Human Clinical Trial Begins For Texas A&M-Discovered Drug To Treat Angelman Syndrome

The first therapeutic drug for Angelman syndrome (AS) — discovered by Texas A&M researchers — has begun human trials, bringing it one step closer to potentially becoming available to patients.

GTX-102 was discovered by a team led by Dr. Scott Dindot, a professor in the College of Veterinary Medicine and Biomedical Sciences’ (VMBS) Department of Veterinary Pathobiology and the executive director of molecular genetics at Ultragenyx. 

AS is a rare genetic disorder that affects approximately 1 in 15,000 live births per year. Symptoms, which usually appear when a child is 2 to 3 years old, include developmental delay, absent speech, movement or balance issues and seizures.

There are no approved therapies for AS, and the current standard of care is focused on behavioral therapy and controlling specific symptoms, specifically the seizures that often affect patients with AS.

GTX-102 is the first investigational drug that targets the genetic root cause of AS — loss of a gene in the brain called UBE3A inherited from the mother. Individuals with AS have genetic mutations that cause the silencing of maternal UBE3A; to replace it, GTX-102 turns on the paternal copy of the same gene, which is usually silenced.

The phase three clinical trial, run by Ultragenyx, aims to enroll 120 individuals and will run for 48 weeks.

“GTX-102 is unique not only because it targets the genetic cause of AS but also because it’s the first disease-modifying drug for AS to advance into clinical development,” Dindot said. “There are only a few examples of disease-modifying drugs being used to treat genetic disorders and even fewer examples that are being developed to treat neurodevelopmental disorders such as AS.”

“Dr. Dindot and the team at Texas A&M took a novel approach when designing GTX-102 that allows for potent knock down of the silencing of expression of the paternal copy of the UBE3A gene to directly address the underlying cause of disease,” said Eric Crombez, M.D., chief medical officer at Ultragenyx. “Our goal with the Phase 3 Aspire study is to confirm the safety and clinical efficacy of GTX-102 in a global randomized trial with a population that represents the majority of patients with Angelman syndrome. We also have plans to initiate a second study this year to further assess safety and efficacy across additional genotypes and ages.”

“It’s just incredible that there are people who have dedicated their lives to something as rare as AS. When Brantley was first diagnosed, there was nothing out there to treat it. We had to navigate everything virtually on our own. But now, we are starting to see options for treatment, and we’re so proud that Aggies are involved.”

For Jake Edwards — father of Brantley, a 12-year-old boy with AS — the research conducted by Dindot and Ultragenyx represents hope for improving his son’s quality of life.

“For Brantley to have even a minimal amount of speech would be amazing,” Jake said. “We’d love for him to be able to tell us if something is hurting, or even what he wants for his birthday or Christmas. I don’t think there’s a single word that could describe what that would mean.

“It’s just incredible that there are people who have dedicated their lives to something as rare as AS,” he said. “When Brantley was first diagnosed, there was nothing out there to treat it. We had to navigate everything virtually on our own. But now, we are starting to see options for treatment, and we’re so proud that Aggies are involved.”

When Innovation Makes A Difference

GTX-102 works by traveling through the body’s spinal fluid directly to the brain.

“It targets the gene that causes the disorder,” Dindot said. “If you have a headache, you might take medication for the pain, but you’re not really treating the source of the headache. GTX-102 goes after the source of the condition.”

In previous phases of GTX-102’s clinical trial, children who received the investigational drug have shown marked improvement in many areas impacted by AS.

“Typically, kids with AS have severe developmental delay and intellectual disability,” Dindot said. “They have absent speech, meaning they can make sounds but can’t form words. They have motor coordination issues, sleep issues, and many have epilepsy.  People with AS require full-time lifelong care and are unable to live on their own.”

Advancing The Treatment And Diagnosis Of AS

As treatments for AS improve, there continues to be a need for earlier diagnoses so that children can begin treatment as early as possible.

“There’s usually no evidence of this disorder in families; it’s a sporadic condition,” Dindot said. “One of the first signs might be that a mother will notice something is different; they’ll notice that their baby doesn’t cry or move very much. As the child grows up, they’ll notice that they miss all their developmental milestones, like sitting up, babbling and walking.

“But developmental delay isn’t a guaranteed sign of AS,” he said. “There can be other causes. So, the child may not receive genetic testing until around 1 or 2 years of age, and that’s often if the parents are persistent and have access to advanced medical care.”

Thankfully, as genetic testing technology advances, the costs are much lower and the process is faster than it used to be.

“Genetic testing is becoming very common in medical practice,” Dindot said. “Almost all types of insurance will cover it if there is a reason. One issue is that there’s a shortage of clinical geneticists and genetic counselors, who are the ones who read and interpret the results of the genetic test so that the family understands what they mean. 

“It can take some families several months to a year after the test before they get to talk to a genetic counselor,” he said.

Though the effects of GTX-102 are already remarkable, Dindot hopes that in the future, the process will become less invasive for individuals with AS and their families.

“The drug is administered through lumbar intrathecal injection,” he said. “Every three months, families have to visit the hospital to have this done. The goal in the future is to find new ways to administer the drug and improve where it goes in the brain.”

Phase Three Moves Forward

The first patient in the clinical trial has been dosed, and Ultragenyx is currently recruiting 120 children ages 4 to 17 as participants. Participants must have a genetically confirmed diagnosis of full maternal UBE3A gene deletion. The trial is randomized, though participants in the control group will be able to cross over into treatment after 48 weeks. 

For more information, visit the clinical trial’s website or contact Ultragenyx at trialrecruitment@ultragenyx.com.

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GTX-102 is an investigational [antisense oligonucleotide (ASO) OR therapy] that is not currently approved by any health authority.