17 A phase 2, randomized trial evaluating the safety and efficacy of Pozelimab and Cemdisiran in patients with paroxysmal nocturnal hemoglobinuria

Topic: 12. Bone marrow failure syndromes incl. PNH - Clinical Background: Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-rare acquired genetic disease characterized by chronic intravascular hemolysis due to uncontrolled complement activation. Cemdisiran and pozelimab are investigational treatments that act together to suppress terminal complement activity. Cemdisiran is an N-acetylgalactosamine-conjugated small interfering RNA (siRNA) that suppresses liver production of complement component C5, while pozelimab is a fully human monoclonal antibody inhibitor of C5. The combination of pozelimab and cemdisiran is being evaluated in an ongoing phase 2 study (NCT04811716) that enrolled patients with PNH who have transitioned from pozelimab monotherapy. Aims: To present safety and efficacy data from the completed open-label treatment period (OLTP) of this phase 2 trial. Methods: Patients (n=24; all had received meningococcal vaccination) were randomized (1:1) into one of two treatment arms; both arms received subcutaneous (SC) cemdisiran 200 mg every 4 weeks (Q4W) plus pozelimab 400 mg SC at a frequency of either Q4W (arm 1) or every 2 weeks (Q2W; arm 2). The study consists of four periods: a screening period (7–8 days), an open-label treatment period (OLTP; 28 weeks), an optional open-label extension period (OLEP; 52 weeks), and a safety follow-up period (52 weeks). Results: At the time of this analysis, all patients had completed the OLTP; 23 entered the optional OLEP. During the OLTP, 20 patients (83.3%) maintained control of lactate dehydrogenase (LDH; ≤1.5 x upper limit of normal [ULN]) at all timepoints (most patients maintained an LDH <1.0 x ULN) (Figure 1). Most patients (75%, n=18) met the criteria for hemoglobin stabilization (did not receive a blood transfusion and had no decrease in hemoglobin ≥2 g/dL). Two patients had breakthrough hemolysis (both associated with complement activating conditions) and required a blood transfusion. CH50, a measure of total complement hemolysis activity, remained fully suppressed in all patients at all post-baseline time-points. At data cut-off, 16 patients (66.7%; seven from arm-1 and nine from arm-2) experienced a total of 46 treatment-emergent adverse events (TEAEs); none leading to treatment discontinuation; 43 were of mild-to-moderate intensity. Three severe TEAEs occurred in 2 patients, one patient had anemia, another patient had 2 events - gastroenteritis in association with an event of breakthrough hemolysis. Three patients in arm 2 had 1 serious TEAE each (COVID-19, upper respiratory tract infection, aforementioned gastroenteritis). No serious/severe TEAEs were considered related to study treatment, and all resolved. There were no meningococcal infections, thrombotic events, or deaths. Summary/Conclusion: The combination of pozelimab and cemdisiran was generally well tolerated in patients with PNH, regardless of treatment arm. Overall, 83.3% maintained adequate control of hemolysis, most maintaining normalization of LDH with 75% achieving hemoglobin stabilization during the OLTP. These findings support the ongoing development of this combination therapy in the treatment of patients with PNH.Keywords: Complement, PNH, Hemolysis, Clinical trial