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

Study Overview
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Brief Summary
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Determine the safety, tolerability and pharmacokinetics of single doses of ARCT-810 in clinically stable patients (stable on standard of care treatment, e.g. diet ± ammonia scavengers) with ornithine transcarbamylase deficiency (OTCD).

Detailed Description
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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.

Official Title
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A Phase 1b Randomized, Double Blinded, Placebo Controlled, Ascending Dose Study to Assess the Safety, Tolerability, and Pharmacokinetics of Single Doses of ARCT-810 in Clinically Stable Patients With Ornithine Transcarbamylase Deficiency

Conditions
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Ornithine Transcarbamylase Deficiency

Intervention / Treatment
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* Biological: ARCT-810
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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 b, 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARCT-810<br>Ascending single doses of ARCT-810 administered intravenously | Biological: ARCT-810<br>* ARCT-810 is an investigational medicinal product comprising Ornithine Transcarbamylase (OTC) mRNA formulated in a lipid nanoparticle (LNP) under development.<br>|
| Placebo Comparator: Placebo<br>Single doses of 0.9% Saline administered intravenously | Other: Placebo<br>* The placebo for this study is 0.9% sterile saline.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence, severity and dose-relationship of adverse events (AEs) | Safety and tolerability of ARCT-810 assessed by determining the incidence, severity and dose-relationship of AEs by dose | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in area under the curve after single dose of ARCT-810 | Area under the plasma concentration versus time curve (AUC) from time zero to the last quantifiable time point | Up to 4 weeks | 
| Maximum observed plasma concentration (Cmax) after single dose of ARCT-810 | The maximum observed plasma concentration (Cmax) | Up to 4 weeks | 
| Time at which Cmax occurred after single dose of ARCT-810 | The time at which Cmax occurred (Tmax) | Up to 4 weeks | 
| AUC0-inf after single dose of ARCT-810 | AUC from time zero extrapolated to infinity | Up to 4 weeks | 
| AUCExtrap after single dose of ARCT-810 | The relative portion of AUC0-inf extrapolated beyond AUC0-t | Up to 4 weeks | 
| T1/2 after single dose of ARCT-810 | Terminal half-life | Up to 4 weeks | 
| MRT0-inf after single dose of ARCT-810 | The mean residence time extrapolated to infinity | Up to 4 weeks | 
| CL after single dose of ARCT-810 | Total body clearance, calculated as dose divided by AUC0-inf | Up to 4 weeks | 
| Vss after single dose of ARCT-810 | Volume of distribution | Up to 4 weeks |