Phase 1b Study to Assess Safety, Tolerability, and Pharmacokinetics of ARCT-810 in Stable Adult Subjects With Ornithine Transcarbamylase Deficiency

This is a single ascending dose study of ARCT-810 in which approximately 12 (up to a maximum of 20) clinically stable patients with ornithine transcarbamylase deficiency (OTCD) are planned to be enrolled.

Each study subject's participation length is approximately 8 weeks, from screening through last study visit. The study comprises an up to 4-week screening period, and a 4-week diet run-in period, to occur concurrently, followed by a 1-day dosing period and a 28-day post-treatment period.

Study participants will be allocated to one of the three single-dose treatment groups (also referred to as cohorts), to test different doses of ARCT-810. Four subjects will be enrolled in each group. Within each cohort, subjects will be randomized 3:1 to receive ARCT-810 or placebo as an IV infusion.

Inclusion criteria

• Adequate cognitive ability to consent and recall symptoms over a 1-week time period
• Males and females ≥18 years of age with documented diagnosis of ornithine transcarbamylase deficiency (OTCD) confirmed with genetic testing, or willing to consent to OTC gene sequencing and deletion/duplication testing
• Subject's ornithine transcarbamylase deficiency (OTCD) is stable as evidenced by

• no clinical symptoms of hyperammonemia AND
• an ammonia level <100 µmol/L (170 µg/dL) at the screening evaluation

Subjects must remain free from symptoms of hyperammonemia throughout the screening period.

• If using nitrogen ammonia scavenger therapy, must be on a stable regimen (no change in dose or frequency) for ≥ 28 days prior to providing informed consent and throughout the screening period
• Must have maintained a stable protein-restricted diet (+/- amino acid supplementation) for at least 28 days prior to providing informed consent and continue to maintain a stable diet for the duration of the study
• Good general health other than OTCD, in the opinion of the Investigator
• Willing to refrain from strenuous exercise/activity and alcohol for 72 hours before study visits
• Willingness to comply with procedures and visits
• Willingness to follow contraception guidelines

Exclusion criteria

• History of clinically significant disease(s), in the opinion of the Investigator
• Clinically significant screening laboratory values
• Uncontrolled diabetes
• Clinically significant anemia
• Subjects who develop infection during screening must be asymptomatic for at least 7 days prior to dosing
• Unwillingness to comply with study requirements
• History of positive HIV, hepatitis C, or chronic hepatitis B
• Uncontrolled hypertension
• Malignancy within 5 years prior to study
• Treatment with another investigational drug, biological agent, or device within 30 days of screening, or 5 half-lives of investigational drug
• Treatment with any oligonucleotide or mRNA within 6 months of screening, with exceptions for some vaccinations and investigational treatments
• History of gene therapy, hepatocyte or mesenchymal stem cell transplantation
• Prior organ transplant
• History of severe allergic reaction to a liposomal product
• Recent history of, or current, drug or alcohol abuse
• Dependence on inhaled (smoked or vaped) or oral cannabis products
• Systemic corticosteroids within 6 weeks prior to screening
• Blood donation of 50 to 499 mL within 30 days of screening or of .499 mL within 60 days of screening
• Other conditions, in the opinion of the Investigator, that would make the subject unsuitable for participation