Efficacy and safety of HSK39297 monotherapy in patients with paroxysmal nocturnal hemoglobinuria (PNH)

Abstract Introduction Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder characterized by complement-mediated hemolysis, thrombophilia, and bone marrow failure. Despite anti-C5 therapy (e.g., eculizumab), many patients remain anemic due to residual intravascular hemolysis and C3-mediated extravascular hemolysis (EVH). HSK39297, a novel oral Factor B inhibitor, targets proximal complement activation and enables a once-daily administration regimen, offering potential advantages over existing therapies. This phase 2 trial evaluated the efficacy and safety of HSK39297 monotherapy in complement inhibitor- naïve PNH patients. Methods In this open-label, multicenter study (NCT06561841), 47 adults with PNH (granulocyte clone >10%, lactate dehydrogenase [LDH] >1.5× upper limit normal [ULN], hemoglobin [Hb] <100 g/L) were randomized 1:1:1 to receive HSK39297 (cohort A: 75 mg/125 mg twice daily [BID], cohort B: 100 mg BID, or cohort C: 200 mg once daily [QD]) for 24 weeks. The primary endpoint was the proportion of patients achieving Hb increase of ≥20 g/L without red blood cell (RBC) transfusions between weeks 4 and 24. Secondary endpoints included LDH reduction > 60% or normalization, changes in Hb levels, reticulocyte count, indirect bilirubin, PNH clone size, C3 fragment deposition, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scores, and safety. Pharmacokinetics and pharmacodynamics were assessed. Results At week 24, 42 of 47 patients (89.4%) met the primary endpoint (cohort A: 87.5%; B: 86.7%; C: 93.8%). Transfusion avoidance was achieved in 95.7% of patients. Mean Hb increased by 50.7 g/L. LDH levels reduced by ≥60% or normalized in all patients (47/47, 100%). C3d+ RBC levels remained low (0.34% at week 24). Consistent improvements were observed in other markers of hemolysis and FACIT-Fatigue scores. Adverse events (AEs) occurred in 72.3% of patients ,mostly of which were grade ≤2（CTCAE5.0）. 59.6% of patients experienced drug-related AEs, with headache (34.0%) being the most frequently reported. No breakthrough hemolysis or thromboembolic events were reported. The 200 mg QD cohort showed sufficient exposure to sustained complement inhibition at the trough. Conclusions HSK39297 monotherapy significantly improved hematologic and clinical outcomes in complement inhibitor- naïve PNH patients, demonstrating robust efficacy across all doses and a favorable safety profile. The 200 mg QD regimen demonstrated optimal efficacy and pharmacokinetics and is therefore proposed for further investigation in phase 3 trials.