Ultragenyx Announces Positive 36-Week Data for OTC Gene Therapy

Rare Daily Staff

Ultragenyx Pharmaceutical Inc. is reporting encouraging late-stage trial results for its experimental gene therapy for ornithine transcarbamylase (OTC) deficiency, a rare inherited disorder in which the body cannot safely clear ammonia. The company says the one-time treatment lowered ammonia levels and showed signs of easing the daily treatment burden that patients and families live with.

OTC deficiency is the most common urea cycle disorder, a group of conditions in which a missing or faulty liver enzyme prevents the body from converting ammonia, a toxic waste product, into urea for excretion. When ammonia builds up, patients can develop sudden episodes of confusion, behavior changes, and other neurologic symptoms that can progress to coma, permanent brain injury, or death if not treated quickly. To try to prevent these crises, patients typically must follow a strict low-protein diet and take multiple medications every day to help the body get rid of excess ammonia.

Ultragenyx’s experimental therapy, called DTX301 or avalotcagene ontaparvovec, is designed to address the underlying cause of the disease. It uses a harmless, engineered virus to deliver a working copy of the OTC gene directly to liver cells through a single intravenous infusion. The hope is that once those liver cells start making more of the missing enzyme, the urea cycle can function more normally over the long term, reducing ammonia levels and potentially allowing patients to rely less on chronic drugs and rigid dietary rules.

The phase 3 Enh3ance study tested this approach in 37 people with late-onset OTC deficiency at sites across 10 countries. Participants were randomly assigned to receive either the gene therapy or a placebo and were followed for 36 weeks without knowing which treatment they received. This kind of randomized, blinded design is considered the gold standard for evaluating whether a new therapy truly makes a difference.

By the end of that 36-week period, patients who received DTX301 had lower overall ammonia exposure compared with those on placebo and, on average, kept their ammonia levels within the normal range. For many, this improvement came even as they began to scale back on other treatments, cutting doses of ammonia-lowering “scavenger” drugs and relaxing their strict low-protein diets. Among the small group of participants who entered the trial with clearly abnormal ammonia levels, most moved into the normal range soon after the infusion and maintained that control during the blinded part of the study.

Patients reported that these changes translated into how they felt and functioned day to day. On a standard questionnaire that asks people to rate their symptoms and overall well-being, a clear majority of those who received the gene therapy described their condition as “much improved” or at least moderately better. In contrast, only a minority of patients who received placebo reported that level of improvement.

Safety has been a major concern in gene therapy, but Ultragenyx said DTX301 was generally well tolerated. The most common side effects were temporary, liver-related issues that doctors managed with steroids. There was one serious case of acute hepatitis considered related to treatment, which also resolved with steroid therapy. The company said it did not see some of the more severe complications reported with certain other gene therapies, such as damage to blood vessels, nerve problems, or cancer.

Serious ammonia spikes, known as hyperammonemic crises, and related complications were more frequent in the placebo group during the 36-week randomized period. Investigators reported five hospitalizations for these crises and one death among patients who did not receive the gene therapy, compared with one such crisis and no deaths in the DTX301 group. A few participants in each arm discontinued the trial, including the patient in the placebo group who died from a hyperammonemic event.

A second main analysis from Enh3ance is still to come and will look more closely at how much the one-time infusion reduces overall treatment burden over a longer follow-up period, including reliance on ammonia-scavenger drugs and strict dietary restrictions. Those 64-week data will also include patients who initially received placebo and later crossed over to get the gene therapy.

“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,” said Eric Crombez, chief medical officer of Ultragenyx. “Importantly, the improvement in ammonia control was maintained as some patients began reducing use of alternate pathway medications and liberalizing their protein-restricted diet.”

Photo: Eric Crombez, chief medical officer of Ultragenyx