On 21 December 2018, the US Food and Drug Administration (FDA) approved ravulizumab-cwvz (ULTOMIRIS™, Alexion Pharmaceuticals, Inc.) for adult patients with paroxysmal nocturnal haemoglobinuria (PNH).
Approval was based on two open-label, randomised, active-controlled, non-inferiority phase III 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 haemolysis. 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 randomised to receive either ravulizumab-cwvz or eculizumab. Patients randomised to ravulizumab-cwvz received a loading dose followed by maintenance dosing every 8 weeks. Patients randomised 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 haemolysis as directly measured by normalisation 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 normalisation 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 haemolysis and proportion of patients with stabilised haemoglobin levels. Non-inferiority of ravulizumab-cwvz to eculizumab was demonstrated across the endpoints.
In Study 302, efficacy was established based on haemolysis 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 stabilised haemoglobin and proportion of patients with breakthrough haemolysis. 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.
Full prescribing information is available here.
FDA granted this application priority review and orphan product designation.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System.