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

 

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

 

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

 

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

 

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

 

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

 

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

 

Attacking only the bad protein, preserving the good one

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

Slowing the shrinking of the brain

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

 

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

 

uniQure drug slows disease progression in trial

 

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

 

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

 

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

 

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

 

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

 

 

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

 

Hoping to accelerate approval

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

Swaying the FDA to be more flexible

 

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

 

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

 

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

 

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

 

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

 

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

 

A Breakthrough Therapy designation

 

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

 

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

 

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

 

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

 

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

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.)

Continued progress, but also caution, in the fight against Huntington’s disease

CHDI Foundation’s 14th Annual Huntington’s Disease Therapeutics Conference gets under­­ way today in Palm Springs, CA, in the wake of key developments in the search for the first HD treatments.

On January 28, pharma giant Roche announced that it had enrolled the first participant in GENERATION HD1, its historic global Phase 3 clinical trial of a gene-silencing drug that, if successful, could slow, halt, and perhaps even reverse HD symptoms. (Click here to read the announcement to the HD community by Roche ).

In the coming months, Roche aims to enroll a total of 660 clinical trial volunteers in 15 countries. They will receive either the drug (called RG6042) or a placebo in monthly spinal taps over 25 months.

The start of the trial comes less than a year after the presentation of the impressive Phase 1 trial results at last year’s Therapeutics Conference. RG6042 significantly reduced the levels of the mutant huntingtin protein in the cerebrospinal fluid of the clinical trial volunteers. Because of those results, Roche took the unusual step of skipping a Phase 2 trial and going directly to Phase 3.

Roche’s announcement follows a record year for new drug approval by the U.S. Food and Drug Administration (FDA), with 59 drug approvals overall, noted George Yohrling, Ph.D., the senior director of mission and scientific affairs for the Huntington’s Disease Society of America (HDSA). The previous record was 53 in 1996.

Of last year’s approvals, 34 involved orphan conditions like HD (fewer than 200,000 patients) – a sign, said Dr. Yohrling, that the pharmaceutical industry has not ignored those disease communities. He spoke in a January 16 webinar reviewing progress in HD research in 2018.

Roche to buy Spark

On February 23, The Wall Street Journal reported that Roche had agreed to pay $4.8 billion to acquire Spark Therapeutics, Inc., a Philadelphia-based biotech firm focusing on gene therapy approaches to genetic diseases, including HD. Spark’s co-founders include HD researcher Beverly Davidson, Ph.D.

With a record 360 participants from around the world, the CHDI conference opens this evening at the Parker Palm Springs hotel and runs through February 28. At the conference, I hope to obtain comment from Roche officials about how the acquisition could potentially expand Roche’s approaches to treating HD. Spark has engaged in pre-clinical HD research.

Above, scientists visit the CHDI Resource Fair at the 14th Annual HD Therapeutics Conference. Below, Gene Veritas (aka Kenneth P. Serbin) at the Parker Palm Springs (photos by Gene Veritas).

Exciting announcements about other trials

On January 22, the Dutch-American company uniQure announced that it had received approval from the FDA to start the first-ever HD clinical trial that uses a virus injected into the brain carrying a gene therapy agent to reduce the amount of harmful huntingtin protein. Viruses are used in vaccines and to treat cancer. They are under study for use in HD and other diseases. 

Unlike Roche’s RG6042, which would require long-term and probably lifelong treatment, uniQure’s gene therapy could permanently fix the problem of HD by “altering human DNA or inserting new genetic instructions into human cells,” observed HDBuzz.

However, it also noted that “gene therapy is a high-risk high-reward strategy. The benefits could be long-lasting – but so could any side effects.”

In this Phase 1/2 clinical trial, uniQure will primarily test safety and tolerability but also whether its drug is working as designed. It plans to start enrolling clinical trial volunteers in the U.S. in the second half of this year.

In late January, the California Institute for Regenerative Medicine (CIRM), the state’s voter-approved multi-billion stem cell initiative, announced a $6 million grant to prepare the way for a potential HD stem cell clinical trial. CIRM awarded the grant to the lab of Leslie Thompson, Ph.D., of the University of California, Irvine. The therapy could involve the transplanting of stem cells converted into neural (brain) stem cells shown in HD animal models to improve the function of compromised brain cells.

"Based on our pre-clinical studies in mice, human neural stem cells are highly beneficial, reducing the accumulation of a toxic form of the mutant huntingtin protein and improving HD symptoms and impaired electrical currents in the brain," Dr. Thompson explained in a news release.

FDA delays Wave trials

Another company’s plans have been slowed. The FDA has delayed two Phase 1 clinical trial by Wave Life Sciences using a drug – an antisense oligonucleotide – similar to Roche’s RG6042.

Whereas RG6042 reduces the amount of both mutant and normal huntingtin protein, Wave’s drugs target only the mutant.

“In the United States, we received approvals to proceed with the single-dose portions of both trials,” a February 6 Wave prospectus states. “However, the FDA indicated to us that we cannot progress to the multiple-ascending dose portions of these trials in the United States unless we conduct an additional preclinical [animal] study and present the resulting data to the FDA for its review.”

Realistic expectations

The news about Wave might be a cautionary tale for the HD community about realistic expectations. Only ten percent of clinical trial projects result in a drug reaching the market.

Alzheimer’s disease is another case in point. Over the past ten years, all 25 Alzheimer’s clinical trials have failed, noted Jody Corey-Bloom, M.D., Ph.D., the director of the HDSA Center of Excellence at the University of California, San Diego (UCSD), during her annual HD research update last October at the local HD support group.

As Dr. Corey-Bloom explained, most of those Alzheimer’s trials successfully removed seemingly harmful plaque from the brain, but they didn’t cure the disease. 

Such plaque isn’t a factor in HD, however, perhaps increasing hope that the Roche Phase 3 trial has a better chance of producing effective results, she observed. Dr. Corey-Bloom’s well-regarded UCSD clinic is one of the sites for GENERATION HD1.

An end to the ‘wait and see’?

In her presentation, Dr. Corey-Bloom addressed several of the key questions about GENERATION HD1 that have emerged in the HD community, including concerns about the injection of the drug by spinal tap (lumbar puncture).

She noted that spinal taps are a regular part of treating a condition known as pseudotumor cerebri, which produces severe headaches and, if left untreated, blindness. Patients get monthly spinal taps.

“We’ve had people that have probably done lumbar punctures monthly for several years, and they seem to do okay,” she commented.

She was optimistic that, if GENERATION HD1 is successful, Roche and physicians will seek alternatives to spinal taps. They will also pursue expanding access to the drug to presymptomatic gene carriers, she added. (That includes me.)

Dr. Corey-Bloom ended on a positive note.

“I’m always talking about things that will eventually come,” said of previous talks, in which she has cautioned the HD community against unwarranted enthusiasm. “Now we actually have clinical trials, and we have clinical trials that look like they are going to be effective. That’s probably the strongest statement that I’ve made, because I’m always trying to tell people, ‘Let’s just wait and see.’”

However, with the Alzheimer’s trials in mind, Dr. Corey-Bloom also reminded the audience that there is no guarantee GENERATION HD1 will actually affect the disease.

She crossed her fingers for good luck. We in the HD community will need to continue our hard work collaborating with her and the many other researchers engaged in the quest for treatments.

You can watch Dr. Corey-Bloom’s presentation in the video below.