Ravulizumab-cwvz Was Approved by the FDA for Treating Paroxysmal Nocturnal Hemoglobinuria

On 21 December 2018, the US Food and Drug Administration (FDA), approved ravulizumab-cwvz (brand name Ultorimis, company Alexion) for adult patients with paroxysmal nocturnal hemoglobinuria (PNH).

What Is Paroxysmal Nocturnal Hemoglobinuria (PNH)? Symptoms and Treatment

Paroxysmal nocturnal hemoglobinuria (PNH), manifests with signs of hemolysis (breakdown of red blood cells called erythrocytes), bone marrow failure and thrombosis (clots), and is a blood stem cell disease. A PIG-A gene mutationis responsible for the disease developing. Patients without symptoms are monitored at regular intervals. In patients with hemolysis and related complications, C5 complement inhibitor drugs have improved quality of life and made life expectancy similar to that of the general population. However, they are very costly and must be used for life. The need for them must therefore be determined very carefully. Allogeneic stem cell transplantation is the only curative treatment. However, because of the high risk of morbidity (illness) and mortality (death), it should be used in patients with bone marrow failure, malignant transformation or no response to complement inhibitors.

Clinical Trials That Brought FDA Approval to Ravulizumab-cwvz

Approval was based on two open-label, randomized, active-controlled phase 3 clinical trials. These studies were non-inferiority studies. The clinical trials were named ALXN1210-PNH-301 and ALXN1210-PNH-302. In a non-inferiority study, the newly tested drug is evaluated to determine whether it is as effective as the standard treatment for the disease.

Studies 301 and 302

Study 301 included 246 patients with paroxysmal nocturnal hemoglobinuria (PNH) who had not previously received a complement inhibitor drug and were experiencing active hemolysis.

Study 302 enrolled patients treated for at least 6 months with eculizumab (brand name Soliris), totaling 195 clinically stable patients with PNH. In both studies, patients were randomly assigned to two arms to receive ravulizumab-cwvz or eculizumab. Patients receiving ravulizumab-cwvz received a loading dose followed by a maintenance dose 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 thereafter.

Study Results

In study 301, drug efficacywas determined based on transfusion avoidance, an indicator of reduced hemolysis directly measured through normalization of LDH levels. Transfusion avoidance was defined as patients not receiving a transfusion through day 183. Transfusion avoidanceoccurred in patients receiving ravulizmab-cwvz and eculizumab, respectively, at % 73.6and % 66.1. LDH normalization occurred in % 53.6 and % 49.4, respectively (again favoring ravulizmab-cwvz). This study thus showed that ravulizumab-cwvz was at least as effective as eculizumab.

In study 302, drug efficacywas determined as hemolysis measured by the percentage change in LDH from baseline through day 183. In patients receiving ravulizmab-cwvz and eculizumab, the percentage change in LDH was % -0.82 and % 8.4, respectively. Supporting efficacy data were transfusion avoidance, the proportion of patients with stable hemoglobin and the proportion with hemolysis. Ravulizumab-cwvz was shown to be non-inferior in efficacy to eculizumab across all endpoints.

Among patients receiving ravulizumab-cwvz, in at least % 10, the most common adverse effectswere upper respiratory tract infection and headache.

The recommended ravulizumab-cwvz doseconsists of a loading dose followed by maintenance every 8 weeks, administered by intravenous (into a vein) infusion according to the patient's body weight.