With the ‘worst’ FDA head out and Huntington’s disease advocates pressing for bipartisan reform, uniQure announces new plan to seek gene therapy approval

  

On June 17, uniQure announced a new plan to apply to the U.S. Food and Drug Administration (FDA) to seek approval of its gene therapy for Huntington’s disease  – a dramatic shift after the agency had last year blocked the drug despite results showing, for the first time, that HD progression could be slowed.

 

The announcement comes in the wake of the May 12 resignation of the head of the crisis-ridden FDA, which has clashed with uniQure.

 

In a press release, uniQure reported that, at a recent meeting with the FDA, the agency had accepted that the three-year analysis of the drug, AMT-130, which the company has presented as demonstrating efficacy against HD, can serve as the “primary basis” for a drug approval application.

 

uniQure aims to apply in the third quarter of this year. In alignment with the FDA, the company will also conduct a “confirmatory study” to further test the efficacy of AMT-130. According to early-stage clinical trial results reported by uniQure, AMT-130 had demonstrated a 75 percent slowing in HD over a three-year period – a historic achievement.

 

For the confirmatory study, uniQure will work with the FDA to determine how to evaluate a “concurrent control,” that is, a placebo or comparator to measure drug efficacy in those not receiving the drug. According to the press release, this study would not include a sham surgery as a placebo – a requirement introduced in March by the FDA but considered by many to be unethical because of the already harmful symptoms of HD.

 

According to the press release, the FDA has agreed that uniQure can, for a comparator, still use the patient information from the important Enroll-HD database of affected individuals – a major point of contention in the FDA’s surprise reversal of its promises regarding the study of AMT-130.

 

“Today's announcement reflects the outcome we have worked toward throughout our continued regulatory engagement with FDA, and we are deeply grateful for FDA’s genuine commitment to addressing the unmet need of Americans living with Huntington’s disease,” Matt Kapusta, uniQure CEO, stated in the release. “The FDA has agreed that our current clinical data can support a near-term BLA [biologics license application] submission and has committed to work expeditiously with us to align on the design of the required confirmatory study.”

 

‘A meaningful step forward’

 

The new understanding with the FDA represents a significant shift, because, after previously clashing with uniQure, the FDA recommended in March that the firm conduct a full-blown Phase III clinical trial, including the use of a sham surgery.

 

“Today’s announcement from uniQure represents an encouraging and meaningful step forward for the Huntington’s disease community,” Amy Gray, president and CEO of the Huntington’s Disease Society of America (HDSA), stated in a press release. “I applaud the leadership at the FDA for allowing uniQure to take this important step forward in the development of its investigational treatment for Huntington’s disease.

 

Gray added that “this progress did not happen in isolation.” Following “regulatory hurdles,” the HD community “united like never before.” HD advocates delivered to the FDA two petitions with more than 48,000 signatures in favor of AMT-130. According to Gray, more than 11,000 messages to Congress, participation in legislative meetings, and sharing of personal stories added to the impact.

 

“I am deeply grateful to the Members of Congress who stood with Huntington’s disease patients and families during this effort,” Gray said. “Their willingness to engage with the FDA, ask important questions, and advocate for a regulatory framework that reflects the realities of rare disease research helped ensure that the voices of our community were heard.”

A whirlwind of developments

 

The uniQure announcement about AMT-130 came in at the end of a whirlwind of recent developments. The HD community has regrouped in support of improved drug discovery policy at the crisis-ridden FDA.

 

On April 30, uniQure took the case for its drug to the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA) as a first step to seek approval in that country. The company plans to submit an application in the third quarter of 2026.

 

On May 12 FDA Commissioner Marty Makary, a Trump administration appointee, resigned after what STAT considered to be the “worst” leadership of the agency in 25 years because of “a fundamental lack of understanding of the nature of the role, of the functions of his agency, and of the needs of the employees who worked for him.” His departure prompted calls for rebuilding public trust in, and better leadership at, the FDA (click here and here to read more).

