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.)

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.)

Combatting the pandemic, Roche also forges ahead with critical Phase 3 Huntington’s disease clinical trial

Using its expertise to combat a coronavirus pandemic that has left more than 180,000 people dead worldwide and a third of the earth’s people on lockdown, pharmaceutical giant Roche is also forging ahead with its Phase 3 clinical trial for the Huntington’s disease gene silencing drug RG6042, now known by the generic name tominersen.

The final step in a clinical trial program, Phase 3 tests the efficacy of a drug. A successful Phase 3 allows a pharmaceutical company to apply to regulatory agencies for permission to market the drug. In a time of “social distancing” and a shutdown of normal life, Roche and HD clinical trial administrators are seeking to mitigate the risks associated with the spread of COVID-19, the disease caused by the coronavirus.

In an April 20 letter to the global HD community, Roche announced that it had completed recruitment for the trial, GENERATION HD1. A total of 791 symptomatic volunteers across 18 countries have been enrolled, just ten fewer people than Roche projected after the trial got under way last year – almost 99 percent of the target.

“This achievement is a result of the HD community’s commitment from the beginning, and we are very grateful to all trial participants, their families, the clinical trial sites and staff, and the broader HD community who have supported the design, initiation and recruitment phases of the study,” Roche global patient partnership directors David West and Mai-Lise Nguyen stated in the letter.

West and Nguyen reassured the community that “tominersen studies are ongoing at clinical trial sites around the world,” and, in collaboration with local health authorities, “ensuring patient safety and data integrity throughout the studies given the ongoing impact of COVID-19.”

On February 27, Roche announced the generic name for its HD gene-silencing drug candidate RG6042, formerly known as IONIS-HTT_Rx, developed by Ionis Pharmaceuticals, Inc. With assistance from Roche, Ionis ran the successful Phase 1/2a trial for the compound, shown to be safe and tolerable in trial participants. It also lowered the amount of mutant huntingtin protein, a major suspect in the disease, in volunteers’ cerebrospinal fluid. (Slide courtesy of Roche.) 

Aiming to analyze data in 2022

“Given the dynamic situation with COVID-19, we decided to close recruitment at 791 participants globally in order to avoid additional pressure on clinical trial sites who were screening potential participants,” they added, noting that the number of participants is “sufficient” to assess tominersen’s efficacy.

Roche is “working closely with the research teams, trial sites and local authorities to reduce any new risks posed by COVID-19 and ensure the trial can continue as long as it is safe to do so,” the letter stated. Roche advises participants to “discuss individual circumstances with their respective study sites.”

“Where patients and families can no longer go into [the] hospital to receive treatment or assessments, research teams will be in close contact over the phone to monitor their health and discuss any potential adverse events or any other issues,” the letter added.

Roche expects to complete the trial and start analyzing data by 2022, after each of the volunteers has completed the 25-month program involving intrathecal (spinal) injections of tominersen or a placebo, tests, medical evaluations, and digital monitoring, West and Nguyen stated.

If tominersen demonstrates efficacy and safety, Roche will submit applications to national health authorities to obtain approval as a treatment.

“During these exceptional times, we continue to consider how we can best support the community and welcome any suggestions,” the letter concluded.

In an April 21 e-mail to me, West noted that GENERATION HD1 recruitment was “completed within expected timelines,” unaffected by the COVID-19 crisis. In line with plans announced last October, Roche will also extend the study to China “as soon as possible,” West added.

Combatting COVID-19

The April 20 statement on GENERATION HD1 followed a general statement by Roche on March 19 discussing the March 11 announcement of the pandemic by the World Health Organization and the company’s efforts to combat it.

“We recognise that the public and private sectors across the globe need to work together to help effectively manage this developing situation,” said the statement, noting that Roche was engaged in developing a COVID-19 “diagnostics test which was granted Emergency Use Authorization by the U.S. Food and Drug Administration.”

Scientists, physicians, and public officials have stated repeatedly that vastly increased testing for the virus is needed in the battle against the pandemic.

Roche also confirmed initiation of COVACTA, a global Phase 3 clinical trial to evaluate the safety and efficacy of its rheumatoid arthritis drug Actemra/RoActemra in treating patients with severe COVID-19 pneumonia. The study started to enroll patients on April 3, with a target of 330 globally, including the U.S., Canada, and Europe.

