KP104, a bifunctional C5 mAb–Factor h fusion protein, demonstrates sustained long-term efficacy and safety in complement inhibitor–naïve PNH patients: 2-year results from A phase 2 study with 8-week post-treatment safety follow-up.

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.