Background: Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by hemolysis due to uncontrolled activity of the alternative pathway (AP) of complement. BCX9930 is an oral Factor D inhibitor that targets the rate-limiting enzyme of AP with the potential to prevent both intravascular hemolysis and extravascular hemolysis. We previously reported safety and effectiveness of BCX9930 at 22 weeks in subjects naïve to complement inhibitors (CI; McDonald et al. EHA 2021). Here, we report further long-term safety, tolerability, and effectiveness of BCX9930.
Aims: This analysis evaluated effectiveness of BCX9930 in subjects completing at least 48 weeks of treatment at target dose of 400 mg BID or 500 mg BID. Additionally, safety data are presented for all subjects (n=16, including 6 subjects with an inadequate response to C5 inhibitors) enrolled in an open-label, dose-ranging study (NCT04330534) and extension study (NCT04702568).
Methods: Study BCX9930-101 enrolled subjects with PNH with either no history of C5 inhibitor use or those with an inadequate response to C5 inhibitors (transfusion within 3 months of screening or Hb <10 g/dL). Subjects in each of three multiple dose cohorts received BCX9930 at 50 to 400 mg orally twice daily (BID) titrated to target dose of 400 or 500 mg BID. CI-naïve subjects deriving clinical benefit after 28 days of treatment could receive up to 48 additional weeks of BCX9930 before continuing into an extension study.
Safety and effectiveness outcomes were evaluated monthly. Effectiveness endpoints were change from baseline (CFB) to 48 weeks in hemoglobin (Hb), red blood cell (RBC) transfusions, lactate dehydrogenase (LDH), absolute reticulocyte count (ARC), and % PNH Type II+III RBC clone size relative to PNH white blood cell (WBC) clone size. CFB in fatigue was assessed by Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale (clinically important difference ≥3-point change, higher scores indicate less fatigue).
Results: Ten CI-naïve adult subjects enrolled in BCX9930-101 and 9 completed at least 48 weeks of treatment. Mean (SD) age and time since PNH diagnosis were 29.2 (8.09) years and 2.6 (1.70), mean (SD) number of RBC units transfused in 12 months prior to study entry was 7.6 (8.2), and median (range) treatment exposure at 400 mg or 500 mg BID was 470 (350, 533) days. Mean (SEM) Hb CFB to Week 48 was 3.75 (0.89) g/dL (8.25 [0.60] g/dL to 12.0 [0.85] g/dL), and all 9 subjects were transfusion-free versus 2 of 9 in 12 months prior to study. At Week 48, mean (SEM) ARC CFB was – 57 (21.8) 103/µL (178 [20.7] vs. 121 [15.5] 103/µL), mean (SEM) % PNH RBC/WBC clone size increased from 51.9% (4.4%) to 93% (2.7%), and mean (SEM) LDH CFB was –70.5% (6.18%). Clinically meaningful improvements in FACIT-Fatigue scores were observed over 48 weeks, with mean (SEM) CFB of 5.3 (1.82) points (mean score 40.7 vs 46.0). The most common adverse events in all subjects (n=16) were headache (38%), self-limited rash (25%), and abdominal pain (19%).
Summary/Conclusion: BCX9930 at doses up to 500 mg BID was generally well-tolerated. Notable improvements from baseline to 48 weeks were observed in Hb, LDH, ARC, and fatigue scores, with concomitant increases in PNH RBC clone size. Proximal AP inhibition of Factor D by BCX9930 demonstrated sustained relief of anemia and fatigue, and freedom from transfusions, supporting ongoing pivotal trials of BCX9930 monotherapy for treatment of PNH.