Roche is also examining other drugs in its portfolio for potential testing to treat COVID-19.

(Click here to read more on Roche’s efforts against the coronavirus.)

A key supplementary trial

The February 27 announcement of the generic name tominersen took place at the 15th Annual Huntington’s Disease Therapeutics Conference, sponsored by CHDI Foundation, Inc., in Palm Springs, CA. (For an overview of the conference, click here.)

Scott Schobel, M.D., M.Sc., Roche’s associate group medical director and medical leader of the GENERATION HD1 effort, introduced the name when presenting the preliminary results of the so-called open label extension study (OLE) study of the compound. For 15 months, Roche continued to give the drug to all of the 46 participants of the successful Ionis trial, completed in December 2017. That same day, Roche posted the slides of Dr. Schobel’s presentation on its website.

The OLE reinforced the findings of the Phase 1/2a trial, which showed tominersen to be safe and tolerable in trial participants. Tominersen also lowered the amount of mutant huntingtin protein, a major suspect in the disease, in volunteers’ cerebrospinal fluid.

Also, when still in progress in early 2019, the OLE led Roche to temporarily halt GENERATION HD1 to redesign it in line with the OLE’s promising early data. 

In the original GENERATION HD1 design, participants would undergo monthly spinal tap (lumbar puncture) procedures over 25 months. One-third of participants would receive tominersen each month and one-third every other month. Another third would get a placebo.

In the updated trial, which resumed in June 2019, Roche decreased lumbar punctures to once every other month over the same period of time. In this revised design, one-third of participants are receiving tominersen every other month and one-third every four months. Another third will receive a placebo every other month. (Click here to read more.)

Less frequent dosing eases the burden on participants, their families, and clinical trial administrators.

The OLE also investigated potential biomarkers (signs of the disease and drug efficacy) for use in GENERATION HD1.

The OLE formed part of Roche’s strategy for skipping the usual Phase 2 trial to test efficacy and entering directly into Phase 3 to confirm efficacy in a larger population (click here to read more).

Scott Schobel, M.D., M.Sc., presenting open label extension study data for tominersen at the 15th Annual HD Therapeutics Conference (photo by Gene Veritas)

The ‘ultimate’ question: efficacy

After his presentation, Dr. Schobel met briefly with HD advocates to discuss his presentation and GENERATION HD1.

For the HD community, the takeaway message was the OLE’s confirmation of a less frequent dosage, and its helpful data for GENERATION HD1. Except for one person who decided to drop out to take a trip around the world, all of the OLE participants had continued taking the drug, putting them now at 20 months of follow-up, he explained.

Roche has great “confidence” in the sufficiency of the less frequent dosing in GENERATION HD1, Dr. Schobel emphasized.

With the OLE, Roche has “been able to learn” and apply it directly to GENERATION HD1 “in a way that we couldn’t have done if did a more traditional drug development path, which we feel great about,” he said.

What remains is the “ultimate” question: will tominersen be an effective treatment?

“We’re well-positioned with GENERATION HD1 to answer that question,” Dr. Schobel concluded.

If the trial is successful, tominersen will become the first treatment to slow, halt, and perhaps even reverse the symptoms of Huntington’s disease. 

(I hope to report soon on other ways in which COVID-19 has impacted the HD community and research.)

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

Roche: less frequent dosing for Phase 3 Huntington’s clinical trial, easing burden on patients

With preliminary data in hand, the pharmaceutical firm Roche has announced that it will reduce the frequency of dosing in its historic Phase 3 Huntington’s disease gene-silencing clinical trial, thus easing the burden on the participants, their families, and clinics.

In the recently initiated trial, GENERATION HD1, volunteers will now undergo a bi-monthly instead of a monthly spinal tap (lumbar puncture), Roche announced in a letter to the HD community on March 21, 2019. Lumbar punctures are routine and generally safe procedures, although they can cause side effects such as headaches and bleeding. In GENERATION HD1 it will be a 20-minute outpatient procedure.

