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)

 

 

Wonderful news: uniQure’s one-and-done drug slows Huntington’s disease

 

AMT-130, a one-time gene therapy developed by uniQure, has successfully slowed the progression of Huntington’s disease.

 

While that is not a cure, and the therapeutic process is hardly simple, it is the first evidence that scientific progress translates into meaningful results for those suffering from HD.

 

The treatment is far more complex than a pill: it involves 12 to 18 hours of delicate brain surgery. A neurosurgeon injects AMT-130 directly into the brain 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).

 

According to clinical trial results reported by uniQure on September 24, AMT-130 achieved its main goal (primary endpoint) and demonstrated a 75 percent slowing in the progression of the disease over a three-year period.

 

“High-dose AMT-130 also demonstrated statistically significant slowing of disease progression as measured by TFC, a key secondary endpoint, and favorable trends across additional clinical measures,” the release stated. TFC is total functional capacity. It refers to a person’s ability to function – a key loss in HD.

 

Other progress

 

The company, based in Lexington, MA, and Amsterdam, reported that AMT-130 also reduced the measure of a protein known as neurofilament light, a marker of disease that reveals stress on the brain.

 

The clinical trial showed “favorable trends” in other second measures of motor (movement) and cognitive function, the release stated. Movement disorders and cognitive loss are major HD symptoms. Trial results demonstrated that AMT-130 is safe and well-tolerated.

 

“I believe these groundbreaking data are the most convincing in the field to date and underscore potential disease-modifying effects in Huntington’s disease, where an urgent need persists,” Sarah Tabrizi, M.D., Ph.D., a leading HD specialist at University College London, stated in the release. “These data indicate that AMT-130 has the potential to meaningfully slow disease progression – offering long-awaited hope to individuals and families impacted by this devastating disease.”

 

 

David Margolin, M.D., Ph.D., uniQure's vice president for clinical development, presents data illustrating ATM-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).

 

Transforming the HD landscape

 

AMT-130 seeks to lower the amount of harmful mutant huntingtin protein in the brain cells of patients. Whether the drug has actually done this has yet to be verified.

 

In early 2026, uniQure plans to apply to the U.S. Food and Drug Administration (FDA) for drug approval. Pending drug approval, the drug would be launched in the U.S. later in 2026.

 

“We are incredibly excited about these topline results and what they may represent for individuals and families affected by Huntington’s disease,” stated Walid Abi-Saab, M.D., chief medical officer of uniQure. “These findings reinforce our conviction that AMT-130 has the potential to fundamentally transform the treatment landscape for Huntington’s disease, while also providing important evidence supporting one-time, precision-delivered gene therapies for the treatment of neurological disorders.”

 

Hopes for a life-long treatment

 

“This is the first time any drug has been shown to alter the course of HD in people in a clinical trial,” the scientist-written website HDBuzz stated. “uniQure believes that AMT-130 has the potential to be a treatment that lasts for life.”

 

uniQure officials told HDBuzz that, beyond the FDA, they plan to seek approval with other regulators, including the European Medicines Agency, which oversee drug approvals in Europe.

 

HDBuzz cautioned that key details need to be worked out before AMT-130 can be administered to a large group of people beyond the fewer than 30 people whose data were analyzed by uniQure.

 

Only some of those individuals received the high dose of the drug that proved effective. Also, because AMT-130 requires an operation, the company must find a way to provide access to the drug, and at an affordable level, to a larger number of people.

 

On the whole, despite the caveats and complexities, this is wonderful news for the HD community.

 

"We never in our wildest dreams would have expected a 75% slowing of clinical progression," Dr. Tabrizi told the BBC.

‘The first at-bat is never a grand slam’: how Huntington’s disease drug research has matured with the Roche and Wave setbacks

Despite the disappointing clinical trial results reported last week by Roche and Wave Life Sciences, Huntington’s disease drug researchers see an upside: they are using the data collected to achieve new insights, offering renewed hope of effective treatments.

 

The news of these setbacks produced one of the most heartbreaking moments of the last several decades for the HD community and researchers.

