Delaying but not blocking AMT-130, uniQure’s emerging gene therapy to slow Huntington’s disease progression, the U.S. Food and Drug Administration (FDA) “strongly recommended” that the company conduct a full-blown, Phase III clinical trial, rather than assess an application for drug approval based on an earlier trial that showed historic efficacy.
The news came in a March 2 uniQure press release, relying on official minutes from the company’s January 30 high-priority meeting with the FDA about the AMT-130 program. The drug has been shown to slow the progression of by HD symptoms by as much as 75 percent.
As discussed below, this action reflects the more conservative trend of at least parts of the FDA under the Trump administration.
Based on the meeting minutes, the FDA has maintained its new decision that data from the earlier AMT-130 Phase I/II trial, using the global Enroll-HD patient database as a comparison, cannot be used as primary evidence for a drug application, the release stated.
The company added: “The FDA strongly recommended uniQure conduct a prospective, randomized, double-blind, sham surgery-controlled study. uniQure intends to continue engaging with the FDA regarding Phase III development considerations and plans to request a […] meeting in the second quarter of 2026 to further discuss potential study design approaches.”
A prospective, randomized, double-blind study is a standard clinical trial in which neither patients nor researchers know who receives the drug. A sham (pretend) surgery, which uniQure did on a few clinical trial participants early in the Phase I/II study, will now be required as a placebo, which is standard in most clinical trials. Relying on Enroll-HD data had taken the place of the sham surgery, which uniQure had stopped doing for ethical reasons. Injecting AMT-130 into the brain involves a twelve-plus-hour brain operation.
uniQure’s plans
“While we did not reach alignment on a submission pathway based on the Phase I/II data, we believe the totality and durability of our data warrant continued substantive dialogue” with the FDA regarding “regulatory flexibility,” uniQure CEO Matt Kapusta stated. “We remain committed to engaging with the FDA to determine a clear, scientifically grounded, and efficient path forward for AMT-130. We are deeply grateful for the resilience and support of the Huntington’s disease community and remain committed to standing with patients and their families.”
“Regulatory flexibility” refers to FDA programs that, for example, allow potential accelerated drug approval. uniQure had previously pursued that.
Based on its studies so far, which include three years of analysis, uniQure plans to share a four-year analysis, “which we expect to complete in the third quarter of 2026,” Daniel Leonard, the company’s director of global patient advocacy, wrote in a letter e-mailed to the HD community. “We believe the extended follow-up will provide additional insight into both the durability and the magnitude of the effects of AMT-130.”
Removing bias from the study
Last September, uniQure had reported that AMT-130 demonstrated a 75 percent slowing in the progression of HD over a three-year period. However, in crisis under the Trump administration, the FDA backtracked on its word regarding the firm’s plans to submit its application in early 2026, prompting 48,000-plus people to sign two petitions to the agency asking to keep its promise.
On February 24, a top uniQure scientist presented an updated analysis of AMT-130 at the 21st Annual HD Therapeutics Conference.
David Margolin, M.D., Ph.D., uniQure’s vice president for clinical development, gave the first scientific presentation at the Therapeutics Conference. He addressed the question, raised by the FDA, regarding the use of data from Enroll-HD, instead of a placebo, in the AMT-130 clinical trial.
“We relied on an external comparator cohort, which is selected from participants in the Enroll- HD Natural History Study, which has advantageous characteristics as a comparator,” Dr. Margolin explained. However, whereas the AMT-130 clinical trial takes MRI measurements of the brain, including the crucial striatum, Enroll-HD participants do not.
To mitigate the “potential bias” from this difference, uniQure used a statistical technique known as “propensity score matching,” Dr. Margolin stated. As he explained, this involves finding in Enroll-HD individuals similar to those in the uniQure trial and including them as controls.
The volume of the striatum (which demonstrates the loss of brain tissue in HD) as a factor in the AMT-130 trial “becomes moot,” Dr. Margolin continued. Other patient characteristics from Enroll-HD “can fully substitute” for that measure, such as neuropsychological testing and measurements of a person’s involuntary movements, he said.
