Huntington’s disease community urges FDA to get on the right side of history for uniQure gene therapy

 

Even as uniQure, in a December 4 press release, has reconfirmed – based on meeting minutes – the decision by the U.S. Food and Drug Administration (FDA) to roll back its permission to apply for a Huntington’s gene therapy drug approval, more than 43,000 people have signed two petitions demanding the agency to uphold its original plan.

 

As recounted here, uniQure and others in the frustrated biotech sector believe that the FDA has become dysfunctional under the Trump administration.

 

In September, uniQure announced that its drug, AMT-130, had slowed the progression of HD by 75 percent over three years – a historic first.

 

Then, on November 3, uniQure announced that, after its October 29 meeting with the FDA, the agency had abruptly switched gears regarding AMT-130.

 

On December 8, the life sciences hub BioSpace reported that “rare disease leaders” want “regulatory consistency” after a “chaotic year” at the FDA.

 

Overcoming the ‘whiplash of the FDA’s about-face’

 

The key biotech site STAT has continued to report on the crises in leadership and turmoil at the FDA.

 

As of December 9, two online petitions to the FDA from HD advocates have garnered more than 43,000 signatures.

 

Click here and here for the petitions.

 

In the words of the scientist-written site HDBuzz, “The HD community has not remained silent through the whiplash of the FDA’s about-face from just five months prior, when they stated that data from the ongoing trials would be sufficient to support accelerated approval.”

 

Honors for AMT-130 researcher

 

“We are committed to collaborating with the FDA to advance AMT-130 to patients and their families as rapidly as possible,” CEO Matt Kapusta stated in the company’s December 4 release. “The support we have seen these last weeks from the Huntington’s disease community, including patients, families, caregivers, clinicians and advocates, reinforces the urgency of the unmet need in Huntington’s disease.”

 

Further validation of uniQure and the AMT-130 clinical trial came on December 8, when the key journal Nature announced that Sarah Tabrizi, M.D., Ph.D., a leading HD specialist at University College London and one of the medical leaders of the AMT-130 clinical trial, is “part of Nature’s 10, a list of people who shaped science in 2025.”

 

Titled “Sarah Tabrizi, Huntington’s hero,” the article about her describes her decades-long efforts to treat HD.

 

“I want to see if we can prevent Huntington’s from ever occurring,” Dr. Tabrizi told Nature.

 

As we approach the holiday season and the hopes that HD advocates will persuade the FDA to resume its support of the agreed-to plan for AMT-130, the recognition of Dr. Tabrizi and the community’s massive efforts signal that the FDA should be on the right side of history in this urgent fight to end devastating diseases.

 

Dr. Sarah Tabrizi at the 2020 Huntington's Disease Therapeutics Conference, Palm Springs, CA (photo by Gene Veritas, aka Kenneth P. Serbin)

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.

At Therapeutics Conference, landmark study of young gene carriers highlights how Huntington’s disease researchers seek to solve critical puzzles

Armed with ever more impressive data and a deeper understanding of Huntington’s disease, scientists and drug hunters convened at the 15th Annual HD Therapeutics Conference this week, facing the complex puzzles that still hinder the quest for treatments for this deadly neurological disorder.

One of those puzzles: how to not only treat symptoms, but to prevent them, especially in young presymptomatic carriers of the HD gene, so that they don’t have to spend their lives fearing the currently inevitable onset of this devastating disease.

On February 26, Sarah Tabrizi, FRCP, Ph.D., of University College London, answered key questions about what kinds of health consequences young presymptomatic gene carriers suffer decades before they’re likely to develop the disease in midlife.

Previous studies have demonstrated that brain shrinkage can occur as early as 15 to 18 years before predicted age of onset. Ranging in age from 18-40, the 64 gene carriers in Dr. Tabrizi’s HD Young Adult Study went through state-of-the art brain scans and cognitive testing, and also provided samples of blood and cerebrospinal fluid (CSF) for analysis. These at-risk volunteers are, on average, 24 years from estimated onset.

This study, in line with “The Path to Prevention” (one of five major themes of the 2020 conference), is aimed at helping identify the optimal time to treat gene carriers to slow or prevent their neurological decline.

