18 A phase 2, open-label study evaluating the safety and efficacy of combination pozelimab and cemdisiran therapy in patients with paroxysmal nocturnal hemoglobinuria who switch from eculizumab

Topic: 12. Bone marrow failure syndromes incl. PNH - Clinical Background: Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-rare, acquired disorder, leading to impaired expression of complement-regulating proteins on the surface of hematopoietic cells. Complement component C5 inhibitors are part of the standard of care for patients with PNH; however, these are generally intravenous treatments. Pozelimab and cemdisiran are investigational agents with a subcutaneous (SC) maintenance regimen that may be self-administered; both inhibit terminal complement through complementary mechanisms of action. Pozelimab is a fully human monoclonal antibody inhibitor of C5, while cemdisiran is an N-acetylgalactosamine-conjugated small interfering RNA that suppresses liver production of C5. Aims: The efficacy and safety of the combination of pozelimab and cemdisiran was evaluated in an ongoing open-label, single-arm study in patients with PNH who switched from eculizumab therapy (NCT04888507). The completed safety and efficacy data of the 32-week open-label treatment period (OLTP) are presented. Methods: This phase 2 trial consisted of a screening period (up to 42 days), a 32-week OLTP, an optional 52-week open-label extension period, and a 52-week post-treatment safety follow-up period. Patients with PNH (≥18 years of age; vaccinated against meningococcal infection) treated with stable eculizumab therapy for ≥12 weeks prior to screening transitioned to the combination of pozelimab and cemdisiran over a 4-week period, and thereafter received the combination (fixed dose pozelimab 400 mg and cemdisiran 200 mg) SC every 4 weeks. Results: Six patients were enrolled. Five patients completed the OLTP (Day 225); one patient discontinued treatment after 29 days due to a treatment-emergent adverse event (TEAE). At baseline, lactate dehydrogenase (LDH) was well controlled on eculizumab. In the year prior to enrollment, no patient had a history of a blood transfusion, but one patient had a history of breakthrough hemolysis. During the 32-week OLTP, no patient had an LDH greater than 1.5 x the upper limit of normal (ULN; Figure 1) or experienced an event of breakthrough hemolysis, including the two patients who were previously treated with higher doses of eculizumab (1200 mg and 1500 mg every 2 weeks, respectively). Furthermore, all but two LDH values remained normal (≤1.0 x ULN) at all timepoints evaluated (Figure 1). During the OLTP, all patients achieved hemoglobin stabilization (did not receive a red blood cell transfusion and had no decrease in hemoglobin level of ≥2 g/dL), and no patient required a blood transfusion. CH50, a measure of terminal complement activity, remained fully suppressed at 0 kIU/L throughout the study. One patient discontinued study treatment due to two mild, non-serious TEAEs of headache at Days 2 and 16. One subject experienced a serious TEAE of endometrial hyperplasia for long standing, intermittent post-menopausal bleeding that required hospitalization for pre-emptive hysterectomy/ovariectomy; the event was deemed not related to the study treatment by the investigator and sponsor. There were no meningococcal infections, TEAEs due to potential large drug-target-drug immune complexes, thrombotic events or TEAEs leading to death. Summary/Conclusion: Results suggest that in patients with PNH transitioning from eculizumab treatment (including patients receiving higher than standard doses), the combination of pozelimab and cemdisiran was generally well tolerated, providing sustained control of intravascular hemolysis without any breakthrough hemolysis events. Findings support the ongoing development of pozelimab and cemdisiran combination therapy.Keywords: PNH, Clinical trial, Hemolysis, Hemolytic anemia