal hemoglobinuria: results of 2 phase 1b/2 studies

Abstract

Ravulizumab (ALXN1210), a humanized monoclonal antibody to complement component C5, was engineered from eculizumab to have a substantially longer terminal half-life, permitting longer dosing intervals for paroxysmal nocturnal hemoglobinuria (PNH) treatment. Two phase 1b/2 multicenter open-label studies evaluated efficacy and safety of multiple doses and regimens of ravulizumab in PNH patients naive to complement-inhibitor treatment. Patients in study 103 (n = 13) received ravulizumab 900 mg (lower trough exposure) or 1800 mg every 4 weeks (higher trough exposure); those in study 201 (n = 26) received 1000 mg every 4, 1600 mg every 6, 2400 mg every 8, or 5400 mg every 12 weeks. Trough exposure levels with study 201 dosing regimens were similar to the study 103 900-mg every-4-weeks regimen. Rapid sustained reduction of plasma lactate dehydrogenase (LDH) occurred across all cohorts (73%-90% at end point vs baseline). A greater proportion of patients had normalized LDH (<234 U/L) at least once from days 29 to 253 in the higher- (85.7%) vs lower-trough-exposure (50.0%-83.3%) cohorts; the weighted average of the proportion of instances of LDH normalization from days 29 to 253 was highest in higher- vs lower-trough-exposure cohorts (62.3% vs 31.4%-54.5%). No patients in the higher-trough-exposure cohort, but 1 to 2 patients in all lower-trough-exposure cohorts, experienced breakthrough hemolysis. Ravulizumab improved quality of life (QoL) measures in all cohorts. Two patients experienced meningococcal infections; both recovered and continued in the study. In summary, ravulizumab provided rapid and sustained reduction in complement-mediated hemolysis and improved QoL at dosing intervals up to 12 weeks. This trial was registered at www.clinicaltrials.gov as #NCT02598583 (study 103) and NCT02605993 (study 201).

Conflict of interest statement

Conflict-of-interest disclosure: A.R. has received honoraria, consulting fees, and research support from Alexion Pharmaceuticals, Inc. S.T.R., R.A., A.I.D., and L.S. are employees and stockholders of Alexion Pharmaceuticals, Inc. E.S.B. was an employee of Alexion Pharmaceuticals, Inc. at the time of the study and is a stockholder in the company. A.H. has received honoraria and consulting fees from Alexion Pharmaceuticals, Inc. H.S. has received travel support, honoraria, and research support (to University of Ulm) from Alexion Pharmaceuticals, Inc. L.T. has received travel support from Alexion Pharmaceuticals, Inc. A.G.K. has received honoraria, travel support, and consulting fees from Alexion Pharmaceuticals, Inc. R.A.W. has received honoraria, research support, and travel support from Alexion Pharmaceuticals, Inc. J.S. has received research support (to Royal Melbourne Hospital), honoraria, consulting fees, and travel support from Alexion Pharmaceuticals, Inc. J.W.L. has received honoraria, travel support, and research support (to Seoul St. Mary’s Hospital) from Alexion Pharmaceuticals, Inc. The remaining authors declare no competing financial interests.

© 2018 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Overview of study designs. (A) Study 103. Patients in cohort 1a (n = 2) received ravulizumab 400 mg on days 1 and 8, 600 mg on day 15, and 900 mg administered every 28 days beginning on day 29 for a total of 5 maintenance doses. Patients in cohort 1b (n = 4) received ravulizumab 600 mg on days 1 and 15, and then 900 mg administered every 28 days beginning on day 29 for a total of 5 maintenance doses. Patients in cohort 2 (n = 7) received ravulizumab 600 mg on day 1, 900 mg on day 15, and then 1800 mg administered every 28 days beginning on day 29 for a total of 5 maintenance doses. After receiving 5 maintenance doses, each cohort entered a 2-year extension period at the same dosage and frequency as during the maintenance period. *Enrollment into cohort 1b began after the first two 400-mg doses were confirmed safe and tolerable in the first 2 patients. **Enrollment into cohort 2 began 14 days after the first maintenance dose of 900 mg was administered to the second patient in cohort 1a and a data monitoring committee reviewed cumulative safety and tolerability data and confirmed no identified safety risks. (B) Study 201. Patients in cohort 1 (n = 6) received ravulizumab1400 mg on day 1, 1000 mg on day 15, and then 1000 mg administered every 28 days beginning on day 29 for a total of 8 maintenance doses. Patients in cohort 2 (n = 6) received ravulizumab 2000 mg on day 1, 1600 mg on day 22, and then 1600 mg every 42 days beginning on day 43 for a total of 5 maintenance doses. Patients in cohort 3 (n = 7) received ravulizumab 1600 mg on days 1 and 15, and then 2400 mg every 56 days beginning on day 29 for a total of 4 maintenance doses. Patients in cohort 4 (n = 7) received ravulizumab 3000 mg on day 1, and then 5400 mg every 84 days for a total of 3 maintenance doses. After the treatment period, each cohort entered a 2-year extension period at the same dosage and frequency that was received during the treatment period. D, day; q8w, every 8 weeks; wks, weeks.

Figure 2.

Influence of dosing time interval and dose by cohort. (A-B) Study 103. LDH over time by patient. Dotted lines delineate the following LDH categories: normal, 53 to <234; 1× to 1.5× ULN, 234 to 351; >1.5× to 2× ULN, 352 to 468; >2× ULN, > 469. (C) Study 201. Mean (95% confidence interval) LDH over time. Doses shown for each cohort are maintenance doses. Green arrows represent the primary efficacy end point.