A phase 3 study of ravulizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH) showed noninferiority compared to eculizumab, however the primary endpoint was not statistically significantly superior.
The data was presented at the 60th Annual Meeting of the American Society of Hematology
in San Diego, CA.
Ravulizumab, formerly called ALXN1210, is a complement C5 inhibitor. In this study, ravulizumab was given every 8 weeks (q8w) after a loading dose and compared to eculizumab given every 2 weeks (q2w). All patients were naïve to complement inhibitor therapy and clinically stable with eculizumab therapy.
“The primary objective of this study was to assess the noninferiority of ravulizumab compared to eculizumab in adult PNH [patients] who were clinically stable after having been treated with eculizumab for at least 6 months,” wrote abstract authors led by Austin G. Kulasekararaj, MBBS, MD, MRCP, FRCPath, Department of Haematological Medicine, King’s College Hospital, London, United Kingdom.
The open-label study screened 208 patients and randomized 197 patients to the 2 study arms. Of those, 195 participants received ravulizumab (n = 97) or eculizumab (n = 98) and 191 completed 183 days of treatment. Demographics and baseline clinical characteristics were similar between the 2 treatment groups.
Patients had previously received eculizumab for an average of 5.8 years. Additionally, all patients had received a vaccination against N. meningitidis
In the primary endpoint, percentage change in lactate dehydrogenase (LDH) levels, ravulizumab was statistically significantly noninferior to eculizumab (difference of –9.21%; 95% CI: –18.84 - .42]). Results were considered noninferior if the upper bound of the 95% confidence interval for the primary endpoint was <15%.
Ravulizumab was also statistically significantly noninferior to eculizumab for all key secondary endpoints: breakthrough hemolysis (difference of -5.1; 95% CI, -18.89 - 8.89), change in Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue score (difference of 1.47; -.21 - 3.15), transfusion avoidance (difference of 5.5; 95% CI, -4.27 - 15.68), and hemoglobin stabilization (difference of 1.4; -10.41 - 13.31).
“[Patients] can be safely and effectively switched from eculizumab given q2w to ravulizumab given q8w,” wrote the investigators.
The most common adverse event in the trial was headache, which occurred in 26.8% versus 17.3% of patients for ravulizumab and eculizumab, respectively. There were no meningococcal infections or discontinuations due to adverse events.
Ravulizumab is currently under Priority Review by the US Food and Drug Administration
(FDA) with a Prescription Drug User Fee Act (PDUFA) date of February 18, 2019. If approved, ravulizumab will be the first long-acting complement inhibitor for patients with paroxysmal nocturnal hemoglobinuria, an ultra-rare disease.
A previous phase 3 study of ravulizumab compared to eculizumab
also demonstrated noninferiority in the co-primary endpoints of transfusion avoidance and normalization of LDH levels.
The abstract, “Results from a Phase 3, Multicenter, Non-Inferiority Study of Ravulizumab (ALXN1210) Versus Eculizumab in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria Currently Treated with Eculizumab
,” was presented at the American Society of Hematology Annual Meeting in December 2018.