“Comprehensive cognitive testing was normal,” as compared to 67 non-HD-affected individuals, reported Dr. Tabrizi in her presentation to the conference. “There were no significant psychiatric differences, which I found very interesting, because I would have predicted they would’ve been big differences.”

Dr. Tabrizi said that "there’s always been a thought that carrying the HD gene hard-wired you for psychiatric burden,” but the Young Adult Study suggests that such symptoms become more prominent closer to onset.

“I think that was – and I don’t say this lightly – a landmark presentation,” Robert Pacifici, Ph.D., the chief scientific officer for CHDI Foundation, Inc., the conference sponsor, told me today, adding that Dr. Tabrizi’s team carried out the study with “a high degree of rigor and granularity.”

“The participants seem to be remarkably well,” Dr. Pacifici observed. The absence of many of the neurological and other problems typical of HD is an encouraging prospect for developing safe and well-tolerated treatments that could “not just reverse, but actually prevent” HD, he said.

Dr. Pacifici lauded the study volunteers for their "unbelievably selfless participation," including submitting to the study's "incredibly rigorous battery."

Above, Dr. Sarah Tabrizi presenting her talk on the HD Young Adult Study at the 2020 HD Therapeutics Conference, February 26, 2020, and, below, a closeup of Dr. Tabrizi (photos by Gene Veritas, aka Kenneth P. Serbin)

Overall, ‘good news’ for young gene carriers

The young gene carriers in the study did appear to go through a small change in the area of the forebrain known as the striatum, consisting primarily of the putamen and the caudate, the deep brain regions that are most affected by HD. The striatum helps to control our movements and rewards system.

The study found a significant reduction in the size of the putamen, but an insignificant reduction in the caudate. Nevertheless, Dr. Tabrizi explained that, based on this study, these differences (in comparison with the normal subjects) were “not associated with predicted years to onset.”

“So what we now know, based on the data, is that the striatum never appears to be the same size as the control group,” she explained. 

The “very slightly smaller” striatum may suggest a “neurodevelopmental effect” (the way the brain develops) that is “well compensated for,” Dr. Tabrizi said, meaning that the brain adjusts without clear damage. She added that it “might be why the striatum is vulnerable later in life, because it has a double hit.” As mentioned by Dr. Tabrizi, this interpretation resonates with the research of Peg Nopoulos, M.D., who has studied the compromised development of the brains of people affected by juvenile HD.

Alternatively, neurodegeneration early on could be “too subtle and variable” to associate with predicated age of onset, Dr. Tabrizi noted.

Other imaging results showed no decrease in the white matter (the tissue in the brain made of nerve fibers and possibly involved in cognitive problems in HD) or any other aspect of the brain measured in the study, indicating that the subjects were still “very far from onset,” Dr. Tabrizi continued.

“This is really good news,” Dr. Tabrizi stated.

Douglas Langbehn, M.D., Ph.D., a psychiatrist and biostatistician at the University of Iowa who did the statistical analysis for the HD Young Adult Study, listens to Dr. Tabrizi at the Therapeutics Conference (photo by Gene Veritas).

The ongoing search for reliable biomarkers

The study also involved the ongoing search for reliable biomarkers (signs of disease and drug efficacy).

The study detected mutant huntingtin protein in the subjects’ cerebrospinal fluid. “CSF mutant huntingtin was higher in those closer to [predicted] onset, suggesting that some injury is releasing mutant huntingtin [from the brain], but very subtle,” Dr. Tabrizi said.

Several other biomarkers were elevated in the subjects’ CSF, again indicating an early, subtle injury, but most of those subjects had readings showing levels very close to those of the unaffected control subjects, Dr. Tabrizi continued. Furthermore, six other biomarkers were normal, she added.

The Young Adult Study points to the one CSF biomarker in particular, neurofilament light, a marker of brain damage, as potentially helpful in measuring disease progression and treatment response in people decades from onset, Dr. Tabrizi concluded.

A drug that kept neurofilament light at very low levels could prevent degeneration of the brain, she added.

You can watch Dr. Tabrizi’s presentation in the video below.

A moving keynote address

With a record attendance of 380, the conference opened on February 24 with a moving keynote speech by Amy Merkel, a 45-year-old nurse from Wisconsin and the founder of Starfish Yoga.

