Complement dysregulation underpins the physiopathology of
paroxysmal nocturnal hemoglobinuria (PNH). Cemdisiran, an RNA interference
investigational treatment, silences
complement component 5 (C5) expression in the liver. Previously reported results showed sustained reduction in C5 levels following cemdisiran monotherapy, with >90% reduction in patients with PNH. This phase 1/2 study evaluated single (Part A, n = 32; 50-900 mg) or multiple (Part B, n = 24; 100-600 mg) ascending doses of cemdisiran or placebo (double-blind, randomized 3:1) in healthy adults, or cemdisiran in patients with PNH who were naive to, or receiving,
eculizumab (Part C, n = 6; 200 or 400 mg weekly; open-label). The primary objective was to assess the safety and tolerability of cemdisiran. Other assessments included change in
complement activity,
lactate dehydrogenase levels, and inhibition of
hemolysis following cemdisiran treatment. Cemdisiran was generally well tolerated in this study. Overall, 75%, 89%, and 100% of subjects in Parts A, B, and C, respectively, experienced ≥1 non-serious adverse event (AE). Most events were Grade 1 or 2 in severity and the most common AEs included
nasopharyngitis and
headache. Cemdisiran elicited robust, sustained reductions in the
complement activity in healthy adults and patients with PNH. In Part C, exploratory analyses showed that cemdisiran monotherapy was insufficient to prevent
hemolysis in patients with PNH as measured by serum
lactate dehydrogenase levels. Cemdisiran and
eculizumab combination
therapy reduced the dose of
eculizumab required to provide adequate control of
intravascular hemolysis. These results demonstrate a potential benefit of cemdisiran coadministration in patients who are inadequate responders to
eculizumab alone.