Contributions
Abstract: EP589
Type: E-Poster Presentation
Session title: Bone marrow failure syndromes incl. PNH - Clinical
Background
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and potentially life-threatening disorder characterized by red blood cell (RBC) hemolysis, resulting from uncontrolled activity of complement leading to episodes of intravascular hemolysis (IVH), extravascular hemolysis (EVH), chronic hemolytic anemia, and thromboembolism. Administration of C5 inhibitors reduces IVH, but PNH RBCs become opsonized and susceptible to EVH. Complete normalization of hemoglobin (Hb) is only seen in a fraction of patients, while most continue to experience some degree of anemia and fatigue. BCX9930 is a potent, selective inhibitor of complement Factor D that blocks the initiation of the alternative pathway (AP) and has the potential to treat both IVH and EVH as an oral therapy.
Aims
To evaluate the safety, tolerability, and effectiveness of BCX9930 on EVH and residual IVH in PNH patients with an inadequate response to C5 inhibitors in an open-label, dose-ranging Study BCX9930-101 (NCT04330534).
Methods
Six patients receiving a C5 inhibitor with an inadequate response (received a transfusion within 3 months of screening or Hb < 10 g/dL) were enrolled. Oral BCX9930 was added to the C5 inhibitor for 28 days with an increase in BCX9930 dose on Day 15; treatment was with either 200mg BID escalated to 400mg BID (n= 2) or 400mg BID escalated to 500mg BID (n = 4). On Day 28, patients deriving benefit could continue BCX9930 in a long-term extension study.
Results
Two patients are receiving ravulizumab and 4 eculizumab (>900mg every 2 weeks in 3). At baseline, mean Hb was 8.9 g/dL, absolute reticulocyte count (ARC) was 196.3 x103/µL, and proportion of PNH Type II + III RBCs was 48%. Five patients received RBC transfusions (range 1-15) in the 3 months prior to screening. As of the last follow-up visit, all 6 patients have continued in the long-term study with a total duration of BCX9930 therapy of ≥58 days. Meaningful improvements across hemolysis biomarkers and fatigue scores were demonstrated. After the first week of dosing with 400mg BID, all 4 patients had a ≥ 1g/dL increase in Hb. As of the last treatment visit, the mean Hb in the absence of transfusions increased by 3.4 g/dL to a mean of 12.3 g/dL and mean ARC decreased to 86.4 x103/µL. Increased EVH control was further demonstrated by the increase in proportion of PNH Type II+III RBCs to a mean of 71%. One patient received 3 RBC transfusions during the treatment period, as compared to 15 transfusions in the 3 months prior to screening. No other patients have been transfused since initiating BCX9930. Self-reported fatigue (FACIT-fatigue total score) improved by a mean of 7.5 points, well above the minimal important difference (3 points). Five patients reported adverse events (AEs); the most common drug-related AEs were self-limited rash (3) and dizziness (2). No serious or Grade 3 or 4 AEs were reported and there were no trends in safety laboratory values
Conclusion
Oral BCX9930 at doses up to 500mg BID was safe and generally well-tolerated over at least 58 days in PNH patients with inadequate response to a C5 inhibitor. Following initiation of BCX9930, notable improvements were observed in Hb, ARC, abundance of PNH RBC, fatigue scores and RBC transfusion requirements. Both proximal AP inhibition of Factor D and demonstrated improvements in hemolysis support future evaluation of BCX9930 monotherapy for patients who are inadequately responding to C5 inhibitors.
Keyword(s): Paroxysmal nocturnal hemoglobinuria (PNH)
Abstract: EP589
Type: E-Poster Presentation
Session title: Bone marrow failure syndromes incl. PNH - Clinical
Background
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and potentially life-threatening disorder characterized by red blood cell (RBC) hemolysis, resulting from uncontrolled activity of complement leading to episodes of intravascular hemolysis (IVH), extravascular hemolysis (EVH), chronic hemolytic anemia, and thromboembolism. Administration of C5 inhibitors reduces IVH, but PNH RBCs become opsonized and susceptible to EVH. Complete normalization of hemoglobin (Hb) is only seen in a fraction of patients, while most continue to experience some degree of anemia and fatigue. BCX9930 is a potent, selective inhibitor of complement Factor D that blocks the initiation of the alternative pathway (AP) and has the potential to treat both IVH and EVH as an oral therapy.
Aims
To evaluate the safety, tolerability, and effectiveness of BCX9930 on EVH and residual IVH in PNH patients with an inadequate response to C5 inhibitors in an open-label, dose-ranging Study BCX9930-101 (NCT04330534).
Methods
Six patients receiving a C5 inhibitor with an inadequate response (received a transfusion within 3 months of screening or Hb < 10 g/dL) were enrolled. Oral BCX9930 was added to the C5 inhibitor for 28 days with an increase in BCX9930 dose on Day 15; treatment was with either 200mg BID escalated to 400mg BID (n= 2) or 400mg BID escalated to 500mg BID (n = 4). On Day 28, patients deriving benefit could continue BCX9930 in a long-term extension study.
Results
Two patients are receiving ravulizumab and 4 eculizumab (>900mg every 2 weeks in 3). At baseline, mean Hb was 8.9 g/dL, absolute reticulocyte count (ARC) was 196.3 x103/µL, and proportion of PNH Type II + III RBCs was 48%. Five patients received RBC transfusions (range 1-15) in the 3 months prior to screening. As of the last follow-up visit, all 6 patients have continued in the long-term study with a total duration of BCX9930 therapy of ≥58 days. Meaningful improvements across hemolysis biomarkers and fatigue scores were demonstrated. After the first week of dosing with 400mg BID, all 4 patients had a ≥ 1g/dL increase in Hb. As of the last treatment visit, the mean Hb in the absence of transfusions increased by 3.4 g/dL to a mean of 12.3 g/dL and mean ARC decreased to 86.4 x103/µL. Increased EVH control was further demonstrated by the increase in proportion of PNH Type II+III RBCs to a mean of 71%. One patient received 3 RBC transfusions during the treatment period, as compared to 15 transfusions in the 3 months prior to screening. No other patients have been transfused since initiating BCX9930. Self-reported fatigue (FACIT-fatigue total score) improved by a mean of 7.5 points, well above the minimal important difference (3 points). Five patients reported adverse events (AEs); the most common drug-related AEs were self-limited rash (3) and dizziness (2). No serious or Grade 3 or 4 AEs were reported and there were no trends in safety laboratory values
Conclusion
Oral BCX9930 at doses up to 500mg BID was safe and generally well-tolerated over at least 58 days in PNH patients with inadequate response to a C5 inhibitor. Following initiation of BCX9930, notable improvements were observed in Hb, ARC, abundance of PNH RBC, fatigue scores and RBC transfusion requirements. Both proximal AP inhibition of Factor D and demonstrated improvements in hemolysis support future evaluation of BCX9930 monotherapy for patients who are inadequately responding to C5 inhibitors.
Keyword(s): Paroxysmal nocturnal hemoglobinuria (PNH)