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"

This Thanksgiving, appreciating stable health and new plans for Huntington’s disease advocacy

This Thanksgiving, I am especially grateful for good health – and all that it enables me to enjoy.

At my annual neurology checkup on October 31, the doctor told me that I remain asymptomatic for Huntington’s disease. My more extensive annual Enroll-HD examination earlier in the year also showed no symptoms. 

I tested positive for the HD gene in 1999. Next month, I turn 59. At that age, my mother had already been diagnosed and was rapidly losing the ability to walk, talk, and care for herself. She died in 2006 at the age of 68 after a long struggle.

I never imagined that at this point I could still pursue my passion for writing, teach at the university, and support my family.

As I frequently tell students, colleagues, and my family, “health is first.” Without it, achieving goals and handling responsibilities can become very difficult, if not impossible.

Studying the history of the HD cause

I am putting the final touches on a book in my field of Brazilian history, scheduled to be published next June, From Revolution to Power in Brazil: How Radical Leftists Embraced Capitalism and Struggled with Power. I began the research more than two decades ago, not long after learning of my mother’s HD diagnosis. Seeing the project come to fruition is thrilling and profoundly fulfilling.

With the Brazil project complete, I will carry out my long-gestating plan to shift my main scholarly focus to the history of science, technology, and medicine. Last month I proposed a new, multi-year research project, titled “Racing Against the Genetic Clock: A Social, Scientific, and Personal History of the Huntington’s Disease Movement.”

I aim to study how key facets of the movement intertwined with major developments in the biotechnological and medical revolutions of the past 200 years. I believe that the HD cause can serve as a guidepost for other disease communities and inform key bioethical questions related to them.

I also want to help the HD community reflect on its path through history. 

More than ever, my scholarly work and HD advocacy will meld. (Click here to read more.)

Seeing our daughter enter college

On a personal level, good health allowed me to join my wife Regina last August in helping our HD-free daughter Bianca set up for her first semester at the University of Pennsylvania, where she is studying in its College of Arts and Sciences.

I had always feared that HD would prevent me from experiencing this special moment – just as HD had stopped my mother from interacting with Bianca as a baby and young child.

I am more determined than ever to see Bianca graduate from college and find her way in life. I’m hoping that GENERATION HD1, the historic Roche Phase 3 clinical trial of a gene-silencing HD drug, will result in an effective treatment not only for patients, but as a preventive measure for presymptomatic gene carriers like me. Roche hopes to enroll the first volunteers starting in early 2019.

Looking ahead, I hope to retire on my own timeline – not because of HD.

Regina, Bianca, and Kenneth Serbin (aka Gene Veritas) during Penn Family Weekend, October 21, 2018 (family photo)

The preciousness of life

I’ve been extremely fortunate to reach this point without HD symptoms—or other significant health problems. Many HD brothers and sisters of my generation are struggling with symptoms. 

Like so many in HD families and other difficult situations, I’ve learned to value each moment of life.

Others face different health issues. At this time last year, I lost two wonderful friends about my age, generous supporters of the HD cause, taken quickly and unexpectedly by other conditions. I’ve missed them dearly, and think about them daily as a reminder of the preciousness of life.

Tomorrow, I want to enjoy Thanksgiving.

God and nature willing, I’ll awake the next day ready to love my family, continue the fight to defeat HD, and dream of a day when a cure frees me to assist people less fortunate.

Happy Thanksgiving! And the best of health for you and yours.

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.)

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

Pharmaceutical giant Roche’s September 16 announcement of the 2019 start of its Phase 3 Huntington’s disease clinical trial has raised great expectations about whether this drug could be the first effective treatment for this devastating disorder.

The short answer: it’s still too soon to tell.

During a September 26 Huntington’s Disease Society of America (HDSA) hour-long webinar on the trial, Roche representatives received hundreds of questions via chat from HD community members. They had time to answer only a few, with HDSA pledging to compile and post answers to unanswered questions on its website soon. (Click here to watch the webinar.)

Likewise, in response to my September 16 posting about the Roche announcement, many people in Facebook HD discussion groups have sought further information about the trial.