“This analysis supports the validity of the three-year efficacy results,” Dr. Margolin concluded. uniQure will publish results of the AMT-130 trial in a scientific journal.
Dr. David Margolin (above) displaying a slide demonsrating AMT-130's efficacy in slowing HD progression and (below) enjoying down time at the Therapeutics Conference (photos by Gene Veritas, aka Kenneth P. Serbin)
‘At the precipice’ of effective treatments
Held at the Parker hotel in Palm Springs, CA, the HD Therapeutics Conference concluded on February 26. It is sponsored by CHDI Foundation, Inc., the largest private backer of the quest for HD therapies.
Like potential remedies in other HD programs, such as Roche’s tominersen, AMT-130 lowers (reduces) the amount of defective huntingtin protein.
“We have multiple shots on goal in the huntington-lowering arena, things like uniQure,” CHDI Chief Scientific Officer Robert Pacifici, Ph.D., told me in an interview on February 27. “While it's true that none of them have made it out the other end with a positive ruling in a pivotal Phase III trial, we're at the precipice of the types of signals that will indicate that there is a clinically meaningful benefit by lowering huntingtin.”
Such benefit must be confirmed through a Phase III trial or conditional approval by the FDA.
This “exciting” development encourages other companies to invest in late-state trials, Dr. Pacifici added, noting that lowering huntingtin hits at the root causes of HD.
Dr. Pacifici at the conclusion of the Therapeutics Conference (photo by Gene Veritas)
A ‘more conservative’ FDA
Cristina Sampaio, M.D., Ph.D., CHDI’s chief medical officer, joined the foundation in 2011 after serving on two entities in the European Medicines Agency (EMA), the FDA’s counterpart in Europe.
In a February 25 interview, Dr. Sampaio, who advises companies on their clinical trial programs, observed that companies other than uniQure have faced changes in course with the FDA.
Under the Trump administration, she said, the FDA become “more conservative,” especially in the Center for Biologics Evaluation and Research, the unit in charge of evaluating drugs such as AMT-130. News reports have also noted the conservative trend.
FDA ‘ping pong’ not healthy
At the same time, Dr. Sampaio stated that changes in the FDA’s approval process are “problematic” for uniQure and other firms.
“Companies rely on what they discuss with FDA,” Dr. Sampaio said. “This for them is vital. It's how they define their projects, it's how they define how long it will take to the market, it's how they define their budget, how much it will cost.”
Changing positions from one day to the next “creates a lot of uncertainty to the market,” she observed. “This ping pong of FDA is not healthy.”
As news organizations have reported, changes in leadership at the FDA, firings, and the exit of mid- and high-level managers have created “uncertainty” and “turmoil” at the agency, Dr. Sampaio said.
More susceptible to politics
Whereas decisions about drugs in Europe tend to be more “democratic,” the FDA is “hierarchical,” making it more susceptible to politics, Dr. Sampaio observed.
Even so, she added, outside of normal lobbying, “there was no evidence” until now that political influence was affecting the FDA.
“But until these big changes with the Trump administration, the FDA was very respected as an independent body,” Dr. Sampaio asserted.
External comparisons are good science
Dr. Sampaio noted that the uniQure AMT-130 clinical trial program began in 2019 as an exploratory venture, mainly to test for safety. As time passed and the personnel at the firm changed, the goals for AMT-130 became “more ambitious.”
“But this was not pre-planned,” she said. “And this is a weakness. That said, I believe they have been as careful as they can be, given the circumstances, and given the data they have.” The 17 patients about which data have been revealed is also a “small” number, she acknowledged.
The decision to use Enroll-HD as a comparison was also first “pushed by the FDA,” Dr. Sampaio noted, albeit under the previous administration.
Use of Enroll-HD as an “external comparator” is good science, Dr. Sampaio emphasized, noting that in oncology a similar technique has been used for more than a decade.
AMT-130 data moving in the right direction
Significantly, all of the AMT-130 data go “in the same direction,” showing improvement in the symptoms, she said. “This is very powerful.”
