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

• ClinicalTrials.gov Identifier: NCT04442347
• Recruitment Status: Active, not recruiting
• First Posted: June 22, 2020
• Last Update Posted: April 7, 2023
• Sponsor: Arcturus Therapeutics, Inc.
• Information provided by (Responsible Party): Arcturus Therapeutics, Inc.

Study Description

Brief Summary:

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).

Condition or disease	Intervention/treatment	Phase
Ornithine Transcarbamylase Deficiency	Biological: ARCT-810; Other: Placebo	Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 12 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Masking Description: Double Blinded, Placebo Controlled
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: November 3, 2020
• Estimated Primary Completion Date: August 2023
• Estimated Study Completion Date: August 2023

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Incidence, severity and dose-relationship of adverse events (AEs) [ Time Frame: 4 weeks ]
   Safety and tolerability of ARCT-810 assessed by determining the incidence, severity and dose-relationship of AEs by dose

Secondary Outcome Measures :

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

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Florida

University of Florida

Gainesville, Florida, United States, 32608

United States, Minnesota

M Health Fairview Masonic Children's Hospital

Minneapolis, Minnesota, United States, 55454

United States, New York

The Mount Sinai Hospital

New York, New York, United States, 10029

United States, Pennsylvania

Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, United States, 15224

United States, Texas

University of Texas Southwestern Medical Center at Dallas

Dallas, Texas, United States, 75390

Baylor University

Waco, Texas, United States, 76706

United States, Utah

University of Utah

Salt Lake City, Utah, United States, 84112

United States, Wisconsin

Children's Wisconsin - Milwaukee Hospital

Milwaukee, Wisconsin, United States, 53226

Sponsors and Collaborators

Arcturus Therapeutics, Inc.

More Information

• Responsible Party: Arcturus Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT04442347
• Other Study ID Numbers: ARCT-810-02
• First Posted: June 22, 2020
• Last Update Posted: April 7, 2023
• Last Verified: April 2023

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Ornithine Carbamoyltransferase Deficiency Disease; Urea Cycle Disorders, Inborn; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Metabolic Diseases