 

On June 1, the FDA announced that Acting Commissioner Kyle Diamantas would meet with rare disease group leaders to seek to steady operations and mend fences with disease groups. That meeting took place on June 3.

 

Jeff Allen, CEO of Friends of Cancer Research, described the encounter as a “breath of fresh air.”

 

The FDA did not invite HDSA and other HD advocacy organizations to join the meeting. The FDA declined to answer questions. As of publication time, a message left at the National Organization for Rare Disorders seeking comment had not been returned.

 

A key briefing on rare diseases

 

However, on June 2, HDSA CEO Gray moderated a panel of five rare disease community representatives at a bipartisan congressional townhall briefing in Washington, D.C., titled “The Pathway to Cures and Treatments for Rare Diseases.”

 

“Rare disease families need a clear and sustainable pathway to research, treatments, and care,” said Gray in an HDSA press release about the event, available on YouTube. “This briefing is an important opportunity to bring patient advocacy organizations, scientific leaders, policy experts, and lawmakers together to discuss how we can advance meaningful progress for families impacted by rare diseases.”

 

With more than 40 people in attendance, the meeting highlighted the suffering of people with rare diseases, the urgent need for effective treatments, and the need to improve the FDA’s procedures. It included comments from both a Democratic and a Republican member of the House of Representatives.

 

The Pathway to Cures and Treatments for Rare Diseases congressional townhall briefing at the Rayburn House Office Building, Washington, D.C., June 2. From left to right, Kathryn Bryant Knudon, The Speak Foundation; Emily Gantman, Ph.D., CHDI Foundation; Lauren Moore, Ph.D., National Ataxia Foundation; Monet Stanford, PharmD, Washington Analysis; Tamara Maiuri, Ph.D., HDSA; Amy Gray, HDSA; and Rep. Jake Auchincloss (screenshot by Gene Veritas, aka Kenneth P. Serbin)

 

Bringing ‘smart’ leadership to the FDA

 

Rep. Jake Auchincloss, a Democrat from the greater Boston area and a member of a family of physician-scientists, said that he was “passionate” about the issue of rare disease drug development. He is on the Subcommittee on Health of the Committee of Energy and Commerce.

 

The subcommittee oversees the FDA. Auchincloss’s focus includes clinical trial reform, which the panelists agreed was important for rare disease drug development.

 

“While the science has never been better in trying to unlock those answers, the politics has never been worse,” Auchincloss said at the briefing.

 

Auchincloss spoke of the need for change on three fronts involving science and research: to bring U.S. research spending back to its previously high levels; to bring “smart” leadership back to the FDA; and to require insurance companies to cover the many new rare disease therapies on the horizon.

 

Auchincloss added that the “most urgent issue now” is to stop the Trump administration’s “unprecedented” cutting of National Institutes of Health grants without the time-honored standard peer review.

 

‘Cut the red tape’

 

Rep. Morgan Griffith, a Republican who represents far western Virginia, chairs the Subcommittee on Health. He supports the cause of the ALS (amyotrophic lateral sclerosis) community and pediatric cancer. He spoke about how people with rare diseases in remote areas have difficulty accessing clinical trials in urban areas.

 

Griffith also spoke movingly of the two HD families he has gotten to know.

 

He agreed with Auchincloss’s approach regarding the FDA and clinical trial reform. The two speak regularly on these issues.

 

“We have to figure out a better way to do it,” Griffith said. “It needs to be bipartisan.”

 

Auchincloss is not seeking more money from the government but simply to “cut through the red tape” regarding drug development, Griffith said, adding that people with rare diseases should not be required to “jump through the same hoops” as those participating in clinical trials for less difficult conditions such as nausea.

 

‘We were finally heard’

 

On September 17 and 18, news about AMT-130 dominated bioscience headlines after the uniQure announcement – and provided a needed boost to the HD community.

 

“I’m literally crying right now,” Lauren Holder, a Help4HD International Advocate and, like me, an HD gene carrier, told STAT. “I’m so happy that I don’t even know how to put what I’m feeling into words.”

 

Holder added, “This is the best-case scenario for our community.”

