Pivotal Phase 3 trial of GTX-102 expected to launch by year’s end
Ultragenyx will test gene therapy in Angelman patients in upcoming trial
Note: This story was updated Aug. 13, 2024, to correct the spelling of the measure of cognitive development to Bayley-4.
Authorities in both the U.S. and Europe have provided positive feedback to Ultragenyx Pharmaceutical regarding plans for a Phase 3 clinical trial testing its gene therapy candidate GTX-102 in people with Angelman syndrome.
Now, having completed an end-of-Phase 2 meeting with the U.S. Food and Drug Administration (FDA), Ultragenyx said it is planning to launch the Phase 3 trial by year’s end. The study is expected to be pivotal, meaning that if the results are positive, they could form the basis for applications seeking approval of GTX-102.
“FDA alignment on our Phase 3 study design for GTX-102 allows for rapid initiation of a global double-blind sham-controlled pivotal study by the end of this year,” Eric Crombez, MD, chief medical officer of Ultragenyx, said in a company press release. In a double-blind trial, neither researchers nor participants know which patients are being given the treatment and which the placebo. In a sham-controlled study, patients given the placebo undergo the same procedures as other participants but are not given the treatment being tested.
Main goal of Phase 3 trial is seeing if GTX-102 improves cognition
Angelman syndrome is caused by a mutation in the UBE3A gene. Everyone inherits two copies of this gene, one from each biological parent — though the copy inherited from the biological father is normally inactive. Angelman develops when the copy inherited from the biological mother is mutated or missing entirely.
GTX-102, which is administered via injection into the spinal canal, is an antisense oligonucleotide that aims to inhibit the molecule that keeps the paternal copy of the UBE3A gene from being active in cells. This molecule is called UBE3A antisense transcript, or UBE3A-AS.
Ultragenyx now is running a Phase 1/2 study called KIK-AS (NCT04259281) that’s testing multiple doses of GTX-102 in children with Angelman syndrome. The study finished recruitment earlier this year, with 74 patients enrolled. According to the trial site, KIK-AS is expected to be completed by December.
At the meeting with the FDA, Ultragenyx discussed interim data from KIK-AS with the agency. This included the study’s early findings on a measure of cognitive development called the Bayley-4. Per the company, patients treated with GTX-102 in KIK-AS have shown “rapid, progressive and clinically significant improvement in cognition, as assessed by Bayley-4, that was far greater than the minimal change observed in natural history data.” (Natural history studies track the progression of a disease in the absence of treatment.)
KIK-AS specifically enrolled patients who have a full deletion in the maternal UBE3A gene; patients with this type of mutation tend to be on the more severe end of the spectrum of Angelman syndrome. The upcoming Phase 3 trial is also slated to enroll about 120 patients with a full maternal deletion.
Participants in the Phase 3 study will be given GTX-102 or a placebo for about one year, with the main goal of testing if the treatment improves cognition as assessed by the Bayley-4. Other measures of cognitive function, as well as assessments of motor function, behavior, sleep, and communication abilities, also will be evaluated. After the placebo-controlled part of the study ends, patients given the placebo will have the option to roll over into an extension part in which they would get active treatment.
Along with the FDA’s positive feedback, Ultragenyx also received a similar positive reaction to its planned Phase 3 trial design from the European Medicines Agency. The company also is planning to meet with regulators in Japan in the next few weeks to review the trial design.
In addition to this pivotal study in patients with a full UBE3A gene deletion, we are working to initiate a study to evaluate GTX-102 in patients with other mutations. This will allow for the potential treatment of more children and adults impacted by this devastating disease.
Apart from the Phase 3 trial in patients with a maternal deletion, Ultragenyx and the FDA also have discussed plans to launch a study of GTX-102 in patients with Angelman caused by other types of mutations, with the goal of potentially allowing access to treatment for a broader range of Angelman patients.
“In addition to this pivotal study in patients with a full UBE3A gene deletion, we are working to initiate a study to evaluate GTX-102 in patients with other mutations. This will allow for the potential treatment of more children and adults impacted by this devastating disease,” Crombez said.
Further information about Ultragenyx’s clinical trials is available on the company’s webpage for patients.
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