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December 21, 2018

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761108s000lbl.pdf

Approval was based on two open-label, randomized, active-controlled, non-inferiority phase 3 studies: ALXN1210-PNH-301 (NCT02946463) and ALXN1210-PNH-302 (NCT03056040). Study 301 enrolled 246 patients with PNH who were complement inhibitor naïve and had active hemolysis. Study 302 enrolled 195 patients with PNH who were clinically stable after having been treated with eculizumab for at least the past 6 months. In both trials, patients were randomized to receive either ravulizumab-cwvz or eculizumab. Patients randomized to ravulizumab-cwvz received a loading dose followed by maintenance dosing every 8 weeks. Patients randomized to eculizumab received a dose on Days 1, 8, 15, and 22, followed by maintenance treatment on Day 29 and every 2 weeks.

In Study 301, efficacy was established based upon transfusion avoidance and reduction of hemolysis as directly measured by normalization of LDH levels. Transfusion avoidance was defined as patients who did not receive a transfusion and did not meet the protocol specified guidelines for transfusion from baseline up to Day 183. Transfusion avoidance was seen in 73.6% and 66.1% of patients who received ravulizmab-cwvz and eculizumab, respectively (rate difference 6.8; 95% CI: -4.66, 18.14) and LDH normalization was seen in 53.6% and 49.4% of patients who received ravulizumab-cwvz and eculizumab, respectively (odds ratio 1.19; 95% CI: 0.80. 1.77). Supportive efficacy data included LDH percent change, breakthrough hemolysis and proportion of patients with stabilized hemoglobin levels. Non-inferiority of ravulizumab-cwvz to eculizumab was demonstrated across the endpoints.

In Study 302, efficacy was established based on hemolysis as measured by LDH percent change from baseline to Day 183. LDH percent change was -0.82% and 8.4% for patients who received ravulizmab-cwvz and eculizumab, respectively (rate difference 9.2; 95% CI: -0.42, 18.8). Supportive efficacy data included transfusion avoidance, proportion of patients with stabilized hemoglobin and proportion of patients with breakthrough hemolysis. Non-inferiority of ravulizumab-cwvz to eculizumab was demonstrated across all endpoints.

The most frequent adverse reactions in at least 10% of patients taking ravulizumab-cwvz were upper respiratory infection and headache.

The recommended ravulizumab-cwvz dosing regimen consists of a loading dose followed by maintenance dosing every 8 weeks, administered by intravenous infusion, based on the patient’s body weight. View full prescribing information for details.

FDA granted this application priority review and orphan product designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

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