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.

‘Striving for a cure’: highlights from the 19th Annual Huntington’s Disease Therapeutics Conference

 

Progress towards effective treatments for Huntington’s disease relies on the affected families’ collaboration with researchers exploring the frontiers of science.

 

The potentially pathbreaking findings featured at the recently completed 19th Annual HD Therapeutics Conference, sponsored by the nonprofit CHDI Foundation, Inc., led CHDI Chief Scientific Officer Robert Pacifici, Ph.D., to declare that the community will achieve therapies.

 

In this article I highlight the scientists’ work with a photo essay on their conference presentations and some of their key observations.

 

I cover most of the presentations. For detailed reports on the conference, see the articles in HDBuzz by clicking here, here, and here. Later CHDI will post videos of the presentations on its website. It is also preparing a video “postcard” of the event.

 

In recent decades, Huntington’s breakthroughs have resulted from the increasing amount of human data, which Dr. Pacifici and other scientists say is the best way to study the disease and develop potential therapies. The presentations at this conference especially reflected this trend. Researchers such as Matthew Baffuto, B.S., of the Heintz Lab at The Rockefeller University (in the photo above), recognized the importance of postmortem donations of HD-affected individuals’ brains and other human samples for their research. Baffuto’s final slide included a dedication: “To the HD patients and families who make this human research possible and for whom we continue to strive for a cure.” (All photos by Gene Veritas, aka Kenneth P. Serbin) (Click on an image to make it larger.)

 

The first wave of attempts by pharmaceutical companies to defeat Huntington’s has involved attempts to lower the amount of the abnormal huntingtin protein (HTT) in patients’ brains. In many of these approaches, this also means lowering the amount of normal HTT. The lab of Jeff Carroll, Ph.D., a scientist at the University of Washington and a HD gene expansion carrier like me, has extensively studied huntingtin lowering in mice. Normal huntingtin is necessary for adult mice to function, Dr. Carroll observed. Huntingtin lowering is not a “bad idea, just that there’s a floor between 50 percent and zero percent HTT,” he said.

 

Tony Reiner, Ph.D., of the University of Tennessee Health Science Center, presented the latest findings of his work comparing HD mouse brains to human tissue from deceased HD-affected individuals. He also focuses on how HD affects the various regions of the brain differently. This photo illustrates how Dr. Reiner uses antibodies to measure the complications that arise in HD mouse brains.

 

Sarah Tabrizi, M.D., Ph.D., of University College London, discussed her lab’s research on somatic expansion, the tendency of the abnormal huntingtin gene to expand with time and become more harmful to the brain. She presented data on developing drugs to interact with modifier genes, which can impact somatic expansion and therefore the age of disease onset. Dr. Tabrizi focused on the modifier gene MSH3 as an ideal therapeutic target. For this research, the Tabrizi lab has utilized stem cells, CRISPR gene editing techniques, and antisense oligonucleotides, used in huntingtin lowering drug programs and other HD research projects.

 

Ricardo Mouro Pinto, Ph.D., of Harvard University Medical School, presented his lab’s work on genetic modifiers of somatic expansion. Dr. Pinto has implicated the so-called DNA mismatch repair pathway as a critical driver of somatic expansion. His lab is also developing CRISPR-based strategies as potential therapies. Dr. Pinto’s team was recently awarded a grant from the Hereditary Disease Foundation to continue the search for therapies.

 

Mark D. Bevan, Ph.D., of Northwestern University, spoke on his lab’s latest findings in HD mice, in particular the dysregulation and rescue of subthalamic nucleus, involved in the suppression of movement. Dr. Bevan highlighted the need for both huntingin-lowering and somatic expansion therapies to have widespread delivery into the brain.

 

Osama Al-Dalahmah, M.D., Ph.D., of the Columbia University Irving Medical Center, discussed the major role of astrocytes in HD. There are over 100 different brain cell types. Astrocytes are cells that provide physical and chemical support to other cells such as neurons, key in the brain. As a neuropathologist, Dr. Al-Dalahmah analyzes post-mortem brain tissues. Among other observations, he noted that astrocytes can be neuroprotective. His lab is working on ways to protect neurons in HD.

 

Scientist Baffuto’s wide-ranging presentation focused on specifying cell types in unraveling both the molecular mechanisms underlying somatic expansion and also the path of the disease. The Rockefeller team developed what it describes as an “innovative methodology” for deep profiling of cellular processes in the brain. The technique is fluorescence-activated nuclear sorting (FANS). As shown in one of Baffuto’s slides, they used FANS to detail the disease process in key areas of postmortem HD-afflicted brains: the striatum, cortex, thalamus, hippocampus, amygdala, and cerebellum.

