Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired hemolytic disorder caused by somatic mutations in the PIG-A gene with significant unmet medical needs. Pathological activation of complement factor B (CFB), a critical regulatory component of the alternative complement pathway, contributes to disease progression. VSA012 is a novel CFB-targeted siRNA under clinical development which specifically silences hepatic CFB mRNA expression and suppresses complement overactivation, thereby potentially improving hemolytic symptoms.

Objective: This study aimed to assess the safety, tolerability, preliminary efficacy, pharmacokinetics and pharmacodynamic (PK/PD) profile of VSA012 in Chinese PNH patients who were complement inhibitor-naïve or had received complement inhibitor therapy and subsequently washed out.

Method: This ongoing multicenter, non-randomized, multiple-ascending-dose, open-label phase Ib clinical trial (NCT06848296) enrolled Chinese PNH patients who were either complement inhibitor-naïve or had not received complement inhibitor therapy within 3 months prior to enrollment. Patients were assigned to 60 mg or 120 mg cohorts and received subcutaneous injections of the corresponding dose of VSA012 on Day 1 (D1) and D29. The study comprises a screening phase (up to 10 weeks), treatment phase (D1-D29), and 24-week follow-up phase (D30-D196). This report presents the interim analysis of safety, efficacy and PD data collected with a data cut-off (DCO) date of 24/07/2025.

Results: Eighteen participants received VSA012 treatment (60 mg: n = 8; 120 mg: n = 10). As of the DCO, data were collected in all the subjects of 60 mg group up to D56, and in only 5 subjects of 120 mg group up to D29. No serious adverse events (SAEs) or injection site reactions were observed. In 60 mg group, 16 treatment-emergent adverse events (TEAEs) occurred in 4 subjects, including one subject with 2 Grade 2 AEs (abdominal discomfort and cardiac chest pain) and the remaining AEs were Grade 1. No AEs were reported in 120 mg group. For key PD parameters of 60 mg group, CFB levels showed 76.1% and 95.9% reduction from baseline at D14 and at D42; CAP decreased to 30.2% and 83.9% from baseline at D14 and D42. The decrease in CFB and CAP were associated with the amelioration of LDH and hemoglobin (Hb) levels. In 60 mg group, mean LDH levels declined to approximately 1.5×ULN (upper limit of normal) by D14 and were normalized by D29; LDH (Mean ± SD) reduced from 1454 ±751 U/L at baseline to 368 ± 112 U/L at D14, representing a 70% reduction from baseline; and further decreased by 82% from baseline at D42. After the first dose of VSA012 at 60 mg, Hb levels began to rise slowly at D14: all subjects avoided blood transfusion without occurrence of breakthrough hemolysis. In 60 mg group, mean Hb increased from 7.0 ± 1.5 g/dL at baseline to 7.8 ± 1.2g/dL) at D14 (12% increase) and further to 9.8 ± 0.9 g/dL at D56 (43.5% increase); 6 subjects (75%) had an Hb increase≥2 g/dL. In addition, VSA012 at 60 mg demonstrated marked improvements in PNH clone-red blood cell proportion, reticulocyte counts, total bilirubin levels, and FACIT-F scores. Although limited data were currently available for VSA012 120 mg group, the same trends of efficacy and PD parameters have been observed as for the 60 mg group.

Conclusion: The preliminary data of interim analysis demonstrated a favorable safety profile and sustained clinical benefits of such a siRNA drug, VSA012 in PNH patients. In VSA012 60 mg group, 6 out of 8 PNH patients (75%) achieved an Hb increase≥2 g/dL within 56 days. Further investigations with longer follow-up duration are ongoing to confirm these preliminary findings of VSA012.

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2025
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