A small company, Starfish focuses on encouraging constructive coping skills, primarily for people affected by past imprisonment, sexual abuse, and neurological disorders, including HD.

Amy, who titled her talk “Life is Good,” belongs to a family deeply affected by HD. She recounted her extended family’s decades-long struggles with HD. Amy received a standing ovation.

Stay tuned to this blog for additional reporting on the conference, including an overview provided in my interview with Dr. Pacifici.

Above, HD advocate Amy Merkel addresses the 15th Annual Therapeutics Conference, and, below, poses with researchers Dr. Sarah Tabrizi (far left), Leslie Thompson, Ph.D. (second from right), and Gillian Bates, Ph.D. (photos by Gene Veritas).

New Ionis data show positive trends in clinical measures of Huntington’s disease drug trial volunteers

Exploratory analysis of new data showed positive trends in several clinical signs of Huntington’s disease in the recently concluded Ionis Pharmaceuticals, Inc., gene-silencing Phase 1/2a clinical trial, the company announced April 24.

“Results from exploratory analyses of data from the study demonstrated correlations between reductions in mutant huntingtin (mHTT), the disease-causing protein, and improvements in clinical measures of Huntington's disease,” an Ionis press release stated about its drug IONIS-HTT_Rx.

Initiated in September 2015 and completed in December 2017, the trial tested the drug in 46 symptomatic volunteers at nine sites in Canada, Germany, and the United Kingdom.

Because of the very limited size, duration, and scope of the Phase 1/2a trial, the newly studied clinical signals have only statistical importance. They do not demonstrate whether an individual patient got better, or by how much a person did better on a particular test.

However, they provide hope for the HD community because they showed an association between reducing, or lowering, mHTT, and the improved scores. The new data will help pave the way for the planned Phase 3 trial to test efficacy.

“These important clinical results further demonstrate that targeting the reduction of the toxic mutant huntingtin protein with IONIS-HTT_Rx has the potential to be disease-modifying,” Frank Bennett, Ph.D., Ionis senior vice president of research and franchise leader for neurological programs, stated in the release.

Sarah Tabrizi, FRCP, Ph.D., of University College London, the lead investigator of the Phase 1/2a trial, also presented the new information on April 24 at the annual meeting of the American Academy of Neurology (AAN) in Los Angeles. Out of more than 3,000 submissions, the talk was one of four selected for the top-featured session at the meeting, which drew more than 12,000 professionals.

Checking movements and cognitive loss

On March 1, at the 13th Annual HD Therapeutics Conference in Palm Springs, CA, Dr. Tabrizi revealed that the drop of 40-60 percent in mutant protein observed in the cerebral spinal fluid (CSF). Based on numerous animal studies done by Ionis, that corresponds to to a decrease of 55-85 percent in the cortex of the brain. The cortex is the most developed area of the brain and the source of thought and language, abilities severely hampered by HD. In the caudate – which helps control movement, another critical problem in HD – the corresponding decrease (based on animal data) ranged from 20-50 percent.

The new data demonstrate associations between reduction in mHTT (measured in CSF) and improvement on two clinical tests commonly used in HD clinical studies: the total motor score test (measuring impairments in movements) and the symbol digit modalities test (measuring cognitive loss).

The press release further noted a significant correlation between huntingtin reduction and an improved score on the Composite Unified Huntington's Disease Rating Scale (cUHDRS), which measures decline in patients.

Two tests showed neutral results: the stroop word reading (checking for cognitive loss) and the total functional capacity (assessing ability to perform daily tasks).

A slide from Dr. Tabrizi's talk at the AAN meeting illustrating improved scores in two clinical tests (top two graphs) and neutral scores in two others (bottom graphs) (slide courtesy of Ionis)

Larger, longer studies needed

At the AAN meeting, Dr. Tabrizi emphasized that the three-month Phase 1/2a trial was not designed to measure a true clinical benefit from IONIS-HTT_Rx. It sought primarily to gauge safety and tolerability of the drug.

The researchers used so-called “exploratory post-hoc analysis.”

As explained by Ionis officials in an e-mail, post-hoc means that Ionis did not predefine the analyses in the clinical trial protocol. Such analyses cannot provide conclusive proof of a drug effect. These analyses are common in early-stage clinical trials, where drug companies look for interesting signals worthy of careful evaluation in later-stage trials.

