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

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

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.

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.