First-in-Human Study of BCX9930 in Healthy Volunteers and Patients With PNH

Conditions

Paroxysmal Nocturnal Hemoglobinuria

Keywords

Paroxysmal Nocturnal Hemoglobinuria, first-in-human, Factor D, complement inhibitor, alternative pathway inhibitor, BioCryst, proof-of-concept

Brief summary

This is a 3-part Phase 1 dose-ranging study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single (Part 1) and multiple (Part 2) ascending doses of BCX9930 in healthy subjects and in subjects with paroxysmal nocturnal hemoglobinuria (PNH; Part 3). Pharmacokinetics is an analysis of how the body handles the study drug BCX9930 and pharmacodynamics is an analysis of the activity that the study drug BCX9930 may have in the body.

Detailed description

Up to 6 sequential ascending dose cohorts are planned to be dosed in a sequential manner in Part 1 of the study. Eight subjects will be treated with a single dose of the study drug per dose cohort (6 subjects per cohort will receive BCX9930 and 2 subjects per cohort will receive matching placebo). Escalation to the next higher dose level will occur only after completion of a review of clinical safety and pharmacokinetics by the Sponsor and PI. Up to 7 ascending, multiple dose cohorts will be enrolled in a sequential manner in Part 2 of the study. In Cohorts 1 through 3, twelve subjects will be treated with either a 7-day or 14-day course of study drug (10 subjects per cohort will receive BCX9930 and 2 subjects per cohort will receive matching placebo) administered orally. In Cohorts 4 through 7, twelve subjects will be treated with a 3-day course of study drug (10 subjects per cohort will receive BCX9930 and 2 subjects per cohort will receive matching placebo) administered orally. The daily dose may be split into 2 times daily (BID) or 3 times daily (TID) dosing for the multiple ascending dose part as needed. Escalation to the next higher dose level in Part 2 will occur only after completion of a review of clinical safety and pharmacokinetics by the Sponsor and PI. Part 3 of the study consists of up to 2 sequential ascending multiple dose cohorts of up to 8 subjects; each cohort may enroll up to 4 subjects with PNH who are naïve to both eculizumab and ravulizumab and up to 4 subjects with PNH who are currently being treated with either eculizumab or ravulizumab. In each cohort, subjects will receive one daily dose of BCX9930 on Days 1 to 14 and a higher daily dose on Days 15 to 28. Cohort 2 will start after independent data monitoring committee (DMC) review of Cohort 1 data and communication of their evaluation to Part 3 investigators. In South Africa, subjects that have clinical benefit from BCX9930 will be allowed to continue dosing for up to 48 weeks.

Austin Kulasekararaj, Wolfgang Füreder, Andrew McDonald, Jacques Le Roux Malherbe, Sanyam Gandhi et al. (13 authors)

HemaSphere2022-06-016 citations

10.1097/01.hs9.0000846188.51290.75

P825: FACTOR D INHIBITION WITH ORAL BCX9930 MONOTHERAPY LEADS TO SUSTAINED CONTROL OF HEMOLYSIS AND SYMPTOMS OVER 48 WEEKS IN SUBJECTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA NAÏVE TO C5 INHIBITORS

Andrew McDonald, Jacques Le Roux Malherbe, Austin Kulasekararaj, Wolfgang Füreder, Morag Griffin et al. (11 authors)

HemaSphere2022-06-014 citations

10.1097/01.hs9.0000846184.35066.7a

POS-040 BCX9930, AN ORAL FACTOR D INHIBITOR IN DEVELOPMENT FOR THE TREATMENT OF COMPLEMENT-MEDIATED KIDNEY DISEASES, INHIBITS COMPLEMENT ALTERNATIVE PATHWAY ACTIVITY IN HEALTHY SUBJECTS

X. Chen, J. Wang, F. Zhu, C. Parker, M. Cornpropst et al. (8 authors)

Kidney International Reports2022-06-01

10.1016/j.ekir.2022.04.062

Preclinical Characterization of BCX9930, a Potent Oral Complement Factor D Inhibitor, Targeting Alternative Pathway-Mediated Diseases Including Paroxysmal Nocturnal Hemoglobinuria (PNH)

Xilin Chen, Xiaogang Cheng, Qingde Liu, Saritha Muppa, Cynthia Parker et al. (9 authors)

Blood2020-11-053 citations

10.1182/blood-2020-133921

BCX9930, an Oral Factor D Inhibitor, for the Potential Treatment of Alternative Pathway Mediated Diseases: Interim Results of a Phase 1 Study in Healthy Subjects

Matthew Davidson, Amanda Mathis, Stuart Mair, Diane Gesty‐Palmer, Melanie Cornpropst et al. (10 authors)

Blood2020-11-044 citations

10.1182/blood-2020-138475

BCX9930, a Potent, Selective, Oral Factor D Inhibitor, Demonstrates Proof-of-Concept As Monotherapy in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)

Austin Kulasekararaj, Jacques Le Roux Malherbe, Andrew McDonald, Melanie Cornpropst, Phil Collis et al. (11 authors)

Blood2020-11-044 citations

10.1182/blood-2020-138838

Interventions

DRUGBCX9930

BCX9930 capsules for oral administration

DRUGPlacebo

placebo to match BCX9930 capsules for oral administration

Study design

Allocation

NON_RANDOMIZED

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Masking description

Part 3 is not masked; Parts 1 and 2 are participant and investigator masked.

