Study of CMP-CPS-001 in Healthy Volunteers and Participants With Abnormal Heterozygous OTC Genotype

This is a randomized, double-blind (Sponsor-open), and placebo-controlled study.

The SAD part will be conducted in approximately 48 healthy volunteers, in 4 cohorts of 12, randomized 3:1 to receive a single subcutaneous dose of CMP-CPS-001 or placebo. Participants will be followed for 42 days after dosing.

The MAD part will be conducted in approximately 48 healthy volunteers, in 4 cohorts of 12, randomized 3:1 to receive 3 monthly doses of CMP-CPS-001 or placebo. Participants will be followed for 56 days after the last dose.

Up to 12 participants in Australia and up to 12 participants in EU with abnormal heterozygous OTC genotype will be randomized 3:1 to receive 3 monthly doses of CMP-CPS-001 or placebo. Participants will be followed for 56 days after the last dose.

• CMP-CPS-001 (Drug): CMP-CPS-001 consists of an antisense oligonucleotide solution that will be administered subcutaneously.
• Placebo (Other): Placebo is 0.9% normal saline solution and will be administered subcutaneously.

Primary outcomes

• Adverse events [Screening until 42 days (SAD) or 112 days (MAD, OTC) after dosing]: Incidence of adverse events, including dose limiting toxicities, after administration of CMP-CPS-001

Secondary outcomes

• Plasma PK [Pre-dose (Day 1) until 42 days (SAD) or 112 days (MAD, OTC) after dosing]: Plasma concentration of CMP-CPS-001
• Urinary excretion of CMP-CPS-001 [42 days (SAD) or 111 days (MAD, OTC) after dosing]: Urine concentration of CMP-CPS-001
• Pharmacodynamic effect of CMP-CPS-001 on ureagenesis [Run-in (Day -7) until 42 days (SAD) or 112 days (MAD, OTC) after dosing]: Ureagenesis rate test determination

Sex: All, ages: 16 Years to 65 Years, accepts healthy volunteers

Inclusion Criteria:

* Participants 18 (SAD, MAD, OTC in AUS) or 16 (OTC in EU) to 65 years inclusive at time of informed consent
* BMI ≥18.0 and ≤32 kg/m2 at screening, and ≤110 kg
* Willing and able to sign informed consent form
* OTC cohorts: female and must have confirmed heterozygous OTC genotype

Exclusion Criteria:

* Any significant disease or disorder which, in the opinion of the Investigator, may either put the study participant at risk because of participation in the study, may influence the results of the study, or may affect the study participant's ability to participate in the study
* Clinically relevant illness within 7 days before the first dose of study drug
* History of intolerance to subcutaneous injection or relevant abdominal scarring
* Laboratory results outside normal ranges at screening and judged as clinically relevant by the Investigator for liver function, kidney function, and platelets
* Positive viral serology test results for human immunodeficiency virus type 1 or 2 antibodies, hepatitis B surface antigen or hepatitis C virus antibody
* Any other safety laboratory result considered clinically significant and unacceptable by the Investigator

• Gloria Wong, MD, Principal investigator, Q-Pharm Pty Ltd
• Margreet Wagenmakers, Principal investigator, Erasmus Medical Center