Study design of A phase 3, open-label trial for pozelimab and cemdisiran combination therapy in patients with paroxysmal nocturnal hemoglobinuria with inadequate control of intravascular hemolysis

Abstract Background and significance: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening disease, characterized by complement-mediated hemolysis. Treatment for PNH includes C5 inhibitors such as eculizumab/biosimilar, ravulizumab, and crovalimab, however, patients under terminal complement inhibition can experience residual intravascular hemolysis due to incomplete C5 blockade. The combination of pozelimab (a monoclonal antibody that prevents activation of C5) and cemdisiran (a silencing RNA that reduces production of circulating C5) is a novel approach being investigated for its ability to achieve durable inhibition of the terminal complement pathway. The aim of this study is to assess if the combination of pozelimab and cemdisiran can adequately control intravascular hemolysis, as assessed by lactase dehydrogenase (LDH), in patients with PNH who are being treated with other C5 inhibitors and experiencing inadequate control of intravascular hemolysis. Study design and methods: This phase 3, single arm, multicenter, global efficacy and safety study (EU CT: 2024-519709-37-00) plans to enroll 35 patients with PNH who have inadequate control of intravascular hemolysis on their current C5 inhibitor therapy. Key inclusion criteria include patients ≥18 years of age, with a diagnosis of PNH confirmed by a history of high-sensitivity flow cytometry , current treatment with marketed eculizumab/biosimilar, ravulizumab, or crovalimab at the labeled dose for at least 6 months, and LDH persistently 1.5 × upper limit of normal (ULN) for 6 months prior to the study attributed to intravascular hemolysis. Key exclusion criteria include receipt of an organ transplant, history of bone marrow transplantation or other hematologic transplants, body weight 40 kg at screening visit, and patients with known or suspected C5 mutation as per investigator discretion that is refractory to their current C5 inhibitor treatment. Following a screening period, patients will be transitioned from their current C5 therapy to the combination of pozelimab 400 mg SC and cemdisiran 200 mg SC every 4 weeks. The study will consist of a 28-week treatment period; all patients who complete the treatment period will continue to receive the combination of pozelimab and cemdisiran during the 52-week extension (ext) period. Following the ext period, patients may enroll in an expanded access program for continued treatment with pozelimab and cemdisiran. Patients who do not enter the extended access program, or who prematurely discontinue study treatment at any time during the treatment or ext period, will undergo a post-treatment safety follow-up period lasting 46 weeks after the last dose of study drug administration. The overall study duration for each patient will range from approximately 92–138 weeks. The primary endpoint will be the percentage change in LDH from baseline to week 28. The secondary endpoints for the treatment period will include the normalization of LDH from week 4 to 28, adequate control of hemolysis from week 4 to 28, transfusion avoidance, change from baseline in total CH50 assessed through week 28, and occurrence and severity of all adverse events and treatment-emergent adverse events from baseline through week 28. During the ext period, the secondary endpoints will include percent change in LDH from baseline to ext week 24 and ext week 52, normalization of LDH at each visit through ext week 52, inclusive, and adequate control of hemolysis at each visit through ext week 52. Recruitment for this study is expected to begin around November 2025.