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)

 

 

uniQure’s AMT-130 at the forefront of 21st Huntington’s Disease Therapeutics Conference

  

AMT-130, the uniQure gene therapy that successfully slowed the progression of Huntington’s disease before being obstructed from approval by the U.S. Food and Drug Administration (FDA), stands at the forefront of the leading HD research conference that starts today, February 23, in Palm Springs, CA.

 

The 21st Annual Huntington’s Disease Therapeutics Conference, which I have described as the Super Bowl of HD research, takes place at the Parker hotel. It is sponsored by CHDI Foundation, Inc., the largest private funder of HD research.

 

“In recent years HD drug discovery has become increasingly anchored in strong human genetic and clinical evidence, allowing us to focus on mechanisms most likely to yield disease-modifying benefit,” wrote Robert Pacifici, Ph.D., the CHDI chief scientific officer, in his welcome letter to the conference attendees. “Few developments capture this momentum more clearly than the recent topline results announced by uniQure from the pivotal Phase I/II study of AMT-130 suggesting that lowering [decreasing] mutant huntingtin in people confers a real clinical benefit, an important proof of biological principle.”

 

Dr. Pacific did not refer to the FDA roadblock but asserted that the AMT-130 “findings represent an encouraging milestone for the HD community.”

 

For its clinical trial analysis uniQure has relied on the CHDI-backed Enroll-HD, the global registry of HD-affected individuals and their families. uniQure has presented its data at the therapeutics conferences.

 

Dr. Robert Pacifici, wearing a Team Hope shirt from the Huntington's Disease Society of America, overseeing the 2025 Therapeutics Conference (photo by Gene Veritas, aka Kenneth P. Serbin)

 

AMT-130 talk in the lead-off

 

Dr. Pacifici and the conference planners scheduled a report on AMT-130 as the first presentation at the start of the opening science session on February 24.

 

David Margolin, M.D., Ph.D., uniQure’s vice president for clinical development, will give a talk titled “AMT-130 slows Huntington's disease progression at 3 years: Propensity score weighting mitigates potential bias from striatal volume absence in Enroll-HD.”

 

Because AMT-130 has been administered via a spinal injection that involves 12-plus hours of surgery, uniQure had no placebo group – those not getting an operation –but instead chose to use data from Enroll-HD as a comparison group.

 

After extensive consultations with the FDA in 2024, uniQure had gotten permission from the agency to use the Enroll-HD data. In November 2025, the FDA told uniQure that Enroll-HD data might no longer be “adequate.”

 

The HD community mobilized immediately, garnering 48,000-plus signatures on two petitions delivered to FDA headquarters on January 22.

 

The abstract of Dr. Margolin’s presentation does not reference the FDA but states that the Enroll-HD data about loss of striatal volume (shrinkage in the striatum, located deep in the brain and severely affected in HD) was helpful in the analysis of the clinical trial data. He reasserted the importance of MRI measurements of such brain loss.

 

Awaiting news about the FDA

 

uniQure announced on January 9 that it had scheduled a high-priority meeting with the FDA, which according to regulations had to occur within 30 days. The FDA must produce final minutes of the meeting.

 

As of this writing, uniQure has not reported on the results of the meeting.

 

At the conference, the several hundred scientists, biopharma reps, and advocates like me will anxiously await the latest news on AMT-130.

 

Stay tuned for my reports on the event.

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

 

At the recent 20th Huntington’s Disease Therapeutics Conference, four 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.

 

PTC Therapeutics, Roche, Wave Life Sciences, and uniQure made 15-minute presentations. This clinical trials update took place during the first session on February 25, the first day of the three-day event.

 

Sponsored by the nonprofit CHDI Foundation, Inc., the largest private funder of HD research, the conference took place in Palm Springs, CA.

 

Possible impact

 

All four programs use drugs to lower the amount of harmful mutant huntingtin protein in the brain cells of patients. Blocking the bad protein could help prevent the death of brain cells, a major driver of HD.

