Abstract
Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disorder of hematopoietic stem cells characterized by hemolysis, bone marrow failure, and thrombosis. NTQ5082, a novel oral selective inhibitor of complement factor B (CFB) with a long half life enabling once daily dosing, is currently under clinical development for PNH.
Methods: This was a multicenter, open-label, phase 2 study conducted in China (NCT06764303). Adult patients aged ≥18 years with complement inhibitor-naïve PNH and signs of active hemolysis were eligible for inclusion. All patients had to be vaccinated against Neisseria meningitidis and Streptococcus pneumoniae ≥14 days before the first treatment of NTQ5082. Patients were randomized 1:1 to two cohorts. Patients in the cohort A started receiving NTQ5082 100 mg QD on Day 1 for 2 weeks. If LDH levels on Day 15 were not reduced by ≥40% from baseline, the dose was up-titrated to 300 mg QD for the remainder of the 12-week period. Patients in the cohort B received 200 mg QD for the entire 12 weeks. After the 12-week treatment period, if there were no safety issues, patients entered a long-term extension study. If failed to derive meaningful clinical benefit—defined as either a <10 g/L rise in Hb from baseline or continued transfusion dependence—entered a dose-tapering period, followed by a safety follow-up. The primary endpoint was the proportion of patients who achieved an increase in Hb concentration of ≥20 g/L compared to baseline at Week 12. Secondary endpoints included proportions of patients with Hb ≥120 g/L, patients without RBC transfusions after the first 4 weeks of dosing, and mean changes from baseline in Hb, reticulocyte count, LDH, total/indirect bilirubin and FACIT-F score.
Results: A total of 25 patients (mean age 43.8 years, 13 female) were randomized to either cohort A (n=12) or B (n=13). At baseline, all patients had signs of active hemolysis (mean LDH: 1701.1 U/L) and clinically significant anemia (mean Hb: 72.7 g/L), with approximately 52% patients being transfusion-dependent. On Day 15 after treatment with NTQ5082, no patients in the cohort A required dose up-titration. Treatment with NTQ5082 resulted in a clinically meaningful improvement in Hb levels in both the cohort A (least squares [LS] mean: 53.8 g/L, 95% CI: 42.7-65.0 g/L) and the cohort B (LS mean: 49.6 g/L, 95% CI: 40.6-58.6 g/L). All treated patients remained transfusion-free up until at least Week 12. The mean percentage reductions in LDH levels from baseline by 85.9% (95% CI: 82.7%-89.1%) and 82.2% (95% CI: 77.5%-86.8%) in cohort A and cohort B, respectively. At Week 12, all 25 patients in the two cohorts achieved the primary endpoint with increases in Hb concentrations by ≥20 g/L compared with baseline. And the percentage of patients achieving Hb ≥120 g/L was 50% (6/12) in the cohort A, and 61.5% (8/13) in the cohort B at Week 12, which represents a high level among the CFB inhibitors with disclosed clinical data. Meanwhile, treatment with NTQ5082 showed consistent improvements for other markers of hemolysis. The mean (SD) percentage change from baseline in reticulocyte count was -42.6% (14.3%) in the cohort A and -46.5% (23.2%) in the cohort B. Mean (SD) percentage change from baseline in total bilirubin levels was -53.7% (13.2%) and -42.5% (29.9%), and the change in indirect bilirubin was -58.6% (19%) and -47.5% (32.1%) in the two cohorts, respectively. Furthermore, most patients showed a clinically meaningful improvement in their FACIT-Fatigue scores from baseline, with mean (SD) changes of 9.2 (7.9) points in the cohort A and 9.2 (8.8) points in the cohort B. NTQ5082 was generally well tolerated. All treatment-related adverse events (TRAEs) were mild to moderate in severity. The most common TRAEs were upper respiratory infections (16.7% in the cohort A) and headache (16.7% in the cohort A and 7.7% in the cohort B). Conclusion: NTQ5082 monotherapy at 100 mg or 200 mg once daily led to rapid and durable hemolysis control and transfusion-free improvement in Hb levels in complement inhibitor-naïve PNH patients. Both dosages of NTQ5082 were well tolerated. With its once-daily dosing regimen, robust improvement in Hb, and a favorable safety profile, NTQ5082 is positioned as a highly competitive CFB inhibitor for the treatment of PNH.
