Revolutionizing PNH Treatment: Poze-Cemdi Outperforms Ravulizumab

In the realm of rare diseases, paroxysmal nocturnal hemoglobinuria (PNH) has long been a challenge for patients and healthcare providers alike. However, a novel combination therapy, poze-cemdi, has emerged as a potential game-changer in managing this ultra-rare, life-threatening complement-mediated blood disorder. In a recent head-to-head exploratory cohort of a Phase 3 trial, poze-cemdi demonstrated superior control of intravascular hemolysis compared to ravulizumab, a current standard-of-care complement factor 5 (C5) inhibitor.

PNH is characterized by an acquired genetic mutation that leads to the destruction of red blood cells (hemolysis) by the complement system. This results in a range of symptoms, including fatigue, shortness of breath, and life-threatening blood clots. Inhibition of C5, a protein involved in complement system activation, is an established treatment approach to prevent intravascular hemolysis and reduce the symptoms and risk of life-threatening complications of PNH.

The combination of pozelimab and cemdisiran (poze-cemdi) targets C5 through complementary mechanisms. Pozelimab is a fully human monoclonal antibody designed to block the activity of C5, while cemdisiran is an investigational siRNA therapeutic that reduces circulating levels of C5. This dual-targeting strategy enables complete, rapid, and durable inhibition of terminal complement, leading to greater control of intravascular hemolysis.

In the exploratory cohort of the ACCESS-1 trial, poze-cemdi outperformed ravulizumab in controlling intravascular hemolysis. At 26 weeks, 96% of patients receiving poze-cemdi achieved adequate LDH control (≤1.5 x ULN) compared to 80% with ravulizumab. Moreover, 93% of poze-cemdi patients achieved LDH normalization (≤1 x ULN), compared to 65% for ravulizumab. These results suggest that poze-cemdi's combination of an antibody and siRNA targeting C5 offers enhanced durability and effectiveness compared to ravulizumab's monoclonal antibody approach.



The infrequent, four-week subcutaneous delivery of poze-cemdi offers potential long-term benefits over ravulizumab's intravenous administration. Subcutaneous delivery allows for self-administration, reducing the treatment burden and improving patient quality of life. Additionally, the combination of pozelimab and cemdisiran enables complete, rapid, and durable inhibition of terminal complement, leading to greater control of intravascular hemolysis. This could result in fewer clinic or home visits, lower healthcare costs, and potentially improved patient outcomes.



The potential cost savings and improved quality of life for patients with PNH who switch from ravulizumab to poze-cemdi are significant. With 96% of patients achieving adequate LDH control and 93% achieving normalization, poze-cemdi outperforms ravulizumab (80% and 65% respectively). Additionally, its infrequent four-week subcutaneous delivery reduces clinic or home visits, potentially lowering healthcare costs. However, the initial cost of poze-cemdi must be considered. If the price is comparable to ravulizumab, the improved efficacy and reduced administration burden could make poze-cemdi a cost-effective first-line treatment.

In conclusion, the novel combination of pozelimab and cemdisiran (poze-cemdi) has shown promising results in controlling intravascular hemolysis in patients with PNH, outperforming ravulizumab in a head-to-head exploratory cohort of a Phase 3 trial. Poze-cemdi's complementary mechanisms enable complete, rapid, and durable inhibition of terminal complement, leading to more patients achieving target lactate dehydrogenase (LDH) levels compared to ravulizumab. With infrequent four-week subcutaneous delivery, poze-cemdi offers potential for self-administration, reducing treatment burden and clinic visits. If these results are repeated in the registrational cohort, poze-cemdi could transform PNH treatment, potentially leading to significant cost savings and improved quality of life for patients.