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. 

Currently, there are 13 complement inhibitors in the market approved for various complement dysregulation disorders. Current market landscape of complement inhibitors include C5, C3, Factor-B, and Factor-D inhibitors. Besides Alexion Pharmaceuticals (a subsidiary of AstraZeneca), the market consists of major players, including but not limited to Novartis’ FABHALTA (iptacopan), Apellis’ EMPAVELI (pegcetacoplan), Astellas’ IZERVAY (avacincaptad pegol), and UCBs’ ZILBRYSQ (zilucoplan).

At present, there are only three approved drugs that address both intravascular and extravascular hemolysis in PNH patients. KP104 presents a unique alternative by inhibiting both the terminal and alternative pathway, and thus overcoming the shortcomings associated with the C5 inhibitors. 

Long term results from the Phase II study have been presented at the EHA 2024. As of the data cutoff, patients had received 33-58 weeks of treatment. After completing 12/13 weeks of primary treatment phase, all patients entered a long-term extension phase, during which they transitioned from the starting dose to a weight-tiered optimal biological dose (OBD).

Primary endpoint was >= 2 grams per deciliter (g/dL) increase in hemoglobin level from baseline. Secondary endpoints included blood transfusion avoidance, improvement in the Functional Assessment of Chronic Illness Therapy – Fatigue Scale (FACIT-Fatigue) score, and reduction in serum lactate dehydrogenase (LDH) levels. 

As of the data cutoff April 24, 2024, 100% (n = 18/18) of patients sustained an hemoglobin (Hgb) increase of ≥2 g/dL from baseline, with mean (SD) Hgb levels increasing by 7.0 (2.1) g/dL over baseline, and 88.9% (n = 16/18) patients achieving Hgb normalization (≥12 g/dL). LDH <1.5xULN was achieved by 94.4% (n = 17/18) patients with a mean (SD) % LDH reduction of 84.3 (8.7) % from baseline. Additionally, all patients remained free from RBC transfusions between day 1 and week 65 of KP104 treatment. Significant clinical improvements were also observed in all other secondary endpoints: normalization of absolute reticulocyte counts, bilirubin levels, and FACIT-fatigue scores after switching to OBD.

 

Regarding safety, all 18 patients remained free from major adverse vascular events, and no severe adverse events were reported. Only one patient in the lowest dose cohort experienced a temporary BTH due to an episode of gastroenteritis. The issue was promptly resolved after an additional dose, and this patient remained free of BTH. 

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 PNH. Major players such as Genentech (crovalimab), Ionis/Roche (RG6299), Alnylam (cemdisiran), and others are advancing their therapies through early and late-stage development.

KP104 is being developed by Kira Pharmaceuticals, and currently investigated in PNH patients and other complement dysregulation disorders. KP104 is a first-in-class bi-functional biologic designed to address complement-mediated diseases and potentially provide greater benefits than single-target complement agents. The company is actively preparing for global Phase III development.

Initial Findings from the Phase II study show that KP104 demonstrates a promising safety profile and effectively manages both IVH and EVH. Treatment with KP104 also achieved rapid and sustained normalization of LDH, significant improvement in Hgb levels, complete avoidance of blood transfusions, and clinically meaningful enhancements in the FACIT-Fatigue score. 

 

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.