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).

A key new ally in the search for Huntington’s disease treatments

With the new partnership between Roche and Isis Pharmaceuticals, Inc., reported here on April 11, the search for Huntington’s disease treatments has gained an accomplished and ambitious ally in the person of Luca Santarelli, M.D., Ph.D.

Dr. Santarelli, the 44-year-old head of neuroscience and small molecule research at Roche’s world headquarters in Basel, Switzerland, will oversee the Roche-Isis effort to bring Isis’s proposed gene-therapy drug to a long-awaited crucial clinical trial, tentatively scheduled to start in the first half of 2014.

A native of Italy, Dr. Santarelli in the early 2000s made an astounding discovery about Prozac-type antidepressants while conducting postdoctoral research at Columbia University in New York City: these drugs actually led to neurogenesis, the birth of new neurons in the brains of adults.

With these findings, Dr. Santarelli joined Nobel laureate Dr. Eric Kandel, Dr. Rene Hen of Columbia, and Dr. Fred Gage of the Salk Institute for Biological Studies in San Diego to found a company, Brain Cells, Inc., that focused on the development of novel antidepressants for stimulating neurogenesis.

In 2005, Dr. Santarelli joined Roche. He quickly rose in the company ranks and now oversees efforts to design drugs for brain disorders and related conditions, including schizophrenia, depression, Alzheimer’s disease, multiple sclerosis, spinal muscular atrophy, and neurodevelopmental disorders such as autism and Down syndrome.

Nature’s Trojan horses

Now, turning their attention to HD, Santarelli and Roche researchers will collaborate with Isis to speed progress towards the clinical trial, infusing $30 million into the project.

They also will seek ways to make the potential Isis drug easier for trial participants and eventual patients to absorb. Instead of Isis’s potentially riskier and certainly less comfortable method of implanting a quarter-sized port near the rib cage connected to a catheter running to the area of the spinal cord, Roche aims to create a drug that patients could take through an intravenous or subcutaneous (under the skin) injection. (It’s still too early to tell where in the body patients would receive such a potential subcutaneous injection.)

To design this kind of drug, Roche will use a so-called “brain shuttle,” a new approach to transporting drugs past the highly impermeable blood-brain barrier, which protects the brain from foreign objects.

The blood-brain barrier also makes it difficult for so-called large molecule drugs to enter the organ and thus has presented researchers with a major hurdle to treating brain disorders and diseases.

Dr. Santarelli, in a phone interview on April 22, was asked to explain the brain shuttle in everyday terms.

“It works by hijacking a biological system that is normally used to shuttle proteins into the brain,” he told me. “It uses cellular receptors outside the blood brain barrier and uses them as Trojan horses to take in a cargo.”

Dr. Luca Santarelli (photo courtesy of Roche)

The cargo could include an antisense oligonucleotide, or ASO, the specially designed piece of artificial DNA made by Isis that, in mice experiments, has reduced the amount of the harmful huntingtin protein in brain cells and produced a “Huntington’s holiday,” a disappearance of the symptoms.

“A cargo can be an ASO,” Dr. Santarelli continued. “It could also be a peptide or an antibody. Receptors are on the outside (of the blood-brain barrier), but they also move to the inside. They are built by nature to allow certain large molecules (to move in).”

Explaining the concept

No brain shuttle drug yet exists. I was eager to know exactly what kind of shuttle Roche might have in mind and how it could work with the ASOs.

However, because of the trade secrets involved in private drug research, Dr. Santarelli declined to comment.

Nevertheless, he emphasized that the brain shuttles are “built by nature to allow the transfer of large proteins inside the brain.” Different shuttles have different capacities, he added, and they work in a “controlled fashion.”

“The concept of proteins that shuttle large molecules has been known for a while,” he said, referring to the decade-plus research on the phenomenon.

Dr. Santarelli cited the example of the shuttle known as transferrin.

