Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening hematologic disease characterized by intravascular and extravascular hemolysis (IVH and EVH) mediated by effectors of the complement terminal and alternative pathways (TP and AP), respectively. 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). 

A few of the potential emerging complement inhibitors are crovalimab (C5 inhibitor), nomacopan (C5/LTB4 inhibitor), CAN-106 (C5 inhibitor), ruxoprubart (Anti-Bb antibody), and KP104 (C5 and Factor H inhibitor).

Interim results from the open-label, Phase II proof-of-concept clinical trial were presented at the EHA. Primary endpoints are safety and tolerability. Key secondary endpoints are change from baseline in Hb, lactate dehydrogenase (LDH), absolute reticulocyte counts (ARC), and number of transfusions. Eligibility criteria include confirmed PNH diagnosis by flow cytometry (RBC clone size >10%) and suboptimal response to ravulizumab. 

As of data cut-off date, 13 patients were enrolled and included in this prespecified interim analysis. The initial cohort of seven patients received ≥2 doses of 3 mg/kg OMS906 before escalating to 5 mg/kg; the next 6 patients started at 5 mg/kg OMS906. Clinical responders (increase in Hb levels ≥2.0 g/dL) at week 24 were eligible to receive 5 mg/kg IV OMS906 as monotherapy. 

 

Following OMS906, mean Hb increased from baseline by 3.39 g/dL (N=13, p <0.001) at week 4 and 3.27 g/dL (N=7, p <0.001) at week 24. All patients were free from transfusion following OMS906 treatment. The 3 mg/kg dose did not demonstrate sufficient durability, while 5mg/kg showed greater magnitude of response at week 4 post dose and greater durability to the next dose (week 8), consistent with the expected PK/PD profile of OMS906. The addition of OMS906 to Rravulizumab also resulted in rapid and sustained reductions in ARC in Patients With PNH. At Day 29, mean ARC decreased by 146.43 ×109/L (N=13; p <0.0001). 

 

Treatment-related adverse events observed in 38.5% of patients were mostly mild-moderate grade. No patients met criteria for clinical breakthrough hemolysis.  

KOL insights

“While C5 inhibitors are very effective, there are some shortfalls, including incomplete responses and rare refractory patients. Primary or secondary failure of C5 inhibitors due to extravascular hemolysis is addressed by more proximal-acting inhibitors targeting factor B, factor D, and C3, among many others.”— MD, PhD, FACP, 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), Alnylam (cemdisiran), Kira (KP104) and others are advancing their therapies through early and late-stage development

OMS906 (zaltenibart) is an investigational human monoclonal antibody targeting mannan-binding lectin-associated serine protease-3 (MASP-3), the key activator of the complement system’s alternative pathway. Apart from PNH, it is currently being investigated in C3 Glomerulopathy and Idiopathic Immune Complex-Mediated Glomerulonephritis. Phase III programs for OMS906 in PNH and C3G are scheduled to begin in late 2024 and early 2025, respectively, according to the company. 

Initial findings from the Phase II dose finding study (NCT05972967) showed that OMS906 was well tolerated with no patient having met the criteria for clinical breakthrough hemolysis. Notable improvements included mean hemoglobin increase by 3.39 g/dL at week 4 and sustained responses at week 24. Clinical response was achieved in 92.3% of patients by week 4, with higher response rates observed at 5 mg/kg. 

These findings suggest that OMS906 at 5 mg/kg demonstrates superior efficacy and durability compared to the 3 mg/kg dose. 

 

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.