Ultragenyx gene therapy DTX301 cuts plasma ammonia in Phase III OTC deficiency trial

Edited by Robert McTiernan··3 min read

Novato, California-based Ultragenyx Pharmaceutical announced Phase III results for DTX301 (avalotcagene ontaparvovec), an AAV8 gene therapy for ornithine transcarbamylase deficiency, reporting a statistically significant reduction in plasma ammonia compared with placebo at 36 weeks. OTC deficiency is the most common urea cycle disorder, and no disease-modifying therapy is currently approved for the condition, leaving patients reliant on lifelong dietary restriction and ammonia scavenger medications that do not eliminate the risk of metabolic crises.

Trial specifics

The Phase III Enh3ance study (NCT05345171) is a randomized, double-blind, placebo-controlled trial enrolling 37 patients across 16 sites in 10 countries. Participants were randomized 1:1 to receive a single intravenous infusion of DTX301 or placebo during a 36-week randomized control period, with primary endpoint focused on 24-hour plasma ammonia area under the curve at Week 36. DTX301-treated patients (n=18) showed an 18% reduction in 24-hour plasma ammonia AUC compared with placebo (n=19), reaching statistical significance (p=0.018). Eight of nine patients with abnormal baseline ammonia levels achieved normal values, and these were generally maintained through Week 36. Treated patients achieved this ammonia control despite a mean 27% reduction in ammonia scavenger medications and an approximately 13% increase in protein intake, while the placebo group showed no change in either measure. At Week 24, 71% of treated patients rated themselves as “much improved” on the patient global impression of change scale for overall OTC symptoms, compared with 0% on placebo, while DTX301 was described as well tolerated. The most common treatment-emergent adverse events were mild to moderate transient hepatic reactions managed with steroids. One serious adverse event of acute hepatitis was assessed as treatment-related and resolved with steroid treatment. Hyperammonemic crises requiring hospitalization occurred five times in the placebo group, including one death, compared with one event and no deaths in the treated group.

The study is continuing to a second primary endpoint evaluating reduction in treatment burden across both the original treatment arm and placebo-crossover patients through 64 weeks of follow-up. Ultragenyx said data from this portion are expected in the first half of 2027. DTX301 holds Orphan Drug Designation in the US and EU and Fast Track Designation from the US FDA. The company did not disclose a timeline for a regulatory submission.

The AllSci BriefSystematic R&D and deal news. Daily.

Research context

DTX301 is an AAV8 vector-based gene therapy designed to deliver a functional copy of the OTC gene to hepatocytes via a single intravenous infusion. OTC deficiency results from mutations in the gene encoding ornithine transcarbamylase, a mitochondrial enzyme in the liver that catalyzes a step in the urea cycle responsible for converting ammonia to urea for excretion. Loss of enzyme activity leads to accumulation of ammonia in the blood, which can cause neurological damage and death. By transducing liver cells with a functional gene, DTX301 aims to restore urea cycle activity and reduce dependence on exogenous ammonia management.

Current standard of care consists of ammonia scavenger drugs such as sodium phenylbutyrate and glycerol phenylbutyrate (Ravicti, Horizon Therapeutics), combined with strict dietary protein restriction. Liver transplantation is used in refractory cases but carries substantial procedural risk and is limited by organ availability. No gene therapy or other disease-modifying treatment is approved for OTC deficiency.

Key competitors include:

  • Horizon Therapeutics’ glycerol phenylbutyrate (Ravicti), an approved ammonia scavenger with ongoing Phase 2 studies in expanded pediatric populations.
  • Homology Medicines’ HMI-102, an AAVHSC15 gene therapy in Phase 1 development for OTC deficiency.