Ultragenyx Reports Positive Results from Phase 1/2 Study of Gene Therapy in OTC Deficiency

Rare Daily Staff

Ultragenyx Pharmaceutical reported positive longer-term safety and efficacy data from the first three cohorts of the ongoing phase 1/2 study of DTX301, an experimental adeno-associated virus gene therapy for the treatment of ornithine transcarbamylase deficiency, the most common urea cycle disorder.

All three patients in Cohort 3 confirmed as responders, and three complete responders from the previous two cohorts clinically and metabolically stable after longer-term follow-up. Data from the study were presented at the American Society of Gene & Cell Therapy virtual 2020 Annual Meeting.

Ornithine transcarbamylase (OTC) deficiency 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 people are affected by OTC deficiency worldwide, approximately 80 percent of whom 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, is severe, and can be fatal at an early age. Approved therapies, which must be taken multiple times a day for the patient’s entire life, do not eliminate the risk of future metabolic crises. Currently, the only curative approach is liver transplantation.

Ultragenyx’ DTX301 is an experimental 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 phase 1/2 dose-escalation study evaluated the change in the rate of ureagenesis, ammonia levels, neurocognitive assessment, biomarkers, and safety of DTX301 in adult 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.

Six of nine patients in the study have responded to the gene therapy (three female, three male), including all three patients in Cohort 3, the highest dose, who are now confirmed responders. The three previously disclosed complete responders, who have discontinued all ammonia scavengers and liberalized their diet, remain clinically and metabolically stable after longer-term follow-up.

“We are seeing durable and clinically meaningful responses to DTX301,” said Eric Crombez, chief medical officer of the Ultragenyx Gene Therapy development unit. “We are extremely encouraged that the patients who have stopped alternate pathway medications and liberalized dietary restrictions continue to do very well over these longer periods of time.”

Updated data shows that all three patients in Cohort 3 are confirmed responders. Patient 7 has maintained normal ammonia levels since treatment and continues to be stable after liberalizing diet and discontinuing ammonia scavenger medications. Patient 8 has experienced a significant and sustained reduction in her elevated baseline ammonia levels, has increased her protein intake, and discontinued one of her two ammonia scavenger medications with a plan to taper the other medication once she is able to return to the clinic post COVID-19 restrictions. Patient 9’s ammonia levels has seen his rate of ureagenesis increase 188 percent to 73 percent of normal at week 24 and has not yet discontinued other medications or changed his diet.

Two complete responders in Cohorts 1 and 2 (Patients 1 and 4) have shown ongoing durable responses for 2 years and 1.5 years, respectively. Both patients have discontinued alternate pathway medications and liberalized restricted protein diets for more than one year, and remain stable with ammonia levels maintained in the normal range. They remain in excellent clinical condition with no significant adverse events, hospitalizations, or other events related to OTC deficiency. The third responder from the earlier cohorts (Patient 6) continues to do well, and is currently tapering her medications and liberalizing her diet.

As of the data cutoff date, there have been no infusion-related adverse events and no treatment-related serious adverse events reported in the study. As previously reported, six patients experienced mild, clinically asymptomatic elevations in ALT levels, similar to what has been observed in other programs using AAV-based gene therapy.  All six of these patients have responded to reactive tapering courses of steroids, and all patients remain clinically stable.

A fourth cohort of three patients at the Cohort 3 dose is planned using prophylactic steroids. Dosing in this cohort is currently on hold due to the COVID-19 pandemic, but data are still expected in the second half of 2020, barring further delays related to clinical site closures due to COVID-19.

Ultragenyx is currently planning the phase 3 study of DTX301 in parallel to conducting the prophylactic steroid cohort. The company intends to hold an end of phase 2 meeting with the U.S. Food and Drug Administration in the second half of 2020, based on data from the first three cohorts of the phase 1/2 study. The use of prophylactic steroids in the Phase 3 study is anticipated, and ammonia is expected to be a primary endpoint based on direct FDA feedback to date. The Phase 3 study is currently expected to begin enrollment in the first half of 2021, barring any significant delays due to COVID-19.

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