FDA’s Rewrites the Rules for Promising Huntington’s Gene Therapy

A gene therapy may substantially slow the progress of Huntington’s disease, but a recent shift in FDA guidance has created uncertainty that might delay promising advancements in the hunt for a treatment. 

Last year, the company uniQure shared promising data for AMT-130, a therapy delivered through a single brain surgery, and planned to file for regulatory approval in the early part of this year. The trial used external controls, historical data from people with Huntington’s, which the FDA had said was sufficient for regulatory approval. 

The excitement was short lived, as the Food and Drug Administration (FDA) informed uniQure in November 2025 that its trial data comparing participants who received the drug to external controls to show effectiveness was no longer sufficient for the drug approval application. 

The change mobilized Huntington’s advocates who organized two online petitions that garnered more than 48,000 signatures. Signers — including HD Reach, Help4HD International, the Huntington’s Disease Foundation, the Huntington’s Disease Society of America (HDSA), and the Huntington’s Disease Youth Organization — delivered the petitions at FDA headquarters on Jan. 22. The petition didn’t succeed: After a recent meeting, the FDA told uniQure that the data is not sufficient to show effectiveness and strongly recommended a new trial.

“The community is not looking for any shortcuts. They want drugs to be safe and effective, and they want to uphold scientific rigor,” said Amy Gray, president and CEO of the Huntington’s Disease Society of America (HDSA), adding that they “just want the FDA to honor their previous guidance.”

Why urgent treatments are needed for Huntington’s

Huntington’s is an incurable neurodegenerative disease caused by a mutation in the HTT gene, which leads to the production of toxic forms of the huntingtin protein. Unlike other neurodegenerative diseases which start later in life, Huntington’s symptoms start while someone is in their 30s or 40s, first affecting movement and coordination and later progressing to cognitive decline and psychiatric problems. 

This new genetic treatment could potentially change the course of the disease. In a three-year, 17-patient, Phase 1/2 trial, it appeared to slow down disease progression. The therapy uses a small piece of genetic code, called microRNA, designed to prevent the mutated form of the huntingtin protein from forming. It’s packed into a virus and delivered to the brain via a one-time 12- to 18-hour brain surgery.

Since the study didn’t have a placebo group, the researchers compared the progression to historical data that followed patients progressing with the disease. The researchers used the 18-point composite Unified Huntington’s Disease Rating Scale, which combines movement and cognitive symptoms, as well as day-to-day function, to monitor changes in their condition. On this scale, higher scores indicate more decline.

On average, historical data showed that people with the disease decline by 1.52 points over three years. However, the study participants who received the gene therapy declined by 0.38 points, a difference of 1.14 points (or a slowing of the disease by 75 percent). One of the participants who had to retire due to his symptoms was even able to return to work.

Though the FDA initially agreed that the company could use the historical data, also called external controls, instead of an experimental control group, the agency changed its mind. Advocates worry that this would require participants to undergo an invasive surgery without receiving an intervention, which, Gray said, is considered unethical within the community.

What does the change in guidance mean for uniQure and other companies?

Since the FDA changed their guidance, uniQure met with the FDA in January to discuss their prospects for approval. The FDA “strongly recommended” that the company should conduct a sham-surgery controlled trial. The company will meet with the FDA again to discuss plans for designing this Phase 3 study. UniQure is also running two more combination Phase 1 and 2 trials of the drug in the U.S. and Europe to find out the ideal, safest dose for the treatment.

“What we’re really looking for is a transparent and predictable regulatory environment,” said Gray.

The decision to bar external controls would mean that some participants in trials would undergo surgery without receiving any treatment and devalue the use of datasets that follow the disease trajectory. Such decisions, experts cautioned, could make clinical trials more expensive and difficult to run and the last-minute shifts in regulatory guidance from the FDA may affect other companies working on similar treatments for neurodegenerative diseases. 

Gray said this could “create a climate of uncertainty that can scare off investment and scare off companies.” 

Still, there’s hope within the Huntington’s community. “There’s a lot of promise now that the biological proof-of-concept is done,” said Gray. “We know that huntingtin-lowering gene therapy can slow the disease.” 

With several drug companies working on the disease, the hope is that an effective therapy could be approved in the coming years.