Safety, Tolerability, and Pharmacokinetics of ARCT-810 in Stable Adult Subjects With Ornithine Transcarbamylase Deficiency

• ClinicalTrials.gov Identifier: NCT04442347
• Recruitment Status: Recruiting
• First Posted: June 22, 2020
• Last Update Posted: October 8, 2020
• 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.

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) subjects are planned to be enrolled. The length of each study participant is approximately 8 weeks from screening to last study visit. The study comprises an up to 4-week Screening and a 4-week Diet Run-in period to run 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 different study groups (also called cohorts), to test different doses of ARCT-810. There will be 4 participants 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
• Estimated Study Start Date: October 2020
• Estimated Primary Completion Date: November 2021
• Estimated Study Completion Date: December 2021

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:

• Males and females ≥18 years of age with documented diagnosis of late onset OTC deficiency confirmed with genetic testing.
• Subject's Ornithine Transcarbamylase deficiency (OTCD) is stable as evidenced by a) no clinical symptoms of hyperammonemia and b) 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.
• If using nitrogen ammonia scavenger therapy, must be on a stable regimen for ≥ 28 days prior to signing informed consent and must remain on the same regimen throughout the screening period
• Must have maintained a stable protein restricted diet +/- amino acid supplementation for at least 28 days prior to signing informed consent and continue to maintain a stable diet for the duration of the study
• No clinically significant abnormal findings on medical history, clinical laboratory test results (other than ammonia) vital sign measurements, 12-lead ECG results, or physical examination
• Males must be surgically sterile or willing to use adequate contraception; females must be post-menopausal, surgically sterile or willing to use adequate contraception

Exclusion Criteria:

• History of clinically significant disease(s) (other than OTCD)
• Abnormal hepatic enzymes, significant renal impairment, clinically significant anemia or uncontrolled diabetes
• Blood Pressure greater than 160/100 mm Hg
• Malignancy within 5 years prior to study
• Treatment with another investigational drug, biological agent, or device within one month of screening, or 5 half-lives of investigational drug, whichever is longer
• Gene therapy within 1 year prior to screening
• Prior organ transplant
• Positive viral serology test results for HIV type 1 or 2 antibodies, hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibody

Contacts and Locations

Contacts

Contact: Steve Hughes, MD; 858-900-2660; steveh@arcturusrx.com

Contact: Manely Yafeh; 858-900-2660; Manely@arcturusrx.com

Locations

United States, Texas

University of Texas Southwestern Medical Center at Dallas; Recruiting

Dallas, Texas, United States, 75390

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: October 8, 2020
• Last Verified: October 2020

• 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