Roche based the change on new data taken from 46 volunteers after nine months into the 15-month, so-called open-label extension trial (OLE) that it started for its drug RG6042. Those individuals previously participated in the successful Phase 1/2a clinical trial of RG6042, originally developed by Ionis Pharmaceuticals, Inc. The drug substantially lowered the amount of mutant huntingtin protein, the purported cause of the disease, in the patients’ cerebrospinal fluid. All OLE participants received the drug (as opposed to 25 percent getting the placebo in the 1/2a trial).

“The 15-month open-label extension of the Phase1/2a study is evaluating RG6042 treatment in doses every month (every four weeks) and every two months (every eight weeks),” the Roche announcement stated. “Review of nine-month data showed effects on lowering mutant huntingtin protein levels in the cerebral spinal fluid that support the exploration of less frequent dosing. Based on the totality of the data, including safety and tolerability, there appears to be no overall advantage to treatment monthly versus every two months.”

GENERATION HD1 has three cohorts of clinical trial volunteers, known as “arms.” The planned 660 participants at 80-90 sites around the world are randomly assigned to one of the arms. The study is double-blinded: neither the volunteers nor the trial physicians and their staff know which arm the volunteers are assigned to.

As a result of the update to the trial, all participants will undergo bi-monthly punctures over 25 months. In “arm 1” of the study, the dosing schedule will switch from a monthly puncture and administering the drug bi-monthly (with a placebo in between) to a bi-monthly puncture with no placebo at all. Arm 3 will go from getting a monthly puncture with placebo to a bi-monthly puncture with placebo. 

To test the possibility of reducing potential future drug dosing even further, arm 2 will go from a monthly puncture with the drug to a bi-monthly puncture but with the drug given only every four months (with a placebo in between).

“I am delighted by today’s news that the Generation HD1 protocol will be amended to be less burdensome to trial participants, families and HD clinics around the globe,” George Yohrling, Ph.D., the senior director of mission and scientific affairs for the Huntington’s Disease Society of America, commented in an e-mail. “We are all indebted to the 46 trailblazing research heroes participating in the Phase 1/2a and open-label extension studies that showed us we could not only lower huntingtin in humans, but could do so without monthly infusions of RG6042. Their contributions have forever changed the landscape of HD drug development.”

“The amended trial is good news for the HD community,” LaVonne Goodman, M.D., the founder of Huntington’s Disease Drug Works and a physician to many HD patents, wrote in an e-mail. “For the shorter term, it will make for fewer visits and spinal taps for all involved in the trial. And for the longer term, if the trial at completion is successful by clinical measures, it may further establish whether quarterly dosing is adequate and effective. If so, that would make it easier on the larger number of patients who would need to receive this drug life-long.”

Simplifying the study

Dr. Goodman added: “It was fortunate that the Roche analysis and amendment came at the very beginning of the GENERATION HD1 trial, so that changes could be made without a major time disruption.”

A statement on the Ionis website observed that the new trial design “will greatly simplify the operation of the study.”

Although amending the trial will cause a “slight delay” as Roche seeks regulatory approvals, “we don’t expect this delay will change the timing of study completion, and may even accelerate time to study completion,” the Ionis statement concluded.

“Our team is working to rapidly activate the updated study protocol around the world,” the Roche statement said.

Individuals who had already started GENERATION HD1, which began in January, will be eligible to switch to GEN-EXTEND, an OLE study in which everybody receives RG6042 (no placebo). Participants will receive drug every two or four months.

Great news for the HD community

As the Roche statement noted, the data from the Phase 1/2a OLE do not address the efficacy and long-term safety of the RG6042. That is the purpose of GENERATION HD1.

The update from Roche came in the wake of remarks by GENERATION HD1 scientific coordinator Scott Schobel, M.D., that the company is “actively thinking” about when and how to expand research to target groups beyond the current criterion of early- to mid-stage HD patients aged 25-65. That includes asymptomatic gene carriers like me and sufferers of juvenile HD (click here to read more).

The scientist-written site HDBuzz described the amended trial design as a “surprise” but also a “good thing.”

“Clearly Roche and their partners didn’t predict that we’d be able to deliver [the drug] only every four months when they started the GENERATION HD1 study,” its article on the Roche statement observed. “The fact that they’ve seen data convincing them that we can get away with it is great news for the future of this program, and for future HD community members receiving treatment.”