 

In a post-conference interview with me, CHDI Chief Scientific Officer Robert Pacifici, Ph.D., said that the companies’ plans to move their programs towards drug approval is “great news.”

 

“All of them expressed their commitment to moving forward with their interventions, and that’s not trivial,” Dr. Pacifici said. “That means a lot of time, a lot of money invested on their part. They wouldn’t be doing it if they didn’t think there was great promise there.”

 

Each firm has overcome the basic safety hurdles necessary for moving to a Phase 3 clinical trial, the final step before the U.S. Food and Drug Administration (FDA) approves a drug, Dr. Pacifici added.

 

This article, the first of two, focuses on trials from PTC and Wave. Part II will examine the Wave and uniQure updates.

 

Votoplam, a potential pill for HD

 

With 60 companies represented at the conference, CHDI selected those “that had something new to say” in terms of clinical development, Dr. Pacifici told the attendees.

 

Amy-Lee Bredlau, M.D., PTC’s senior medical director, began her talk on the company’s huntingtin-lowering drug by noting progress: the compound, PTC518, is now called votoplam, a nonproprietary drug name assigned by PTC’s new, larger partner on the project, the international pharmaceutical firm Novartis.

 

“I think this is a really great collaboration,” Dr. Bredlau said.

 

As Dr. Bredlau explained, votoplam is a huntingtin splicing modulator, reducing the production of both the mutant and normal huntingtin proteins.

 

In contrast with riskier delivery methods, some presented in the session, votoplam is a pill. That makes it easy for patients to take the drug.

 

CHDI and PTC started the search for a huntingtin-lowering pill with a joint project initiated in 2018.

 

A delay in HD progression

 

PTC ran a successful Phase 1 clinical trial of votoplam in 2020 and 2021, providing initial evidence of safety and the lowering of the huntingtin protein.

 

At the conference, in an interim analysis, Dr. Bredlau presented data from the first 32 of the 156 volunteers enrolled in PIVOT-HD, PTC’s one-year global Phase 2 trial, which has verified the safety and tolerability of the substance. The first group of participants in PIVOT-HD began in 2022.

 

PIVOT-HD demonstrated that, by the third month, votoplam enters trial volunteers’ brains and lowers the huntingtin protein, she said. At month 12, the lowering was sustained. The trial also showed no spikes in neurofilament light chain (Nfl), a protein whose presence indicates degeneration of brain cells in diseases like HD. Scientists hope that lowering huntingtin will limit Nfl.

 

Significantly, Dr. Bredlau observed that these volunteers had a delay in the progression of HD symptoms, as indicated by several key clinical measures.

 

She said PTC is “very excited” about those trends, which “look very promising,” adding that “we’re really hopeful that we’ll see a strengthening of the signal at the end of the 12-month study,” when results from the remaining volunteers will be studied.

 

PTC will release full results of PIVOT-HD in this (second) quarter of 2025, said Dr. Bredlau, adding that the firm hopes that the results secure permission for a Phase 3 trial, to be run by Novartis.

 

Dr. Amy-Lee Bredlau of PTC Therapeutics presents data from the PIVOT-HD clinical trial demonstrating trends of a delay in progression of Huntington's disease symptoms (photo by Gene Veritas, aka Kenneth P. Serbin).

 

GENERATION HD2 fully in progress

 

Peter McColgan, M.D, Ph.D., global development leader for Roche, updated the pharmaceutical giant’s HD program. He focused on the Phase 2 trial of the huntingtin-lowering drug tominersen.

 

Tominersen is an antisense oligonucleotide – a “laser-guided missile” against HD – originally developed by Ionis Pharmaceuticals, Inc. Like votoplam, tominersen lowers both the normal and mutant huntingtin protein.

