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.)

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.

CHDI keynoter Charlotte Raven reflects on her fight against Huntington’s disease and the dashed hopes of a clinical trial

 

Like many affected by Huntington’s disease, renowned British journalist Charlotte Raven longed for the chance to participate in a clinical trial of a potential treatment for the incurable disorder.

 

Charlotte was diagnosed with Huntington’s in 2005. She inherited the genetic mutation from her father, who, after a long battle, died from HD in 2016.

 

In 2019 Charlotte had her wish fulfilled in London. As part of its HD clinical trial program to evaluate the efficacy of tominersen – the historic first attempt to attack the disease at its genetic roots – the pharmaceutical giant Roche was recruiting volunteers for GEN-PEAK, a small, Phase 1 study run in tandem with the larger, main, Phase 3 study.

 

Charlotte became “patient 1,” the first individual in GEN-PEAK to receive tominersen. If successful, the main trial would result in all participants in the program, including GEN-PEAK volunteers, receiving the treatment.

 

In her keynote speech at the recent 17th Annual HD Therapeutics Conference, Charlotte recalled the immense hope she felt about tominersen, shared by HD families around the globe: “Ever since I’d been picked to be on the trial, I’d woken up every morning thinking about the drug. It was like being in love. It was what I needed, wanted, looked forward to.”

 

A heartrending presentation

 

Those hopes were dashed on March 22, 2021, with Roche’s announcement that it was halting dosing of tominersen because of unfavorable efficacy data.

 

“Now that pinprick of light had been blacked out,” Charlotte told the 300 researchers, biopharma executives, and advocates gathered at the conference, held in Palm Springs, CA, and sponsored by CHDI Foundation, the nonprofit virtual biotech firm dedicated to developing HD therapies. “The world ended again; it felt exactly the same as the moment of my original diagnosis.”

 

Struggling with HD symptoms and assisted by her twelve-year-old son John, Charlotte bravely delivered a heartrending presentation, reading from a computer screen. Because Charlotte’s speech is slurred, the audience was provided access to an online script. She received a standing ovation.

 

Despite the bad news of 2021, drug hunters expressed renewed optimism about potential therapies. As reported in my previous article, the ensuing three days of scientific talks focused on multiple approaches. Indeed, Roche said it would test tominersen again in an improved clinical trial.

 

Assisted by son John, Charlotte delivers her keynote address (photo by Gene Veritas, aka Kenneth P. Serbin).

 

‘Feeling your personality crumble’

 

Charlotte’s keynote traced her career as an ambitious and controversial journalist and social commentator, her family’s fight against HD, and her efforts to cope with the symptoms and resulting limitations on her work and life.

 

The speech echoed Charlotte’s book Patient 1: Forgetting and Finding Myself, published last November. CHDI gave each conference attendee a copy.

 

In Patient 1, Charlotte provides a detailed, hauntingly beautiful portrait of the challenges posed by HD to both her and her extended family. Writing with help from her brother Daniel, as yet untested for the mutation, Charlotte intimately describes the toll HD has taken on her, robbing her of her memories and producing crippling anxiety.

 

“I wanted this book to be an accurate record of what it is like to exist with HD and to feel your brain and personality crumble,” Charlotte writes.

 

It also includes the first published account of the Roche program from a patient perspective.

 

‘A new leaf of hope’

 

During her CHDI keynote, to rest, Charlotte took two short breaks.

 

In the first interlude, with Charlotte looking on, her daughter Anna, 17, took the stage to speak of the special bond she has developed with her mother because of HD.

 

“Growing up under the shadow of Huntington’s has meant I’m often not the only priority, and sacrifices need to be made to make sure that my mom is properly looked after,” said Anna, who helps care for her mother.

 

Untested, both Anna and John have a 50-50 chance of inheriting the HD mutation. HD genetic testing protocols recommend against testing before age 18.

 

“Seeing and hearing about all these people working and researching to find treatments amazes me every day and makes everything seem a little less bleak,” Anna said. “The future for me, my brother, and my mom is unknown, but we have a new leaf of hope, and for that I would like to say thank you from the bottom of my heart.”

 

In the second interlude, Charlotte’s neurologist and clinical trial physician, Ed Wild, M.D., Ph.D., described her intellectual mettle. Dr. Wild wrote the Afterword to Patient 1. At the conference, he also recalled how “injecting 120 milligrams of tominersen into Charlotte’s spine in 2019” was one of his “proudest moments” in his career of helping HD patients.

 

Watch the entire keynote presentation in the video below, which includes the option of closed captioning.

 

 

The best team for defeating HD

 

Charlotte finished the speech with a tribute to researchers and a reflection on how confronting HD has “humbled me, and helped me connect more with the people around me, which is a new skill that I’ve been working on with commitment and persistence.”

 

“GEN-PEAK may have turned out to be a blind alley, but it was still a step on the journey towards a cure, and I still feel proud to have been part of it,” she said. “I’ve lived a fairly selfish life in lots of ways, so it seems oddly fitting that this last thing I did to save myself, might end up saving others instead.”

 

Charlotte noted an irony: she could write Patient 1, with its portrayal of HD's impact, only because the disease had mentally “compromised” her.

 

“I feel like I’ve finally been able to portray my family and friends as they really are instead of as I’d like them to be,” she added. “They are coming to life.”

