EFFICACY and SAFETY of POZELIMAB PLUS CEMDISIRAN in PATIENTS with PAROXYSMAL NOCTURNAL HAEMOGLOBINURIA WHO ARE NAIVE to COMPLEMENT INHIBITION.
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All Authors
Griffin, M.
Jang, J.-H.
Aurand, L.
Magyar, A.
Dain, B.
Perlee, L.
Souttou, A.
Patriquin, C.
LTHT Author
Griffin, Morag
LTHT Department
Oncology
Haematology
Haematology
Non Medic
Publication Date
2024
Item Type
Conference Abstract
Language
Subject
ADULT , DRUG-RELATED SIDE EFFECTS AND ADVERSE REACTIONS , AGED , CONTROLLED CLINICAL TRIALS AS TOPIC , DRUG THERAPY , SUBSTANCE WITHDRAWAL SYNDROME , SEIZURES , WOMEN , HEADACHE , DRUG DOSAGE CALCULATIONS , MEN , HAEMOGLOBINURIA , CLINICAL TRIALS AS TOPIC , RANDOMISED CONTROLLED TRIAL , WORLD HEALTH ORGANIZATION , ANTIBODIES, MONOCLONAL , HAEMOGLOBINS , ANTIGENS , ANXIETY , CERTIFICATION , CORONERS AND MEDICAL EXAMINERS , CURRICULUM , COMPUTER-ASSISTED LEARNING , EDUCATION , INTENSIVE CARE UNITS , MORTALITY , MULTIMEDIA , PHYSICIANS , SURVEYS AND QUESTIONNAIRES , LEARNING , TOTAL QUALITY MANAGEMENT
Subject Headings
Abstract
Background: Paroxysmal nocturnal haemoglobinuria (PNH) is an ultra-rare, acquired disorder, leading to impaired expression of complement regulators on the surface of haematopoietic cells. Standard of care includes complement component C5 inhibitors (e.g. eculizumab, ravulizumab). Pozelimab and cemdisiran are investigational agents that work together to inhibit terminal complement through complementary mechanisms of action. Cemdisiran is an N-acetylgalactosamine-conjugated small interfering RNA that suppresses liver production of C5; pozelimab is a fully human anti-C5 monoclonal antibody. Here, we present the interim results from an exploratory arm of a phase 3, open-label, C5 inhibitor-controlled trial (NCT05133531). Aim(s): Compare the efficacy and safety of the combination of pozelimab + cemdisiran (combo) vs ravulizumab in adult patients with PNH who are complement inhibitor-naive or had not recently received complement inhibition. Control of haemolysis was assessed by evaluating changes in lactate dehydrogenase (LDH) over 26 weeks. Method(s): Patients were randomised 1:1 to receive combo or ravulizumab. Patients on combo received pozelimab and cemdisiran subcutaneously every 4 weeks (400 mg and 200 mg, respectively) with a single IV pozelimab dose on day 1 (30 mg/kg). Ravulizumab was administered IV every 8 weeks per labelled weight-based dosing, starting 2 weeks after the IV loading dose. The primary endpoint was the percent change in LDH from baseline to Week 26. Adequate control of haemolysis and normalisation of LDH were defined as LDH <=1.5 and <=1.0 times the upper limit of normal (ULN), respectively. Secondary endpoints included effects on haemoglobin, and serum concentrations of total pozelimab and ravulizumab. Result(s): A total of 48 patients (combo, n=25; ravulizumab, n=23) were randomized and included in this interim analysis (data cut-off: 12 October 2023). At baseline, mean LDH was 6.5 x ULN and 6.1 x ULN for the combo and ravulizumab groups, respectively. At Week 26, mean LDH was 0.8 x ULN for combo and 1.1 x ULN for ravulizumab (mean reduction in LDH from baseline to Week 26 was 83% vs 79%, respectively). Ten patients (63%) who completed combo treatment remained transfusion-free versus nine (60%) who completed ravulizumab treatment. One patient in each group met the endpoint criteria for breakthrough haemolysis. At the time of this analysis, 76% of combo-treated patients and 87% of ravulizumab-treated patients experienced treatment-emergent adverse events (TEAEs); the most common was headache, occurring in seven patients (28%) in the combo group and three (13%) in the ravulizumab group. Two patients (8%) in the combo group experienced serious TEAEs: one with cellulitis following trauma, and one with fever, seizure and haemolytic crisis within 1 week of the first dose of study treatment, and prior to achieving adequate LDH control; both resolved with treatment. No serious TEAEs were reported in the ravulizumab group. Summary/Conclusion: Based on interim data, in treatment-naive patients with PNH the combination of pozelimab and cemdisiran was generally well tolerated and provided robust control of LDH through 26 weeks, with mean LDH below the lower limit of normal. Results support the ongoing development of pozelimab and cemdisiran combination therapy in PNH and other complementmediated diseases.
Journal
HemaSphere