 

After Roche’s unsuccessful trial of tominersen in 2021, the company redesigned a less ambitious and more focused trial of the drug in people less affected by the disease. Called GENERATION HD2, it started in early 2023.

 

Dr. McColgan reported that GENERATION HD2, by January, had fully recruited its target of 301 volunteers at 70 sites in 15 countries.

 

“This is a massive achievement,” he said.

 

The trial will assess tominersen’s safety, the use of biomarkers (signs of a disease and a medication’s efficacy), and the drug’s effectiveness.

 

Tominersen is not a pill. It is administered via a spinal tap.

 

Roche aims to complete the trial by the end of 2026.

 

Dr. Peter McColgan of Roche with a slide showing the global recruitment for the GENERATION HD2 clinical trial (photo by Gene Veritas)

 

Roche’s multiple approaches

 

Dr. McColgan also described how Roche has expanded its focus to include other possible HD treatments and related research.

 

“We believe the fastest way to get treatments to patients is to pursue multiple programs in parallel,” Dr. McColgan said.

 

In collaboration with its colleagues at Spark Therapeutics – acquired by Roche in 2019 – Roche scientists are exploring other potential molecules for targeting HD. Spark specializes in gene therapies.

 

HD researchers continue to weigh the approach of drugs such as votoplam and tominersen, which lower both the mutant and normal huntingtin protein, versus those that attack only the mutant. The latter types are known as allele-selective. They leave the normal protein to carry out its essential actions unhampered.

 

Dr. McColgan said that Roche and Ionis are investigating an allele-selective antisense oligonucleotide.

 

Roche is also participating in the HD Regulatory Science Consortium. Using data from the original tominersen trial and other patient data, this collaboration seeks to improve the measurement of clinical trial volunteers’ performance in clinical trials, said Dr. McColgan.

 

Roche is also collaborating with CHDI to improve the measurement of Nfl (neurofilament light chain) as a key biomarker.

 

“Nfl increases across the stages of HD,” Dr. McColgan observed.

 

The latest news on tominersen

 

All clinical trials are regularly checked by an independent data monitoring committee.

 

Volunteers in the tominersen trial not on placebo have received either 60mg or 100mg of the drug.

 

On April 17 Roche issued a letter to the HD community stating that the committee overseeing the tominersen trial has found “no concerns … regarding participant safety or signs of symptom worsening with either tominersen dose.”

 

In addition, the letter said, “the 100mg dose was found to be more likely than the 60mg dose to result in clinical benefit. Therefore for the remainder of the study only the 100mg dose will be tested against placebo, and the 60mg dose will be discontinued.” Those receiving 60mg will now get 100mg.

 

“We are incredibly grateful to the 301 participants and their companions enrolled in GENERATION HD2,” the letter stated. “Each study visit contributes to collecting data that helps the entire HD research community learn more about tominersen, Huntingtin-lowering strategies, and the further understanding of HD.”

 

In Part II of this article I will report on Wave’s and uniQure’s clinical trial updates

 

(Disclosure: I hold a symbolic amount of Ionis shares.)

More optimistic than ever, CHDI head scientist sees unprecedented mobilization in the fight to treat Huntington’s disease

 

In the wake of last week’s 20th Annual Huntington’s Disease Therapeutics Conference, the chief scientific officer for CHDI Foundation, Inc., declared that HD scientists had mustered unprecedented efforts toward therapies (treatments).

 

“I’ve been in the drug discovery business for over 30 years now,” Robert Pacifici, Ph.D., the CHDI head scientist, told me in a 37-minute video interview after the conference, referring to the key theme of crucial modifier genes, a focus of the meeting. “I’ve never seen the mobilization of efforts as quickly and as deliberately – from the identification of those genes to the understanding of how those genes mechanistically are having their effect – to actually developing candidate therapies that are modifying those processes.”

 

Dr. Pacifici observed that, in the HD field, “everybody’s pushing wherever they can to accelerate therapeutics. But we all know that sometimes you just hit roadblocks, you hit bottlenecks.”

