A Senate probe of the FDA and a letter from advocates to Trump could aid in approval of Huntington’s disease gene therapy

  

Two key political developments could aid uniQure’s effort to seek approval of its historically efficacious Huntington’s disease gene therapy, AMT-130, from the U.S. Food and Drug Administration (FDA): a senatorial probe of the FDA and a letter to President Trump from rare-disease advocates.

 

As reported widely, uniQure is preparing for yet another meeting with the FDA to discuss the potential Phase III large-scale clinical trial required by the agency to further test the efficacy of AMT-130. Since its start in 2019, the Phase I/II trial has involved some 45 people. In September 2025, uniQure revealed that 17 of the individuals receiving the highest dose of AMT-130 had a slowing of progression of HD by 75 percent. The FDA, seen by many biotech observers to have become dysfunctional under the Trump administration, then surprisingly reneged on a promise to allow uniQure to apply for approval in 2026.

 

On March 9, Wisconsin Sen. Ron Johnson, a Republican, announced that he had launched an investigation of the FDA because it had rejected drug applications for several rare diseases.

 

Senator Ron Johnson (official congressional photo)

 

Johnson described the FDA’s request for a new AMT-130 trial, which would include a deeply invasive sham surgery for participants not getting the actual drug, as “bureaucratic idiocy.”

 

AMT-130 requires a twelve-hour surgery to inject the drug deep into the brain. The sham surgery would serve as a placebo in the clinical trial.

 

“You’re expecting people to go through sham surgeries where they get holes drilled in their heads?” Johnson said. “That’s just unbelievable.”

 

As part of his probe, Johnson is seeking denial letters from the FDA. Referring to the agency, he said that the “stories are outrageous. It just appears that they’re looking for excuses to say no.”

 

The senator added: “We’re going to find out exactly what issues the FDA listed for their ‘nos’.”

 

A sham surgery could pose ‘significant risk’

 

Johnson’s office did not respond to my request for an interview.

 

Walid Abi-Saab, M.D., uniQure’s chief medical officer, told the key publication Neurology Today that a sham controlled study “could impose significant risks and burden to patients” and that some people may consider it unethical.

 

Dr. Abi-Saab added that volunteers facing the sham surgery could not access other potentially disease-modifying therapies advancing through trials involving several years of observation.

 

Early in the AMT-130 program, uniQure used a sham surgery in several individuals but then stopped precisely because of ethical concerns.

 

Advocacy groups such as the Huntington’s Disease Youth Organization (HDYO) also have cautioned against the sham surgery.

 

In a March 6 e-mail, the organization stated that the “use of a sham neurosurgical procedure – requiring participants to undergo the risks of major surgery to the head including a lengthy time period under anesthesia without the possibility of therapeutic benefit – places an unnecessary burden on individuals already facing a progressive and fatal condition.” HDYO urged the use of “alternative trial designs … while minimizing avoidable risk to participants.”

 

Seeking to restore regulatory clarity

 

According to a report by Reuters, on April 1 the Rare Disease Advocacy, Biotechnology, and Investor Coalition sent a letter to President Trump, U.S. Health Secretary Robert F. Kennedy Jr., Medicare head Mehmet Oz, M.D., and FDA Commissioner Marty Makary, M.D.

 

The letter urged the leaders to restore regulatory clarity at the FDA as it considers a new leader for the agency’s Center for Biologics Evaluation and Research.

 

Headed by Vinay Prasad, M.D., who has resigned for the second time, the Center evaluates gene therapies such as AMT-130. Dr. Prasad’s departure follows a series of controversies involving the review of vaccines, gene therapies, and biotech drugs, including reversals of FDA promises. Biopharma executives, investors, members of Congress and others have criticized his actions.

The coalition includes nearly 100 patient disease advocacy groups, biotech executives, and investors. The letter noted that the Center had become less flexible in overseeing rare disease clinical trials.

 

The group has observed a drop in rare disease investment because of the uncertainties caused by the FDA.

