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)

 

 

FDA recommends a full clinical trial for uniQure Huntington’s disease drug, further delaying potential approval

  

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.

With ‘great promise’ for treating Huntington’s disease, four drug programs press ahead (Part II)

 

At the recent 20th Huntington’s Disease Therapeutics Conference in February, four pharmaceutical companies provided updates on their key clinical trial programs, demonstrating that they had overcome basic safety hurdles and revealing plans to have their drugs potentially approved as therapies (treatments) for delaying the progression of HD symptoms.

 

All four programs use drugs to lower the amount of harmful mutant huntingtin protein in the brain cells of patients.

 

In the first of two articles on these programs, I described the projects of PTC Therapeutics and Roche.

 

In this article, I cover the presentations made by Wave Life Sciences and uniQure.

 

These updates took place during the conference’s first session on February 25, the first day of the three-day event.

 

In a post-conference interview Robert Pacifici, Ph.D., the chief scientific officer for CHDI Foundation, Inc., the conference sponsor, told me that that there is “great promise” regarding these four programs’ potential HD therapies.

 

Attacking only the bad protein, preserving the good one

 

Jane Atkins, Ph.D., Wave’s senior vice president for portfolio strategy and program management, provided an update on the company’s groundbreaking program.

 

Like Roche’s tominersen, Wave’s WVE-003 is an antisense oligonucleotide, an artificial strand of DNA that blocks or lowers the production of the huntingtin protein.

 

However, whereas tominersen and PTC’s votoplam (a splicing modulator) reduce both the mutant and normal huntingtin protein, Wave’s drug is uniquely allele-selective: it attacks just the bad protein and allows the good one to carry out its essential actions unhampered.

 

Clinical trials for drugs usually go through three phases. If the last is successful, the drug can receive approval from the U.S. Food and Drug Administration (FDA).

 

In 2021, in small clinical trials, precursors WVE-120101 and WVE-120102 failed to reduce the bad protein. Wave then developed WVE-003, which entered a clinical trial that same year.

 

At the conference, Dr. Atkins reported that in June 2024 the Phase 1b/2a SELECT-HD study of WVE-003 produced positive results, “including the first allele-selective silencing in any disease.”

 

“A growing body of literature” supports the importance of the good huntingtin protein, she explained, as it sustains the health of brain cells.

 

Slowing the shrinking of the brain

 

In the clinical trial, the bad protein was reduced as much as 46 percent in some volunteers, exceeding the overall goal of 30 percent, Dr. Atkins said, noting that the drug was safe and well-tolerated.

 

Significantly, the study also demonstrated a slowing in the atrophy (shrinking) of the caudate, a key part of the brain dramatically affected in HD, leading to a decline in cognition, function, and movement, Dr. Atkins said. Such atrophy occurs before symptoms appear, she noted, so being able to observe this change early makes the atrophy a good measure of a drug’s effectiveness.

 

The slower shrinking “was the first time this was shown in the clinic,” Dr. Atkins said. “We were super-excited to see this.”

 

With these promising results, Wave plans to put WVE-003 into a combined Phase 2/3 clinical trial, Dr. Atkins said. The company later this year expects to seek FDA approval of the trial. Wave proposes to use caudate atrophy as a primary endpoint, that is, a main measure of WVE-003’s effectiveness.

 

Wave is also investigating WVE-003’s potential impact on somatic expansion, Dr. Atkins said. Somatic expansion is the tendency of the mutant huntingtin gene to continue expanding over time. Many scientists now believe that this process triggers HD symptoms.

 

Somatic expansion is understood as a two-step process where expansion of the gene (step 1) triggers disease (step 2) that drives HD. Wave believes that lowering the bad protein selectively (with WVE-003) is likely to address the second step.

 

As with tominersen, WVE-003 is administered via a spinal tap. Votoplam is a pill.

 

 

Dr. Jane Atkins of Wave Life Sciences displays a slide demonstrating the slowing of caudate atrophy in the WVE-003 clinical trial (photo by Gene Veritas, aka Kenneth P. Serbin).

 

uniQure drug slows disease progression in trial

 

David Margolin, M.D., Ph.D., uniQure’s vice president for clinical development, gave a presentation on the latest developments regarding AMT-130, the firm’s gene therapy drug that reduces the levels of both the good and bad huntingtin protein.