 

“This happened because dedicated patient advocates refused to give up, because this community continued to show up, speak up, and fight, even when it felt like no one was listening,” she said. “Today, it feels like we were finally heard.”

As FDA faces demands for greater clarity, uniQure presses ahead in search for Huntington’s disease gene therapy approval

  

As the reportedly dysfunctional U.S. Food and Drug Administration (FDA) faces demands for greater clarity in the wake of rare-disease drug denials, uniQure continues to seek a path to get AMT-130, its historically efficacious Huntington’s disease gene therapy, approved.

 

On March 2, after having surprisingly reneged last year on its promise to allow uniQure to apply for AMT-130 approval in 2026, the FDA “strongly recommended” that the firm conduct a new, full Phase III clinical trial.

 

In March, Wisconsin Sen. Ron Johnson, a Republican, launched an investigation of the FDA’s rejections of rare disease drugs. He 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.”

 

In an April 1 letter, the Rare Disease Advocacy, Biotechnology, and Investor Coalition urged President Trump and top administration health officials to restore regulatory clarity at the FDA.

 

A new way to win approval?

 

A possible avenue to AMT-130 approval opened on April 14. Teresa Buracchio, M.D., head of the FDA’s Office of Neuroscience, said at the National Organization for Rare Disorders (NORD) symposium in Arlington, VA, that the agency’s “plausible mechanism framework” for approval of bespoke gene therapies might be applied “to approve other therapies.” The news site Fierce Biotech reported on the symposium.

 

A bespoke therapy is given to a single individual, such as “Baby KJ,” the world’s first individual to be treated with a personalized (customized) CRISPR gene editing therapy, in 2025. KJ was born with a rare metabolic disease, severe carbamoyl phosphate synthetase 1 (CPS1) deficiency. The child is now thriving.

 

After FDA leaders raised the topic of individualized therapies in a November 2025 The New England Journal of Medicine article, the FDA in February issued a draft guidance for a new path to such treatments, calling it the “plausible mechanism framework.”

 

Dr. Buracchio observed that the framework is not specifically an approval pathway but a set of regulatory principles being applied to customized therapies for the first time, Fierce Biotech reported.

 

The special challenges of HD science

 

The Fierce Biotech article noted that Dr. Buracchio’s comments “offered some clarity to a confused rare disease sector rattled by high-profile regulatory drama.” That drama has resulted in part from uniQure’s use of patient registry data (also known as a natural history study) to analyze AMT-130, which was rejected by the FDA “even as such methods are part of the criteria that could enable approvals for tailored gene-editing therapies under the plausible mechanism framework.”

 

In March, the FDA had pointed out that AMT-130 is not an individualized therapy.

 

However, Dr. Buracchio said that the plausible mechanism framework “shouldn’t be a disadvantage” to non-individualized therapies.

 

Dr. Buracchio stated that the FDA is open to applying the plausible mechanism framework “conceptually” to Huntington’s disease broadly, or other diseases of comparably-sized populations.

 

A therapy needs to show “substantial evidence of effectiveness and a substantial improvement that’s clear and distinct from the natural history of the disease,” she said, noting that KJ demonstrated marked improvement in symptoms and reached developmental milestones.

 

By comparison, a slowly progressive neurodegenerative disease like HD “is going to be a harder case to make,” Dr. Buracchio said. “That’s because slowing the rate of decline is much harder. So, to me, this is less of a number issue and more of a nature of the disease issue.”

 

Presenting AMT-130 to the rare disease symposium

 

At the NORD symposium, David Margolin, M.D., Ph.D., uniQure’s vice president for clinical development, gave a presentation on AMT-130, addressing the FDA’s concerns.

 

As reported by Fierce Biotech, in response to the FDA’s requirement that the company run a Phase III trial and Dr. Buracchio’s point about the slowness of HD, Dr. Margolin stated that this slow progression makes it nearly impossible to show clear efficacy over a short period. This creates an “ethical challenge” when giving some patients a placebo or having them undergo the sham surgery.