 

“We believe it is of the utmost importance that the FDA chooses [for the Center] a leader who understands the unique challenges of rare disease development and respects and values the views of patients and physicians,” their letter stated.

 

A chance for the FDA ‘to reset’

 

An April 1 report by the news site BioPharmDive echoed the advocates’ critical analysis of the FDA.

 

The report observed that, after a “turbulent year” at the FDA caused by “constant leadership changes” and “erratic decision making,” the agency is as “unpredictable as it’s ever been.”

 

BioPharmDive concluded that Dr. Prasad’s departure by the end of April “could give the FDA a chance to reset.”  Commissioner Makary promised to name a replacement before he leaves.

 

‘We can’t afford delays for rare diseases’

 

On February 26, Florida Sen. Rick Scott, another Republican, chaired a hearing of the Senate Special Committee on Aging, which addressed the FDA’s difficulties.

 

At the hearing, physicians, biotech leaders and rare disease patient advocates criticized the FDA for stifling innovation.

 

The hearing discussed FDA reversals of previous agreements that it had made with drug makers. One advocate pointed out that, from 2024 to 2025, the FDA had 65 percent fewer advisory committee meetings for new drugs and biologics (a medicine derived from a living organism as opposed to a chemical), including for rare diseases.

 

At the hearing, New York Sen. Kirsten Gillibrand, a Democrat, pointed out that about one in ten Americans have a rare disease. She stated that the FDA is “not working how it should be” as laid out by Congress.

 

“This is heartbreaking for patients, and it’s why we can’t afford delays and disruptions in treatment,” Gillibrand observed. “Rare diseases can progress rapidly, cause irreversible harm and, in some cases, premature death.”

CHDI chief scientist: ‘at the precipice’ of treatments, Huntington’s disease community must ‘persevere’ through the stress

  

As researchers have hypothesized that lowering (reducing) the amount of abnormal huntingtin protein in the brains of people afflicted with Huntington’s disease hits at the root causes of the disease, leading companies have sought to develop drugs in response, like uniQure’s AMT-130 gene therapy.

 

The huntingtin-lowering approach has become central to the search for disease-modifying therapies that slow, halt, or reverse the course of HD, a progressive disorder still without a treatment after the discovery of the huntingtin gene in 1993.

 

"We have multiple shots on goal in the huntington-lowering arena, things like uniQure, like PTC, like Skyhawk,” Robert Pacifici, Ph.D., chief scientific officer for CHDI Foundation, told me in a video 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.”

 

In our interview, Dr. Pacifici gave his customary overview of the CHDI-sponsored 21st HD Therapeutics Conference, held February 23-26 in Palm Springs.

 

Dr. Robert Pacifici (right), interviewed by Gene Veritas, aka Kenneth P. Serbin, February 27, 2026 (screenshot by Gene Veritas)

 

In my introduction, I noted that, because “it had a lot of progress,” scientifically this was the most “exciting” of the conferences that I have attended since my first in 2010.

 

However, I added, “there was stress for us in the HD community about the uniQure gene therapy program” because we were “shocked” at the abrupt backtracking of the U.S. Food and Drug Administration (FDA) on the drug despite its historic efficacy. This prompted two petitions with 48,000-plus signatures. I recalled that “so many of us in the community are still living with the burden of symptoms, including my sister, now disabled.”

 

Dr. Pacifici agreed that, until the arrival of an effective therapy, the HD community will have “some high degree of hope, but also a high degree of stress, because I think the closer we get, the more stressful it is that we're at the precipice of actually realizing this incredible journey.”

 

Dr. Pacific urged that people “continue to persevere.”

 

Watch my full interview with Dr. Pacifici in the video blow. 

 

 

A 75-percent slowing of the disease

 

At the Therapeutics Conference, a uniQure scientist presented an updated analysis of AMT-130 that “supports the validity” of its “efficacy results.”

 

With uniQure’s announcement last September that AMT-130 had demonstrated a 75 percent slowing in the progression of the disease over a three-year period, the HD community was jubilant (click here and here to read more).