The officials also pointed out that, in analyzing the data using the gold-standard technique for demonstrating effect - comparing clinical test results of drug-treated participants with those on placebo - no improvements were found. This was not a surprise, given the limited scope of a Phase 1/2a trial.

In fact, they added, the trial planners included the clinical tests primarily to monitor for unexpected worsening.

The Ionis officials described the relationship between mHTT-lowering and potential clinical benefit as "subtle."

They emphasized the need for larger and longer trials to demonstrate efficacy.

A 'hint of clinical benefits'

“The measurements were done during the trial, but these statistical analyses were not pre-specified, and so we say that they are post-hoc and exploratory,” Jody Corey-Bloom, M.D., Ph.D., the director of the Huntington’s Disease Society of America (HDSA) Center of Excellence for Family Services and Research (COE) in San Diego, explained in an e-mail.

Dr. Corey-Bloom described the correlations between the clinical measurements and the reduction in the huntingtin protein as “positive but weak. This is very welcome news and clearly in the right direction! We will obviously need larger and longer studies to really confirm a potential clinical benefit, though.”

Swiss pharmaceutical giant Roche, which now holds the license to the Ionis drug, has confirmed that it will take the unusual step of skipping a Phase 2 trial and going directly to Phase 3. Phases 2 and 3 measure a drug’s efficacy. Roche, which renamed the drug RG6042, does not yet have a timeline. (Click here to read more about Roche’s plans.)

"Though press releases and post-hoc analysis can be problematic, the reported improvement in clinical measures in this early clinical trial, if borne out by subsequent study, is a ‘wow’ for the HD community,” LaVonne Goodman, M.D., the founder of Huntington’s Disease Drug Works, commented in an e-mail. “So I look forward to seeing the full data set in a peer-reviewed article. If results from this first trial are borne out in the larger Phase 3 trial, this drug is a game changer for HD. And also great, if results are similar to the present trial, it might take less than the earlier predicted three years to show it.”

“It is quite exciting to see any hint of clinical benefits,” Martha Nance, M.D., the director of the Minneapolis COE, wrote via e-mail. “It is important to know that these clinical results are not definitive, but this report adds to the growing list of favorable results from this groundbreaking trial of gene silencing in HD. The HD community has every right to be excited about these results!”

* * *

For additional coverage of the Ionis news, click here and here.

For HDSA's Q & A on the news, click here.

For background on the development of clinical tests for HD, click here.

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

(This article was updated on April 27, 2018, to include additional comments on the clinical trial analyses by Ionis officials.)

The best news for the Huntington's disease community since the discovery of the gene: Ionis trial data revealed, Roche confirms jump to Phase 3

Researchers revealed impressive, if not conclusive, additional information at CHDI Foundation's 13th Annual Huntington’s Disease Therapeutics Conference yesterday regarding the historic Ionis HD clinical trial: the drop in mutant protein observed in the cerebral spinal fluid (CSF) of participants corresponds to as much as an 85 percent decrease in the cortex of the brain, head physician Dr. Sarah Tabrizi announced.

It’s the best news the HD community has received since the publication of the research confirming the discovery of the gene 25 years ago this month. As scientists have observed, it’s also a major step for disease and drug research in general.

“The magnitude of mutant huntingtin [protein] reduction observed exceeds the effect needed for disease modification in animal models,” Dr. Tabrizi, of University College of London (the lead clinical trial site), told an audience of some 350 scientists, drug company representatives, and HD advocates at the conference in Palm Springs, CA.

Dr. Sarah Tabrizi presenting the IONIS-HTTRx trial data on March 1, 2018 (photo by Gene Veritas, aka Kenneth P. Serbin)

Ionis officials announced in December that the Phase 1/2a trial for the gene-silencing drug IONIS-HTT_Rx “substantially exceeded our expectations” in safely reducing the mutant huntingtin in the CSF.

For the first time, Dr. Tabrizi’s presentation (plus an Ionis press release) specified the level of huntingtin reduction.

During the clinical trial, participants received the drug via spinal injections, and doctors measured the drug’s ability to reduce the protein by extracting CSF samples.

