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.

Roche restarts redesigned Phase 3 Huntington’s disease trial

Three months after announcing it would reduce dosing in its historic Phase 3 Huntington’s disease clinical trial – and pausing for a reset – pharma giant Roche announced on June 20 that it has reopened recruitment for the study, known as GENERATION HD1.

GENERATION HD1 aims to measure whether Roche’s gene-silencing drug, RG6042, will slow, halt, or perhaps even reverse HD symptoms. In late January, Roche announced that it had enrolled the first participant in the trial, which will include a total of 660 volunteers at more than 90 sites in at least 18 countries around the world.

In the original trial design, participants would undergo monthly spinal tap (lumbar puncture) procedures over 25 months. One third of participants would receive RG6042 each month and one third every other month. A third would get a placebo.

However, with new, promising data in hand from an open-label extension (OLE) of the Phase 1/2a trial, on March 21 Roche announced that it would decrease lumbar punctures to once every other month over the same period of time (click here to read more). In this revised design, one third of participants will receive RG6042 every other month and one third every four months. One third will receive a placebo every other month.

The change in dosing required Roche to stop the trial to obtain updated approval from regulatory agencies in the respective countries where the program is operating. Recruitment had to start from scratch, with all new volunteers. Roche completed the necessary details for resuming the trial in just a few months, as it had hoped.

“In March we announced our plan to amend the dosing frequency and study design, which will make study participation less demanding for patients, their families and HD centers,” Mai-Lise Nguyen, Roche’s HD patient partnership director, wrote to the HD community in a June 20 e-mail update on the trial. “Since then, our team has been working to implement study changes and obtain approvals from clinical trial review boards and authorities around the world. Today I am pleased to share that we have reopened the study for recruitment of new patients.”

Mai-Lise Nguyen (photo by Gene Veritas)

Initial authorizations received

With the lumbar punctures, GENERATION HD1 clinicians introduce RG6042 into the cerebrospinal fluid (CSF), which circulates along the spine and bathes the brain. The researchers hope that the drug will penetrate the brain sufficiently and, as a result, stop progression of HD. 

Lumbar punctures are routine and generally safe procedures, although they can sometimes cause side effects such as headaches and bleeding. In GENERATION HD1, the dosing will be a 20-minute outpatient procedure.

Roche changed the dosing based on new data taken from the OLE of the Phase 1/2a clinical trial of RG6042. Phase 1/2a was run by Ionis Pharmaceuticals, Inc., the original developer of the drug. Involving 46 volunteers in Canada, Germany, and the United Kingdom, that trial ended successfully in December 2017: the drug substantially lowered the amount of mutant huntingtin protein, the purported cause of the disease, in the patients’ CSF, which could be an indication of what’s happening in the brain – again, something to be studied in Phase 3.

All 46 participants took part in the 15-month OLE, which is run in support of the overall RG6042 research program. Nine months into the OLE, Roche had data indicating that it could reduce dosing in the larger Phase 3 study. Whereas 25 percent of the Phase 1/2a volunteers got a placebo, all 46 received the drug in the OLE.

“Initial clinical trial authorizations to start the amended GENERATION HD1 study have been received, and we expect to receive the remaining approvals soon,” Nguyen stated. “Recruitment timing will be different at each participating HD clinic/center, because the protocol amendment must be fully approved and in place at each study site before local recruitment may open. Our team is working to rapidly activate the updated study protocol at each site.”

An updated country list

Nguyen provided an updated list of countries currently hosting the GENERATION HD1 sites: Argentina, Australia, Austria, Canada, Chile, Denmark, France, Germany, Italy, Japan, The Netherlands, New Zealand, Poland, Russia, Spain, Switzerland, United Kingdom, and the United States.

Roche recommends that those interested in participating contact their local HD specialists. Individual site information will also be posted at ClinicalTrials.gov and ForPatients.Roche.com.

Individuals who had already started GENERATION HD1 before the announcement of the changes in dosing will be eligible to switch to GEN-EXTEND, an OLE study in which everybody receives RG6042 (no placebo).

Publication of the first data

The resumption of GENERATION HD1 comes in the wake of the first official publication of Phase 1/2a data. That article underscores the impressive results of the trial but also the need for careful study of RG6042 in Phase 3.

Co-authored by 22 scientists, including leaders of the Roche and Ionis HD teams, the article “Targeting Huntingtin Expression in Patients with Huntington’s Disease” appeared in the online edition of The New England Journal of Medicine (NEJM) on May 6 and in print on June 13.

The article confirmed that Phase 1/2a met its primary goal of demonstrating no serious adverse effects of RG6042.

The article also provided details demonstrating the extent to which RG6042 reduced the mutant protein in the CSF. However, it added that researchers still do not yet know whether that reduction in the CSF corresponds to a reduction in the human brain.

A ‘big leap forward,’ but with a critical need for Phase 3

The NEJM article also revealed that two tests showed results that could prove worrisome: temporary increases in the size of the ventricles (fluid-filled spaces) of the brain and in a biomarker (sign of disease) known as neurofilament light.

“Getting to the bottom of these potentially concerning lab tests requires a larger group of people, followed for a longer time,” commented HD researcher Jeff Carroll, Ph.D., in a May 7 HDBuzz.net article. 

In Huntington’s, the ventricles “appear to grow, as the [brain] tissue around them shrinks,” Dr. Carroll explained. This is “the opposite effect one would hope for if the drug was slowing brain shrinkage,” he added.

Regarding neurofilament light, Dr. Carroll observed that “this marker is released by sick and damaged brain cells called neurons, and researchers have previously demonstrated that it increases slowly and predictably in HD mutation carriers.”

The need to understand these test results is “exactly why Roche and Ionis are conducting a new, larger, study called the GENERATION-HD1 study,” Dr. Carroll continued.

Dr. Carroll concluded that “the now published results of the first study with a drug targeting the root cause of HD are a big leap forward for the community. They point towards refinements and cautions we should consider as we test the drug in larger groups of HD patients over a longer time.”

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

Click on the links below for previous articles on RG6042.

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

"Roche ramps up Huntington's disease clinical trial for early- to mid-stage patients, considers ways to expand research"

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

"Roche announces first sites for key Huntington's disease observational study"

"Unpacking GENERATION HD1, the Roche Phase 3 Huntington's disease clinical trial"

"Roche Phase 3 clinical trial for Huntington's disease gene-silencing drug to enroll volunteers in early 2019" 

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

"Roche gears up for pivotal Phase 3 Huntington's disease gene-silencing clinical trial"

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

"Ionis scientists provide initial assessment of successful Phase 1/2a Huntington's disease trial and discuss next steps"

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

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.)

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

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

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

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

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

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

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

Roche to buy Spark

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

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

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

Exciting announcements about other trials

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

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

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

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

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

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

FDA delays Wave trials

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

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

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

Realistic expectations

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

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

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

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

An end to the ‘wait and see’?

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

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

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

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

Dr. Corey-Bloom ended on a positive note.

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

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

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

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

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.)