Ultragenyx reports positive Phase 3 Enh3ance trial results for DTX301 gene therapy in OTC deficiency, showing a significant reduction in plasma ammonia exposure and improved patient outcomes
Written By: Samiksha Jadhav BPharm
Reviewed By: Pharmacally Editorial Team
Ultragenyx Pharmaceutical Inc. reported positive results from the Phase 3 Enh3ance trial (NCT05345171) evaluating DTX301 (avalotcagene ontaparvovec), an investigational AAV8-based gene therapy for ornithine transcarbamylase (OTC) deficiency. The study met its primary endpoint, demonstrating a statistically significant reduction in 24-hour plasma ammonia exposure (AUC0-24) compared with placebo.
At Week 36 of the randomized, double-blind, placebo-controlled period, patients receiving DTX301 (n=18) achieved an 18% reduction in 24-hour plasma ammonia exposure (AUC0-24) compared with placebo (n=19) (p=0.018).
Ammonia levels remained within the normal range through Week 36. Among patients who had abnormal ammonia levels at baseline despite standard care, eight of nine rapidly normalized their ammonia levels, which were generally maintained during the treatment period.
“Given the importance of controlling ammonia levels in OTC deficiency, the additional reduction observed with DTX301 demonstrates the benefit of addressing the underlying cause of the disease,” said Eric Crombez, M.D., chief medical officer of Ultragenyx. He added that improved ammonia control allowed some patients to reduce ammonia-scavenger medications and increase dietary protein intake, highlighting the therapy’s potential to lessen treatment burden.
Patients receiving DTX301 showed early and sustained biochemical improvement. Ammonia levels began declining by Week 6 and remained reduced through Week 36, even as treated patients decreased ammonia-scavenger medication use by 27% on average and increased protein intake by approximately 13%, while the placebo group showed no dietary change.
Patient-reported outcomes also favored treatment. At Week 24, the Patient Global Impression of Change (PGIC) scale showed 71% of treated patients reported being “much improved,” compared with none in the placebo group. When evaluating both symptom burden and impact on daily living, 64% of DTX301-treated patients reported moderate or major improvement, versus 19% of placebo patients reporting moderate improvement.
DTX301 was generally well tolerated, with safety findings consistent with earlier studies. The most common treatment-emergent adverse events were mild to moderate transient liver reactions, typically managed with steroids. One treatment-related serious adverse event of acute hepatitis resolved with steroid therapy. Hyperammonemic crises requiring hospitalization occurred five times in the placebo group, including one death, compared with one event and no deaths in the DTX301 group.
The Enh3ance study enrolled 37 patients in the randomized portion of the analysis, across 16 sites in 10 countries, with participants randomized 1:1 to receive DTX301 or placebo during the 36-week randomized control period. After Week 36, placebo participants cross over to receive treatment. The trial’s second primary endpoint will evaluate reduction in treatment burden, including use of ammonia scavengers and dietary restrictions, with follow-up through 64 weeks. Additional data are expected in the first half of 2027.
DTX301 is an AAV8 gene therapy designed to deliver a functional OTC gene through a single intravenous infusion, enabling stable hepatic expression of the ornithine transcarbamylase (OTC) enzyme, which is required for ammonia detoxification in the urea cycle. The therapy has received Orphan Drug Designation in the United States and European Union and Fast Track Designation in the United States.
OTC deficiency is the most common urea cycle disorder, caused by a genetic defect in a liver enzyme responsible for ammonia detoxification. The disease can lead to recurrent hyperammonemic crises, neurological damage, and death. Current management relies on strict protein-restricted diets and ammonia-scavenger medications, but these approaches do not eliminate the risk of metabolic crises. More than 10,000 people worldwide are estimated to live with OTC deficiency, with about 80% classified as late-onset disease.
References
Ultragenyx Announces Positive 36-Week Data from Phase 3 Study of DTX301 AAV8 Gene Therapy for the Treatment of Ornithine Transcarbamylase (OTC) Deficiency, 12 March 2026, Ultragenyx Announces Positive 36-Week Data from Phase 3 Study of DTX301 AAV8 Gene Therapy for the Treatment of Ornithine Transcarbamylase (OTC) Deficiency—Ultragenyx Pharmaceutical Inc.
Clinical Study of DTX301 AAV-Mediated Gene Transfer for Ornithine Transcarbamylase (OTC) Deficiency, ClinicalTrials.gov ID NCT05345171, https://clinicaltrials.gov/study/NCT05345171
About the Writer
Samiksha Vikram Jadhav is a B.Pharm graduate with a strong academic foundation in pharmaceutical sciences, pharmacology, and drug development. She has a keen interest in healthcare advancements, clinical research, medical writing, and emerging therapies. Her work focuses on presenting developments in the pharmaceutical and healthcare sectors through clear and accurate scientific communication.