Abstract Background：Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematological disorder characterized by complement alternative pathway (AP)-mediated severe hemolysis, life-threatening thrombosis, and impaired bone marrow function. The current standard-of-care for PNH consists of anti-C5 blockade with eculizumab to control intravascular hemolysis (IVH). However, only about one-third of patients achieve normal hemoglobin (Hb) levels, with 25%-35% still requiring transfusions. The primary mechanisms for this incomplete response include the deposition of C3 fragments on circulating red blood cells, which can lead to extravascular hemolysis (EVH) in macrophages of liver and spleen. Additionally, residual IVH or breakthrough hemolysis (BTH) may occur due to competition for C5 binding between upstream C3b and C5 inhibitors. LP-005, a novel bifunctional anti-C5 antibody fusion protein to inhibit both TP and AP activation. We previously reported analysis of 14 PNH patients with active hemolysis showed LP-005 (900mg or 1200mg IV every 4 weeks for 12 weeks) rapidly improved Hb and reduced LDH with favorable safety (He, EHA 2025). Aims: This interim analysis provides a comprehensive update on the efficacy and safety of LP-005 in all 20 enrolled patients in the 12-week, for assessment of sustained treatment effects and safety profiles. Methods: CTR20242478 is a multicenter phase 2 study randomizing adult PNH patients with active hemolysis to intravenous LP-005 (Corhort 1: 900mg or Corhort 2: 1200mg every 4 weeks). The primary objectives are to assess the effect of LP-005 on LDH and Hb levels. Following completion of the 12-week fixed-dose phase, dose will be optimized based on efficacy and safety assessment in two cohorts from week 12 to 48. Results: This interim analysis included 20 patients (10 per cohort) who completed 12 weeks of treatment, with 7 patients in Cohort 1 undergoing dose escalation from 900 mg to 1200 mg before week 24. At data cutoff, 70% of patients (14/20, balanced 7:7 between cohorts) had reached the 24-week assessment, with maximum treatment duration extending to 32 weeks. The enrolled patients (10 males and 10 females, all of Han Chinese ethnicity from China), the mean (SD) age was 39 (12) years, and 11 patients have a prior diagnosis of aplastic anemia. Mean (SD) LDH at baseline was 2013.3 (1265.73) U/L in Cohort 1 and 1694.6 (724.34) U/L in Cohort 2. Mean (SD) Hb level at baseline was 65.0 (11.84) g/L in Cohort 1 and 63.5 (10.30) g/L in Cohort 2. By Week 12, all 20 patients demonstrated positive clinical improvements. Mean (SD) LDH reduced to 1276.4 (1781.76) U/L (by -49.39%) and 246.6 (56.94) U/L (by -82.52%) in Cohort 1 and Cohort 2 respectively, and the LSMean difference (95% CI) in LDH change from baseline is -712.73 (-1433.18, 7.73) for Cohort 2 vs. Cohort 1. In Cohort 1, 4/10 patients (40%) achieved LDH levels below 1.5×ULN, with 3/10 (30%) reaching normal LDH levels, while in Cohort 2 10/10 (100%) and 7/10 (70%) patients attained these thresholds, respectively. Mean (SD) Hb levels increased to 107.6 (25.84) g/dL (by 69.40%) and 104.6 (12.89) g/dL (by 69.27%) in Cohort 1 and Cohort 2 respectively. The LSMean difference (95% CI) in Hb change from baseline is -2.63 (-22.33, 17.07) for Cohort 2 vs. Cohort 1. Additionally, Hb increases ≥2 g/dL from baseline were observed in 9/10 patients (90%) in both cohorts, with 6/10 (60%) in each cohort achieving Hb levels ≥10 g/dL. Positive changes were observed in FACT-fatigue scores seen in all 2 cohorts, with mean (SD) increases of 11.8 (17.53) and 12.0 (26.20) for Cohorts 1and Cohorts 2 respectively. Updated analyses revealed dose-dependent therapeutic effects. Following dose escalation from 900 mg to 1200 mg at Week 12, 7 patients in the 900 mg cohort demonstrated improved efficacy by Week 24. As of the cutoff date, all patients 20/20 (100%) remained transfusion-free. LP-005 maintained a favorable safety profile with no treatment-related SAEs or discontinuation-worthy TEAEs. Mild/moderate TEAEs occurred in 14/20 (70%) patients, all resolving promptly. Conclusion: Updated Phase 2 results show LP-005, a bifunctional complement inhibitor, provides sustained clinical benefits and favorable safety in PNH patients with active hemolysis, demonstrating potential superiority over single-pathway inhibitors with best-in-class efficacy and improved treatment convenience.
GuangSheng et al. (Mon,) studied this question.
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