DTX301 Gene Therapy Lowers Ammonia Levels in Ornithine Transcarbamylase Deficiency at 36 Weeks

Interim results from the phase 3 Enh3ance clinical trial (NCT05345171) suggest that Ultragenyx’s investigational adeno-associated viral (AAV) vector-based gene therapy avalotcagene ontaparvovec (also known as DTX301) may reduce plasma ammonia levels in patients with ornithine transcarbamylase (OTC) deficiency, a rare inherited metabolic disorder associated with life-threatening hyperammonemia.¹ In the randomized, double-blind, placebo-controlled portion of the study, patients treated with DTX301 experienced statistically significant reductions in 24-hour ammonia exposure compared with placebo at 36 weeks.

Enh3ance enrolled 37 participants with OTC deficiency across 16 clinical sites in 10 countries. During the initial 36-week randomized controlled period, patients were assigned in a 1:1 ratio to receive a single intravenous infusion of DTX301 or placebo. After this period, patients in the placebo arm cross over to active treatment and continue follow-up through week 64.

The trial’s first primary end point assessed change in 24-hour plasma ammonia exposure, measured as the area under the curve (AUC₀–₂₄), at week 36. According to the reported results, patients receiving DTX301 (n = 18) demonstrated an 18% reduction in ammonia AUC₀–₂₄ compared with placebo (n = 19), a difference that reached statistical significance (P = .018).¹

Among patients with elevated ammonia levels at baseline despite standard therapy—including ammonia scavenger medications and protein restriction—8 of 9 individuals treated with DTX301 achieved normalization of ammonia levels during the study period. Reductions in ammonia were observed as early as week 6 and were generally maintained through the 36-week evaluation.

Investigators also reported that treated patients maintained normal-range ammonia levels even as mean use of ammonia scavenger medications declined by approximately 27% and dietary protein intake increased by roughly 13% compared with baseline. Placebo-treated participants did not demonstrate similar changes.

Patient-reported assessments suggested improvements in disease-related symptoms among treated participants. Using the Patient Global Impression of Change (PGIC) scale at week 24 (total n=15 reporting), 71% of patients receiving DTX301 were rated as “much improved,” compared with none of the patients in the placebo group. Across evaluations of OTC-related symptoms and the impact of disease on daily living (total n=30 reporting), 64% of treated patients at week 24 reported either moderate or much improvement, whereas improvements were less frequently reported among those receiving placebo (19% moderately improved, none much improved.)

“Given the importance of and effort made to keep ammonia levels under control in patients with OTC deficiency, 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,” Eric Crombez, MD, the chief medical officer of Ultragenyx, said in a statement.¹ “Importantly, the improvement in ammonia control was maintained as some patients began reducing use of alternate pathway medications and liberalizing their protein restricted diet. We are extremely encouraged by these findings given the significant medical needs faced by patients with OTC deficiency, who remain at risk for unpredictable and potentially life threatening hyperammonemic crises.”

DTX301 was generally reported to have a safety profile consistent with prior early-phase studies. The most common treatment-emergent adverse events involved transient hepatic reactions, which were typically mild to moderate and managed with corticosteroid therapy.¹

One serious adverse event of acute hepatitis was considered treatment-related but resolved with steroid treatment. No adverse events related to thrombotic microangiopathy, dorsal root ganglion toxicity, malignancy, or complex immune reactions were reported. Hyperammonemic crises requiring hospitalization occurred 5 times in the placebo group, including 1 fatal event, compared with 1 crisis in the DTX301-treated group and no deaths.

OTC deficiency is the most common urea cycle disorder, caused by pathogenic variants affecting the hepatic enzyme ornithine transcarbamylase, which plays a key role in the detoxification of ammonia produced during protein metabolism.² Elevated ammonia levels can trigger hyperammonemic crises, which may result in hospitalization, neurologic injury, or death.

Current management typically involves lifelong dietary protein restriction and ammonia-scavenging medications designed to provide alternative pathways for nitrogen excretion.³ While these approaches can help reduce ammonia levels, they do not eliminate the risk of acute metabolic crises and can impose a substantial treatment burden on patients and caregivers.

Gene therapy strategies such as DTX301 aim to address the underlying metabolic defect by introducing a functional copy of the OTC gene into hepatocytes using an AAV vector.¹ Preclinical studies have shown that this approach can restore enzyme activity and normalize the metabolic marker urinary orotic acid. DTX301 is intended to enable long-term expression of the OTC enzyme in liver cells, potentially improving ammonia metabolism. The product has previously received Orphan Drug designation in both the United States and European Union and Fast Track designation from the FDA.

According to Ultragenyx he Enh3ance study will continue to evaluate its second primary end point, which examines reductions in treatment burden—including use of ammonia scavengers and dietary restrictions—after all participants receive DTX301. These results are expected in 2027, and they may provide further insight into whether gene therapy can meaningfully alter the long-term management of OTC deficiency.

REFERENCES

1. Ultragenyx Pharmaceutical Inc. Ultragenyx Announces Positive 36-Week Data from Phase 3 Study of DTX301 AAV8 Gene Therapy for the Treatment of Ornithine Transcarbamylase (OTC) Deficiency. Press release. Accessed 2026. https://www.ultragenyx.com

2. Häberle J, Burlina A, Chakrapani A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2019;14(1):117. https://doi.org/10.1186/s13023-019-1090-1

3. Batshaw ML, Tuchman M, Summar M, Seminara J. A longitudinal study of urea cycle disorders. Mol Genet Metab. 2014;113(1-2):127-130. https://doi.org/10.1016/j.ymgme.2014.06.015

4. U.S. Food and Drug Administration. Fast Track Drug Development Program. https://www.fda.gov/drugs/fast-track-breakthrough-therapy-accelerated-approval-priority-review/fast-track