Roche plans to test the efficacy of RG6042, a gene-silencing drug aimed at slowing, halting, and perhaps even reversing HD symptoms, in 660 volunteers over 25 months. The test will take place at 80 to 90 sites in approximately 15 countries. Each month, participants will receive the drug or placebo through a lumbar puncture. Roche will announce the sites gradually in the coming months.

Roche has named the study GENERATION HD1 (short for Global EvaluatioN of Efficacy and safety of Roche/genentech AnTIsense OligoNucleotide for Huntington’s Disease).

Let me try to address some of the key questions about the trial from the HD community, as well as my own relationship to it as a presymptomatic HD gene carrier.

Scott Schobel, M.D., M.S. (left), Roche clinical science leader of product development, announces GENERATION HD1 at the European Huntington's Disease Network Meeting in Vienna, Austria, on September 16, 2018 (photo courtesy of HDBuzz.net).

‘How do I sign up?’

A frequent question from the community: “How do I sign up for the trial?”

During the webinar, Roche officials stressed that patients should consult with their HD doctors and families about eligibility for the trial, the pros and cons of participation, and logistics such as transportation or relocation to a trial site.

J. P. Sacksteder, of Genentech Advocacy Relations, said that Roche will announce the sites as each becomes ready to enroll patients. (Genentech, a major U.S.-based biotech firm, was acquired by the Swiss-based Roche in 2009. All U.S-based Roche personnel and products still use the name Genentech.)

“We ask for your patience and understanding as we share these trial sites,” Sacksteder said, noting that many factors influence site selection, including experience in conducting HD studies. “We understand that each of your situations is unique, so please continue to discuss your situation with your HD specialist.”

Erik Lundgren, lifecycle leader of the Roche HD program, recognized the great “desire” of HD-affected individuals to take part, but also pointed out the substantial “commitment” required in a rigorous, 25-month clinical research project.

Clinicaltrials.gov and HDTrialfinder.org will provide the latest information on GENERATION HD1.

Roche officials further noted that participants could continue taking most HD-related medications, including anti-depressants as well as drugs to control involuntary movements such as Austedo and Xenazine. Excluded drugs are memantine and riluzole. Participants must start any new regimen of medicines at least three months prior to the trial’s start. Individuals cannot participate in a concurrent trial, but are not barred if they had participated in past HD trials.

For those aged 25-65

Roche will recruit volunteers who are between the ages of 25 and 65 at the start of the trial, explained Scott Schobel, M.D., M.S., Roche clinical science leader of product development. 

Based on statistical studies of the HD population, people in the 25-65 age group have a more predictable progression of symptoms than younger or older groups, Dr. Schobel explained. Focusing on that cohort, he said, will furnish trial researchers with the best, most efficient way to measure whether RG6042 alleviates symptoms.

The later a person’s motor onset, the standard diagnosis of HD, the “potentially less of a progression of symptoms over time,” he added. Motor symptoms involve involuntary movements and imbalance.

Thus, including people over 65 in GENERATION HD1 would be less helpful to researchers trying to gauge the drug’s impact.

Dr. Schobel’s assertion about later motor onset reassured me a bit regarding my own potential disease progression as an HD gene carrier. At my latest HD checkup earlier this year, I had not shown such symptoms. My HD-stricken mother’s onset occurred probably in her late 40s, and by age 58 (my current age) she had full-blown HD. She died at 68.

I hope that the lack of motor symptoms at this stage means that, after my inevitable onset, I, too, will have a lesser progression of symptoms.

Healthy gene carriers excluded

However, I can’t participate in GENERATION HD1, because, at this time, presymptomatic gene carriers are ineligible. My question during the webinar requesting further details about this wasn’t answered.

In general, presymptomatic gene carriers haven’t been invited to participate in most HD clinical trials because it’s hard to measure a drug effect on an apparently healthy person.

There are also safety and ethical concerns in involving healthy individuals in a complex clinical trial like GENERATION HD1 – for example, exposing a healthy person to the potential side effects of the trial. 

