Results from a Phase 3, Multicenter, Noninferiority Study of Ravulizumab (ALXN1210) versus Eculizumab (ECU) in Adult Patients (pts) with Paroxysmal Nocturnal Hemoglubinuria (PNH) Naive to Complement Inhibitors (CI)

Objective: This study compares the efficacy and safety of ALXN1210 vs ECU in adult CI-naive PNH pts (NCT02946463). ALXN1210, an innovative C5 inhibitor with high C5 affinity and a 3–4 times longer half-life than ECU, provides immediate, complete, and sustained C5 inhibition with extended dosing intervals.

Methods: In this Ph3, randomized, open-label, noninferiority, global, multicenter study, CI naive PNH pts with ≥1 PNH-related sign/symptom and LDH level ≥1.5xULN at screening were stratified by transfusion history and screening LDH level. Pts, randomized 1:1, received approved ECU dose through day (D) 183 (primary evaluation period) or weight-based ALXN1210 (D1/D15; q8w thereafter). Primary efficacy endpoints were:

• Transfusion avoidance (proportion of transfusion-free pts); noninferior if lower 95% CI bound for the difference between ALXN1210 vs ECU was >-20%

• LDH normalization from D29–183; noninferior if lower 95% CI bound for odds ratio between ALXN1210 vs ECU was >0.39

Key secondary endpoints were:

• % change in LDH from baseline (BL)

• Change in FACIT-Fatigue score from BL

• % pts with breakthrough hemolysis

• % pts with stabilized hemoglobin

Pharmacodynamic effects were measured by free C5.

Results: Of 285 pts screened, 246 were randomized. 125 ALXN1210 and 119 ECU pts completed 26 wks of treatment. ALXN1210 met the primary objective of statistically significant noninferiority vs ECU on co-primary endpoints and key secondary endpoints, with point-estimates favoring ALXN1210 over ECU for all 6 endpoints ([Fig. 1A]-[C]). ALXN1210 achieved immediate, complete, and sustained C5 inhibition (mean free C5 < 0.5µg/mL)([Fig. 1D]). The most frequent treatment-emergent adverse event (AE) was headache (36.0/33.1%; ALXN1210/ECU). Serious AEs were experienced by 8.8/7.4% (ALXN1210/ECU) of pts. Major adverse vascular events occurred in 2 ALXN1210 and 1 ECU pts. There were no meningococcal infections.

Conclusions: Q8w ALXN1210 achieved statistically significant noninferiority to q2w ECU on all primary and key secondary endpoints with an efficacy profile consistent with immediate, complete, and sustained inhibition of C5. Safety was similar in both groups.

Fig. 1

No conflict of interest has been declared by the author(s).