 

Reports such as the BBC’s optimistically portrayed AMT-130.

 

HD and uniQure thrust into the national spotlight

 

Observers and news reports have described the Trump administration’s FDA as dysfunctional and more conservative. After the FDA surprisingly reversed field in November regarding AMT-130, the anxiety and raw tensions over the drug underscored the HD community’s yearning for an effective therapy.

 

On March 2 uniQure revealed that the FDA declined to accept its request to keep the agency’s original promise, in which the firm could apply for accelerated approval for AMT-130. Instead, the FDA “strongly recommended” that the company conduct a full-blown, Phase III clinical trial (click here to read more).

 

The controversy over AMT-130 has highlighted the FDA’s rejection of rare-disease drug programs, thrusting HD and uniQure into the national spotlight. Outlets providing coverage have included STAT, The New York Times, Bloomberg, CNN, CNBC, and the The Wall Street Journal.

 

On March 6 Vinay Prasad, M.D., the controversial head of the division within the FDA charged with evaluating gene therapies like AMT-130, resigned for the second time. While no reason was stated, the Times noted, leaders in the biotech and investor communities had long pressed the White House for his ouster.

 

Assisting the 60-plus companies involved

 

Dr. Pacifici told me that he was an “optimist” regarding the “interaction between the companies and the regulators,” who are “scientific people.”

 

“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,” 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.”

 

Because of the progress with huntingtin-lowering drugs like AMT-130, Dr. Pacifici noted that companies continue to allocate the “significant resources” necessary for Phase III trials.

 

The feedback from trials has enabled scientists to “hone the next generation of huntingtin-lowering therapies” and to address related questions, he added.

 

Dr. Pacifici emphasized that CHDI will continue to advise and assist uniQure and all companies seeking to develop HD therapies. More than 60 firms attended the Therapeutics Conference, which had a record attendance of 445.

 

Other key techniques

 

The conference also focused on other potential techniques in the search for therapies, such as the splicing of DNA “either to make less of a toxic protein or make more of a protein that is beneficial,” Dr. Pacifici explained.

 

Several presentations also discussed potential ways of impacting somatic expansion, the tendency of the abnormal huntingtin gene to expand over time to the point where symptoms are triggered.

 

Dr. Pacifici emphasized the need to intervene in the disease process long before symptoms arise.

 

“There's a long phase in Huntington's disease where people have the gene, but overtly, to at least the lay eye, look perfectly normal and healthy,” he explained. However, because they carry the genetic expansion, “deleterious things” can already occur, he added.

 

Another focus included the ongoing study of brain tissue donated by deceased HD-affected individuals, known as post-mortem tissue. This “unbelievably technological marvel of investigations can then look literally cell by cell at those post-mortem brain sections,” Dr. Pacifici explained.

 

Vast data from Enroll-HD

 

Dr. Pacifici and I both wore caps from Enroll-HD, the global registry of more than 22,000 affected individuals and relatives.

 

CHDI runs Enroll-HD, which provides free data to companies seeking to develop therapies.

 

uniQure’s use of Enroll-HD data as an external comparison for AMT-130 clinical trial participants caused the FDA to oppose the company’s request for an accelerated drug approval.

 

Dr. Pacifici called Enroll-HD “one of the most remarkable prospective registry trials that's ever been run.”

 

The Therapeutics Conference included a presentation on Enroll-HD’s whole-genome-sequencing – mapping a person’s entire DNA – of nearly 20,000 of the people in its database. Announced a year ago, this project has already generated 450 terabytes of data.

 

It has revealed some crucial new clues about the genetics of HD onset: new discoveries about potential modifier genes that slow or hasten the start of the disease.

 

Scientists learn much about HD from studying so-called animal models of the disease, but, as Dr. Pacifici reminded me, only humans actually get HD.

 

Enroll-HD safely and non-invasively collects people’s blood, semen, tears, cerebrospinal fluid and DNA and tracks their symptoms, Dr. Padcific said. Enroll-HD thus helps to answer the big question of “how the disease manifests itself in people” over time and how their individual genetics influence the disease.

