Design of a phase 3 study of AAV-mediated gene transfer of ornithine transcarbamylase (OTC) in patients with late-onset OTC deficiency
2University Hospitals of Cleveland Medical Center, USA
3University of Santiago de Compostela, Spain
4Hospital Universitari Vall d’Hebron, Spain
5University Medical Center Rotterdam, Department of Internal Medicine, Center for lysosomal and metabolic diseases, Erasmus Medical Center, Netherlands
6University of Toronto and Hospital for Sick Children, Canada
7Ann & Robert H. Lurie Children's Hospital of Chicago, USA
8University of Arkansas for Medical Sciences, Pediatrics, College of Medicine, USA
9Metabolic Diseases Service, Clínica Universitaria Reina Fabiola, Argentina
10Hospital Italiano de Buenos Aires, Argentina
11University of California at Los Angeles (UCLA), USA
12University of Utah, USA
13Kumamoto University Hospital, Japan
14University of Colorado School of Medicine and the Children’s Hospital Colorado, USA
15Ultragenyx Pharmaceutical Inc, USA
Objectives: OTC deficiency (OTCD) is an X-linked disorder that leads to acute hyperammonemia, which can result in brain damage and death. DTX301 is an investigational AAV8 vector containing the human wild-type OTC gene. Based on encouraging results from a phase 1/2 study of DTX301, a phase 3 study (NCT05345171) is underway to determine efficacy and confirm safety of DTX301 in patients ≥12 years old with late-onset OTCD.
Methods: This phase 3 randomized, double-blind, placebo-controlled trial will be conducted at ~30 sites worldwide and include ~50 patients ≥12 years old with a confirmed diagnosis of late-onset OTCD. Patients must be on a stable dose of nitrogen-scavenging agents and/or a stable protein-restricted diet for ≥4 weeks prior to screening and have no pre-existing antibodies to the AAV8 capsid.
Patients are randomized 1:1 to receive DTX301 or placebo at first. The DTX301 group will receive one DTX301 injection (IV) and prophylactic steroids on a 58-day taper regimen. The placebo group will receive one IV injection of normal saline and an oral placebo matched to the steroids. At Week 64 (W64), patients will crossover treatment and be followed for up to 260 weeks after receiving DTX301.
Primary endpoints at W64: 1) 24-hour plasma ammonia area under the curve; 2) percentage of patients achieving complete response (discontinuation of all nitrogen-scavenger therapy with no dietary protein restrictions and stabilized or improved plasma ammonia levels).
An unblinded central independent committee (CIC) of independent OTCD experts and a data monitoring committee (DMC) including an independent statistician and independent physicians will provide oversight and monitor patient safety.
Results: The study is ongoing. Multiple patients have been dosed.
Conclusion: This ongoing phase 3 study aims to determine efficacy and confirm safety of DTX301 in patients ≥12 years old with late-onset OTCD by monitoring clinical outcomes, hyperammonemic crises, and biochemical analytes.
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