HDBuzz further noted that other companies using the Ionis-Roche approach (antisense oligonucleotides) can now “consider using longer intervals between treatments.”

As an HD gene carrier and also a sufferer of chronic back pain, I was relieved to learn that the number of lumbar punctures for a potential drug could be as few as three per year.

The Roche announcement coincided with the news that the U.S.-based biotech firm Biogen and its Japanese partner Eisai had announced that they were halting two phase 3 clinical trials for an Alzheimer’s disease drug because an interim analysis concluded that the compound was unlikely to benefit patients. The drug was given through intravenous infusions.

The results of that trial once again underscored the extreme difficulty of treating neurological disorders and the need to the need to have realistic expectations about RG6042 (click here to read more). Not just Alzheimer’s and Huntington’s, but also Parkinson’s, Lou Gehrig’s, and other neurological disorders lack effective treatments.

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

Roche announces U.S., Canada sites for Phase 3 clinical trial of Huntington’s disease drug

Pharmaceutical firm Roche has announced 26 planned sites in the U.S. and Canada for its historic Phase 3 clinical trial of a gene-silencing drug to slow, halt, or perhaps even reverse the progression of Huntington’s disease.

Called GENERATION HD1, the greatly anticipated trial will test the efficacy of the drug, RG6042. Roche expects to start enrolling volunteers in early 2019.

The announcement comes one year after the successful completion of the Phase 1/2a trial to measure the safety and tolerability of RG6042, developed by Ionis Pharmaceuticals, Inc.

RG6042 dramatically reduced the amount of mutant huntingtin protein in the cerebrospinal fluid (CSF) of trial participants. As a result, Roche took the unusual step of skipping a Phase 2 trial (testing efficacy for the first time) and going directly to a Phase 3 (confirming efficacy in hundreds of participants, or more).

In a statement released December 19 to the Huntington’s Disease Society of America (HDSA) and other patient groups, Roche announced the sites listed below, grouped by province/state.

Canada

Alberta, Edmonton – University of Alberta

British Columbia, Vancouver – University of British Columbia

Ontario, Ottawa – Ottawa Hospital

Ontario, Toronto – Centre for Movement Disorders

Nova Scotia, Halifax – Queen Elizabeth II Health Sciences Centre

Quebec, Montreal – Centre Hospitalier de l’Université de Montréal 

U.S.

Alabama, Birmingham – University of Alabama

Arizona, Phoenix – Barrow Neurological Clinic

California, Davis – University of California, Davis

California, Palo Alto – Stanford University

California, Pasadena – Arcadia Neurology Center

California, San Diego – University of California, San Diego

Colorado, Englewood – Rocky Mountain Movement Disorders Center

District of Columbia, Washington – Georgetown University

Florida, Tampa – University of South Florida

Illinois, Evanston – Northwestern University

Maryland, Baltimore – Johns Hopkins University

Massachusetts, Boston – Beth Israel Deaconess Medical Center

Missouri, St. Louis – Washington University in St. Louis

New York, Amherst – Dent Institute

New York, New York – Columbia University

Pennsylvania, Pittsburgh – University of Pittsburgh Medical Center

Tennessee, Nashville – Vanderbilt University Medical Center

Texas, Houston – University of Texas Health Science Center

Utah, Salt Lake City – University of Utah

Washington, Kirkland – Evergreen Health

Roche plans to announce sites in approximately 13 additional countries in the coming months. It hopes to enroll a global total of 660 volunteers with early HD symptoms at 80 to 90 sites. Each participant will receive the drug or placebo monthly over 25 months through a lumbar puncture (spinal tap), the way into the CSF.

The CSF bathes the brain. Because biopsies of the brain are currently not possible, measuring the effect of the drug in the CSF gives researchers a window onto the effects of the drug.

Moving as ‘quickly as possible’

“It is important to note that these sites are not fully activated nor recruiting yet,” the Roche announcement stated. “We hope to complete the final steps as quickly as possible.”

According to the statement, Roche selected sites based on a variety of factors, including prior experience with HD studies, clinic infrastructure capacity, ability to run the study as quickly and completely as possible, patient population, and geographic location.