 

She concluded: “Anna and I cannot get over how HD is such a rare disease, yet somehow attracts so many of the world’s brightest and best scientists. In my complicated journey with empathy, this is the most striking gift I can imagine.”

After setback, Roche to run new clinical trial with Huntington’s disease gene silencing drug

 

After halting dosing in the historic Phase 3 clinical trial for its Huntington’s disease gene silencing drug tominersen last March, pharmaceutical giant Roche announced today that it will start a new, less ambitious Phase 2 trial, limited to younger adult patients with “less disease burden.” The goal is to measure tominersen’s efficacy against the progression of HD.

 

Disease burden is calculated using a person’s age and degree of genetic mutation: the higher the sum of those two factors, the higher the burden. Roche, after initial testing of the drug, skipped Phase 2, which typically tests safety and efficacy of different doses, to pursue a Phase 3 trial, which confirms safety and efficacy in a larger population. Now it is proceeding in a more typical manner.

 

Roche informed the global HD community about the new trial in a letter released today. Roche’s partner Ionis Pharmaceuticals, Inc., the original developer of tominersen, also issued a press release.

 

“New exploratory post hoc analyses of GENERATION HD1 suggest that low exposure (less frequent dosing) tominersen may benefit younger adult patients with lower disease burden,” the Roche letter stated.

 

 

Low dosing meant volunteers received the drug every 16 weeks, while high dosing was every eight weeks.

 

“These findings, together with safety data of low exposure tominersen, support the continuation of the development program with a new Phase II clinical trial in younger adult patients with lower disease burden,” the letter continued. “While the findings are encouraging, confirmation in a randomised, placebo-controlled study is important.”

 

Post hoc analyses involve criteria set after data is seen, and “therefore they are not definitive,” the letter said. Because the trial was not specifically designed to run these analyses, the number of patients in the subgroups are small and the differences to placebo are not "statistically significant" and "could represent a chance result."

 

Even so, “these findings are promising and warrant a new study designed to test tominersen in this specific patient group,” stated Frank Bennett, Ph.D., Ionis' executive vice president, chief

scientific officer and franchise leader for neurological programs, in the press release. “This is an encouraging development for the HD community. We and Roche are grateful to the HD community's continued partnership, which has led to these important insights and a new scientific hypothesis [about tominersen].”

 

Maximizing benefits for HD patients

 

“It’s very exciting,” said Jody Corey-Bloom, M.D., Ph.D., the director of the Huntington’s Disease Society of America (HDSA) Center of Excellence at the University of California San Diego.

 

One of the GENERATION HD1 trial investigators, Dr. Corey-Bloom participated in a Roche-sponsored videoconference about the GENERATION HD1 findings that are serving as the basis for plans for a Phase 2 trial.

 

“They’ve analyzed the data in a very thoughtful manner,” Dr. Corey-Bloom said. “They’re hoping to really maximize benefits for at least a specific group of patients with HD, based on the results of their post hoc analysis.”

 

Roche is still planning the new trial. Therefore, it has not yet announced a timeline, sites, eligibility criteria, or information about dosing.

 

“This is just the news that should instill hope – a clear demonstration of the researchers’ commitment to regroup, redirect, and bravely move forward with its work on tominersen even after the challenges of 2021,” Martha Nance, M.D., the Center of Excellence director at Hennepin Health Care in Minneapolis, MN, commented by e-mail. “HD families, research scientists, and clinicians will need to work together in the coming years to determine when, whether, and how this drug can be delivered safely, effectively, and ethically to people in the earliest stages of HD.”

 

Representatives of Roche will present public updates on tominersen in previously scheduled webinars on January 20 for the European Huntington’s Disease Network (click here to register) and HDSA (click here to register). Another webinar, hosted by the European Huntington Association, will take place on January 24 (click here to register).

 

Roche is “resurrecting” tominersen in the “right way,” wrote Evaluate Vantage biopharma analyst Madeleine Armstrong. “Instead of running another phase 3, or indeed seeking approval, Roche is now going back to phase 2, although details are scant.”

 

With “no approved therapies for Huntington’s,” Roche “looks justified in trying again,” she added.

 

More results at upcoming conference

 

In an initial trial completed in 2017, Ionis had demonstrated that tominersen had successfully lowered the amount of the mutant, purportedly toxic huntingtin protein in the cerebral spinal fluid of a small group of volunteers.

 

Those impressive results led Roche to skip the standard Phase 2 trial and enter directly into Phase 3 (click here to read more). The GENERATION HD1 trial started in early 2019, enrolled a total of around 800 participants globally, and was to end in 2022.

 

However, in March 2021 a monitoring board conducting a standard review of trial data recommended that all dosing of tominersen in GENERATION HD1 be stopped. Roche decided to also stop dosing in a supporting trial. The following month Roche confirmed that trial data indicated that tominersen was ineffective and, in some cases, actually caused volunteers to worsen.

 

Roche is expected to present a detailed scientific update on tominersen at the 17th Annual HD Therapeutics Conference February 28-March 3 in Palm Springs, CA.

 

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

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

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

 

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

 

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

 

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

 

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

 

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

 

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

 

Gaining perspective

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

Huntingtin lowering still in the running

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

Exploring other avenues

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

Sharing knowledge rises all boats

 

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

 

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

 

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

 

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

 

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

 

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