 

Scientists continue to debate exactly what triggers Huntington’s. Assessing the impact of somatic expansion, the Harvard University Medical School team studying HD proposed a new model for how somatic expansion contributes to HD pathology. Bob Handsaker, B.S., explained that, until recently, scientists thought that the DNA triplet repeat creates a toxic protein whenever the CAG repeat length is greater than 40 and that HD pathology arises from lifelong exposure to this toxic protein, similar to how smoking damages the lungs. (The abnormally repeated DNA word CAG is the genetic root of HD.)

 

New research has challenged this idea in three important ways: First, there is much more somatic expansion than had been appreciated, with affected neurons expanding to reach over 400 CAG repeats. Second, this somatic repeat expansion starts slowly and then accelerates over time, like a "slowly ticking DNA clock” in each individual neuron. Third, the evidence suggests that modest somatic expansion, up to a repeat length of 150 CAGs, does not create a protein that is toxic - the toxic effect in each individual neuron only begins above this longer repeat-length threshold. Along with other research presented, this finding underscored that there may be a longer window of opportunity than had previously been appreciated for any therapeutic interventions that act to slow or block somatic expansion. This is because in the first few decades of life in a person with HD, the DNA in most neurons has typically not expanded to reach this toxic threshold.

 

Darren G. Monckton, Ph.D., of the University of Glasgow, presented his new research on biomarkers, signs of a disease and indicators of whether a drug has efficacy. Dr. Monckton focused on biomarkers in areas of the body outside the brain such as blood, in particular regarding the degree of somatic expansion and measuring it over time.

 

Carlos Bustamente, Ph.D., a Venezuelan American geneticist and the founder and CEO of Galatea Bio, Inc., advocated for enabling precision medicine around the globe. Dr. Bustamante observed that new technological advances have made it faster and less expensive to understand human genomes but most of such resources have gone to understanding predominantly northern European communities. He pointed out the need to expand the genetic dataset to other parts of the globe. Dr. Bustamante also explained how genetic differences in the global population have contributed to differences in the geographic prevalence of Huntington's.

 

David Margolin, M.D., Ph.D., the vice president for clinical development at uniQure, presented an update on the early-stage (Phase 1/2) clinical trial of the company’s gene therapy drug, AMT-130, involving 39 trial volunteers in the U.S. and Europe. Dr. Margolin reported that, relative to baseline, volunteers treated with AMT-130 showed evidence of preserved neurological function. So far, the drug has proved to be safe.

 

Amy-Lee Bredlau, M.D., the senior medical director at PTC Therapeutics, presented interim safety and biomarker data for the company’s huntingtin-lowering pill, PTC-518, in PIVOT-HD, a Phase 2 trial. At this stage, the drug has been shown to be safe and has achieved a lowering of huntingtin in the blood – although data do not yet show whether the lowering is also occurring in the brain.

 

From left to right, Roche researchers Jonas Dorn, Ph.D., Peter McColgan, M.D., Ph.D., and Marcelo Boareto, Ph.D., reanalyzed the data from the firm’s first attempt at a Phase 3 huntingtin-lowering trial program, which in 2021 ended without the drug tominersen showing the necessary efficacy for approval as a drug. The scientists discussed ways to improve clinical trial design, including for GENERATION HD2, a less ambitious, Phase 2 trial of tominersen in a smaller number of volunteers. GENERATION HD2 is in progress.

After abrupt shutdown of Triplet Therapeutics, Huntington’s disease community regroups in the fight for therapies

 

Triplet Therapeutics, Inc., a Cambridge, MA-based start-up that aimed to transform the treatment of Huntington’s disease and related disorders, has shut down, citing a lack of new investment partners and the discovery that its proposed HD drug caused adverse effects in animal tests.

 

On October 11, Triplet CEO Nessan Bermingham announced the company’s closure on his LinkedIn page. The abrupt closure was another piece of tough news regarding potential therapies for HD.

 

In March 2021, Roche and Wave reported negative trial results for drugs aimed at reducing the toxic mutant huntingtin protein in patients’ brains. These drugs are antisense oligonucleotides (ASO), a synthetic modified single strand of DNA that can alter production of certain proteins.

 

Triplet’s strategy

 

Triplet had designed its own ASO, but with a different strategy: to stop the deleterious expansion of the mutant huntingtin gene (click here to read more). Known as somatic expansion, this process drives the disease and can hasten the onset of symptoms. By slowing this expansion, Triplet had hoped that its drug would head off the disease early.

