Study for Adolescent and Adult Participants With Ornithine Transcarbamylase Deficiency to Evaluate Safety and Tolerability of ARCT-810

Study Overview
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Brief Summary
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The primary objective is to evaluate the safety and tolerability of repeated doses of intravenously administered ARCT-810.

Detailed Description
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This study is a Phase 2, randomized, placebo-controlled study of ARCT-810 in people living with OTC deficiency 12 years of age and older. After a 4-6-week screening and diet stabilization period, participants will be randomized 3:1 to receive ARCT-810 or placebo. Following the first dose and safety evaluation, participants will receive up to an additional 5 doses of ARCT-810 or placebo, each separated by 14 days. The treatment period is followed by a 12-week observation period.

Official Title
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Phase 2, Randomized, Double-Blind, Placebo-Controlled, Nested Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetics of ARCT-810 in Adolescent and Adult Participants With Ornithine Transcarbamylase Deficiency

Conditions
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Ornithine Transcarbamylase Deficiency, OTC Deficiency, OTCD

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


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Adequate cognitive ability to understand study requirements and give informed consent Males and females aged 12 to 65 years inclusive, at Screening Documented diagnosis of OTC deficiency confirmed with genetic testing Clinical stability (no clinical symptoms of hyperammonemia within 1 month, no hospitalizations for metabolic decompensation within 3 months, ≤ 2 hospitalizations within 1 year) Stable protein-restricted diet, dietary supplements, and ammonia scavenger regimen (if applicable) for at least 28 days. BMI = 18.0 - 32.0 kg/m2, inclusive for adults, and >5th percentile for adolescents ≥12 to 17 years Must be willing to adhere to contraception guidelines Key Exclusion Criteria: History of OTC gene therapy, hepatocyte or stem cell transplantation History of other medical conditions that may make the participant unsuitable for inclusion or could interfere with study participation (e.g., uncontrolled hypertension or diabetes, malignancy, HIV, hepatitis B or C) History of severe allergic reaction to liposomal or PEG-containing products Abuse of illicit drugs, medications or alcohol Clinically significant laboratory abnormalities on screening labs

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 65 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: Sequential Assignment
Interventional Model Description: On Day 1, participants will receive a single dose of Study Drug via intravenous infusion. If the safety observations are considered acceptable, that participant will enter the multiple-dose portion of the study where they will receive a further 5 doses of Study Drug on Days 15, 29, 43, 57 and 71.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARCT-810<br>Participants receive an initial intravenous (IV) infusion ARCT-810. If considered safe and well tolerated, participants will receive up to 5 additional IV infusions of ARCT-810 administered at 14-day intervals. | Biological: ARCT-810<br>* ARCT-810 is messenger RNA (mRNA) coding for Ornithine Transcarbamylase (OTC) formulated in a lipid nanoparticle (LNP) under development.<br>|
| Placebo Comparator: Placebo, Normal Saline<br>Participants receive an initial IV infusion of placebo. If considered safe and well tolerated, participants receive up to 5 additional IV infusions of placebo administered at 14-day intervals. | Other: Placebo<br>* Normal 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 number of AEs by dose | Week 23 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentration area under the curve after first and last doses of ARCT-810 | Area under the plasma concentration versus time curve (AUC) from time zero to the last quantifiable time point | Up to 17 Weeks | 
| Maximum observed plasma concentration (Cmax) after first and last doses of ARCT-810 | The maximum observed plasma concentration (Cmax) | Up to 17 Weeks | 
| Time at which Cmax occurred after first and last doses of ARCT-810 | The time at which Cmax occurred (Tmax) | Up to 17 Weeks | 
| AUC0-inf after first and last doses of ARCT-810 | Plasma AUC from time zero extrapolated to infinity | Up to 17 Weeks | 
| AUCExtrap after first and last doses of ARCT-810 | The relative portion of AUC0-inf extrapolated beyond AUC0-t | Up to 17 Weeks | 
| T1/2 after first and last doses of ARCT-810 | Terminal half-life | Up to 17 Weeks | 
| MRT0-inf after first and last doses of ARCT-810 | The mean residence time extrapolated to infinity | Up to 17 Weeks | 
| CL after first and last doses of ARCT-810 | Total body clearance, calculated as dose divided by AUC0-inf | Up to 17 Weeks | 
| Vss after first and last doses of ARCT-810 | Volume of distribution | Up to 17 Weeks | 
| Urea Cycle Function | Change from baseline in urea cycle function as measured by 13C-urea assay | Week 12 | 
| Plasma Ammonia | Change from baseline in urea cycle function as measured by 24-hour plasma ammonia profile | Week 11 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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OTC, OTCD, Ornithine, Transcarbamylase, mRNA, Ornithine Transcarbamylase Deficiency, OTC Deficiency