If AMT-130 were granted accelerated approval, it would be conditional, with the drug having to be removed from the market if problems emerged, Dr. Sampaio explained. Accelerated approval would also require ongoing study of the drug for safety and efficacy.
Dr. Margolin’s presentation at the therapeutics conference resolved scientific doubt regarding the volume of the striatum, Dr. Sampaio said. “This alleviated the concern that the population in this trial was not representative.”
Dr. Sampaio (right) with Dr. Hoa Huu Phuc Nguyen of Ruhr University Bochum, Germany (photo by Gene Veritas)
Some think AMT-130 needs more work
Blair Leavitt, M.D., a veteran HD researcher and professor of medicine at the University of British Columbia, also weighed in on AMT-130 and the FDA. Dr. Leavitt is the co-founder and co-editor-in-chief of the Journal of Huntington’s Disease.
Dr. Leavitt’s lab received funding from uniQure to conduct research.
“We tested in our mouse model of Huntington's disease and showed benefits of the uniQure approach in that mouse model,” he explained in a February 26 interview at the Therapeutics Conference. He thinks that the uniQure clinical trial was “designed primarily to show the safety and tolerability of the approach and the agent in individuals with Huntington's disease, and it absolutely did that.”
The AMT-130 program has opened “a whole field of gene therapy and gene editing approaches, which is incredibly exciting for our field,” Dr. Leavitt added.
However, Dr. Leavitt thinks more work needs to be done on AMT-130. “I would disagree with some people who have suggested [that the work done so far] is sufficient to prove efficacy,” he said, adding that “a proper controlled trial” is ultimately needed. In effect, this was what the FDA has now recommended to uniQure.
Regarding the 75 percent slowing of symptoms with AMT-130, Dr. Leavitt observed that “we're talking about a decline in all of the patients, on average, but a less decline. That certainly is positive. That might be the best we can hope for with many of our therapies, but ultimately, it's not a complete reversal of symptoms.”
Uncertainty at FDA ‘bad for all’
Dr. Leavitt, as a Canadian citizen, declined to comment on the political impact of the Trump administration on the FDA.
“But I do believe it is a difficult time for drug development,” he said. “The FDA is really the premier regulator for most of the world, and uncertainty at the FDA leads to uncertainty in drug development, and that's bad for all of us.”
Such uncertainty “is the last thing we need at this point, because we are on the precipice of a number of therapies, and I'm sure we're going to have efficacy.”
Others firms’ interactions with the FDA
Veteran HD researcher Jang-Ho Cha, M.D., Ph.D., the chief science and medical officer of Latus Bio, addressed a question from the audience after his February 24 presentation about the company’s HD program.
Ed Wild, M.D., Ph.D.,wanted to know whether Latus had a strategy for engaging with the FDA and its Center for Biologics Evaluation and Research to obtain drug approval. Dr. Wild also asked whether an industry consortium could help “to at least extract some firm guidance?”
“Yes, we have a strategy to engage with them,” Dr. Cha responded. Latus hopes to soon submit an Investigational New Drug (IND) application.
“At this point, we will wait until we have our IND package to show them everything we’ve got,” Dr. Cha continued. “I’m not sure exactly, if we asked a question from the FDA, we would get an answer that we could rely on exactly at this point. We are watching with a lot of interest other companies who are having interactions with the FDA, because it’s relevant to all of us.”
Will the truth conquer all?
Dr. Pacifici offered a concluding reflection regarding the FDA.
“In terms of the interaction between the companies and the regulators, I guess I'm a bit of an optimist in this regard,” Dr. Pacifici told me. “I truly believe that politics and money and all of the other perverse things that surround us, notwithstanding, that at the end of the day, the truth conquers all.”
“I think that these are scientific people,” he said. “I think that they're going to look at the body of data and evidence, and eventually I think they're going to make the very best decision to get things out as quickly and as safely as possible to the patients who so desperately need these treatments.”
For additional coverage, visit HDBuzz.
Next time: Dr. Pacifici’s overview of the conference and his video interview with me.
