Regeneron Pharmaceuticals announced positive Phase 3 data for its investigational combination of pozelimab and cemdisiran (poze-cemdi) 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 findings, 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.
PNH is an ultra-rare, chronic, and life-threatening blood disorder where red blood cells are destroyed by the complement system, leading to hemolysis. This process releases lactate dehydrogenase (LDH), a biomarker used to measure the degree of hemolysis. Symptoms include fatigue, shortness of breath, and life-threatening blood clots. Current treatments often involve C5 inhibitors to prevent intravascular hemolysis.
Improved Hemolysis Control with Poze-Cemdi
The ACCESS-1 trial (Cohort A) randomized patients naïve to complement inhibition to receive either poze-cemdi or ravulizumab. Key results showed:
- 96% of patients achieved adequate LDH control (≤1.5 x ULN) with poze-cemdi, compared to 80% with ravulizumab.
- 93% achieved LDH normalization (≤1 x ULN) with poze-cemdi, compared to 65% with ravulizumab.
- An 84% decrease in LDH from baseline at week 26 was observed with poze-cemdi, compared to 74% with ravulizumab.
"C5 inhibitors are widely considered the mainstay of PNH treatment, but a proportion of patients still do not achieve adequate control of intravascular hemolysis, may experience residual anemia, and may feel significant treatment burden, as many of these therapies require clinic or home visits for intravenous delivery," 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. He added that the combination's complementary mechanisms enabled complete, rapid, uninterrupted, and durable inhibition of terminal complement.
Open Label Extension Results
In a follow-on open-label extension (OLE) trial, patients who completed ACCESS-1 could enroll 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. This included 4 of 5 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, compared to 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%). Serious adverse events (SAEs) occurred in two patients receiving poze-cemdi that were considered unrelated to treatment by the investigator.
Ongoing Studies
Pozelimab and cemdisiran are being evaluated in separate Phase 3 trials for several complement-mediated disorders, including PNH, myasthenia gravis (MG) and geographic atrophy (GA). A separate registrational cohort is ongoing, investigating poze-cemdi against eculizumab.