 

Triplet scientists and others have viewed this approach as a more effective alternative to the “huntingtin lowering” strategy devised by Wave, Roche, and others.

 

Capitalizing on recent groundbreaking HD genetics research, Triplet, founded in late 2018, developed the only clinical trial program to slow or stop somatic expansion in HD. Triplet also had hoped to develop treatments for others among the 50 rare conditions with somatic expansion, which, like HD, are called repeat expansion disorders.

 

 

Brian Bettencourt, Ph.D., Triplet's former senior vice president for research, explains a slide illustrating the firm's pathway to a potential HD drug at the 15th Annual HD Therapeutics Conference, 2020 (photo by Gene Veritas, aka Kenneth P. Serbin).

 

“It is with great sadness we announce the closure of Triplet Therapeutics,” Bermingham wrote on LinkedIn.

 

The “underlying science of targeting repeat expansion disorders” remains “a viable approach from our vantage point,” Bermingham wrote. However, crucially, in animal studies, the data from Triplet’s HD drug “reflected prior experiences” with ASO toxicity in the central nervous system – a reference to the Roche and Wave results.

 

Specifically, the ASO showed signs of harming neurons (brain cells). “As a therapeutic modality, given Roche’s data, our data, lack of efficacy from Wave products, our belief is that neurons may be particularly sensitive to antisense oligonucleotides,” Bermingham told STAT.

 

Triplet secured $59 million in initial financing and investment. After the bad news in 2021 from Roche and Wave, Triplet struggled to raise the money needed for its planned next step: an early phase clinical trial of its ASO. “The clinical data really put a chill on the overall interest or risk perceived within Huntington’s disease,” Bermingham noted.

 

SHIELD HD continues to provide key data

 

To provide data about the disease for the clinical trial it was planning, Triplet has run a separate, two-year study, without a drug, of approximately 70 presymptomatic and early-disease-stage carriers of the HD mutation. Called SHIELD HD, the study involves cognitive testing, brain MRI scans, blood tests, and examination of cerebrospinal fluid drawn from spinal taps (click here to read more). The sites are Canada, France, Germany, the United Kingdom, and the U.S.

 

In March, Triplet scientists presented a preliminary analysis of this data at the 17th Annual HD Therapeutics Conference, sponsored by CHDI Foundation, Inc., the virtual nonprofit biotech focused exclusively on developing HD therapies. CHDI is the largest private funder of HD research.

 

SHIELD HD may end in the next few months. In Bermingham’s announcement about the closure of Triplet, he said that CHDI, “a great partner and patient advocate,” stepped in to help SHIELD HD sites complete their work.

 

Triplet’s representatives are now seeking potential partners to continue the company’s research, including a new plan for a clinical trial.

 

Assessing risk

 

In an online interview with me on October 21, Irina Antonijevic, M.D., Ph.D., the former chief medical officer of Triplet, explained that discovering toxicity of the ASO in the animal studies surprised the firm’s researchers. However, she emphasized that the toxicity was “minimal” at therapeutic dose levels, with the animals not suffering any functional loss.

 

As noted publicly, Triplet had also developed several, more potent backup ASOs, Dr. Antonijevic said. The more potent the drug, the smaller the dose needed, therefore reducing the chance of toxicity or an adverse effect, she added.

 

Nevertheless, in a more risk-averse investment climate, Triplet could not find the necessary partners to carry on its clinical trial program with the added concern about the toxicity, Dr. Antonijevic observed.

 

“I think that they are just sort of very different risks,” she said. “Somebody takes maybe a risk to say, ‘Maybe this drug has a risk, but I have a disease, and I know what this disease will do to me.’”

 

For a drug company, the risk involves “investing millions” and waiting years to see if there is a return on investment, she said.

 

Tweaking drug safety, efficacy, and delivery

 

Triplet’s experience revealed how the field of HD drug development needs to tweak the safety, efficacy, and delivery of ASOs into the brain. Despite the challenges, a number of other firms and many researchers believe ASOs merit more study and clinical trials.

 

Roche has developed a revised clinical trial plan, including lower and thus potentially less toxic doses of its ASO. It will start a second trial of that ASO in early 2023.

 

Wave, building on its failed 2021 early stage trials of two ASOs, put a third drug into another small, early phase trial. Unlike the previous drugs, this Wave ASO successfully reduced the mutant huntingtin protein. Also, for the first time, it did this without lowering the level of the healthy protein – something that occurs with the Roche drug.