The news follows Roche’s announcement last month of 16 sites for the HD Natural History Study, an arm of the RG6042 program to involve 100 observational study volunteers in Canada, Germany, the United Kingdom, and the United States.

The HD Natural History Study will seek to deepen understanding of the natural progression of HD, the role of the mutant huntingtin protein in the disorder, and the assessment of biomarkers (signs of the disease measured in patients) and their efficacy in predicting the effects of the drug. The volunteers will undergo four lumbar punctures to examine their CSF, but receive no drug.

Click here for the full text of Roche’s December 19 statement.

In the U.S. and Canada, HD families can contact Roche/Genentech about the trial at 888-662-6728. Information about the trial is also available at ClinicalTrials.gov.

For additional background on GENERATION HD1, click here.

If effective, RG6042 would be the first treatment to affect the progression of Huntington's.

Stay tuned to this blog for future updates on GENERATION HD1.

Roche announces first sites for key Huntington’s disease observational study

Pharmaceutical firm Roche has identified nine sites in the U.S. and Canada for an observational study that will seek to answer key questions for the company’s upcoming Phase 3 trial of a gene-silencing drug to treat Huntington’s disease.

In a November 7 e-mail to the Huntington’s Disease Society of America (HDSA) and other HD groups, the Swiss-based Roche announced that it plans to carry out its HD Natural History Study, beginning by the end of this year.

The HD Natural History Study is part of Roche’s global development program for the gene-silencing drug, RG6042. The Natural History Study will provide context for GENERATION HD1, the company’s Phase 3 clinical trial of RG6042, which will start enrolling volunteers in early 2019.

The HD Natural History Study will seek to deepen understanding of the natural progression of HD, the role of the mutant huntingtin protein in the disorder, and the assessment of biomarkers (signs of the disease measured in patients) and their efficacy in predicting the effects of the drug.

Initial sites

Roche announced the sites listed below.

Canada

Centre for Movement Disorders, Toronto, ON

University of British Columbia, Vancouver, BC

U.S.

Columbia University, New York, NY

Georgetown University, Washington, D.C.

Hereditary Neurological Disease Center, Wichita, KA

Johns Hopkins University, Baltimore, MD

Rocky Mountain Movement Disorders Center, Englewood, CO

University of California Davis, Sacramento, CA

University of Texas, Houston, TX

“These sites are not fully activated nor recruiting yet, but we hope to complete the final steps as quickly as possible,” wrote Mai-Lise Nguyen, the patient partnership director for the Roche HD team, in the e-mail.

Roche will announce a total of eight additional sites in Germany and the United Kingdom. It hopes to enroll 100 volunteers with early symptomatic (Stage I and II) HD for the 15-month study (preceded by one month of screening). Participants must be between 25 and 65 at the start of the study.

“I am pleased to share that setup has progressed well in all four countries in which the HD Natural History Study is planned,” Nguyen added.

The pivotal Phase 3 trial 

In March, researchers announced the impressive results of the Phase 1/2a trial for RG6042, completed in December 2017 with 46 participants in Canada, Germany, and the United Kingdom. That trial tested primarily safety and tolerability (click here to read more). Those results led Roche to skip the usual Phase 2 trial and go directly to a pivotal Phase 3, named GENERATION HD1.

RG6042 was developed by Ionis Pharmaceuticals, Inc., which partnered with Roche in 2013. Roche now holds the license to the drug.

The GENERATION HD1 trial, to take place at 80 to 90 sites in 15 countries, will test whether RG6042 can slow, halt, and perhaps even reverse HD symptoms in 660 volunteers over 25 months.

Each month, GENERATION HD1 participants will receive the drug or placebo through a lumbar puncture. Physicians will also withdraw samples of participants’ cerebrospinal fluid (CSF) to measure the level of mutant huntingtin and other biomarkers.

Roche will announce GENERATION HD1 sites gradually in the coming months.

Why a natural history study?

Roche officials said that the HD Natural History Study will start by the end of 2018.

Participants in this observational trial will receive no drug. They will undergo four lumbar punctures, with withdrawals of CSF for analysis. They will also undergo MRI scans, blood tests, neurological examinations, and two phone checkups. Like the volunteers in GENERATION HD1, they will use digital monitoring devices.