 

People’s participation in Enroll-HD “makes a huge difference,” Dr. Pacifici observed, adding that the program is positioned to prepare for future research needs as the field evolves.

 

The ‘urgent necessity’ for a therapy

 

On March 5 Amy Gray, the president and CEO of the Huntington's Disease Society of America e-mailed the HD community an update on the controversy involving the FDA, AMT-130, and Enroll-HD.

 

Gray noted the “urgent necessity” of a disease-modifying treatment. She recalled that Congress had directed the FDA to apply “‘regulatory flexibility’ for rare diseases – tailoring approaches when traditional trials are not feasible or would unduly delay access.”

 

Gray added that “innovative trial designs” such as Enroll-HD are appropriate when scientifically justified.

 

“We appreciate uniQure’s stated intent to continue engaging with the FDA,” Gray wrote.

 

Conquering HD

 

Like last year, the 2026 meeting had a session on “new enabling technologies and breakthrough science for neurodegenerative diseases.”

 

“The techniques that people are using would literally have been considered science fiction five years ago,” Dr. Pacifici said.

 

These included a bioengineered “mini-brain,” using actual human cells, that assembled all of the different broad classes of cell types in the brain, Dr. Pacifici explained.

 

The mini-brain was developed and presented at the conference by Alice Stanton, Ph.D., of Massachusetts General Hospital and Harvard Medical School.

 

“We're going to get her to now introduce cells that have the expanded gene and see how that changes so that we could do experiments in a dish instead of in the living organism,” Dr. Pacifici said. "We've got the best, the brightest doing-state-of-the art work."

 

To fill remaining “gaps” and “solve bottlenecks” on the way to therapies, yet more discoveries will be needed, he added.

 

With CHDI’s multi-million-dollar resources, the involvement of big companies, and the participation of HD families, “we’re going to conquer this thing,” Dr. Pacifici predicted.

 

 

Dr. Alice Stanton presenting her talk on her human "mini-brain" invention (above) and taking questions from the audience (below) (photos by Gene Veritas)

 

 

Understanding the FDA’s surprising step back on uniQure drug that slows Huntington’s disease

 

Less than six weeks after uniQure announced that its gene therapy drug slowed the progression of Huntington’s disease by 75 percent over three years, the U.S. Food and Drug Administration (FDA) has backtracked on its conversations with the company regarding the timeline and data needed for potential approval of the remedy.

 

The company’s plan to apply for approval of the drug, AMT-130, in early 2026 and launch it into the market later that year may no longer be possible.

 

In a November 3 press release uniQure announced that, after a recent meeting with the FDA, the company believes that the “FDA currently no longer agrees” that data from its clinical trial of AMT-130 using an "external control" as a comparison "may be adequate to provide the primary evidence in support of” an application for approval.

 

The external control refers to data taken from Enroll-HD, the global HD patient registry of more than 22,200 people, as a baseline, rather than those taking a placebo, to compare with those on AMT-130. After extensive consultations with the FDA in 2024, uniQure had gotten permission from the agency to use the Enroll-HD data.

 

“This is a key shift from prior communications with the FDA in multiple … meetings over the past year,” the uniQure release stated. “Consequently, the timing of the BLA [Biologics License Application] submission for AMT-130 is now unclear.”

 

uniQure expects to receive the final minutes of its meeting with the FDA within 30 days and plans to urgently interact with the agency “to find a path forward for the timely accelerated approval of AMT-130,” the press release continued.

 

“We are surprised by the FDA’s feedback at the recent pre-BLA meeting, which is a drastic change from the guidance the FDA provided in November 2024,” said Matt Kapusta, the uniQure CEO. “This news is unexpected, and we are truly disappointed for people living with HD, who have no disease-modifying treatment options for this devastating disease.”

 

Kapusta added that “we strongly believe that AMT-130 has the potential to bring substantial benefit to patients, and we remain fully committed to working with the FDA to determine the best path forward to rapidly bring AMT-130 to patients and their families in the U.S.”

