Ultragenyx Pharmaceutical’s gene therapy for ornithine transcarbamylase (OTC) deficiency has shown benefit in a Phase III trial, hitting one of the co-primary endpoints.
In the Enh3ance study (NCT05345171), 18 patients treated with DTX301, an investigational AAV8 gene therapy, demonstrated a statistically significant and clinically meaningful 18% reduction in 24-hour plasma ammonia (AUC0-24) compared to 19 patients treated with placebo. The average ammonia level remained in the normal range through to 36 weeks after dosing with the one-time gene therapy.
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Baseline 24-hour ammonia AUC levels were normal in 50% of DTX301-treated patients and 68% of placebo patients, who were all on current care of scavenger medications and strict dietary control of protein intake.
Eight of nine patients with abnormal ammonia AUC0-24 at baseline, despite optimal current drug treatment and diet restriction, reached normal ammonia levels rapidly, which were generally maintained during this treatment period.
Dr Eric Crombez, CMO of Ultragenyx, said: “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.”
Patient global impression scale (PGIC) for OTC symptoms overall showed 71% of treated patients were much improved versus 0% of placebo after 24 weeks.
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By GlobalDataEvaluations of OTC deficiency symptoms and OTC impact on daily living on the same scale showed 64% were either much improved or moderately improved, compared to 19% who were moderately improved on placebo.
DTX301 was well tolerated with an acceptable safety profile, consistent with prior Phase I/II safety data. One serious adverse event (SAE) of acute hepatitis was assessed as treatment-related and resolved with steroids. Hyperammonaemia crises requiring hospitalisation occurred five times in the placebo group, with one death; however, just one event was reported in the treated group and no deaths.
The study will continue to evaluate its second primary endpoint of reduction in treatment burden, including use of ammonia scavengers and dietary management, across both the treatment and placebo-crossover groups following treatment with DTX301 through 64 weeks of follow-up. Data for these endpoints is expected in the first half of 2027.
Ultragenyx will be happy with this data as it continues to seek approval of its Sanfilippo Syndrome Type A (MPS IIIA) gene therapy UX111 in the US. The US Food and Drug Administration (FDA) rejected the drug in July 2025 due to manufacturing concerns. The company has since resubmitted the therapy to the agency.
This teamed with the Phase III trial failure of setrusumab in osteogenesis imperfecta, announced in December 2025, has led to a 10% reduction in its workforce.
Ultragenyx is one of a handful of gene therapy developers with a public listing. Recent analysis from GlobalData’s Strategic Intelligence report, “Cell and Gene Therapy Investment Trends,” reveals that approximately 50% of cell and gene therapy (CGT) venture capital (VC) activity is focused at the Series B-stage, when companies usually shift from platform validation to clinical execution.
CGT capital deployment remains highly concentrated among a small group of major investors, including RA Capital, ARCH Venture Partners, Alexandria Ventures, OrbiMed, and Fidelity International Strategic Ventures, each of which has committed more than $3.5bn across cumulative deals.
Irena Maragkou, senior healthcare researcher at GlobalData, said: “As therapeutic CGT approvals increase, and the CGT market is expected to grow at a rate of 34.2% by 2031, companies must simultaneously prepare for sector-specific challenges such as regulatory complexity and manufacturing scalability. Therefore, biotech companies need to be strategic in investing in differentiated technologies and build execution capabilities to deliver clinical and commercial impact.”
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