Safety and Efficacy of the Terminal Complement Inhibitor Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria: Interim Shepherd Phase III Clinical Study.

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