Regarding presymptomatic individuals and also the excluded juvenile HD population, Roche stated in its September 16 announcement: “We recognize the critical medical need for a treatment for HD, especially for people living with severe forms like juvenile onset HD. In consultation with HD community experts, our team will explore the potential use of RG6042 in populations beyond manifest [symptomatic] HD once there is sufficient scientific and safety rationale.”

At the September 16 announcement of GENERATION HD1, Dr. Schobel pointed out that the drug might act differently in the still developing brains of children and young people.

The ultimate goal of researchers is to develop a preventive treatment.

Concerns about frequent spinal taps

Even if eligible, I would have to seriously consider the risks of undergoing the lumbar punctures. The punctures, also known as spinal taps, introduce the drug into an individual’s cerebral spinal fluid (CSF) and allow researchers to withdraw some CSF for analysis.

Lumbar punctures are routine and generally safe procedures, although they can cause side effects such as headaches and bleeding. The 46 subjects in the Phase 1/2a trial of RG6042, completed in December 2017, had few side effects. Ed Wild, M.D., Ph.D., who conducts research on the CSF in HD, underwent the procedure as a demonstration for the HD community

Still, I’m personally concerned about the lumbar puncture, which, if a medicine is approved, would likely be the initial pathway for it to be administered.

In 1977, at age 17, I suffered two herniated disks in my lower spine while shoveling heavy snow in my hometown of Mentor, Ohio. Ever since, I have struggled with low back pain.

An MRI (magnetic resonance imaging) scan ten years ago revealed that the disks mainly healed, but I suffer daily with muscular pain, or myofascial pain syndrome. Occasionally, severe flareups prevent me from walking and performing some daily activities.

Since that MRI, I’ve consulted regularly with pain management specialists. I’ve also worked with physical therapists to incorporate other exercises into my morning stretching routine to strengthen my core and back.

Along with daily aerobic exercises, I want to stay strong and flexible to help forestall my inevitable HD onset and, later, to help ameliorate symptoms.

Alternative drug delivery methods?

In 2013, as a participant in the PREDICT-HD (Neurobiological Predictors of Huntington’s Disease)  research project at the University of Iowa, I considered a request to provide a sample of my CSF. 

After reviewing my lower spinal MRI, a doctor at Iowa concluded that a lumbar puncture was too risky.

Also, had I suffered any complications after the procedure, I would have had to obtain medical care not in Iowa, but only after returning to my current hometown of San Diego, where I have health coverage.

I wanted to assist with the research, but ultimately believed that the potential risks outweighed the benefits.

Given these concerns, during the webinar I posed two questions regarding the spinal taps. First, what will Roche due to minimize the impact of the 25 monthly procedures? Secondly, how will Roche address the fact that many people in the U.S. suffer from lower back problems?

I look forward to hearing Roche’s ideas, including the latest research on alternatives to spinal taps such as Roche’s “brain shuttle” technology and/or devices for delivering the drug.

If back pain is part the price for an effective HD treatment, I am willing to endure it.

Timeline and cost

Another major concern of the community: if GENERATION HD1 is successful, when might drug approval come?

“I can’t ultimately commit to what that timeline looks like,” Lundgren said. “We are doing everything we can to speed it up.”

First, Roche must enroll all 660 volunteers. “That’s a big variable,” he said. “We can’t complete the study until 25 months after the last patients receive their first dose.”

Then researchers must organize and analyze the data. If the latter appear promising, then Roche must seek regulatory approval from the U.S. Food and Drug Administration and similar agencies around the world.

According to a September 17 article on the scientist-produced site HDBuzz, “Not every patient enrolls on the first day of the trial, so a trial in which each participant is involved for 25 months will take around twice that long to run, and possibly longer.”

It’s also too early to project the cost of the potential drug, Lundgren said. He added that Roche is committed to providing access to those with inadequate insurance.

Working towards the best treatments

Dr. Schobel addressed concerns about the fact that RG6042, developed by Ionis Pharmaceuticals, Inc., is designed to reduce both the harmful mutant huntingtin protein involved in HD and normal huntingtin, essential in cell function. 

According to Dr. Schobel, the drug’s effect “fundamentally is partial and can reverse and is titratable [adjustable], versus those kinds of experiments that are in the scientific literature, which shut off the gene 100 percent. That is not what we’re doing, for either the mutant protein or the so-called normal or total levels of protein. We have the ability to find a sweet spot potentially where there’s benefit and less risk, or even pause dosing.”

