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

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

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Ornithine Transcarbamylase Deficiency
• Intervention / Treatment: Other: Placebo; Biological: ARCT-810

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 12
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: David Geller, MD; Phone Number: 224-727-7636; Email: davidg@arcturusrx.com
• Study Contact Backup: Name: Elizabeth Colon; Phone Number: 231-730-7300; Email: elizabeth.colon@arcturusrx.com

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32608
      • University of Florida
  • Minnesota
    • Minneapolis, Minnesota, United States, 55454
      • M Health Fairview Masonic Children's Hospital
  • New York
    • New York, New York, United States, 10029
      • The Mount Sinai Hospital
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center at Dallas
    • Waco, Texas, United States, 76706
      • Baylor University
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Children's Wisconsin - Milwaukee Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Adequate cognitive ability to consent and recall symptoms over a 1-week time period
2. 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

3. Subject's ornithine transcarbamylase deficiency (OTCD) is stable as evidenced by

   1. no clinical symptoms of hyperammonemia AND b,
   2. 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.
4. 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
5. 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
6. Good general health other than OTCD, in the opinion of the Investigator
7. Willing to refrain from strenuous exercise/activity and alcohol for 72 hours before study visits
8. Willingness to comply with procedures and visits
9. Willingness to follow contraception guidelines

Exclusion Criteria:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Arcturus Therapeutics, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): November 3, 2020
• Primary Completion (Anticipated): August 1, 2023
• Study Completion (Anticipated): August 1, 2023

Study Registration Dates

• First Submitted: June 19, 2020
• First Submitted That Met QC Criteria: June 19, 2020
• First Posted (Actual): June 22, 2020

Study Record Updates

• Last Update Posted (Actual): April 7, 2023
• Last Update Submitted That Met QC Criteria: April 6, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Amino Acid Metabolism, Inborn Errors; Urea Cycle Disorders, Inborn; Ornithine Carbamoyltransferase Deficiency Disease
• Other Study ID Numbers: ARCT-810-02

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No