 

“That kind of news, I hope it’s okay to say: it sucks!” said Robert Pacifici, Ph.D., the chief scientific officer for CHDI Foundation, Inc., of the Roche and Wave trial data. “All of us who hold out so much hope and recognize that there are so many families who so desperately are waiting for much needed relief and therapies – it knocks the wind out of you.”

 

The companies made their first formal scientific presentations of their data at the start of the CHDI-sponsored 16th Annual HD Therapeutics Conference, held virtually from April 27-29. A nonprofit virtual biotech, CHDI focuses solely on developing Huntington’s therapies.

 

Roche confirmed that its drug tominersen failed to alleviate symptoms in its Phase 3 clinical trial; patients receiving the highest of two possible doses may have done even slightly worse than those on placebo. Two early-stage Wave trials failed to meet the goal of reducing the amount of mutant huntingtin protein in the trial participants – an objective already achieved by Roche in an earlier tominersen trial. (Click here to read more.)

 

Dr. Pacifici offered his assessment of the Roche and Wave data and the state of HD drug research in a wide-ranging, 46-minute Zoom interview with me after the close of the event.

 

Dr. Robert Pacifici moderates panel discussion of huntingtin-lowering clinical trial results with Dr. Vissia Viglietta of Wave Life Sciences and Dr. Scott Schobel of Roche (screenshot by Gene Veritas, aka Kenneth P. Serbin)

 

Gaining perspective

 

“My reaction though, now that I’ve come back down to earth, is really not one of surprise,” Dr. Pacifici said. “Drug discovery, as we’ve discussed many times, is a really tough business. The probability of success on any given endeavor is incredibly low.”

 

Dr. Pacifici used a baseball metaphor to explain: “How often does the first batter get up to the plate and hit a grand slam home run? A grand slam, never, because you need to load up the bases with three people. Even a home run is incredibly rare.”

 

The “name of the game” in discovering effective treatments is to carry out as many trials as necessary, “doing it well, failing, but making it a good failure that we can learn from so that subsequent efforts have a much higher chance of success,” Dr. Pacifici explained. “And we continue to snowball and build on that so that we can learn the things to do better, the things that we can do differently, or the things that we should stop doing altogether because we now have confirmed that those are not viable lines of investigation.”

 

The accumulation of experience through research and clinical trials, including the crucial participation of patient volunteers, has produced “an incredibly positive thing,” Dr. Pacifici observed.

 

“Look at how the field has matured,” he said. In the past, scientists would have kept a trial running for three years, waiting for patient improvement, only to discover that “the drug really didn’t even have a chance of working” because it hadn’t done what it was “tasked with doing, which is lowering huntingtin levels.”

 

Now the process is moving “faster” and is “better informed,” Dr. Pacifici said.

 

Watch the entirety of my interview with Dr. Pacifici in the video below.

 

Huntington's disease drug research now a 'mature field' from Gene Veritas on Vimeo.

 

Huntingtin lowering still in the running

 

Dr. Pacifici commented on the critical topic of lowering (reducing) the mutant huntingtin protein, the first strategy aimed at HD’s genetic cause. Scientists believe that the mutant protein is a main driver of the disease. In mouse studies, lowering that protein led to a disappearance of symptoms, and, beginning with the Roche trial, researchers have sought to achieve similar results in humans. Thus, until now, lowering mutant huntingtin has been seen as the potentially most promising path to a treatment.

 

Both Roche and Wave used a type of drug known as an antisense oligonucleotide (ASO), an artificial strand of DNA. Other firms and labs are also investigating ASOs.

 

“When two of those things don’t move forward simultaneously, it’s perfectly reasonable to ask the question, ‘Well, is this one of those times where we’ve learned that this approach is not going to work?’” Dr. Pacifici asked. “I can say unequivocally that that’s not yet the case. There are just too many things that factor into how a drug needs to do its job that remain unanswered.”

 

He said that possible key factors affecting the outcomes of the Roche and Wave trials include the stage of disease of the participants, the concentration of the drug tested, and the proper distribution of the drug within the brain. The particular characteristics of the drugs selected could have also impacted the outcome, he added.