Intervention model description

Each cohort in Part 3 is enrolled as a single group; Parts 1 and 2 follow a parallel study model.

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Yes

Inclusion criteria

Key Inclusion Criteria (Parts 1, 2, and 3): * Able to provide written informed consent * Acceptable birth control measures for male subjects and women of childbearing potential * Is expected to adequately comply with required study procedures and restrictions Key Inclusion Criteria (Parts 1 and 2): * Body mass index (BMI) of 18.0 to 32.0 kg/m2. * Males and non-pregnant, non-lactating females age 18 to 55 years. * Part 2: Must have recent vaccination against Neisseria meningitidis and must be negative for colonisation by Neisseria meningitidis Key Inclusion Criteria (Part 3 only): * Male or non-pregnant, non-lactating female subjects ≥ 18 years old * Have been diagnosed with PNH and have laboratory values indicative of active PNH * Subjects naïve to both eculizumab and ravulizumab treatment, who have no access to, or are considered unsuitable for proven effective alternative options as per the local standard of care OR subjects currently receiving treatment with eculizumab or ravulizumab have been on a stable dose of eculizumab or ravulizumab for 6 months * Must have recent vaccination against Neisseria meningitidis Key

Exclusion criteria

(Parts 1 and 2): * Clinically significant medical history, current medical or psychiatric condition that, in the opinion of the Investigator or Sponsor, would interfere with the subject's ability to participate in the study or increase the risk of participation for that subject. * Clinically significant ECG finding or laboratory/urinalysis abnormality * Use of prescription or over the counter medication within 14 days of dosing * Participation in any other investigational drug study within 90 days of screening * Recent or current history of alcohol or drug abuse within the last 12 months * Current smokers and those who have smoked within the last 12 months * Positive serology for HIV or active infection with HBV or HCV * Pregnant or nursing * Donation or loss of greater than 400 mL of blood within 3 months * History of severe hypersensitivity to any drug or Neisseria meningitidis vaccines (Part 2) * Subject has recently received a live attenuated vaccine within 30 days of dosing or another type of vaccine within 14 days of Day 1 Key

Design outcomes

Primary

Measure	Time frame
Change in Electrocardiogram (QT interval)	Part 1: Day 16
Incidence of graded treatment-emergent adverse events	Part 1: Day 16
Incidence of graded laboratory chemistry abnormalities	Part 1: Day 16
Incidence of graded urinalysis abnormalities	Part 1: Day 16
Incidence of graded coagulation abnormalities	Part 1: Day 16
Incidence of graded hematology abnormalities	Part 1: Day 16
Change from baseline in blood pressure	Part 1: Day 16
Change from baseline in temperature	Part 1: Day 16
Change from baseline in heart rate	Part 1: Day 16
Change from baseline in respiratory rate	Part 3: Day 44 or Week 50 (South Africa only)
Change in Electrocardiogram (PR interval)	Part 1: Day 16
Change in Electrocardiogram (QRS interval)	Part 1: Day 16
Change in Electrocardiogram (RR interval)	Part 1: Day 16

Secondary

Measure	Time frame
Plasma BCX9930 AUCtau	plasma PK parameters are based on blood sampling through Day 6, 14 or 18 for Part 2 (Day depends on dosing duration); and through Day 28 for Part 3
Plasma BCX9930 Tmax	plasma PK parameters are based on blood sampling through Day 4 for Part 1; through Day 6, 14 or 18 for Part 2 (Day depends on dosing duration); and through Day 28 for Part 3
Plasma BCX9930 AUCinf	plasma PK parameters are based on blood sampling through Day 4 for Part 1
Plasma BCX9930 Cmax	plasma PK parameters are based on blood sampling through Day 4 for Part 1; through Day 6, 14 or 18 for Part 2 (Day depends on dosing duration); and through Day 28 for Part 3
Serum AP complement activity	Part 1:through Study Day 4; through Day 6, 14 or 18 for Part 2 (Day depends on dosing duration); and Part 3 through Day 28 or Week 48 (South Africa only)
Plasma Factor Bb	Part 1:through Study Day 4; through Day 6, 14 or 18 for Part 2 (Day depends on dosing duration); and Part 3 through Day 28 or Week 48 (South Africa only)
Number of blood transfusions	Part 3:baseline through Day 28 or Week 50 (South Africa only)
Lactate dehydrogenase	Part 3: absolute and change from baseline through Day 28 or Week 50 (South Africa only)
Hemoglobin	Part 3: absolute and change from baseline through Day 28 or Week 50 (South Africa only)
Absolute reticulocyte count	Part 3: values and change from baseline through Day 28 or Week 50 (South Africa only)
Haptoglobin	Part 3: absolute and change from baseline through Day 28 or Week 50 (South Africa only)
Plasma BCX9930 t1/2	plasma PK parameters are based on blood sampling through Day 4 for Part 1; through Day 6, 14 or 18 for Part 2 (Day depends on dosing duration); and through Day 28 for Part 3

Countries

Austria, South Africa, United Kingdom

Outcome results

None listed