BCX9930 for the Treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH) in Participants With Inadequate Response to C5 Inhibitor Therapy

Phase 2

Terminated

Conditions: Paroxysmal Nocturnal Hemoglobinuria (PNH)

Interventions: Drug: BCX9930
Drug: Eculizumab
Drug: Ravulizumab

Registration Number: NCT05116774

Lead Sponsor: BioCryst Pharmaceuticals

Brief Summary: The purpose of this study was to determine the efficacy and safety of BCX9930 monotherapy for the treatment of PNH compared to continued C5 inhibitor therapy in adult PNH participants with residual anemia despite treatment with a C5 inhibitor.

Detailed Description: This was a randomized, active comparator-controlled, open-label, parallel-group, 2-part study. Parts 1 and 2 were conducted in the same participants.

Part 1 of the study was designed to evaluate the efficacy, safety, and tolerability of oral BCX9930 monotherapy for 24 weeks versus continuing C5 inhibitor therapy in participants with PNH with inadequate response to their current C5 inhibitor therapy. Participants were randomized to either discontinue C5 inhibitor therapy and start BCX9930 monotherapy or to continue C5 inhibitor therapy for the 24-week randomized treatment period. The primary efficacy and safety analyses were based on Part 1.

Part 2 of the study was designed to evaluate the long-term safety, tolerability, and effectiveness of BCX9930 monotherapy when administered through Week 52. All participants in Part 2 received BCX9930. Participants who were randomized to BCX9930 monotherapy in Part 1 continued to receive BCX9930 in Part 2. Participants who were randomized to C5 inhibitor therapy in Part 1 discontinued that therapy at the Week 24 visit and received BCX9930 in Part 2.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 12

Inclusion Criteria

Male or female, aged ≥ 18 years old
Body weight ≥ 40 kg
Documented diagnosis of PNH
Currently being treated with a stable C5 inhibitor regimen
Documentation of current vaccinations against Neisseria meningitidis and Streptococcus pneumoniae or willing to start vaccination series
At screening: PNH clone size of ≥ 10% and hemoglobin ≤ 10.5 g/dL

Exclusion Criteria

Known history of or existing diagnosis of hereditary complement deficiency
History of hematopoietic cell transplant or solid organ transplant or anticipated candidate for transplantation
Myocardial infarction or cerebrovascular accident within 30 days prior to screening, or current and uncontrolled clinically significant cardiovascular or cerebrovascular condition
History of malignancy within 5 years prior to the screening visit
Active bacterial, viral, or fungal infection or any other serious infection within 14 days prior to screening
Treatment with anti-thymocyte globulin within 180 days prior to screening
Initiation of treatment with an erythrocyte or platelet growth factor, or danazol within 28 days prior to screening
Receiving iron supplementation with an unstable dose in the 28 days prior to screening

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
BCX9930/BCX9930	BCX9930	Participants were randomized to receive BCX9930 during Part 1 and continued to receive the same during Part 2. Per protocol amendment, participants who previously received 500 mg twice daily (BID) and remained on study treatment were dose adjusted to 400 mg BID. For all newly enrolled participants, at the initiation of BCX9930 dosing, participants were administered a dose of 200 mg BID for the first 14 days of treatment before increasing to 400 mg BID. The maximum treatment duration on BCX9930 in Part 1 was 24 weeks. The overall maximum treatment duration on BCX9930 was 377 days.
C5-Inhibitor (C5-INH)/BCX9930	Eculizumab	Participants randomized to this group continued the existing C5-INH therapy during Part 1. After the sponsor decided to halt enrolment in the study permanently and terminate the study, participants entered Part 2 where they switched to open-label BCX9930 monotherapy prior to Week 24, if earlier. The maximum treatment duration on C5-INH in Part 1 was 24 weeks. The maximum treatment duration on BCX9930 was 197 days.
C5-Inhibitor (C5-INH)/BCX9930	Ravulizumab	Participants randomized to this group continued the existing C5-INH therapy during Part 1. After the sponsor decided to halt enrolment in the study permanently and terminate the study, participants entered Part 2 where they switched to open-label BCX9930 monotherapy prior to Week 24, if earlier. The maximum treatment duration on C5-INH in Part 1 was 24 weeks. The maximum treatment duration on BCX9930 was 197 days.
C5-Inhibitor (C5-INH)/BCX9930	BCX9930	Participants randomized to this group continued the existing C5-INH therapy during Part 1. After the sponsor decided to halt enrolment in the study permanently and terminate the study, participants entered Part 2 where they switched to open-label BCX9930 monotherapy prior to Week 24, if earlier. The maximum treatment duration on C5-INH in Part 1 was 24 weeks. The maximum treatment duration on BCX9930 was 197 days.

