Safety and Efficacy of the Terminal Complement Inhibitor Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria: Interim Shepherd Phase III Clinical Study.
Authors: Young Neal S. , Antonioli Elisabetta , Rotoli Bruno , Schrezenmeier Hubert , Schubert Jörg , Urbano-Ispizua Alvaro , Coyle Luke , de Castro Carlos , Fu Chieh-Lin , Maciejewski Jaroslaw P. , Mojcik Christopher F. , Rother Russell P. , Hillmen Peter 
Published: April 2020

In paroxysmal nocturnal hemoglobinuria (PNH), lack of the GPI-anchored terminal complement inhibitor CD59 from blood cells renders erythrocytes susceptible to chronic hemolysis resulting in anemia, fatigue, thrombosis, poor quality of life (QoL), and a dependency on transfusions. Eculizumab, a terminal complement inhibitor, reduced intravascular hemolysis and transfusion requirements in transfusion dependent patients with normal or near-normal platelet counts in a randomized placebo-controlled trial (TRIUMPH). SHEPHERD, an open-label, non-placebo controlled 52-week phase III clinical study, is underway to evaluate the safety and efficacy of eculizumab in a broader PNH population including patients with significant thrombocytopenia and/or lower transfusion requirements. Eculizumab was dosed as follows: 600 mg IV every 7 days x 4; 900 mg 7 days later; and then 900 mg every 14±2 days. Eculizumab was administered to 97 patients at 33 international sites. In a pre-specified 6-month interim analysis, the most frequent adverse events were headache (50%), nasopharyngitis (23%), and nausea (16%); most were mild to moderate in severity. No infections or serious adverse events were reported as “probably” or “definitely” related to drug. Intravascular hemolysis, the central clinical manifestation in PNH and the primary surrogate efficacy endpoint of the trial, was significantly reduced in eculizumab patients as assessed by change in lactate dehydrogenase (LDH) area under the curve (p&lt;0.001). LDH levels decreased from a median of 2,051 U/L at baseline to 270 U/L at 26 weeks (p&lt;0.001; normal range 103–223 U/L). Control of intravascular hemolysis resulted in an improvement in anemia as transfusion requirements decreased from a median of 4.0 PRBC units/patient pre-treatment to 0.0 during treatment (p&lt;0.001), approximately 50% of the patients were rendered transfusion independent (P&lt;0.001), and hemoglobin levels increased (p&lt;0.001). Fatigue, as measured by both the FACIT-Fatigue and EORTC QLQ-C30 instruments, was significantly improved with eculizumab treatment as compared to baseline (p&lt;0.001 for each). Other EORTC-QLQ-C30 patient reported outcomes demonstrating improvement included global health status (p&lt;0.001), all 5 patient functioning subscales (p&lt;0.001) and 7 of 9 symptom/single item subscales (p≤0.03). These results demonstrate that the beneficial effects of eculizumab in PNH are applicable to a much broader patient population than previously studied and further underscore that eculizumab treatment markedly reduces intravascular hemolysis, thereby providing clinical benefit to treated patients. The trial will complete in September 2006 and the final results from this 52-week study will be presented.