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Durable efficacy and safety of DTX301: Long-term follow up of a phase 1/2 trial in adults with ornithine transcarbamylase deficiency

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical-Adult
  • Secondary Categories:
    • Clinical-Adult & Pediatric
Introduction:
Ornithine transcarbamylase (OTC) deficiency is an X-linked urea cycle disorder resulting in a life-long risk of episodic hyperammonemia that can lead to cumulative brain damage, coma, or death. DTX301 is an AAV8 vector containing the OTC transgene being investigated for treatment of OTC deficiency. We report the long-term follow up (LTFU) of 11 adults with late-onset OTC deficiency who received a single IV infusion of DTX301 in the Phase 1/2 trial (NCT02991144).

Methods:
The initial study was a global, multicenter, open-label phase 1/2 dose-finding study that lasted 52 weeks with an ongoing long-term extension for an additional 8 years. Patients received one IV infusion of DTX301. Cohort 1 (n=3) received  3.4 x 1012 GC/kg; cohort 2 (n=3) received 1.0 x 1013 GC/kg; cohort 3 (n=3) received 1.7 x 1013 GC/kg; and cohort 4 (n=2) received 1.7 x 1013 GC/kg with a prophylactic oral steroid taper. Relative to baseline in the Phase 1/2 trial, Complete Responders discontinued all ammonia-scavenger medications and protein-restricted diet; Responders had ≥50% reduction in medications and dietary protein restriction relative to baseline.

Results:
Eleven patients were enrolled in the Phase 1/2 trial, and all have continued in the extension study, with up to ~7 years of follow up to date. No treatment-related serious AEs, dose-limiting toxicities, or infusion-related events have been reported. During the primary study, six patients experienced transient changes in liver function due to AAV8 vector administration. All resolved following corticosteroid administration. During LTFU, three patients experienced mild ALT elevations and two experienced hyperammonemia or hyperammonemic crises, all considered unrelated to DTX301. Corticosteroids were generally well tolerated, and no corticosteroid regimen was associated with increased ammonia, hyperammonemia, or hyperammonemic crisis. Five patients had corticosteroid-related AEs. Most were mild (grade 1), though one patient had grade 3 AEs of bone infarction, osteonecrosis, and subcortical collapse that led to knee replacement.  

Seven of eleven patients have shown a meaningful clinical response to DTX301. Four were Complete Responders and 3 were Responders. The 4 Complete Responders each achieved complete response by Week 52. At Week 52, 2 of 11 patients were Responders, and the third patient was classified as a Responder the following year. As of 09 December 2023, 10 of 11 patients have remained clinically stable from the time of DTX301 administration. One patient in Cohort 1 has been reclassified from Complete Responder to Responder after restarting an ammonia-scavenging drug at Week 182 due to personal preference. This patient experienced two serious AEs at Week 300 and Week 333 with hospitalization for malaise consistent with hyperammonemia. No elevated ammonia levels of clinical significance were reported. One patient in Cohort 4 experienced recurrent hyperammonemia and HACs that were considered by the Investigator to be related to the patient’s underlying OTC deficiency. This patient took ammonia-scavenging medication on an alternative schedule, which resulted in elevated ammonia levels, and also experienced 2 viral infections.

At Week 52 and during long-term follow-up, plasma ammonia area under the curve from 0-24 hours (AUC0-24) showed positive trends toward improvement after DTX301 treatment up to 312 weeks. Similarly, rate of ureagenesis increased up to 208 weeks. Some individual patients showed improvements in urinary orotic acid. Plasma glutamine levels showed considerable individual variability but were generally lower for complete responders and responders. Citrulline levels were maintained in Complete Responders when citrulline supplementation was discontinued.

Conclusion:
DTX301 continues to show manageable safety and durable efficacy. The Phase 3 trial (NCT05345171) is currently enrolling adults and children ≥12 years of age.

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