Researchers have studied both the normal and mutant forms of the huntingtin protein since the late 1990s. However, for GENERATION HD1, Roche needs a deeper understanding of mutant huntingtin’s role in the progression of the disease. Only in recent years have researchers started examining the CSF of HD-affected individuals, so a critical question is how mutant huntingtin levels change over time naturally.

That data will provide context for researchers to interpret the GENERATION HD1 data.

Furthermore, the RG6042 program involves just one Phase 3 trial, but regulatory agencies frequently want a second. Thus, the HD Natural History Study can help with the proper interpretation of Phase 3. Roche is collecting additional data from an “open-label extension” study involving all participants in the Phase 1/2a study. Each is receiving the drug.

 “We’re really trying to understand better the natural history of the disease and the predictive power of the biomarkers at baseline to predict clinical outcome,” commented Scott Schobel, M.D., M.S., Roche clinical science leader of product development, in a September 26 HDSA webinar on the RG6042 program.

Dr. Scott Schobel announces GENERATION HD1 at the European Huntington's Disease Network Meeting in Vienna, Austria, on September 16, 2018 (photo courtesy of HDBuzz.net).

Supporting GENERATION HD1

According to Frank Bennett, Ph.D., Ionis senior vice president of research and franchise leader for neurological programs, the Natural History Study aims to further understand the correlation between mutant huntingtin in the CSF and other clinical measures of HD.

“Several studies have previously described the natural history of the disease,” Dr. Bennett stated in an interview posted on the Ionis site on September 17. “Many, however, have focused on specific clinical outcome measures or changes in brain volume using imaging.”

The HD Natural History Study, he noted, will examine participants from various angles: “This study will provide high-quality, longitudinal data to help inform patients and clinicians about the course of HD, including well-validated clinical measures of HD, novel clinical outcomes, measurement of mutant huntingtin in CSF and the use of wearable devices to measure disease burden. Results from the HD Natural History study will provide valuable information in support of our Phase 3 Generation HD1 study.”

(With another scientist, Dr. Bennett recently received the $3 million Breakthrough Prize in Life Sciences. He also received the 2018 Hereditary Disease Foundation Leslie Gehry Brenner Prize for Innovation in Science.) 

The Natural History Study participants could later have an opportunity to take the drug.

“For all patients who complete the HD Natural History study, an open-label extension study with the option of receiving RG6042 (no placebo control) is planned, pending approval by authorities and ethics committees/institutional review boards and if data support the continued development of RG6042,” Nguyen stated.

An HDSA FAQ

As with GENERATION HD1, Roche will not require participants to live within a certain distance of the study sites. However, a seven-page FAQ on the Roche program posted by HDSA on October 17 states that “the travel burden will likely be considered during the screening” of volunteers.

“A major move or a long-distance commitment could create additional stress on a participant and his/her loved ones,” the document continues. “Excessive travel may also make it more likely for someone to drop out of a trial, which could hamper the success of GENERATION-HD1 or the HD Natural History Study. Clinical studies are subject to international, national and local laws and regulations.

“Additionally, factors such as institutional site policies and health insurance may impact your ability to relocate and be accepted into one of the study sites. Eligibility and enrollment are ultimately decided by the study investigator at each site, who takes into account all these factors and may also wish to speak to you or your local HD specialist for more information.”

The FAQ addresses many of the hundreds of questions posed by the HD community before, during, and after the September 26 webinar (click here to read more). Topics include study eligibility requirements, the potential risks of RG6042, and the procedures, examinations, and other activities of the clinical appointments for both GENERATION HD1 and the Natural History Study.

‘Difficult to predict the outcome’

The imminence of the Natural History Study indicates that Roche is on track to carry out its plan to gradually announce GENERATION HD1 sites in the coming months and enroll the first patients in early 2019.

People can track the progress of the Natural History Study at ClinicalTrials.gov. That site and HDSA’s HDTrialFinder will also provide information on GENERATION HD1.

Regarding the duration of GENERATION HD1 and next steps if the drug works, the HDSA FAQ points out that “it’s very difficult to predict the outcome and timing of a large international drug study.[…] If the results are promising, approvals would need to move through regulatory health authorities.”

For now, the watchwords for the HD community are commitment, patience, and hope.

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