 

He said that those difficulties can be overcome with “new technologies, new methods, new techniques,” which often result in “breakthrough moments. They allow you to do things that you just could never contemplate doing before.”

 

Dr. Robert Pacifici, wearing a Team Hope shirt from the Huntington's Disease Society of America, overseeing the 20th Annual HD Therapeutics Conference (photo by Gene Veritas, aka Kenneth P. Serbin)

 

The efforts forming around this hottest of topics in the HD field are “incredibly exciting,” Dr. Pacifici said. The “big news” over the next two years should include getting drugs that imitate the effect of the modifier genes – which research has demonstrated delay the onset of HD symptoms – into clinical trial programs.

 

As reported in this blog, the now defunct Triplet Therapeutics had aimed from 2020-2022 to develop and test a modifier gene drug (click here to read more).

 

Dr. Pacifici said that he is “more optimistic” than ever that HD drugs will get approved.

 

I attended the conference. Below you can watch a video of my interview with Dr. Pacifici.

 

 

 

Attacking the harmful protein

 

While this year’s Therapeutics Conference did not include any major positive announcements like the approval of a drug, Dr. Pacifici observed that it also did not bring the kind of disappointing news experienced by the HD community in 2021 with negative results from trials run by Roche and Wave Life Sciences.

 

The conference did bring reports from both Roche and Wave about their revised clinical trial programs. PCT Therapeutics and uniQure also reported on their ongoing clinical trials.

 

All four programs use drugs to lower the amount of harmful mutant huntingtin protein in the brain cells of patients. This is the first of three approaches to defeating HD, Dr. Pacifici recalled.

 

I will detail these updates soon.

 

‘Lucky’ and ‘unlucky’ genes

 

The second, more recent approach involves the search for drugs to imitate the modifier genes, as Dr. Pacifici noted above. These genes are related to somatic instability – the tendency of the expanded HD gene to expand further with time. This process can be triggered by negative modifier genes.

 

Dr. Pacific described those genes as “lucky” or “unlucky.” A good modifier gene can delay HD onset, whereas the bad one can hasten the start of the disease, he explained.

 

These genes act as “sentinels” in the bookkeeping of our DNA, Dr. Pacifici added. “We want our DNA to stay clean and error-free.”

 

Dr. Pacifici emphasized how more than 12,000 HD-affected individuals and their relatives in genetic research helped lead to the discovery of the modifier genes a decade ago. A study of a large group of people’s DNA is known as a Genome Wide Association Study (GWAS).

 

Fixing broken cells

 

The third approach to treating HD involves yet another set of genes that emerged from the HD GWAS. They were a key topic at the conference.

 

Dr. Pacifici stated that these genes are “every bit as validated” as the ones involving somatic instability. “We just don’t know the effect yet,” he said.

 

Dr. Pacifici added that understanding these genes will help answer a key unanswered question about HD: “what is it actually inside a cell at the molecular level that’s broken” and how to fix it.

 

All three of these areas could be targeted by an eventual cocktail of HD drugs, Dr. Pacifici said.

 

Key new genetic research and ‘rock star’ HD families

 

“We keep on thinking of ways of getting even more information out of persons with HD,” Dr. Pacifici said.

 

CHDI has announced that all 22,000 participants in Enroll-HD, the global registry of HD patients and relatives, will be full-genome-sequenced. That means their entire DNA will be  mapped.

 

“That’s a lot of data,” Dr. Pacifici noted. “It’s going to be the next set of breakthroughs, where we understand not just little bits of DNA information but the whole story for every participant.”

 

This will be “incredibly impactful,” he said.

 

The HD families that have provided all of this crucial data underlying these approaches to treatments are true “rock stars,” Dr. Pacifici said. Their interaction with HD scientists is critical, he concluded, to advancing scientific breakthroughs.