Collaboration Called Key to Moving GTX-102 Development Forward

Potential Angelman syndrome treatment began with Texas A&M researchers

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Ultragenyx will continue clinical development of GTX-102, an investigational treatment for Angelman syndrome, after acquiring GeneTx Biotherapeutics — the company that was developing it — in a $75 million deal earlier this month.

The therapy was originally developed in the laboratory of Scott Dindot, PhD, in the School of Veterinary Medicine & Biomedical Sciences at Texas A&M University. He has collaborated with GeneTx — and now Ultragenyx — to move GTX-102’s development forward.

The efforts led to the Phase 1/2 KIK-AS clinical trial (NCT04259281) of the therapy, for which Ultragenyx recently reported encouraging results demonstrating its safety and efficacy in children with Angelman. The trial aims to recruit up to 83 children with Angelman, ages 4–17, at sites in the U.S., Canada, and U.K.

“This is a really great example of the successful commercialization of a technology from the research stage to the clinical development of a promising therapeutic with a company,” Janie Hurley, program director at Texas A&M AgriLife Research Intellectual Property & Commercialization, said in a press release.

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“We strive to ensure that new discoveries such as this one have the best chance possible to reach those in society who could benefit. Working with companies like GeneTx and Ultragenyx is how we accomplish this goal,” she added.

Angelman syndrome is a rare genetic disorder that results from a missing or malfunctioning copy of the UBE3A gene, which contains instructions for making the ubiquitin protein ligase E3A (UBE3A) protein. UBE3A is involved in helping cells recycle poorly working or excess proteins, enabling them to function properly.

Normally, one copy of the UBE3A gene is inherited from each parent. Both copies are active in most cells, but in some brain cells, only the copy inherited from the mother is active. If the maternal UBE3A gene is dysfunctional or unavailable, as is the case in Angelman syndrome, brain cells can’t properly recycle unwanted proteins, leading to symptoms including developmental delays, speech impairments, movement disorders, and seizures.

Antisense oligonucleotides are short strings of genetic material (DNA or RNA) that can control how much of a protein is made in cells. UBE3A-AS is a naturally occurring oligonucleotide that normally binds to the paternal copy of UBE3A in brain cells and inactivates it.

Treatment research

Dindot and his team identified a region on UBE3A-AS that was particularly important for regulating the activity of the paternal gene. They developed GTX-102, a lab-made antisense oligonucleotide, to bind to that region.

In binding to UBE3A-AS, GTX-102 essentially reactivates the paternal gene, allowing properly working UBE3A to be produced in brain cells, thereby preventing or easing symptoms.

“We targeted a very specific region on the UBE3A-AS transcript that we believe is important for regulating its expression,” Dindot said. “In theory, this treatment goes after the heart of the condition.”

In collaboration with GeneTx and later with Ultragenyx, Dindot and his team worked to move GTX-102 toward clinical development.

Ultragenyx and GeneTx jointly launched the Phase 1/2 KIK-AS clinical trial of the therapy, with Ultragenyx recently taking full control of the study and the entire GTX-102 clinical program.

Interim results from five patients, announced in late 2020, showed signs of GTX-102’s efficacy, but all five children experienced leg weakness after a high-level dose. This led GeneTx and Ultragenyx to pause the trial while treatment protocols were updated. Changes included lowering the dose range and altering the administration route.

The trial resumed in 2021 under these new protocols.

As of an interim analysis last month, the trial had enrolled 14 pediatric Angelman patients from ages 4–17 across study sites in the U.S., U.K., and Canada. Participants are assigned to receive GTX-102, delivered directly into the spinal canal (intrathecally) at increasing doses and monitored for about four months.

Data showed that among 11 treated patients, GTX-102 improved function and lessened disease severity. Various aspects of function, including behavior, motor function, communication, and sleep, were improved among the children.

The therapy was well-tolerated, with no treatment-related, serious adverse effects reported at any dose.

Supported by the promising results, a trial amendment was made to allow testing of the therapy at higher monthly doses. That amendment has been approved in the U.K. and Canada and is pending approval in the U.S. Once sufficient efficacy data are gathered, the trial will enroll 20 patients for long-term follow-up regarding the treatment’s safety and efficacy.

“That the drug made it to a clinical trial is an enormous milestone and now it is just amazing to hear the interim data suggesting that kids’ conditions are improving in multiple areas,” Dindot said. “Over the past decade, there have been probably over a dozen people who have worked on this in my lab — undergraduate and graduate students and scientists — and I really want to recognize them for the hard work they put into the research and development of this drug; it takes a lot of people to do this and I’m proud of what we have accomplished together.”