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 AP rate-limiting enzyme with the potential to prevent both intravascular hemolysis and extravascular hemolysis. We previously presented safety and effectiveness data for BCX9930 at 11 weeks in subjects with an inadequate response (IR) to C5 inhibitors (C5 INH; Kulasekararaj 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 enrolled (n=16, including 10 subjects naïve to C5 INH) 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 INH use or those with an IR to C5 INH (defined as having a transfusion within 3 months of screening or Hb <10 g/dL). For subjects with an IR to C5 INH treatment, BCX9930 was added to C5 INH and subjects were treated with 200 mg orally twice daily (BID) escalated to 400 mg BID, or 400 mg BID escalated to 500 mg BID. Subjects deriving clinical benefit could rollover into an extension study after 28 days, and C5 INH could be withdrawn.
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 RBCs relative to PNH white blood cells (WBC). 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: Six adult subjects with an IR to C5 INH enrolled in Study BCX9930-101 and rolled over into the open-label extension study, and 4 completed 48 weeks of treatment (3 of 4 on BCX9930 monotherapy at Week 48, mean [range] duration on monotherapy 107 [85, 129] days). Mean (SD) age and time since PNH diagnosis were 31 (9.42) and 7.7 (5.80) years, mean (SD) number of RBC units transfused in 12 months prior to study entry was 5.5 (4.4), and median (range) treatment exposure at 400 mg or 500 mg BID was 413.5 (337, 420) days. Mean (SEM) Hb CFB to Week 48 was 2.69 (0.97) g/dL (8.91 [0.56] g/dL to 11.60 [1.27] g/dL). 3 of 4 subjects were transfusion-free at Week 48 versus 1 of 4 in 12 months prior to study. At Week 48, Mean (SEM) ARC CFB was –63 (17.1) 103/µL (204 [15.5] vs. 141 [19.6] 103/µL), and mean (SEM) % PNH RBC/WBC clone size increased from 59% (4.4%) to 92% (3.8%,). Clinically meaningful improvements in FACIT-Fatigue scores were observed over 48 weeks, with mean (SEM) CFB of 10.7 (6.0) points (mean score 37.3 vs. 47.9). The most common adverse events for 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 were observed from baseline to 48 weeks in Hb, ARC, and fatigue scores, with concomitant increases in PNH RBC clone size. Proximal AP inhibition of Factor D by BCX9930 in combination with C5 INH (with 3 of 4 subjects transitioning to monotherapy) led to sustained relief of anemia, fatigue, and reduction of transfusion burden, supporting ongoing pivotal trials of oral BCX9930 monotherapy for treatment of PNH.