Contributions
Abstract: EP585
Type: E-Poster Presentation
Session title: Bone marrow failure syndromes incl. PNH - Clinical
Background
PNH, a rare, chronic, life-threatening disease is characterized by hemolysis due to uncontrolled activity of the complement alternative pathway (AP), and is associated with bone marrow failure, and thrombosis. Terminal complement pathway inhibition with C5 inhibitors may not be sufficient for disease control as up to half of PNH patients remain transfusion dependent with C5 inhibitor treatment. BCX9930 is an orally administered small-molecule factor D inhibitor targeting the proximal AP with the potential to inhibit intravascular hemolysis and prevent extravascular hemolysis in patients with PNH.
Aims
The objectives of this part of the study were to evaluate the safety, tolerability, and effectiveness of BCX9930 in complement inhibitor-naïve patients with PNH.
Methods
Study BCX9930-101 (NCT04330534), an open-label dose-ranging study, enrolled PNH subjects with no prior history of C5-inhibitor treatment into one of three multiple dose cohorts. Subjects in each cohort received BCX9930 at starting doses of 50mg-400mg twice daily (BID) titrated to a maximum of 500mg BID. Safety endpoints included the incidence and severity of treatment-emergent adverse events (TEAEs). Effectiveness endpoints included clinical measurements of hemoglobin (Hb), number of transfusions, lactate dehydrogenase (LDH), absolute reticulocyte count (ARC), and percent PNH red blood cells (RBCs). Fatigue was assessed by the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale; a 3-point change is considered a minimal important difference. This abstract includes data from screening through data cut-off of 22 January 2021 in an open-label extension.
Results
10 adult patients (mean age 30 years) were enrolled in 3 cohorts with starting dose regimens of 50 mg BID (n=4), 200 mg BID (N=4), and 400 mg BID (N=2). Mean time since clinical diagnosis of PNH was 4 years. Six patients required a total of 31 transfusions in the 12 months prior to treatment. The median duration of BCX9930 treatment was 147 days (range 28-340); 9 patients remain on treatment at 400 or 500 mg BID and 5 have been treated > 5 months. BCX9930 was well-tolerated. Nine subjects (90%) had TEAEs; 5 patients had 5 Grade 3 TEAEs of which 2 were considered treatment related and resolved with continued treatment. Two serious adverse events unrelated to study drug were reported (gastritis in 1 patient and fatal disseminated varicella zoster infection in 1 patient).
Hb improved in all patients with a mean improvement from baseline (BL) to the last treatment visit (LTV) of 3.3g/dL. Only 1 patient required 1 transfusion which occurred during the 100 mg BID treatment period. Mean ARC decreased from 180.3 x 109/L to 115.8 x 109/L at LTV. The relative percent of PNH Type II+III RBC to percent PNH WBC increased from 56% at BL to 90% at LTV. Meaningful improvements in FACIT fatigue score were observed with an increase of 7.3 points. During the treatment period with 400 mg BID/500 mg BID, BCX9930 demonstrated a mean (SD) reduction of 67% (13.4) in LDH from BL.
Conclusion
BCX9930, an orally administered potent and specific factor D inhibitor, was safe and generally well-tolerated as monotherapy in complement inhibitor-naïve patients with PNH at doses up to 500mg BID. Inhibition of the AP with BCX9930 reduced hemolysis, with reduction in transfusions and improvements in laboratory parameters. Improvements in fatigue were also observed. This study successfully identified a safe and tolerable BCX9930 dose range with dose-related meaningful clinical improvement, supporting progression to controlled clinical trials of BCX9930 in PNH.
Keyword(s): Paroxysmal nocturnal hemoglobinuria (PNH)
Abstract: EP585
Type: E-Poster Presentation
Session title: Bone marrow failure syndromes incl. PNH - Clinical
Background
PNH, a rare, chronic, life-threatening disease is characterized by hemolysis due to uncontrolled activity of the complement alternative pathway (AP), and is associated with bone marrow failure, and thrombosis. Terminal complement pathway inhibition with C5 inhibitors may not be sufficient for disease control as up to half of PNH patients remain transfusion dependent with C5 inhibitor treatment. BCX9930 is an orally administered small-molecule factor D inhibitor targeting the proximal AP with the potential to inhibit intravascular hemolysis and prevent extravascular hemolysis in patients with PNH.
Aims
The objectives of this part of the study were to evaluate the safety, tolerability, and effectiveness of BCX9930 in complement inhibitor-naïve patients with PNH.
Methods
Study BCX9930-101 (NCT04330534), an open-label dose-ranging study, enrolled PNH subjects with no prior history of C5-inhibitor treatment into one of three multiple dose cohorts. Subjects in each cohort received BCX9930 at starting doses of 50mg-400mg twice daily (BID) titrated to a maximum of 500mg BID. Safety endpoints included the incidence and severity of treatment-emergent adverse events (TEAEs). Effectiveness endpoints included clinical measurements of hemoglobin (Hb), number of transfusions, lactate dehydrogenase (LDH), absolute reticulocyte count (ARC), and percent PNH red blood cells (RBCs). Fatigue was assessed by the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale; a 3-point change is considered a minimal important difference. This abstract includes data from screening through data cut-off of 22 January 2021 in an open-label extension.
Results
10 adult patients (mean age 30 years) were enrolled in 3 cohorts with starting dose regimens of 50 mg BID (n=4), 200 mg BID (N=4), and 400 mg BID (N=2). Mean time since clinical diagnosis of PNH was 4 years. Six patients required a total of 31 transfusions in the 12 months prior to treatment. The median duration of BCX9930 treatment was 147 days (range 28-340); 9 patients remain on treatment at 400 or 500 mg BID and 5 have been treated > 5 months. BCX9930 was well-tolerated. Nine subjects (90%) had TEAEs; 5 patients had 5 Grade 3 TEAEs of which 2 were considered treatment related and resolved with continued treatment. Two serious adverse events unrelated to study drug were reported (gastritis in 1 patient and fatal disseminated varicella zoster infection in 1 patient).
Hb improved in all patients with a mean improvement from baseline (BL) to the last treatment visit (LTV) of 3.3g/dL. Only 1 patient required 1 transfusion which occurred during the 100 mg BID treatment period. Mean ARC decreased from 180.3 x 109/L to 115.8 x 109/L at LTV. The relative percent of PNH Type II+III RBC to percent PNH WBC increased from 56% at BL to 90% at LTV. Meaningful improvements in FACIT fatigue score were observed with an increase of 7.3 points. During the treatment period with 400 mg BID/500 mg BID, BCX9930 demonstrated a mean (SD) reduction of 67% (13.4) in LDH from BL.
Conclusion
BCX9930, an orally administered potent and specific factor D inhibitor, was safe and generally well-tolerated as monotherapy in complement inhibitor-naïve patients with PNH at doses up to 500mg BID. Inhibition of the AP with BCX9930 reduced hemolysis, with reduction in transfusions and improvements in laboratory parameters. Improvements in fatigue were also observed. This study successfully identified a safe and tolerable BCX9930 dose range with dose-related meaningful clinical improvement, supporting progression to controlled clinical trials of BCX9930 in PNH.
Keyword(s): Paroxysmal nocturnal hemoglobinuria (PNH)