Efficacy and Safety of HRS-5965 Monotherapy in Patients with Paroxysmal Nocturnal Hemoglobinuria Who Have Not Received Complement Inhibitors: A Proof-of-Concept, Multicenter, Randomized, Open-Label Study

Introduction: Patients with paroxysmal nocturnal hemoglobinuria (PNH) face ongoing challenges, including persistent hemolytic anemia and a lack of effective oral treatments. HRS-5965, a novel oral selective inhibitor of complement factor B, a key component of the complement alternative pathway, is expected to reduce in both intra- and extravascular hemolysis and lead to transfusion-free improvements in hemoglobin levels, and is currently under clinical development for PNH. Methods: This multicenter, randomized, open-label phase 2 study (NCT06051357) was conducted across two clinical sites in China. Adult patients aged ≥18 years with a diagnosis of PNH, evidenced by a documented clone size of ≥ 10% in monocytes and granulocytes (detected by flow cytometry), lactate dehydrogenase (LDH) levels ＞1.5 × the upper limit of normal (ULN), and hemoglobin (Hb) levels ＜10 g/L, were eligible for inclusion. Patients were randomized in a 1:1 ratio to either the titration dosage group or the fixed-dosage group. Patients in the titration group received an initial oral dose of HRS-5965, 50 mg twice daily (BID), for 2 weeks. On Day 15, if the patient's serum LDH levels had decreased by less than 40% from baseline, the dosage was increased to 100 mg BID for the remainder of the 12-week period (50/100 mg BID group). Patients in the fixed dosage group (75 mg BID group) received a fixed oral dose of 75 mg HRS-5965 BID for the entire 12 weeks. After the 12-week treatment period, the investigator evaluated efficacy and safety. If no safety issues were identified, patients entered an independent extension study. Patients with no treatment benefit (e.g., Hb increase <10 g/L from baseline after receiving 100 mg BID HRS-5965) entered a 1-week taper down period followed by a 3-week safety follow-up. The primary endpoint was the change in hemoglobin from baseline to Week 12. Results: Between October 2023 and January 2024, 26 eligible patients were randomized and received at least one dose of the assigned study treatment (50/100 mg group, n=13; 75 mg group, n=13). The median age was 39.5 years, and 16 (61.5%) patients were male. At baseline, all patients exhibited signs of intravascular hemolysis (mean LDH: 2080.0 U/L) and clinically significant anemia (mean Hb: 74.0 g/L), with a substantial proportion being transfusion-dependent (number of patients who received red cell transfusions in the 12 months prior to study entry: 15 [57.7%]). No patient in the 50/100 mg BID group required dose up-titration on Day 15. The efficacy analysis excluded one patient in the 50 mg group who was diagnosed with aplastic anemia and one patient in the 75 mg group who was diagnosed with myelodysplastic syndrome during the study treatment, both confirmed through a bone marrow biopsy. All 26 patients were included in the safety analysis. At week 12, obvious increases in Hb levels from baseline were observed in both the 50 mg BID group (least squares [LS] mean: 37.6 g/L, 95% CI: 31.5-43.6) and the 75 mg BID group (LS mean: 37.7 g/L, 95% CI: 31.6-43.7). The mean percentage change from baseline in LDH levels was 87% (95% CI: 85%-89%) for the 50 mg BID group and 85% (95% CI: 83%-87%) for the 75 mg BID group. The 12-week mean LDH levels were 255.80 U/L for the 50 mg BID group and 300.86 U/L for the 75 mg BID group, respectively. All patients remained transfusion-free from 2 weeks after the start of treatment up to week 12. At week 12, without transfusions, 12 patients (100%) in the 50 mg BID group and 10 patients (83.3%) in the 75 mg BID group achieved Hb levels that increased by ≥20 g/L from baseline. The treatment-related adverse events (TRAEs) with HRS-5965 were primarily laboratory abnormalities. The most frequent TRAEs were increased blood alkaline phosphatase (15.4% in the 50 mg BID group and 69.2% in the 75 mg BID group), followed by increased alanine aminotransferase (7.7% and 15.4%, respectively). Conclusions: HRS-5965 monotherapy at 50 mg or 75 mg resulted in decreased LDH levels and a rapid, durable, transfusion-free improvement in hemoglobin levels in PNH patients who had not previously received complement inhibitors. Both dosages were well-tolerated. This study provides evidence that HRS-5965 might represent a novel treatment option for this patient population.