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

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.

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 Exclusion Criteria (Part 3):

• Apart from a diagnosis of PNH, any clinically significant medical or psychiatric condition or medical history, other than those associated with PNH disease, that, in the opinion of the Investigator or Sponsor, would interfere with the subject's ability to participate in the study or participation would increase the risk for that subject
• Active bacterial infection
• Hereditary complement deficiency
• History of hematopoietic stem cell /marrow transplantation
• Current participation in any other investigational drug study or participation in an investigational drug study within 30 days of the screening visit
• History of meningococcal disease
• Positive drugs of abuse screen at screening visit
• Pregnant, planning to become pregnant, or having been pregnant within 90 days of Day 1, or lactating
• History of severe hypersensitivity to any drug