Regeneron Pharmaceuticals announced positive Phase 3 data for its investigational pozelimab and cemdisiran (poze-cemdi) combination therapy in patients with paroxysmal nocturnal hemoglobinuria (PNH). The ACCESS-1 trial's exploratory cohort demonstrated that poze-cemdi achieved greater control of intravascular hemolysis compared to ravulizumab, a standard-of-care complement C5 inhibitor. The results, presented at the American Society of Hematology (ASH) 2024 Annual Meeting, support the continued development of poze-cemdi for PNH and other complement-mediated diseases.
Superior LDH Control with Poze-Cemdi
The ACCESS-1 trial evaluated poze-cemdi against ravulizumab in complement inhibitor-naïve PNH patients. The primary endpoint was the percent change in lactate dehydrogenase (LDH) levels at 26 weeks, a key indicator of intravascular hemolysis. Results showed that 96% of patients receiving poze-cemdi achieved adequate LDH control (≤1.5 x ULN) across study visits, compared to 80% with ravulizumab. Notably, at week 26, only one patient in the poze-cemdi arm did not achieve meaningful LDH control, compared to five patients in the ravulizumab arm.
Furthermore, 93% of patients on poze-cemdi achieved LDH normalization (≤1 x ULN) across study visits, compared to 65% with ravulizumab. The poze-cemdi group also experienced an 84% decrease in LDH from baseline at week 26, compared to a 74% decrease in the ravulizumab group.
Complete Complement Inhibition
The CH50 profile observed with poze-cemdi demonstrated complete and uninterrupted inhibition of terminal complement, contrasting with ravulizumab, which showed a loss of inhibition at the end of the dosing interval. This sustained inhibition is attributed to the complementary mechanisms of action of pozelimab and cemdisiran. Pozelimab is a fully human monoclonal antibody that blocks C5 activity, while cemdisiran is an investigational siRNA therapeutic that reduces circulating levels of C5.
Improved Outcomes After Switching to Poze-Cemdi
Patients who completed ACCESS-1 could enroll in an open-label extension (OLE) trial and receive poze-cemdi, including those initially treated with ravulizumab. At the start of the OLE, 68% of patients treated with ravulizumab had adequate LDH control. After switching to poze-cemdi, 95% of patients achieved LDH control, including four of the five patients who had failed to achieve LDH control while on ravulizumab.
Safety Profile
The safety profile of poze-cemdi was generally consistent with approved C5 inhibitors. Treatment-emergent adverse events (TEAEs) occurred in 84% of patients treated with poze-cemdi and 87% treated with ravulizumab. The most common TEAEs (≥10%) for poze-cemdi compared to ravulizumab were headache (28% vs. 17%), upper respiratory tract infection (12% vs. 9%), nausea (12% vs. 4%), anemia (12% vs. 9%), fatigue (8% vs. 13%) and cough (4% vs. 13%).
Implications for PNH Treatment
"In this Phase 3 exploratory cohort, the complementary mechanisms of pozelimab and cemdisiran enabled complete, rapid, uninterrupted and durable inhibition of terminal complement throughout the dosing interval," said Christopher Patriquin, M.D., MSc, Assistant Professor of Medicine, Hematology, at the University of Toronto, hematologist at University Health Network and a trial investigator. "The combination helped more patients achieve target LDH levels compared to the current standard-of-care C5 inhibitor, with the added benefit of infrequent four-week subcutaneous delivery that has potential for self-administration."
The ongoing registrational cohort comparing poze-cemdi against eculizumab will further define the role of this novel combination in the treatment of PNH. The potential use of pozelimab and cemdisiran for the treatment of PNH is investigational and has not been approved by any regulatory authority.