 

In the uniQure clinical trial, a neurosurgeon injects AMT-130 directly into the brains of the volunteers under the guidance of an MRI. As a gene therapy, AMT-130 requires just this one application. (Watch the uniQure video about how AMT-130 is administered here).

 

This small, long-term uniQure Phase 1/2 trial began in 2020. As of April, the number of participants had reached 45, including people from the U.S. and Europe.

 

An interim analysis in mid-2024 showed that “AMT-130 high dose … strongly and significantly reduced disease progression,” Dr. Margolin pointed out. Another analysis found “substantial reduction in risk of clinically meaningful worsening,” he added.

 

As patients continue to go through the trial and beyond, with follow-up, “with every data cut we see… a promising treatment effect becoming more and more evident,” Dr. Margolin said.

 

 

Dr. David Margolin of uniQure presents data illustrating the slowing of HD disease progression in the AMT-130 clinical trial (photo by Gene Veritas).

 

Hoping to accelerate approval

 

The positive results have led uniQure to seek acceleration of FDA approval for AMT-130.

 

Because of HD’s status as a rare disease, in 2017 uniQure received the financially beneficial orphan drug designation from the FDA for AMT-130. In 2019, FDA granted AMT-130 fast track status to further facilitate development of the drug and expedite review.

 

As explained by Dr. Margolin at the conference, in 2024 the FDA defined AMT-130 as a regenerative medicine advanced therapy (RMAT).

 

This category includes life-threatening diseases such as HD. Dr. Margolin said it is applicable to new kinds of drugs such as gene therapy, cell therapy, and tissue-engineered products, and it further accelerates FDA review.

 

In achieving this designation, uniQure presented to the FDA the data from the Phase 1/2 trial, and the FDA agreed that this data can serve as the primary basis for a drug application, Dr. Margolin said.

 

Dr. Margolin indicated that this determination means that uniQure will not need to put AMT-130 into a Phase 3 trial.

 

“An additional investigational study will not be required,” he emphasized. “That accelerates by several years the timeframe in which AMT-130 might become available to a wider U.S. cohort of patients.”

 

Swaying the FDA to be more flexible

 

Because of the lack of therapies that modify the course of this rare and devastating disease, the uniQure project and the company’s dialogue with the FDA have indicated the willingness of the agency to allow flexibility in clinical trial programs and a faster timeline.

 

Dr. Margolin’s talk title included the phrase “alignment on a US Regulatory Path Via RMAT.” Alignment with the FDA could lead to an “accelerated approval” for AMT-130, he observed.

 

Dr. Margolin asserted that uniQure’s dialogue with the FDA “has meaningfully advanced HD regulatory science.”

 

In response to a question from Dr. Pacifici about the negotiations with the FDA, Dr. Margolin stated that uniQure hopes that the lack of disease-modifying therapy is “swaying FDA to be more liberal than they have been in the past.”

 

Dr. Pacifici asked what additional studies uniQure will conduct if it secures the accelerated approval, which would still be only conditional.

 

Dr. Margolin replied that uniQure will discuss that matter with the FDA.“Importantly, even an accelerated approval means the drug will be available to patients,” Dr. Margolin stressed. “It does constrain promotional materials in certain ways, but would have no relevant impact on its potential availability and accessibility to U.S. patients.”

 

A Breakthrough Therapy designation

 

AMT-130 gained RMAT designation because it is a gene therapy. Since the conference, the AMT-130 program has made yet further progress.

 

On April 17, uniQure announced that the FDA granted Breakthrough Therapy designation to AMT-130.

 

“Receiving Breakthrough Therapy designation underscores both the urgent need for effective treatments for Huntington’s disease and the encouraging interim data demonstrating that AMT-130 has the potential to slow disease progression,” said Walid Abi-Saab, M.D., chief medical officer of uniQure, in a press release. “We look forward to working closely with the agency to bring AMT-130 to the Huntington’s disease patient community as quickly as possible.”

 

As explained in the press release, Breakthrough Therapy designation for AMT-130 means that the drug “may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s).” 

 

The firm expects to provide a further FDA update this quarter. In the third quarter, it aims to present data on AMT-130 to support its potential drug application submission.