 

Another possible explanation involves the design of the trials, the techniques for measuring patient response, and biomarkers (signs of disease and a drug’s effects).

 

In addition, even though Roche’s tominersen reduced the level of mutant huntingtin protein in trial volunteers’ cerebrospinal fluid, researchers still do not know whether the samples of protein actually came from the brain and, if so, cells relevant to HD, Dr. Pacifici cautioned. Scientists also lack other critical details about those samples; for example, they could be fragments, he said.

 

Crucially, the “interim analysis” of the Roche data at the Therapeutics conference did not demonstrate whether lowering huntingtin can help people feel, function, or survive better, Dr. Pacifici observed.

 

Even a “whisper of efficacy” would have validated the huntingtin-lowering approach and “prepared the path for subsequent trials with gusto and confidence,” he continued, adding, however, that “the opposite is not true. We still have great hopes that this is a viable mechanism of action.”

 

Wave plans to start a trial of a third ASO later this year. Roche has also stated that it will continue to explore drugs for HD.

 

Exploring other avenues

 

Because the effectiveness of huntingtin-lowering remains an open question for the field, Dr. Pacifici renewed his call to redouble and diversify drug-hunting efforts.

 

Dr. Pacifici noted that other potential huntingtin-lowering approaches are in the works using non-ASO compounds, while others propose different methods of delivery, including a pill. In the Roche and Wave trials, participants received the drug via spinal tap.

 

“If we were in a fantasy world of the 20th new treatment for Huntington’s coming, you would worry about things like convenience: ‘I’d like to have a pill instead of an injection,’” Dr. Pacifici said. “‘I’d like to have a pill I can take once a day. I’d like to have a small pill that’s easy to swallow.’”

 

However, Dr. Pacifici observed, “we’re not at that stage yet.” Even so, “very critical advantages” exist in exploring different modes of delivery, he said.

 

Indeed, another possibility emerged at the conference. A scientist from pharmaceutical giant Novartis presented research on its drug branaplam, a pill used to treat spinal muscular atrophy (SMA), which causes severe muscle weakness in children. Novartis researchers discovered that Branaplam also reduced the amount of the huntingtin protein in a study of SMA patients. Novartis plans a trial of branaplam in HD patients, with details expected in the coming weeks and over the summer (click here to read more).

 

Like other so-called small-molecule drugs, branaplam becomes distributed very evenly across the whole body, including the brain, whereas a drug like an ASO tends to concentrate where it is administered, Dr. Pacifici explained. He added that small-molecule drugs can be dosed “creatively” – for example, weekly instead of daily – to maximize the “beneficial effect” and allow the person a rest from the drug.

 

(I will explore the quest to develop this type of HD drug in a future article.)

 

Dr. Rajeev Sivasankaran of Novartis presents data demonstrating the effect of the drug branaplam on huntingtin RNA in a study of spinal muscular atrophy patients (screenshot by Gene Veritas).

 

Sharing knowledge rises all boats

 

Dr. Pacifici emphasized that success in the fight against HD ultimately depends on the sharing of scientific information – even negative research results that private companies are loathe to reveal to protect their egos and their stock prices.

 

He cited the presentation by featured speaker Aled Edwards, Ph.D., the founder and CEO of the Structural Genomix Consortium, which practices and advocates for open sharing of scientific information, particularly as it applies to protein science, chemical biology and drug discovery. Dr. Edwards spoke on “HD drug discovery in the public domain – a model for CHDI.”

 

“I think the HD field will benefit by everybody realizing how difficult this problem is,” Dr. Pacifici concluded. “It’s not giving up a competitive advantage by being transparent about what happened. It’s sharing data. That knowledge rises all boats. Everybody needs to know about these things.”

 

Sharing of data and other knowledge has also been one of CHDI’s trademarks as a nonprofit. Dr. Pacifici pointed to specifics: knowledge about the disease, potential treatments, biomarkers, and clinical outcome measures (the techniques for measuring patient response).

 

With such sharing, he asserted, everybody will have an increased chance of success.

 

Refusing to do so will “doom us to the same failure we see in other neurodegenerative fields that have outspent us and been at this a lot longer than we have.”