Primary Outcome Measures

Name	Time	Method
Part 1: Change From Baseline in Hemoglobin at Week 24	Baseline, Week 24

Secondary Outcome Measures

Name	Time	Method
Part 1: Number of Participants Who Were Transfusion-free	From Week 4 to Week 24	The number of participants who did not receive any transfusions (packed red blood cells \[pRBCs\] or whole blood) during the period of interest were reported. Participants who were transfusion free were defined for each treatment group as the number of participants who did not receive any transfusions (pRBCs or whole blood) during the period of interest from the start to the end, inclusive, divided by the total number of participants in that treatment group at the start of the period of interest. Participants who (1) discontinued treatment prior to Week 24, or (2) did not receive a transfusion during the period of interest despite recording a hemoglobin (Hb) value ≤ 9 g/dL with symptoms assessed by the investigator as warranting transfusion or a Hb value ≤ 7 g/dL regardless of symptoms were not considered transfusion free.
Part 1: Number of Units of pRBCs Transfused	From Week 4 to Week 24
Part 1: Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score	Baseline, Week 24	The FACIT-Fatigue scale questionnaire was used to determine the level of fatigue experienced by participants. This questionnaire was a 13-item measure that assessed self-reported fatigue and its impact upon daily activities and function. Item scores ranged from 0 ("not at all") to 4 ("very much"), and the total score ranged from 0 to 52, with higher scores indicating greater quality of life.
Part 1: Percent Change From Baseline in Lactate Dehydrogenase	Baseline, Week 24
Part 1: Percentage (%) Reduction in the Rate of pRBC Units Transfused	Prestudy (12 months prior to screening) and from Week 4 to Week 24	The rate of pRBC units transfused from Week 4 to Week 24 was calculated and compared to the rate of pRBC units transfused prestudy during the 12 months prior to screening. The percent reduction in rate of pRBC units transfused was the percent difference in rate relative to the prestudy rate, calculated as: (current rate - prestudy rate)/prestudy rate \* 100%. Total rate among all participants was evaluated here. Rate of pRBC units transfusion was defined as the percentage of participants who received pRBC transfusions.
Part 1: Number of Participants With Hemoglobin ≥ 12 Grams Per Deciliter (g/dL)	Week 24
Part 1: Number of Participants Who Achieved Hemoglobin Stabilization	From Week 4 to Week 24	Hemoglobin stabilization was defined as the participants who avoided 2 g/dL or greater decrease in hemoglobin in the absence of transfusion from Week 4 to Week 24.
Part 1: Change From Baseline in Complement Component 3 (C3)-Opsonized Red Blood Cells (RBCs)	Baseline, Week 24	Red blood cells opsonized by C3 were to be assessed by flow cytometry .
Part 1: Change From Baseline in Total Paroxysmal Nocturnal Hemoglobinuria (PNH) RBC Clone Size	Baseline, Week 24	The total PNH RBC clone size refers to the percentage of PNH affected (ie, Type 2 and 3) RBC cells within the total RBC population.
Part 1: Change From Baseline in Ratio of Total PNH RBC Clone Size to PNH White Blood Cell (WBC) Clone Size	Baseline, Week 24	The total PNH RBC clone size refers to the percentage of PNH affected (ie, Type 2 and 3) RBCs within the total RBC population. The PNH WBC clone size refers to the percentage of PNH-affected WBCs within the total WBC population. The ratio of total PNH RBC clone size to PNH WBC clone size = ratio of percent total PNH RBCs / percent PNH WBCs.
Part 1: Change From Baseline in Absolute Reticulocyte Count (ARC)	Baseline, Week 24
Part 1: Number of Participants With ARC in the Normal Range	Week 24	Number of participants with ARC in the normal range (0.03 - 0.12 10\^6 cells/uL) were reported.
Part 1: Change From Baseline in Haptoglobin	Baseline, Week 24
Part 1: Number of Participants With Haptoglobin ≥ Lower Limit of Normal (LLN) Reference Range	Week 24	Number of Participants With Haptoglobin ≥ LLN Reference Range (≥0.3 g/L) were reported.
Part 1: Change From Baseline in Total Bilirubin	Baseline, Week 24