Efficacy and safety of HRS-5965 monotherapy in complement inhibitor-naïve patients with paroxysmal nocturnal haemoglobinuria.

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, life-threatening disorder characterized by complement-mediated haemolysis, leading to anaemia and thrombosis. HRS-5965 is a novel, oral, selective complement factor B inhibitor targeting the alternative pathway, potentially reducing both intra- and extravascular haemolysis. In this randomized, open-label phase II study, we evaluated the efficacy and safety of HRS-5965 monotherapy in complement inhibitor-naïve adult PNH patients. Twenty-six patients were randomized 1:1 to receive HRS-5965 50 mg orally twice daily (BID) (with potential up-titration to 100 mg BID) or 75 mg BID for 12 weeks. The primary end-point was the change in haemoglobin (Hb) from baseline to Week 12. Both groups showed marked Hb increases, with least squares mean increases of 37.6 and 37.7 g/L for the 50 and 75 mg BID groups respectively. Lactate dehydrogenase levels declined by 87% and 85% from baseline. The most common treatment-related adverse events were mild lab abnormalities, including increased alkaline phosphatase and alanine aminotransferase. In conclusion, HRS-5965 monotherapy at either 50 or 75 mg BID resulted in substantial Hb improvements and reduced haemolysis with an acceptable safety profile, suggesting its potential as a promising oral therapy for complement inhibitor-naïve PNH patients.