IONIS-HTT_Rx lowered mutant huntingtin an average of 40 percent, with a maximum reduction of 60 percent. As Dr. Tabrizi explained, projecting from the numerous, painstaking animal studies done by Ionis, the reductions in the cortex range from 55-85 percent.

Frank Bennett, Ph.D., Ionis senior vice president of research and the franchise leader for neurology programs (left) and Anne Smith, Ph.D., Ionis director of clinical development (middle), confer with Dr. Tabrizi moments before the two women's historic presentation of the IONIS-HTTRx trial data. Dr. Bennett led the Ionis efforts to develop the drug (photo by Gene Veritas).

The cortex – along with the striatum, which is critical to motor control and managing the reward system – is the area of the brain most affected by HD. It is the most developed area of the brain, the source of thought and language, abilities severely hampered by HD.

Watch Dr. Tabrizi in the short video excerpts below explain this data and thank the 46 brave clinical trial volunteers and the many others involved in the effort. I also recommend watching the full video – which includes further trial data and a helpful overview of the project by Anne Smith, Ph.D., of Ionis – by clicking here.

 Ionis trial reduces bad Huntington's disease protein from Gene Veritas on Vimeo.

The plans for RG6042, the drug’s new name

The presentation by Drs. Smith and Tabrizi – the first public presentation of the trial data – can perhaps help inspire the HD community and researchers to become engaged in the next, crucial step: testing the drug’s efficacy.

Based on its partnership agreement with Ionis, Swiss pharmaceutical giant Roche, which now holds the license to the drug, will carry out a longer trial with hundreds of participants, including sites in the U.S.

The main question: will symptoms of this progressive, deadly disease stabilize, or even be reversed?

In an interview at the conference, Roche officials told me that – as Ionis had indicated – the company would take the unusual step of skipping a Phase 2 trial (testing efficacy for the first time) and going directly to a Phase 3 (confirming efficacy in hundreds, or more, participants).

They pointed to the excellent results of the Phase 1/2a trial; Ionis’ superb development of the drug; the nonprofit CHDI’s expertise and leadership; and the enthusiasm from – and urgent need of – the HD community.

Roche has officially changed the name of IONIS-HTT_Rx to RG6042. “R” stands for Roche, and “G” for Genentech, a major U.S.-based pharmaceutical company acquired by Roche in 2009 for $46.8 billion. The number 6042 is a standard drug number assigned by the company. If Phase 3 is successful, a drug issued for commercial sale will get a brand name.

All U.S-based Roche personnel and products still use the name Genentech.

Roche has not yet determined a start date or timeline for Phase 3. I will provide a detailed report on the interview and Roche’s plans, and also my personal reactions to the conference, in upcoming articles.

Members of the Roche HD clinical trial team watch Dr. Tabrizi's presentation. From left to right, Scott Schobel, M.D., M.S., clinical science leader of product development; Lauren Boak, Ph.D., global development team leader; Erik Lundgren, lifecycle leader of the HD program; and Mai-Lise Nguyen, the patient partnership director for the HD program (photo by Gene Veritas). 

Time for excitement, but also caution

CHDI Chief Scientific Officer Robert Pacifici, Ph.D., called the results of the Ionis trial “incredibly exciting.”

However, he also cautioned the HD community.

“Drug discovery is a really time-consuming and inefficient process, and, sadly, fraught with many failures,” Dr. Pacifici said. “The first time you put something into people, no matter how prepared, you never know whether it’s going to be safe and well-tolerated. What the initial trial showed was that at those doses, with the route of delivery, with that population of folks, it is indeed safe and well-tolerated. (If it wasn’t, it would stop in its tracks.) Once you get to this stage, a lot of the uncertainty about timelines goes away.

“This is really the time to be incredibly careful and incredibly deliberate. It’s going to take a while now to orchestrate the Phase 3 trial. That’s the pivotal trial that tells you whether or not the drug works.”

Everything needs to be done “by the book” to get a really “conclusive result,” he added.

If the trial fails, it will still provide scientists and physicians with guideposts for future research and trials, he said.

“We owe a huge debt of gratitude to those patients who signed up for that initial trial,” Dr. Pacifici concluded. “It’s going to require not only more of that type of participation, but a lot of patience.”