 

“This is, as far as we know, the first time anyone has ever selectively lowered only one copy [of a total of two] of a protein inside of a human body,” the HD science site HDBuzz commented on Sept. 30.

 

The method of delivery is important for all drugs, especially for ones introduced into the brain. The Roche and Wave trials use spinal taps (intrathecal injections). Triplet had projected using an

injection via a small reservoir implanted on the top of the brain. The firm uniQure is injecting its drug using brain operations.

 

Developing a pill

 

Drug developers point out that the most convenient HD drug would be a pill – taken orally, at home, and without medical assistance. These drugs are known as small molecules.

 

Several firms have embarked on small molecule clinical trial programs for HD.

 

An important trial of one of these small molecule drugs, a huntingtin-lowering pill developed by Novartis, was halted in August for safety reasons. Some of the trial volunteers on the drug developed problems with their nerves, known as peripheral neuropathy.

 

FDA requests more data from PTC

 

On October 18, another firm enrolling people in a clinical trial for a small molecule, PTC Therapeutics, Inc., was asked by the U.S. Food and Drug Administration (FDA), to provide further information before allowing a clinical trial of its HD drug, PTC518. PTC announced that enrollment is ongoing for the planned 12-month Phase 2 trial in several European countries and Australia.

 

Both branaplam and PTC518 are so-called splicing molecules.

 

“PTC pioneered the development of splicing molecules and we have learned about the essential elements to successfully develop these molecules,” Jeanine Clemente, the senior director of corporate communications at PTC, wrote me in an October 20 e-mail in response to my questions about the FDA decision. “We cannot comment on the FDA’s thoughts regarding branaplam or splicing molecules, in general.”

 

However, Clemente pointed out that PTC518 is highly specific and selective for the huntington gene.” She added that, in many important ways, “PTC518 is different than branaplam.”

 

HDBuzz also noted that PTC518 “may have more ideal drug properties, compared to branaplam.”

 

The FDA has asked PTC for additional data to support the dose levels and duration proposed in the trial, Clemente wrote.

 

Clemente added that PTC enrolled its trial entirely with patients outside of the U.S., including approvals to conduct the study at all proposed dose levels. “There have been no treatment-associated adverse events reported to date,” she stated. “We will continue to work with the FDA to potentially enable enrollment of U.S. patients in the trial.”

 

Keeping perspective in a difficult fight

 

Triplet will host a podcast later this year to discuss the “birth, life and death” of the firm, CEO Bermingham stated in his announcement of the closure.

 

The HD community must keep the Triplet shutdown – and all news regarding the ups and downs of the search for HD therapies – in perspective, noted Martha Nance, M.D., the director of the Huntington’s Disease Society of America Center of Excellence at Hennepin County Medical Center in Minneapolis.

 

“We would not do research if we already knew all the answers,” Dr. Nance wrote me in an October 18 e-mail. “HD patients and families have bravely faced their difficult disease for generations, and the doctors and scientists are doing their best, along with patients and families, to find a brighter path.”

 

As an asymptomatic HD gene expansion carrier who has not yet participated in a clinical trial, I had high hopes for the Triplet program, with its focus on attacking the disease in the early stages. I was deeply saddened to hear that the firm closed. I also felt in the gut once again the hard reality of marshalling resources – including financial support – for combating rare diseases.

 

Companies like Triplet are venture capital-funded businesses pursuing high-risk, high-reward endeavors, and many such endeavors fail. So we are fortunate to have a nonprofit like CHDI as a backstop.

 

Dr. Nance’s wisdom reminded me of the need to join with my fellow HD and rare disease advocates to regroup in the fight for therapies.

 

“Finding a solution to brain cell death in HD is not easy,” she observed. “And as we edge closer to an answer, each failure seems more dramatic. It would be nice if the answer would just reveal itself, if the answer to HD was simple and easy, but we will not let the setbacks of the last two years prevent us from moving forward.”

Roche confirms second, more focused, trial of Huntington’s disease drug will start early next year

 

As anticipated, the pharmaceutical firm Roche will retest its Huntington’s disease gene silencing drug, tominersen, by enrolling a more limited group of volunteers for a new clinical trial, which should start in early 2023.

 

Roche announced the new trial, GENERATION HD2, on September 18 at a meeting of the European Huntington’s Disease Network (EHDN) in Bologna, Italy. Roche also issued a letter to the HD community.

 

Roche halted the GENERATION HD1 trial of tominersen in March 2021 because of lack of efficacy against HD symptoms.

