Phase 1/2 trial data may support AMT-130 approval, FDA says
Company to meet with FDA in first half of 2025
The U.S. Food and Drug Administration (FDA) has agreed that results from two ongoing Phase 1/2 clinical trials, compared with an external control group of untreated patients, might be sufficient to support an application seeking accelerated approval of AMT-130 for Huntington’s disease, the treatment’s developer said.
Key measures will include changes in the composite Unified Huntington’s Disease Rating Scale (cUHDRS), which assesses disease severity, and in levels of neurofilament light chain (NfL), a nerve damage marker, in the fluid that surrounds the brain and spinal cord.
“We are very pleased to reach agreement with the FDA on core components of an Accelerated Approval pathway for AMT-130,” Walid Abi-Saab, MD, chief medical officer of developer uniQure, said in a company press release.
The accelerated approval pathway is a mechanism the FDA can use to give conditional authorization to treatments based on early clinical trial evidence that they’re probably effective. As a condition of accelerated approval, drug developers have to conduct further testing to prove the therapy provides clinical benefits as expected.
“This is an important milestone for the Huntington’s disease community as it puts us on the most rapid and efficient pathway to deliver a potentially life-changing therapy to people living with this devastating neurodegenerative disorder,” Abi-Saab said.
Saving time
“The accelerated approval pathway avoids the need for additional lengthy and costly pre-submission study, thereby reducing our time to potential licensure by approximately five years,” Matt Kapusta, uniQure’s CEO, said on a company webcast.
The company said it is working on steps to prepare a regulatory application, and expects to discuss further application requirements with the FDA in the first half of next year.
Huntington’s is caused by mutations in the HTT gene, which provides instructions to make the huntingtin protein. When a gene is read to produce a protein, the genetic code is transcribed into a temporary molecule called messenger RNA (mRNA), which is then used as a template to make the protein.
AMT-130 is a gene therapy designed to target HTT gene’s mRNA, marking it for destruction, and ultimately preventing the production of the mutant huntingtin protein that’s thought to drive Huntington’s.
To increase its effects in the brain, the one-time therapy is administered directly into the caudate nucleus and the putamen, two deep brain regions heavily affected by Huntington’s
AMT-130 earlier this year became the first investigational Huntington’s therapy to be granted FDA regenerative medicine advanced therapy (RMAT) designation. This designation aims to speed the development of potentially important new treatments. One of its perks is allowing the therapy’s developer to meet with the FDA more frequently during the drug development process.
The company recently conducted such a meeting with the FDA, at which it presented data from two ongoing Phase 1/2 clinical trials testing AMT-130 in Huntington’s patients, one being run in the U.S. (NCT04120493), and the other in Europe (NCT05243017).
uniQure announced in July interim analyses from these studies, in which two-year data from 21 trial participants given the low or high dose of AMT-130 were compared with those from natural history studies. The external control group consisted of 154 untreated Huntington’s patients with demographic and clinical features similar to those of the trial participants.
Results indicated that AMT-130 treatment led to an 80% significantly slower disease progression, as assessed with the cUHDRS, and significantly lower NfL levels, by 11%, in the fluid that surrounds the brain and spinal cord.
At the FDA meeting, Uniqure presented these findings along with data from three additional patients given the high dose and followed for at least two years.
Moving along
“We went into the meeting looking for clarity on two important topics,” Abi-Saab said in the webcast. “One, that the potential therapeutic benefit of AMT-130 may be demonstrated relative to a natural history external control group in the ongoing Phase 1/2 studies. And two, that data from the ongoing Phase 1/2 studies may serve as the primary basis for an accelerated approval application of AMT-130.”
The FDA signaled broadly in the affirmative, meaning “that an additional registrational trial for accelerated approval will not be required,” Abi-Saab said.
The agency also indicated that changes in the cUHDRS may be used as an intermediate clinical goal to support such an application, and that the reduction in NfL levels “may serve as supportive evidence of therapeutic benefit,” Abi-Saab said.
In the meantime, enrollment for the trials’ third group of patients, meant to assess the effects of an immunosuppression regimen on the therapy’s safety, is wrapping up, and dosing is expected to be completed in the first months of 2025.
Preliminary safety updates for this group, as well as three-year efficacy data from the same 21 patients included in the July interim analyses, are anticipated next year.
AMT-130 also received orphan drug designation in the U.S. and in Europe, and fast track designation in the U.S. for the treatment of Huntington’s. All these regulatory statuses are meant to accelerate the therapy’s clinical development and regulatory review.
About the Author