You can watch my interview with Dr. Pacifici about the conference and the Ionis trial in the video below.

 A time for excitement, but also great care and deliberation from Gene Veritas on Vimeo.

* * *

Ionis hosted a live webcast at 11 a.m. Eastern Time today. A webcast replay, including slides with clinical trial data, are available by clicking here.

For detailed coverage of the HD conference presentations, visit hdbuzz.net.

Visit my Vimeo album, to be periodically updated in the coming weeks, for other presentations and interviews at the conference.

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

Ionis drug successfully reduces toxic Huntington’s disease protein, paving way for Phase 2 trial of effect on patients

In an initial clinical trial that marks a significant step toward finding an effective Huntington’s disease treatment, the Ionis Pharmaceuticals gene-silencing drug safely reduced the production of the toxic mutant protein implicated in HD, the firm announced today.

Ionis has handed development of the expected Phase 2 trial to its partner in the project, the multinational pharmaceutical giant Roche, earning a $45 million license fee, today’s Ionis press release stated. The drug is called IONIS-HTT_Rx: “HTT” stands for both the huntingtin gene and the protein it produces, and “Rx” signifies a remedy.

The trial was officially classified as Phase 1/2a. A Phase 1 trial measure’s a drug’s safety and tolerability in a small number of participants, while a Phase 2 trial examines efficacy in a larger group of patients. Though mainly Phase 1, this trial had elements of a Phase 2: actual HD patients took part, and it sought to determine whether the drug’s basic mechanism worked.

“We are encouraged by the performance of IONIS-HTTRx in the Phase 1/2a clinical study,” Frank Bennett, Ph.D., Ionis senior vice president of research, stated in the release.

The reductions of the mutant protein “observed in the study substantially exceeded our expectations,” Dr. Bennett added. The study, which involved 46 participants with early HD symptoms, did not assess whether that reduction slowed disease progression.

Ionis stated that “dose-dependent reductions of mHTT were observed” in the trial: the higher the dosage, the greater the reduction in the amount of the mutant protein.

“We were equally encouraged by the safety profile of the drug,” Dr. Bennett stated.

“The results of this trial are of ground-breaking importance for Huntington’s disease patients and families,” stated Dr. Sarah Tabrizi, professor of clinical neurology, director of the University College London’s Huntington Centre, and the global lead investigator on the Phase 1/2a study. “For the first time, a drug has lowered the level of the toxic disease-causing protein in the nervous system, and the drug was safe and well tolerated. The key now is to move quickly to a larger trial to test whether IONIS-HTT_Rx slows disease progression.”

Frank Bennett, Ph.D. (above, photo by Kristina Bowyer, Ionis) and Dr. Sarah Tabrizi (below, photo by Gene Veritas)

Pharma giant Roche steps in

Ionis officials stated in June that a Phase 2 study could start as soon as 2018. Typically, all three phases of a clinical trial project take at least five years, although nobody can predict the actual course of a trial.

In 2013, Ionis, a mid-sized drug-discovery firm that does not produce or sell drugs or conduct clinical trials on its own, partnered with Roche, one of the world’s largest and most successful pharmaceutical companies (click here and here to read more). Roche’s expertise includes neurodegenerative brain diseases.

Roche will now take over the development of IONIS-HTT_Rx, including the Phase 2 and potential Phase 3 trials and bringing the drug to market. It will hold the license to the drug.

Roche also will administer the open-label extension of the Phase 1/2a study, announced in June, whereby all patients – including those who got a placebo – will continue to receive the drug. The extension allows researchers to gather more data, examine the drug’s effects over a longer period of time, and better prepare for Phase 2. Patients also potentially benefit by receiving the drug longer.

Phase 2 to include United States

By attacking Huntington’s disease near its genetic roots, IONIS-HTT_Rx could potentially reduce, partly reverse, and even prevent symptoms. Ionis drugs are antisense oligonucleotides, artificial strands of DNA. The drug aims to turn off the huntingtin gene messenger RNA that contains the instructions to make the huntingtin protein in brain cells.

Forty-six patients took part in the Phase 1/2a trial at sites in Canada, Germany, and England.