The Roche-Ionis approach differs from the two current Phase 1b/2a clinical trials by Wave Life Sciences, whose drugs target only the harmful protein by using genetic markers present in most but not all people with HD. (Click here to watch a presentation on the trials by Wave’s Michael Panzara, M.D., MPH.) 

These and other clinical trials seek to find the best approach. Scientists have said that a combination of approaches, or an “HD cocktail,” may be needed to treat this complex disease.

(I hold a symbolic amount of Ionis shares.)

This article is dedicated to the many donors and walkers who supported the Serbin Family Team in the 2018 HDSA-San Diego Team Hope Walk, held today. See photos below. Thanks to you, we raised over $4,000 towards the care and cure of HD! You can still donate by clicking here.

The Serbin Family Team of the 2018 Hope Walk: above, from left to right, Lance Ramsey, Adi Drapkin, Alexandra Drapkin, Regina Serbin, Gene Veritas (aka Kenneth P. Serbin), Maria Ramos, Peter Kim, Yuka Kim, and Lily Kim (in stroller). Below, from left to right, Tom Johnson, Yuka Kim, Peter Kim, Lily Kim (in stroller), Judy Melville, Gene Veritas, Patrick Melville, Sean Naficy, and Sam Melville (personal photos).

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

The major drug company Roche expects to start enrolling subjects worldwide (including the U.S.) in early 2019 in its historic Phase 3 clinical trial of RG6042, a gene-silencing drug aimed at slowing, halting, and perhaps even reversing the symptoms of Huntington’s disease.

Roche made the announcement today at the bi-annual plenary meeting of the European Huntington’s Disease Network in Vienna, Austria, and issued a statement to the global HD community providing details (click here for the statement).

Designed by Roche partner Ionis Pharmaceuticals, Inc., and previously known as IONIS-HTT_Rx, RG6042 demonstrated impressive results in the Phase 1/2a trial completed by Ionis in December 2017.

On March 1, at CHDI Foundation's 13th Annual Huntington’s Disease Therapeutics Conference, researchers revealed that RG6042 caused Phase 1/2a trial volunteers to experience a drop of 40 to 60 percent in the harmful mutant huntingtin protein in their cerebral spinal fluid (CSF). According to the researchers, projecting from tests in animals, that corresponds to as much as an 85 percent decrease in the cortex of the brain. However, this trial did not measure actual efficacy – only safety and tolerability. (Click here to read more.)

Scientists have identified mutant huntingtin protein, resulting from a defective huntingtin gene inherited by HD patients and carried by presymptomatic individuals like me, as a principal cause of HD.

Because of the solid Phase 1/2a results, Roche has taken the unusual step of skipping a Phase 2 trial (testing efficacy for the first time) and going directly to a robust Phase 3, where researchers hope to test efficacy in 660 volunteers over 25 months at 80 to 90 sites in approximately 15 countries, to be announced gradually in the coming months. Phase 1/2a involved only 46 individuals, who received the drug over just three months at nine sites in Canada, Germany, and the United Kingdom.

In a detailed interview at the CHDI meeting, Roche officials confirmed that U.S. sites would take part in Phase 3 (click here to read more).  

GENERATION HD1: can it stop or slow HD?

“Following the completion of the Phase I/IIa first-in-human study of RG6042 in December, there are several important questions that still need to be answered before this investigational medicine can potentially be approved by Health Authorities in countries around the world,” said today’s Roche statement, signed by Mai-Lise Nguyen, the patient partnership director for the firm’s HD program.

Roche has named the study GENERATION HD1. 

As outlined by Nguyen, GENERATION HD1 will gauge the effects of reducing mutant huntingtin and whether RG6042 can “slow or stop the progression of HD.” It will also further examine the drug’s safety in a larger group of people over more time.