 

As presented by Dr. Margolin at numerous conferences, including the key 21st Annual HD Therapeutics Conference in February, AMT-130 demonstrated a 75 percent slowing of HD progression over three years. (The conference is sponsored by CHDI Foundation, Inc., the largest private funder of HD research.) This was the first time that a drug has delayed HD.

 

Dr. David Margolin at the 2026 HD Therapeutics Conference (photo by Gene Veritas, aka Kenneth P. Serbin)

 

Enroll-HD in place of a placebo

 

A second Fierce Biotech article on the NORD symposium focused on how academics and biopharma leaders are breaking the mold of traditional clinical trials with creative methodologies, aiming to garner interest and support from peers and regulators.

 

A common approach in rare disease drug development is the use of an external control or comparator, which replaces the placebo in a classic clinical trial. As noted, instead of a sham trial, uniQure took this approach by using data from the HD patient registry, called Enroll-HD.

 

With more than 22,000 participants, Enroll-HD is “one of the most remarkable prospective registry trials that's ever been run,” according to CHDI Chief Scientific Officer Robert Pacifici, Ph.D.

 

Tracy Beth Høeg, M.D., Ph.D., the acting director of the FDA’s Center for Drug Evaluation and Research, stated at the NORD event that the agency is finalizing guidance on external controls. This, she added, will hopefully “give clarity to sponsors about what sort of evidence we would be looking for and willing to accept for approval of rare disease drugs.”

 

As reported by Fierce Biotech, Dr. Margolin spent much of his NORD talk on uniQure’s use of a statistical technique known as “propensity score matching.” As he explained at the Therapeutics Conference, this involves finding in Enroll-HD individuals similar to those in the uniQure trial and including them as controls. At the NORD meeting, he pointed out that the difference between AMT-130 clinical trial participants and the individuals uniQure selected from Enroll-HD was negligible.

 

Dr. Margolin also responded to the FDA’s criticism that one of the clinical trial measurements uniQure used for AMT-130 was too subjective, leaving the participants susceptible to a placebo effect that could not be detected when using Enroll-HD.

 

An ongoing dialogue with the FDA

 

“I know there’s active dialogue with FDA and the Huntington’s disease organizations regarding how to interpret and best utilize these clinical scored measures, and that’s an ongoing process,” Dr. Margolin stated.

 

Meanwhile, the HD community and its allies continue to pressure Congress and public officials to focus on HD and bring AMT-130 a fair hearing at the FDA.

 

Or, in the current political and business climate, perhaps the HD community also needs a vast stroke of good luck, celebrity connections, and publicity, as biotech observers have noted with dark humor.

 

Joe Rogan to the rescue?

 

On April 18, Pearl Freier, president of Cambridge Biopartners, Inc., asked on the social media platform X how the HD community could overcome an FDA rejection based on the “personal negative opinion” of FDA Commissioner Marty Makary and/or U.S. Secretary of Health and Human Services Secretary Robert F. Kennedy Jr.

 

She added: can the HD community make a deal with growth stage venture capital firm and prediction market company “Kalshi and/or Polymarket?”

 

Adam Feuerstein, the senior writer covering biotech at the essential STAT, responded to Freier’s post: “I guess people living and dying with Huntington’s disease need an influencer/podcaster to text Trump. That’s how the FDA works these days.”

 

Feuerstein linked to an X post detailing how popular podcaster Joe Rogan revealed how the president “IMMEDIATELY offered FDA approval for a psychedelic treatment in a text chain Because the data was SO CONVINCING and STUNNING.” The treatment is for depression and other conditions.

 

Finding comfort in Pope Francis’ embrace of the HD community

 

These are trying times for the world, with the U.S. again in a major war and world peace once again at risk. For the HD community, it is distressing that AMT-130 is rejected after seven years of clinical study by uniQure.

 

For comfort I remember highlights of the HD cause such as Pope Francis’ 2017 audience with HD families, declaring that the disease should be “hidden no more” and HD families respected and loved. I also look with hope to the first American head of the Church, Pope Leo XIV, who has continued Francis’ emphasis on mercy.

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)