Ultragenyx Gene Therapy DTX301 Demonstrates Significant Ammonia Reduction in Phase 3 OTC Deficiency Trial
Key Insights
DTX301 achieved an 18% reduction in 24-hour plasma ammonia levels compared to placebo at 36 weeks in the Phase 3 Enh3ance study, meeting its primary endpoint with statistical significance (p=0.018).
Eight of nine patients with abnormal baseline ammonia levels reached normal levels rapidly and maintained control throughout treatment, while many reduced scavenger medications and liberalized protein-restricted diets.
Patient-reported outcomes showed 71% of treated patients reported being "much improved" in overall OTC symptoms at Week 24, compared to none in the placebo group.
Ultragenyx Pharmaceutical Inc. announced positive 36-week results from its Phase 3 Enh3ance study of DTX301, an investigational AAV8 gene therapy for ornithine transcarbamylase (search) (OTC) deficiency. The therapy achieved statistically significant improvements in ammonia control compared with placebo, marking a potential breakthrough for patients with this rare metabolic disorder that causes dangerous ammonia buildup in the blood.
Primary Endpoint Success
In the randomized, placebo-controlled portion of the trial involving 37 patients across 10 countries, DTX301-treated patients (n=18) demonstrated an 18% reduction in 24-hour plasma ammonia levels at Week 36 compared to placebo (n=19), with statistical significance (p=0.018). Importantly, treated patients maintained average ammonia levels within the normal range throughout the treatment period.
Eight of nine patients who began the study with abnormal ammonia levels despite optimal current drug treatment and dietary restrictions reached normal ammonia levels rapidly, which were generally maintained during the treatment period. This improvement occurred even as patients reduced their use of alternate pathway medications by a mean of 27% and increased protein intake by approximately 13% relative to no change in the placebo group.
Clinical Impact and Patient Outcomes
"Given the importance of and effort made to keep ammonia levels under control in patients with OTC deficiency (search), the further reduction in ammonia levels in patients treated with DTX301 demonstrates the benefit of this gene therapy and of directly addressing the underlying cause of this disease," said Eric Crombez, M.D., chief medical officer of Ultragenyx.
Patient-reported outcomes strongly favored DTX301 treatment. At Week 24, 71% of treated patients reported being "much improved" in overall OTC symptoms, compared with none in the placebo group. For OTC deficiency (search) symptoms and impact on daily living, 64% of treated patients showed either much improved (43%) or moderately improved (21%) outcomes, while only 19% of placebo patients showed moderate improvement with none reporting much improvement.
Safety Profile and Tolerability
DTX301 demonstrated an acceptable safety profile consistent with prior Phase 1/2 data. The most common treatment-emergent adverse events were mild to moderate transient hepatic reactions managed with steroids. One serious adverse event of acute hepatitis (search) was assessed as treatment-related but resolved with steroid therapy.
Notably, the placebo group experienced five hyperammonemia (search) crises requiring hospitalization, including one death, while the treatment group had only one such event with no deaths. Two patients in the placebo arm discontinued the study, including one death due to hyperammonemia crisis, compared to one patient in the DTX301 arm who discontinued after Week 36 for non-clinical reasons.
Study Design and Next Steps
The Phase 3 Enh3ance study enrolled 37 patients randomized 1:1 between DTX301 and placebo during the 36-week randomized control period. DTX301 is administered as a single intravenous infusion at a dose of 1.7 x 10^13 GC/kg, designed to deliver stable expression and activity of OTC.
The study continues to its second primary endpoint, evaluating reduction in treatment burden including use of ammonia scavengers and dietary management through 64 weeks of follow-up. These data are expected in the first half of 2027, with placebo patients crossing over to treatment after the 36-week unblinding.
Disease Background and Unmet Need
OTC deficiency (search), the most common urea cycle disorder, affects an estimated 10,000 people in commercially accessible geographies. The condition is caused by a genetic defect in a liver enzyme responsible for detoxification of ammonia, leading to acute hyperammonemic episodes that can result in hospitalization, cognitive and neurologic impairments, and death.
Current management relies on strict protein-limited diets and ammonia scavenger medications (search) taken multiple times daily for life. However, these approved therapies do not eliminate the risk of future metabolic crises, and many patients still experience elevated ammonia excursions when evaluated over 24-hour periods.
DTX301 has received Orphan Drug and Fast Track designation in both the United States and European Union, reflecting the significant unmet medical need in this patient population.