Paroxysmal nocturnal haemoglobinuria (PNH) is an ultra-rare, acquired disorder, leading to impaired expression of complement regulators on the surface of hematopoietic 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. Alnylam’s Cemdisiran is an N-acetylgalactosamine-conjugated small interfering RNA that suppresses liver production of C5; pozelimab is a fully human anti-C5 monoclonal antibody, developed by Regeneron pharmaceuticals and currently approved for Chaple’s disease (CD55-deficient protein-losing enteropathy)

Established therapies in the market include Alexion/AstraZeneca’s SOLIRIS (eculizumab) and ULTOMIRIS (ravulizumab), Novartis’ FABHALTA (iptacopan), Apellis’ EMPAVELI (pegcetacoplan), Astellas’ IZERVAY (avacincaptad pegol), and UCBs’ ZILBRYSQ (zilucoplan). 

Interim results from an exploratory arm of a Phase III study were presented at the EHA 2024. The primary endpoint was the percent change in lactate dehydrogenase (LDH) from baseline to Week 26. Adequate control of haemolysis and normalization 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.

As of 12 October 2023, mean LDH was 0.8 x ULN for the combination (pozelimab plus cemdisiran) and 1.1 x ULN for ravulizumab. Moreover, 88% of patients treated with the combination therapy achieved adequate control of LDH (≤1.5 times ULN), compared to 78.3% with ravulizumab, over the 26 week treatment period. Furthermore, 63% who completed combination treatment remained transfusion-free versus 60% who completed ravulizumab treatment.

At the time of this analysis, 76% of combo-treated patients and 87% of ravulizumab - treated patients experienced treatment-emergent adverse events (TEAEs). 

KOL insights

“Most instances of breakthrough hemolysis are caused by a provoking factor, including a complement-amplifying condition, with the most common being bacterial or viral infection, pregnancy, surgery, and trauma. Not all hemolysis in PNH is due to complement-amplifying conditions. Other factors can also provoke hemolysis in PNH”– MD, United States

Conclusion 

PNH is a rare acquired disorder of the pluripotent hematopoietic stem cell. The only disease-modifying therapeutic strategies for PNH are complement inhibition therapies. Alexion/AstraZeneca’s SOLIRIS (eculizumab) was the first complement inhibitor approved in 2007 for Paroxysmal Nocturnal Hemoglobinuria (PNH). Major players such as Genentech (crovalimab), Ionis/Roche (RG6299), Omeros (OMS906), Kira (KP104), and others are advancing their therapies through early and late-stage development.

Regeneron’s pozelimab is a complement C5 monoclonal antibody currently under investigation in combination with Alnylam’s cemdisiran for treating complement-mediated disorders like PNH and myasthenia gravis. In August 2023, FDA approved VEOPOZ (pozelimab) for CHAPLE disease (CD55-deficient protein-losing enteropathy).

Initial findings from the Phase III study demonstrated the superior clinical efficacy of the combination (pozelimab plus cemdisiran) over ravulizumab. Mean LDH reduction from the baseline was found to be 83% and 79%, for the combination and ravulizumab, respectively. Furthermore, the mean percentage improvement of haemoglobin from baseline at week 26 was 24.3 in the combination treatment group versus 17.6 in the ravulizumab group. 

 

For more insight into the patient's burden/epidemiology, treatment, and changing market landscape-related advancements, refer to Paroxysmal nocturnal hemoglobinuria (PNH) - Market Insight, Epidemiology and Market Forecast – 2034, report.