 

 

David Margolin, M.D., Ph.D., uniQure's vice president for clinical development, presents data illustrating AMT-130's slowing of the progression in Huntington's disease at the 20th Annual HD Therapeutics Conference, Palm Springs, CA, February 25, 2025 (photo by Gene Veritas, aka Kenneth P. Serbin).

 

FDA claims to ‘unleash gene therapies’

 

The October 30 Huntington’s Disease Society of America (HDSA) webinar on AMT-130, featuring uniQure’s chief medical officer, Walid Abi-Saab, M.D., offered no inkling of the FDA’s new position.

 

Some 1,000 people attended the webinar – a sign of the excitement about AMT-130 in the HD community. Reuniting after 17 years of estrangement, my own family has found great hope in the possibility of this treatment, though we understand that the drug is not a cure and might not even reach the public.

 

The FDA so far has provided no comment to the media on the matter. At the top of its website’s homepage it has the phrase “first six months of FDA reforms,” including “unleashing cell and gene therapies.”

 

As this blog reported in July, under the Trump administration the uncertainty of public funding for science has created serious challenges to HD research.

 

Politics and society play a role

 

Science and medicine do not act in a vacuum and are impacted by politics and society, as HD family member and historian Alice Wexler brilliantly illustrated in her book The Woman Who Walked into the Sea: Huntington’s and the Making of a Genetic Disease (click here to read my review).

 

In July, a New York Times report titled “Inside the Collapse of the FDA” detailed how Health and Human Services Secretary Robert F. Kennedy Jr., is “dismantling the agency.”

 

The key biotech and life sciences website STAT reported that since uniQure and the FDA had set drug submission “benchmarks” last year, “the agency has undergone considerable changes. Vinay Prasad, a physician with a reputation for taking a more conservative view of gene therapies, now oversees the division with authority over AMT-130.”

 

Dr. Prasad heads the Center for Biologics Evaluation and Research.

 

Only last week STAT reported that a “slow-boiling feud” between Dr. Prasad and his staff “is threatening the future of the center that regulates the nation’s vaccines, biological products, and blood supply.”

 

According to the report, officials in the center described it as “rife with mistrust and paranoia” and with fears of “retaliation” for pushing back on Dr. Prasad. The center has lost hundreds of employees this year to retirements, layoffs, and resignations. Dr. Prasad has also pushed out senior leaders, including “top cell and gene therapy regulators,” STAT reported.

 

Prasad has also played a role in limiting access to Covid-19 vaccines, according to STAT and the New York Times.

 

The HD community is ‘highly mobilized’

 

The scientist-written website HDBuzz noted that, although “the reason for the change of heart” of the FDA is “not currently clear,” “it makes the timeline for advancing AMT-130 less clear, with additional uncertainty as the U.S. government shutdown continues.”

 

“The decision by the FDA to not agree that an external control group can be used to apply for a [drug application] doesn’t change the data” of AMT-130’s actual effect in the clinical trial run by uniQure, HDBuzz stated. It simply means that the FDA would want to see more data, possibly from a trial designed with a placebo control group, before moving forward with a BLA for AMT-130.

 

HDBuzz also noted that uniQure is working with the equivalent of the FDA in the United Kingdom and Europe, with an approval there possibly leading to acceptance elsewhere.

 

HDBuzz stated that “we push forward – together.”

 

On November 5 HDSA and four other HD entities issued a joint statement: following the regulatory update about uniQure, “it’s clear that stronger alignment and collaboration among Huntington’s disease (HD) patient and family organizations are more critical now than ever.” The four are Huntington’s Disease Foundation (formerly Hereditary Disease Foundation), HD Reach, Help4HD International, and Huntington’s Disease Youth Organization.  

 

“The next steps here are uncertain,” the brokerage and investment banking firm Stifel wrote, “but given the highly mobilized patient community in Huntington’s, and other external political forces that may have influence on the agency, the story here may not be over.”