S864 A PHASE 2 OPEN-LABEL PROOF OF CONCEPT STUDY OF THE ORAL, SMALL MOLECULE FACTOR D INHIBITOR, ACH-4471, IN UNTREATED PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH)
Authors: P. Browett, A. Kulasekararaj, J.W. Lee, R. Notaro, R. Brodsky, M. Huang, M. Geffner, A. Risitano
Journal: HemaSphere (2019)

Background: Ravulizumab, a novel C5 complement inhibitor, was approved by FDA for treating paroxysmal nocturnal hemoglobinuria (PNH) and is under review in EMEA and Japan. In the largest phase 3 study in complement inhibitor-naive PNH patients (pts) conducted to date, qw8 ravulizumab was noninferior to qw2 eculizumab for all primary and secondary endpoints after 26 wks. To evaluate long-term efficacy and safety, all pts had the option of continuing to receive ravulizumab in an extension study. Aims: To characterize the durability of efficacy responses to ravulizumab through 52 wks and to evaluate the efficacy profile of ravulizumab after switching from eculizumab in adult PNH pts naive to eculizumab therapy (NCT02946463). Methods: This phase 3, randomized, active-controlled, open-label study was conducted in 123 centers in 25 countries. Pts were randomly assigned to receive eculizumab (n = 121) or ravulizumab (n = 125) for 26 wks, after which pts in the ravulizumab arm continued ravulizumab maintenance therapy (R-R arm), while pts in the eculizumab arm were then switched to ravulizumab (E-R arm). Results of the co-primary [lactate dehydrogenase normalization (LDH-N), transfusion avoidance] and key secondary endpoints [breakthrough hemolysis (BTH) and LDH levels] are provided descriptively. Plasma free C5 levels were obtained through 52 wks. Results: During the first 26 wks, 74% of pts in the R-R arm avoided transfusion, compared to 77% avoiding transfusion in wks 27–52. More than 90% (n = 83) of pts who avoided transfusion during the initial 26 wk period maintained this response through 52 wks, and 38% (n = 12) who required transfusion in the 0–26 wk period avoided it in wks 27–52. In the E-R arm, 66% (26 wks) vs 67% (52 wks) avoided transfusion; 87% (n = 69) who avoided transfusion for 26 wks maintained this response through 52 wks. Additionally, 28% (n = 11) who required transfusion during the 26 wks while on eculizumab avoided it through 52 wks once switched to ravulizumab. In the R-R arm, LDH-N occurred in 48% of pts (n = 60) at 26 wks and in 44% of pts (n = 54) at 52 wks. Similarly, in the E-R arm, at 26 wks, LDH-N was 42%, and was 40% at 52 wks. At the end of 26 wks, pts on ravulizumab had a 77% (SEM = 1.4) mean reduction in LDH from baseline and this was maintained through 52 wks (77%, SEM = 1.2). All pts (n = 119) in the ravulizumab treatment group continued to maintain free C5 <0.5 μg/mL at all time points through 52 wks (Figure). In pts initially randomized to eculizumab, the switch to ravulizumab showed improved free C5 control, and no patients had free C5 >0.5 μg/ml after the switch. Of the 125 pts initially on ravulizumab, 5 pts (4%) had BTH in the first 26 wks vs 4 pts (3%) during wks 27–52. In the E-R arm, 13 pts (11%) experienced BTH during the first 26 wks vs 2 pts (2%) in wks 27–52 after the switch to ravulizumab. During wks 27–52, none of the BTH events in both arms were associated with free C5 >0.5 μg/ml, the threshold associated with complete inhibition of hemolysis. These results demonstrate maintenance of complete free C5 control in pts receiving ravulizumab. Ravulizumab was well tolerated and the most common treatment-related adverse events decreased in frequency with increased treatment duration.Summary/Conclusion: Ravulizumab demonstrated consistent and durable efficacy over 52 wks of treatment. Importantly, all pts who had suboptimal free C5 control receiving eculizumab achieved complete free C5 inhibition after the switch to ravulizumab. Complete suppression of free C5 level was associated with a decreased incidence of BTH.