“Today is an exciting day for the Huntington’s disease community,” a joint Ionis-Roche letter to the HD community stated. “Future studies for the program will be conducted globally, including in the U.S. Roche will announce details about future studies, including eligibility criteria and planned start dates, as this information becomes available.”

More than a decade of research

IONIS-HTT_Rx resulted from more than a decade of research involving Ionis, Roche, the lab of neurobiologist Donald Cleveland, Ph.D., at the University of California, San Diego, and CHDI Foundation, Inc., the nonprofit virtual biotech firm aimed solely at finding (and funding) HD treatments.

On December 3, Dr. Cleveland received the $3 million Breakthrough Prize, the world’s richest science award, sponsored by Google, Facebook, and other entities. It is twice the value of the Nobel Prize. Dr. Cleveland received recognition for his career contributions to the life sciences, including work on a cause of Alzheimer’s disease. (Click here to read more.)

Dr. Cleveland was honored at the 2012 gala of the San Diego Chapter of the Huntington’s Disease Society of America. For a recent article explaining the Dr. Cleveland’s role in the Ionis project, click here.

In interviews today, I hope to obtain further details about the progress regarding IONIS-HTT_Rx.

HDBuzz’s take: a historic breakthrough

The HD research site HDBuzz, produced by scientists, stated that today’s announcement is “likely to stand as one of the biggest breakthroughs in Huntington’s disease since the discovery of the HD gene in 1993.”

The site’s article, written by Jeff Carroll, Ph.D. – an HD-gene carrier like me and a scientist dedicating his career to finding HD treatments – asserted that the “most exciting” part of today’s news is that “dose-dependent reductions of mutant huntingtin were observed.”

The clinical trial administrators know this because they examined samples of participants’ cerebrospinal fluid, which runs along the spine and into the brain. Participants received injections of the drug via a spinal tap.

“This means that patients treated with IONIS-HTTRx have reductions in the huntingtin protein in their cerebrospinal fluid,” Dr. Carroll wrote. “Based on this result, it looks like the drug is doing what it’s meant to do, and that huntingtin lowering has been achieved!”

Dr. Wild concluded: “This is a great day in the HD community, and it sets us on the path to even more exciting work in 2018. For the first time in history, HD patients are being treated with drugs known to reduce the amount of huntingtin protein in their brain. Until we conduct the next trial, we won’t know if this reduces the impact of HD. And while we know the drug is safe in the short term, we will also have to watch carefully for any long-term adverse effects. But we’re facing this problem with renewed excitement and hope. It’s the best early Christmas present we could have hoped for.”

Jeff Carroll, Ph.D., at the 2012 CHDI-sponsored HD therapeutics conference (photo by Gene Veritas)

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

Chief Huntington’s disease drug hunter: ‘every confidence first treatments’ in the works

Surveying the vast progress in Huntington’s disease research and a “blitz” of clinical trials now in progress, a key scientific leader in the efforts has predicted that they will produce treatments for the incurable neurological disorder.

“I have every confidence that this batch of clinical candidates that are now being tested are going to yield the first treatments for Huntington’s,” said Robert Pacifici, Ph.D., the chief scientific officer for CHDI, the multi-million-dollar non-profit virtual HD biotech.

Dr. Pacifici’s remarks came in an interview on February 24 in Palm Springs, CA, at the organization’s 11th Annual HD Therapeutics Conference, sponsored by CHDI Foundation, Inc., the backer of the initiative.

Nobody can foretell the result of a clinical trial, and Dr. Pacifici did not specify a timeline for an effective treatment reaching the market. However, he offered examples of the immense progress towards developing treatments.

“It’s really frustrating for people, I know, to say, ‘That’s good news, that’s good news, but where’s the treatment, where are the drugs?’” Dr. Pacifici said. “The thing I would point to is that so many of the things we said were going to happen actually have happened. And so many of the things that have happened have actually yielded the outcome that we wanted.”

Dr. Pacifici cited three recent key advances: the ongoing research in biomarkers (signals) to measure the efficacy of potential drugs’ in reducing the harmful presence of abnormal huntingtin protein in brain cells; major progress in identifying modifier genes that delay or hasten disease onset; and the start of clinical trials.

The trials post the most “difficult” challenge in the process, he said.

“We want to make sure that we do things in a way that obviously is very careful,” he said, explaining the primacy of drug safety. “The last thing we want to do is harm anybody.”

