Abstract Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening hematologic disorder characterized by complement dysregulation on affected blood cells, leading to both intravascular (IVH) and extravascular hemolysis (EVH). KP104 is a novel bifunctional recombinant protein drug composed of a humanized anti-C5 monoclonal antibody fused to the regulatory domain of complement factor H, with dual inhibitory activity of both terminal and proximal complement pathways. Aims: Final analysis of efficacy and safety outcomes from a 2-year Phase 2 trial (NCT05476887) of KP104 in complement inhibitor–naïve PNH patients, including data from an 8-week safety follow-up after end of treatment (EoT). Methods: Eighteen complement inhibitor–naïve patients were enrolled across three dose-escalation cohorts (n=6 per cohort). Following 12–13 weeks of initial dosing, all patients transitioned to a weight-based optimal biologic dose (OBD) given SC Q2W as reported previously (ASH 2023 the second occurred in a patient with coexisting MPN while on OBD. No major vascular events and no new safety signals beyond those previously reported (ASH 2024) were observed. A total of 12 patients participated in a follow-up study spanning 4-8 weeks post–EoT, including one patient with concurrent aplastic anemia. At EoT, 83.3% (10/12) of patients achieved Hgb normalization (≥12 g/dL), with a mean Hgb of 13.9 ± 1.7 g/dL, and all patients (100%, 12/12) had LDH levels ≤1.5× ULN. Following KP104 discontinuation, Hgb normalization was maintained in 83.3% (10/12) at week 4 (mean Hgb: 13.7 ± 2.4 g/dL), 77.8% (7/9) at week 6 (mean Hgb: 12.7 ± 2.6 g/dL), and 80.0% (4/5) at week 8 (mean Hgb: 11.2 ± 3.3 g/dL). LDH levels ≤1.5× ULN were observed in 66.7% (8/12) at week 4, 37.5% (3/8) at week 6, and 20.0% (1/5) at week 8. No new safety signals emerged during the post–EoT follow-up. Conclusion: KP104 demonstrated robust and durable efficacy, with a favorable safety profile, over the entire 2-year treatment period in complement inhibitor–naïve PNH patients. All patients achieved transfusion independence, with sustained improvements in hemoglobin and LDH levels throughout the treatment period. Importantly, a substantial proportion of patients maintained clinical benefit during the 4-8 weeks safety follow-up post-EoT, suggesting a significant efficacy cushion beyond active dosing of the drug. These findings demonstrate the potential of KP104 as an attractive monotherapy for PNH with desired efficacy and safety.
Zhang et al. (Mon,) studied this question.