Ultragenyx gets phase 3 win for urea cycle disorder gene therapy

Ultragenyx Pharmaceutical announced positive results from its phase 3 study of DTX301, an investigational AAV8 gene therapy for the treatment of ornithine transcarbamylase (OTC) deficiency, the most common urea cycle disorder.

At week 36 in the randomized, double-blind placebo-controlled period of the Enh3ance study, DTX301-treated patients (n=18) demonstrated a statistically significant and clinically meaningful 18% reduction in 24-hour plasma ammonia (AUC0-24) compared to placebo (n=19) and maintained average ammonia AUC0-24 in the normal range through week 36.

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 the treatment period.

“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,” said Eric Crombez, MD, chief medical officer, Ultragenyx.

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 also resolved with steroids.

Enh3ance study will now continue to its second primary endpoint which evaluates 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 are expected in the first half of 2027.

OTC deficiency is caused by a genetic defect in a liver enzyme responsible for detoxification of ammonia. DTX301 is an investigational AAV type 8 gene therapy designed to deliver stable expression and activity of OTC following a single intravenous infusion. It has been shown in preclinical studies to normalize levels of urinary orotic acid, a marker of ammonia metabolism.

The study results are good news for Ultragenyx amid a recent rough patch. Last month, the company announced a 10% workforce reduction, alongside revealing that it had received an incomplete response letter regarding its resubmitted its BLA seeking accelerated approval for its AAV9 gene therapy, UX111, as a treatment for patients with Sanfilippo syndrome type A. Ultragenyx had resubmitted the BLA for UX111 after getting hit with a CRL in July 2025.