LAUSR

Background/Objective: In 2 large, phase 3 clinical studies, ravulizumab (ALXN1210), an innovative C5 inhibitor administered every 8 weeks, achieved noninferiority to eculizumab in complement inhibitor-naive and -experienced patients (pts) with paroxysmal nocturnal hemoglobinuria (PNH). The objective of this analysis was to characterize ravulizumab pharmacokinetics (PK) and pharmacodynamics (PD). Potential PD differences between ravulizumab and eculizumab were also examined to explore a possible mechanistic explanation for the robust clinical results observed in the phase 3 studies. The consistent ravulizumab vs eculizumab results across all primary and secondary clinical endpoints may be attributable to more complete inhibition of free C5 (defined as serum free C5 level <0.5 μg/mL, which is associated with complete inhibition of hemolysis in vitro). Methods: Two phase 3, randomized, open-label, noninferiority studies (NCT02946463, study 301; NCT030560040, study 302) included pts ≥18 years of age with confirmed PNH. Pts in study 301 were complement inhibitor-naive, with lactate dehydrogenase (LDH) levels ≥1.5 times upper limit of normal (xULN), and ≥1 PNH-related sign/symptom at screening. Pts in study 302 were clinically stable after having been treated with eculizumab for ≥6 months, with LDH levels ≤1.5 xULN at screening. Pts received weight-based dosing regimens of ravulizumab q8w or eculizumab 900 mg q2w in accordance with PNH labeling for 183 days. Study protocols did not allow dose escalation. Coprimary efficacy endpoints in study 301 were transfusion avoidance and LDH normalization; the primary endpoint in study 302 was percent change from baseline in LDH. Serum samples for PK/PD analyses were collected on study days 1, 8, 15, 22, 29, 43, 57, 71, 85, 99, 113, 127, 141, 155, 169, and 183. PK/PD outcomes included serum drug concentrations as well as serum free complement protein C5 and total C5. Free C5 was quantified in ravulizumab-treated pts utilizing a Gyros-based fluorescence assay, and in eculizumab-treated pts using an electrochemiluminescence ligand binding assay. Noncompartmental PK parameters were assessed for ravulizumab. Results: In study 301, 246 pts received study drug (ravulizumab, n=125; eculizumab, n=121); 195 received study drug in study 302 (ravulizumab, n=97; eculizumab, n=98). Ravulizumab met the primary objective of statistically significant noninferiority compared with eculizumab for all primary and key secondary endpoints in both studies. The PK profile of ravulizumab was similar in both studies (and when stratified by weight-based dosing [data not shown]), with Tmax of approximately 2.5 hours (Table 1). Following population PK modeling, mean (SD) post hoc terminal elimination half-life in all 222 pts was 49.7 (8.9) days. Ravulizumab steady-state therapeutic concentrations were rapidly achieved following the first dose and were sustained throughout the 183-day treatment period in both studies. Complete suppression of free C5 was attained by the end of first ravulizumab infusion (mean serum free C5 concentrations <0.5 μg/mL) and was sustained throughout the entire 183-day treatment period for all pts at all time points in both studies. In contrast, mean free C5 concentrations did not consistently remain <0.5 μg/mL with eculizumab in either study (Panels 1 and 2). In studies 301 and 302, 15 (12.4%) and 7 (7.1%) eculizumab-treated pts experienced ≥1 individual postbaseline serum free C5 level ≥0.5 μg/mL over the 183-day treatment period. In study 301, total mean (SD) C5 levels increased in the ravulizumab and eculizumab groups from 104 (24.4) and 106 (26.3) μg/mL at baseline to 183 (36.5) and 196 (38.5) respectively, at day 183. In study 302, total mean (SD) C5 levels were elevated in the ravulizumab and eculizumab groups at baseline (203 [29.5]) and 207 [37.3] μg/mL) and remained elevated at day 183 (197 [29.3] and 227 [40.2] μg/mL). Conclusions: In 2 large, phase 3 studies of PNH pts who were either naive to or receiving prior complement inhibitor therapy, ravulizumab q8w led to immediate, complete, and sustained complement C5 inhibition in all pts, whereas the effect of eculizumab q2w was less consistent. In pts treated with ravulizumab, free C5 suppression below the free C5 threshold was associated with complete inhibition of intravascular hemolysis, providing a mechanistic basis for the consistency of the point estimates for all endpoints. Ortiz: Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Risitano:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Ra Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Pfizer Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amyndas Pharmaceuticals: Consultancy. Hillmen:Celgene: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion Pharmaceuticals, Inc: Consultancy, Honoraria; Acerta: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding. Kulagin:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Pradhan:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Rottinghaus:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Aguzzi:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Wells:Alexion Pharmaceuticals, Inc.: Honoraria, Other: Travel Support , Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria. Szer:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support , Research Funding.