Rare Daily Staff

Ultragenyx Pharmaceutical reported positive topline results from Cohort 3 of its phase 1/2 study of its experimental gene therapy for ornithine transcarbamylase deficiency, the most common urea cycle disorder.

Ornithine transcarbamylase deficiency (OTC) is caused by a genetic defect in a liver enzyme responsible for detoxification of ammonia. Individuals with OTC deficiency can build up excessive levels of ammonia in their blood, potentially resulting in acute and chronic neurological deficits and other toxicities. It is estimated that more than 10,000 patients are affected by OTC deficiency worldwide, of which approximately 80 percent are classified as late-onset and represent a clinical spectrum of disease severity. In the late-onset form of the disease, elevated ammonia can lead to significant medical issues for patients. Neonatal onset disease occurs only in males, presents as severe disease, and can be fatal at an early age. Currently, the only curative approach is liver transplantation.

DTX301 is an experimental AAV type 8 gene therapy. It has been shown in preclinical studies to normalize levels of urinary orotic acid, a marker of ammonia metabolism. DTX301 was granted Orphan Drug designation in both the United States and Europe.

The phase 1/2 study evaluates the change in the rate of ureagenesis, ammonia levels, neurocognitive assessment, biomarkers, and safety of DTX301 in patients with OTC deficiency. Three patients have been dosed in each of three dose cohorts. Patients in the first three cohorts received steroids to reactively manage ALT elevations. In the fourth cohort, three patients will receive the same dose as cohort 3, the highest dose tested, and all will receive a prophylactic tapering course of steroids.

Ultragenyx reported that there were two confirmed female responders as well a third potential male responder in Cohort 3 who requires longer-term follow-up to confirm response status.

In Cohort 2, one female patient has newly demonstrated a response starting at Week 52 which was confirmed at Week 78. The two previously disclosed responders in Cohort 1 (at 104 weeks) and Cohort 2 (at 78 weeks) also remain clinically and metabolically stable. Six of the nine patients in the study demonstrated a response.

“We are encouraged to see a more uniform response at the higher doses including three female responders. To date, three patients in the study have discontinued alternate pathway medication and liberalized their diets while remaining clinically and metabolically stable,” said Eric Crombez, chief medical officer of the Ultragenyx Gene Therapy development unit. “We are moving to prophylactic steroid use in the next cohort as we believe this could further enhance the level and consistency of expression that we have demonstrated so far.”

Ultragenyx is continuing discussions with the U.S. Food and Drug Administration (FDA) regarding the potential phase 3 study design. Ammonia is expected to be a primary endpoint based on direct FDA feedback to date, with ureagenesis as a measure of biologic activity that supports the decision for patients to discontinue alternate pathway medications.

Photo: Eric Crombez, chief medical officer of the Ultragenyx Gene Therapy development unit

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