Safety, Tolerability and PK/PD Evaluation of Intravenous Administration of MRT5201 in Patients With OTC Deficiency

Study Overview
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Brief Summary
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This Phase 1/2, first-in-human study will evaluate the safety and tolerability of single escalating doses of MRT5201 administered intravenously to subjects with OTC Deficiency (OTCD). This study will also evaluate the effect of a single dose of MRT5201 on metabolic markers of OTCD and ureagenesis; and determine an acceptable dosing interval of MRT5201.

Official Title
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A Phase 1/2 Single Ascending Dose Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Intravenously Administered MRT5201 in Subjects With Ornithine Transcarbamylase Deficiency

Conditions
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Ornithine Transcarbamylase Deficiency

Intervention / Treatment
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* Biological: MRT5201
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have a documented diagnosis of OTCD. Documented history of ≥1 symptomatic hyperammonemia event with ammonia ≥100 µmol/L Subject's OTCD is stable as evidenced by meeting the following criteria: Ammonia level <175 µmol/L during the Screening Period and at Baseline (Day -1) No clinical symptoms of hyperammonemia during the Screening Period and at Baseline (Day -1) If using nitrogen scavenger therapy, must be on a stable regimen for ≥28 days prior to signing informed consent Subject has maintained a stable protein restricted diet (which may or may not include medical foods) and/or amino acid supplementation with no changes in calorie or protein goals and no changes in medical food and/or amino acid supplementation for ≥ 28 days prior to signing informed consent. Exclusion Criteria: Any laboratory abnormality that may put the subject at increased risk by participating in this study. Have any significant concurrent or past medical condition that would represent an unacceptable risk to the subject or might jeopardize the collection of high-quality data from the study. These include but are not limited to: History of liver transplant, including hepatocyte therapy/transplant History of liver disease Positive viral serology test results for HIV type 1 or 2 antibodies, hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibody Type I or Type II diabetes that is poorly controlled, in the opinion of the Investigator Poorly controlled hypertension (defined as systolic blood pressure [BP] > 150 mm Hg or diastolic BP > 90 mm Hg) Use of anticoagulants or platelet inhibitors, including but not limited to heparin and non-steroidal anti-inflammatory drugs (NSAIDS). Acetaminophen is permitted Participation in previous clinical studies evaluating investigational OTCD therapies directed at expressing functional OTC protein (eg, OTC gene therapy studies, other mRNA replacement therapy) that has led to the presence of anti-OTC antibodies.

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: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MRT5201<br>Single Ascending Low, Mid, and High doses of MRT5201 | Biological: MRT5201<br>* Codon-optimized human ornithine transcarbamylase messenger ribonucleic acid with lipid-based nanoparticles<br>|
| Placebo Comparator: Placebo<br>Placebo comparator using 5% dextrose in water at the same administration rate as study drug. | Other: Placebo<br>* 5% dextrose in water<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of treatment-emergent adverse events by treatment group | The incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) for each dosing cohort by treatment group, assessed by severity and relationship to study product. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics parameters of MRT5201 | Pharmacokinetics of MRT5201 as measured by levels of mRNA | 1 month after single dose | 
| Effect of a single dose of MRT5201 on ureagenesis | Change from Baseline in 4-hour ureagenesis AUC at weeks 2, 3, 4, and 5 after a single dose of MRT5201 | Up to 1 month after single dose | 
| Effect of single dose of MRT5201 on metabolic markers of OTCD | Change from Baseline in 8-hour ammonia AUC | 6 months after single dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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OTC, Urea Cycle Disorder, UCD