In a recent press release, biopharmaceutical company Ultragenyx Pharmaceutical Inc. (“Ultragenyx”) shared positive safety and efficacy data from Phase 1/2 clinical trials on gene therapy solutions for ornithine transcarbamylase (OTC) deficiency and glycogen storage disease type 1a (GSD1a). In the former trial, researchers evaluated DTX301 for patients; in the latter, the therapy being evaluated was DTX401. Beyond this data, Ultragenyx also hopes to soon began a Phase 1/2/3 clinical trial to evaluate UX701 for patients with Wilson disease.

Gene Therapy Programs

DTX301 for OTC Deficiency

Developed by Ultragenyx, DTX301 is an investigational gene therapy using adeno-associated viral (AAV) vectors. In this case, it is an AAV8 treatment. DTX301 intravenously delivers a stable and functional copy of the OTC gene to patients, helping to metabolize ammonia through urinary orotic acid. Both the FDA and EMA granted DTX301 Orphan Drug status.

The Phase 1/2 study enrolled 9 patients. Of these, approximately 66% responded positively to DTX301, with at least half of these having sustained responses at least 2-3 years later. DTX301 is safe and well-tolerated. During the trial, no patients experienced severe side effects and none were hospitalized due to DTX301 or OTC deficiency.

In the cohort which also received prophylactic steroids, two patients were dosed. Both experienced no safety problems and had solid metabolic control. Due to COVID-19, the third patient has not been dosed. However, Ultragenyx hopes to dose this patient by the end of January 2021.

Moving forward, Ultragenyx hopes to hold a Phase 3 clinical trial at some point in 2021. 50 patients will enroll. The planned dose is 1.7 x 10^13 GC/kg. The primary endpoint is how much ammonia levels change over a 24-hour period.

DTX401 for GSD1a

For GSD1a, researchers are advancing the DTX401 gene therapy program. Altogether, 9 patients enrolled in the Phase 1/2 clinical trial. DTX401 is an investigational AAV8 gene therapy. The therapy is administered intravenously. It works by delivering functional G6Pase-α and reducing levels of glycogen in the liver. In both America and Europe, DTX401 received Orphan Drug designation. However, in America, the therapy has also received both Fast Track and Regenerative Medicine Advanced Therapy designations.

During the trial, patients were able to taper or discontinue their oral glucose replacement with cornstarch while on DTX401.  Over a 1-year period, the mean reduction in cornstarch throughout all three cohorts was 77%. At the same time, patients were able to better monitor and control their glucose levels, and experienced higher energy. For patients who continued to be monitored for 2+ years, the mean reduction in cornstarch is 91%. Throughout treatment, patients experienced better glycemic control and also saw improvements in weight loss. Self-reported data suggests that patients also experienced improved quality of life (QOL) and lowered their stress levels.

Additionally, DTX401 was relatively safe and well-tolerated. This safety carried over even when patients were also using other therapeutic options, such as prophylactic steroids. Following meetings with the FDA and EMA, Ultragenyx also hopes to hold a Phase 3 clinical trial on DTX401 during 2021. 50 patients will enroll. The planned dose is 1.0 x 10^13 GC/kg.

UTX701 for Wilson Disease

UTX701 was developed using Ultragenyx’s proprietary HeLa producer cell line (PCL) platform. This investigational AAV9 treatment was granted Orphan Drug designation within the United States and Europe. UTX701 intravenously administers a functional ATP7B copper transporter, helping to remove copper from the body. Although there are not currently clinical trials centered around UTX701, an Investigational New Drug (IND) application was submitted to the FDA in December 2020. If all goes well, Ultragenyx should be able to begin clinical trials evaluating this therapy for Wilson disease later in 2021.

Wilson Disease

Caused by ATP7B gene mutations, Wilson disease is a rare genetic disorder in which the body is unable to metabolize or excrete copper. While some copper plays a role in our health, the over-accumulation of copper in the brain, liver, and organs could lead to a variety of health issues. An estimated 30,000-50,000 people worldwide have Wilson disease. Without treatment, Wilson disease is fatal. Typically, symptoms appear between ages 6-45, although it is most common for symptoms to appear between 13-19. Symptoms vary, but may include:

• Kayser-Fleisher ring, or a brown ring around the iris
• Depression
• Homicidal or suicidal ideations
• Hepatitis
• Fatigue
• Appetite loss
• Abdominal pain and inflammation
• Muscle stiffness
• Loss of coordination
• Unintended weight loss
• Jaundice (yellowing of the skin and eyes)
• Difficulty walking or swallowing
• Fluid accumulation in the extremities
• Easy bruising and bleeding

Learn more about Wilson disease here.

OTC Deficiency

OTC gene mutations cause ornithine transcarbamylase (OTC) deficiency, a genetic urea cycle disorder characterized by ammonia accumulation in the blood. Normally, ornithine transcarbamylase plays a role in the urea cycle. When this is not working properly, ammonia accumulates to a toxic level, impacting the liver and nervous system. Because OTC deficiency is an X-linked disorder, males are much more likely to inherit this than females. In the rare case that a female has OTC deficiency, it is often relatively mild. The neonatal-onset form of OTC deficiency is more severe than the late-onset form.

Symptoms of neonatal-onset OTC deficiency include:

• Liver enlargement
• Poor muscle tone
• Irritability
• Vomiting
• Lethargy
• Refusal to eat
• Seizures
• Difficulty breathing
• Developmental and intellectual delays
• Cerebral palsy

Symptoms of late-onset OTC deficiency occur in periodic episodes, often following another illness. These include:

• Irritability
• Lethargy
• Nausea and vomiting
• Hyperactivity
• Confusion
• Impaired coordination
• Slurred speech
• Self-harming behavior

Without treatment, OTC deficiency can be fatal. Learn more about OTC deficiency here.

Glycogen Storage Disease Type 1 (GSD1a)

Mutated G6PC or SLC37A4 genes cause Glycogen storage disease type 1 (GSD1a), or von Gierke disease, which is characterized by glycogen accumulation within the cells. This rare and severe glycogen storage disease can affect multiple organs throughout the body. 1 in every 100,000 people is estimated to have GSD1a. Currently, there are no approved treatments for GSD1a.

Typically, GSD1a symptoms appear within 6 months of birth. Symptoms may change or progress as children age. These symptoms include:

• Insomnia or difficulty sleeping through the night
• Appetite loss
• Low blood sugar
• Excess fat and uric acid in the blood
• Seizures
• Spleen and kidney enlargement
• Diarrhea
• Puberty delay
• Osteoporosis
• Gout
• Polycystic ovaries
• Kidney disease

Learn more about GSDIa here.