Noting that the search for drugs has no guarantees, Dr. Pacifici nevertheless concluded that these are “exciting times” for the community of HD families, researchers, and supporters of the cause.

You can watch my interview with Dr. Pacifici in the video below.


'Every confidence first Huntington's disease treatments' in the works from Gene Veritas on Vimeo.

First Ionis patients safe

Until recent years, such good news seemed like a remote possibility for HD Therapeutics Conference participants and, indeed, for the entire HD community.

Because of the growing number of HD clinical trials and therefore greater hope for effective treatments, Dr. Pacifici and fellow CHDI conference organizers launched a new feature at this year’s conference, the “Clinical Trials Update Blitz.” Representatives from four different trials presented their latest news in 15-minute presentations.

The most anticipated update focused on the historic trial by Ionis Pharmaceuticals, Inc., to attack the root cause of HD via gene-silencing.

Trial principal investigator Sarah Tabrizi, M.D., Ph.D., of University College London reported that all patients in the very first cohort in the Phase 1b/2a trial – aimed at testing primarily safety and tolerability – completed the trial without incident.

Dr. Sarah Tabrizi updating the historic Ionis gene-silencing trial (photo by Gene Veritas)

The first group of participants received the first dosing of the drug, IONIS-RTT_RX, in October 2015. They received three additional doses at 28-day intervals and were monitored by trial administrators.

“We completed Cohort A, in London and Vancouver, four subjects, and the DSMB [independent data safety monitoring review board] met and allowed us to move to cohort B,” Dr. Tabrizi said. (A DSMB, a standard in all clinical trials, halts a study if patient safety is threatened.)

Administrators of the Ionis trial are currently recruiting volunteers for Cohort B, to be followed by Cohorts C and D, as outlined in the plans for the experiment. In all, 36 patients will take part in Phase 1b/2a. If all cohorts are successful, Ionis will seek approval for a full-blown, larger Phase 2 trial to test drug efficacy.

For further background on the trial, watch Dr. Tabrizi’s update in the video below.


First Patients Safe in Ionis Trial for Huntington's Disease Treatment from Gene Veritas on Vimeo

More than a disease

Drawing a record 325 participants from academia, the pharmaceutical business, and the medical field, the conference highlighted cutting-edge HD research, including the structure and function of the huntingtin protein; the huntingtin gene and the human genome; potential gene-silencing treatments; restoration of cell health; and ways to measure clinical trial outcomes.

Although highly dedicated to HD research, many of the non-physician scientists have little if any contact with HD families. This has prompted CHDI to open each conference with a keynote by a representative of the HD community to drive home the human reality of the disease and the urgent need for treatments. (I keynoted the 2011 meeting.)

This year Astri Arnesen and Svein Olaf Olsen, a married couple who have led the HD cause in their native Norway and in the European Huntington Association, delivered a powerful keynote about HD and marital commitment, denial, genetic testing, and raising a family. They titled their presentation “HD – more than a disease!”

Astri and Svein Olaf received a standing ovation.

I will explore their story and provide an overview of the key scientific findings in a second report on the conference.

Svein Olaf Olsen (left) and Astri Arnesen (photo by Gene Veritas)

An upbeat mood

As in past years, the CHDI meeting moved me profoundly.

I identified with the many difficult feelings and experiences recounted by Astri and Svein Olaf.

Once again, the scientists’ presentations reminded me of HD’s devastation of the brain – and of my vulnerability as a carrier of the HD mutation.

But this was a very upbeat conference. I had never spoken before to Dr. Tabrizi, but we hugged as if we were old friends after I congratulated her on the initial clinical trial report. The HD community has waited so long for such news!

Later, after I worked late into the evening on this article and missed the buffet dinner, Jerry Turner, the CHDI staffer in charge of conference logistics, arranged for a care plate of sumptuous leftovers from the kitchen of the Parker hotel, the gracious host of the conference.

I toasted to the success of the Ionis clinical trial and to CHDI’s commitment to the project with Doug Macdonald, Ph.D., CHDI’s director of drug discovery and development and its point man on gene-silencing.

As I told another scientist, I look forward to the day when we can all toast the discovery of an effective treatment.

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