 

However, after months analyzing the GENERATION HD1 data, Roche reported in January that tominersen might benefit younger patients with less advanced symptoms. The new 16-month study, GENERATION HD2, will verify efficacy in that group.

 

GENERATION HD1 enrolled clinical trial volunteers ranging in age from 25-65 and included people with more advanced disease.

 

GENERATION HD2 will limit participation to people aged 25-50 who have “prodromal (very early subtle signs of HD) or early manifest HD,” the Roche letter stated.

 

“I am very excited about this new trial,” Jody Corey-Bloom, M.D., Ph.D., wrote me in a September 19 e-mail.

 

Dr. Corey-Bloom directs the Huntington’s Disease Society of America (HDSA) Center of Excellence  at the University of California San Diego, a site for GENERATION HD1 and again for GENERATION HD2.

 

“A lot of thought has gone into the new trial,” Dr Corey-Bloom observed. “I think this is a very well-planned trial!”

 

Roche world headquarters in Basel, Switzerland (photo by Norman Oder)

 

Key adjustments in dosing

 

According to the Roche statement, GENERATION HD2 aims to sign up approximately 360 participants in approximately fifteen countries (Argentina, Austria, Australia, Canada, Denmark, France, Germany, Italy, New Zealand, Poland, Portugal, Spain, Switzerland, the United Kingdom, and the United States). Additional locations might be added.

 

The study will have three cohorts. One third will receive placebo, one third 60 mg of tominersen, and one third 100 mg. To ensure the objectivity of the trial, neither the participant nor study team will know what the participant receives.

 

In contrast with GENERATION HD1, the new trial also will administer lower doses of tominersen. In GENERATION HD1, all volunteers receiving the drug took 120 mg. In GENERATION HD2, participants taking the drug will get either 60 mg or 100 mg.

 

Another key difference involves the frequency of dosing. GENERATION HD1 administered the drug every two or four months, whereas the new study will dose at only four months.

 

These adjustments are a major goal of the study: to determine whether lower or less frequent dosing can be beneficial. Such lower dosing or less frequent dosing potentially avoids some of the problems seen in GENERATION HD1. In that trial, the higher dose did not benefit volunteers (click here and here to read more).

 

As in the first trial, in GENERATION HD2 tominersen will be administered via lumbar puncture (spinal tap).

 

Renewed but cautious hope for preventing HD

 

The Roche letter reported that GENERATION HD1 and all other related tominersen studies have closed.

 

“These studies comprised the first-ever Phase III [efficacy] clinical program to test the huntingtin-lowering hypothesis,” the letter noted, referring to tominersen’s mechanism of lowering the amount the huntingtin protein involved in HD. “Additionally, it was because of the HD community’s commitment to research that the trials recruited faster than anticipated, and thus generated data faster than anticipated.”

 

That commitment, the letter observed, “inspires all researchers to continue pursuing potential options for people impacted by the disease.”

 

Roche will announce additional information about GENERATION HD2 in the coming months.

 

After the devastating news about tominersen 18 months ago, its potential seemed dead. Now, though enthusiasm about tominersen has perhaps diminished, a new, albeit less ambitious, path perhaps has emerged for the drug.

 

"Overall, the announcement of the new GENERATION HD2 trial at the EHDN meeting was well received by the audience in Bologna, which was a mix of clinicians, scientists, and families," HDSA CEO Louise Vetter, who attended the meeting, wrote me in an e-mail. "The fact that this trial is clearly a dose-finding study was notable, and it seem representative of the more conservative mood in the HD clinical science right now."

 

“While the results of GENERATION HD1 were certainly disappointing for everyone, they don’t mean that huntingtin-lowering isn’t a viable therapeutic approach,” Sarah Hernandez, Ph.D., the Director of Research Programs for the HD-focused Hereditary Disease Foundation, wrote me in an e-mail. “Targeting huntingtin directly targets the cause of HD and remains one of the strongest therapeutic hypotheses.”

 

GENERATION HD1’s results “also don’t mean that HTT lowering won’t eventually work for a broad population of people with HD,” Dr. Hernandez added. “They just mean that tominersen seems to require a more narrow patient group for efficacy. The new GENERATION HD2 trial seeks to define exactly what that patient group is, which could be very significant in moving the field forward.”

 

My hope is that GENERATION HD2’s aim to treat individuals earlier in the disease could generate valuable insights for a major goal in the science of HD and other neurodegenerative diseases: a therapy to prevent symptoms from appearing in disease gene carriers like me.