Members of the Roche HD clinical trial team watch the presentation of the RG6042 Phase 1/2a results at the 13th Annual HD Therapeutics Conference in Palm Springs, CA, March 1, 2018. From left to right, Scott Schobel, M.D., M.S., clinical science leader of product development; Lauren Boak, Ph.D., global development team leader; Erik Lundgren, lifecycle leader of the HD program; and Mai-Lise Nguyen, patient partner director (photo by Gene Veritas).

The trial will also study whether less than a monthly dose, which was used in Phase 1/2a, can prove effective. One third of participants will receive monthly doses of 120 mg, one third a bi-monthly dose of 120 mg, and another third a placebo dose monthly. As in the Phase 1/2a trial, participants will receive the drug via a lumbar puncture (a so-called intrathecal injection). 

To assure objectivity, the study will be “double-blinded” – neither the participants nor the researchers or site staff will know which dosage is administered. To reinforce objectivity, even the bi-monthly recipients (who won’t know they’re in this group) will take part monthly; they'll get the placebo every other month. Site information will be posted on the site www.HDTrialFinder.org.

Today’s statement underscored the “urgency” felt by Roche to conduct GENERATION HD1 but pointed out that not all patients and research clinics will be able to participate. “Please understand the studies are designed to provide Authorities with the required data so that the benefit-risk of RG6042 can be determined as quickly as possible,” it stated.

For now, because Roche needs to demonstrate the efficacy and safety of RG6042, the firm will offer access to the drug only through participation in clinical trials. This means patients cannot make early access (prior to regulatory approval), so-called compassionate use, or “right to try” requests.

At this time, presymptomatic gene carriers and juvenile HD patients are ineligible for GENERATION HD1.

Additional studies

In addition, Roche will conduct a second, 15-month observational study – without a drug – called The HD Natural History Study. Starting towards the end of this year, it will gauge the natural progression of the disease in up to 100 participants with early-stage HD at up to 17 sites in Canada, Germany, the United Kingdom, and the U.S.

By seeking to deepen understanding of the role of the mutant huntingtin protein in HD, the Natural History Study will provide context for GENERATION HD1. Participants will undergo four lumbar punctures, plus MRI scans, blood tests, and neurological examinations. Like the volunteers in GENERATION HD1, they will use digital monitoring devices.

Meanwhile, all 46 participants in the Phase I/IIa study continue to receive RG6042 as part of an “open-label extension” study run by Ionis to assess the safety and tolerability of longer use of the drug. Those who got placebo originally now get the medicine.

Fast-tracking drug evaluation

The EHDN update comes in the wake of an August 2 announcement by Ionis and Roche that RG6042 received “PRIME” (PRIority MEdicine) status from the European Medicines Agency (EMA), a regulatory body similar to the U.S. Food and Drug Administration (FDA).

“We are very pleased that the European Medicines Agency has granted PRIME designation for RG6042, as there is an urgent medical need to find treatment options for families affected by Huntington’s disease,” Sandra Horning, M.D., Roche’s chief medical officer and head of global product development, stated in a press release.

According to the EMA, firms benefitting from PRIME “can expect to be eligible for accelerated assessment” in the drug approval process, reducing the standard timeframe of 210 days to 150 days.

A major step, but not the last

In March, after witnessing the revelation that RG6042 successfully lowered mutant huntingtin protein in the CSF, I wrote: “It’s the best news the HD community has received since the publication of the research confirming the discovery of the gene 25 years ago this month. As scientists have observed, it’s also a major step for disease and drug research in general.”

The August 24 issue of the magazine Science published a balanced article about the Ionis-Roche clinical trials titled “Daring to Hope,” including the struggles of Canadian woman and Phase 1/2a trial and open-label extension participant Michelle Dardengo. She describes some improvements in her symptoms – although doctors caution that her situation is merely anecdotal and not proof of actual drug effectiveness.

Michelle’s 27-year-old son Joel has also tested positive for HD. He was more skeptical about her apparent improvement.

“I do wish for the best,” Joel states in the article. “At the same time, I do prepare for the worst.”

Like all of the HD community, Michelle, Joel, and I must wait for the completion of GENERATION HD1 early in the next decade to see if RG6042 can help save us from HD.

For discussion of the Roche announcement at the EHDN meeting, see the HDBuzz Twitter feed for September 16, 2018.

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