“We know that transferrin works in this way,” he said. “Transferrin is a protein that carries around iron in the bloodstream. Iron doesn’t go around freely. It’s absorbed and transferred around to the organs. It (transferrin) binds with iron – iron gets released into the brain.”

Advantages of the brain shuttle

By carrying an ASO into the brain in this revolutionary manner and avoiding the discomfort of a lumbar (lower-back) puncture or other long-term invasive approach, the brain shuttle approach helps drug discovery in two key ways.

First, it allows researchers to include people in clinical trials who previously were not eligible – namely, people genetically at risk for a disease but without symptoms. In terms of ethics and comfort, it is difficult to justify their participation because of the risk posed by invasive procedures.

With the brain shuttle, however, discomfort is reduced. So is the ethical barrier, because the injury risk diminishes.

Secondly, by including presymptomatic people in drug studies, researchers can measure how a drug affects a patient before the disease develops, thus providing clues about how to stop the disease from ever occurring.

Only a few years ago, this kind of approach to neurological drug research seemed futuristic. The lack of opportunities to participate in clinical trials and the absence of a strategy to prevent the disease in asymptomatic people have proved especially frustrating for the HD community, where people like me await in great fear the onset of a disease foretold by genetics.

A unique Alzheimer’s trial: intervening early

With Isis, Dr. Santarelli and Roche are working to raise the hope of preventing asymptomatic gene carriers from ever experiencing onset.

Roche is especially well-positioned because, as Dr. Santarelli pointed out, it focuses on both drug development and disease diagnostics.

Roche’s “strategic objective” is to intervene “as early as possible” in the course of the disease, he emphasized.

“As an organization, we’ve done this in Alzheimer’s,” he explained.

In developing its proposed Alzheimer’s drug, now under study in a clinical trial involving 800 patients, Roche has taken the unique step of including individuals who have not yet developed dementia, but have merely mild cognitive impairment, Dr. Santarelli said. (Click here for further background.)

In the trial Roche is using molecular testing to diagnose and select trial subjects at risk for Alzheimer’s. This is done by performing a lumbar puncture to obtain a sample of cerebral spinal fluid (CSF) to check the presence of amyloid, the substance that forms plaques in the brain of Alzheimer’s patients and is considered one of the causes of the disease.

If successful, the Roche drug will not only clear plaques from the brains of the Alzheimer’s patients but also delay (or stop) the progression of the disease, Dr. Santarelli said.

The diagnostic technique used in the trial to measure CSF amyloid is experimental and has yet to reach the market, Dr. Santarelli noted.

He stressed that the Roche approach involves both the more traditional clinical (observational) measurement of the patients’ symptoms and, with this new measurement technique, a molecular measurement.

Roche's “culture of combining diagnostics and therapeutics” will definitely provide useful for the development of HD drugs, Dr. Santarelli observed.

A number of other HD research efforts also focus on the search for molecular measurements.

Patient involvement

Because of the highly experimental nature of the brain shuttle and the newness of Roche’s neurological diagnostics, Dr. Santarelli could not forecast when these approaches will bear fruit in HD research.

“We have to go through all the experimentation,” he said of the partnership with Isis.

Whatever the timeline, Roche will depend on collaboration with the HD community, as it has with advocates for other diseases.

“You guys are playing an extremely important role for lowering barriers to making progress in this area,” he said. “I feel personally honored that I can make a contribution in this area.”

Quickening the pace towards a Huntington’s disease gene-silencing clinical trial: pharma giant Roche, Isis enter partnership

With an infusion of $30 million and access to new technology from the Swiss pharmaceutical giant Roche, Carlsbad, CA-based Isis Pharmaceuticals, Inc., hopes to shorten the timetable for a clinical trial of a potential breakthrough drug for Huntington’s disease. It would attack the disease at its genetic roots and could serve as a preventive medicine.

The partnership, announced April 8, puts Isis in a position “to move very aggressively to getting the drug into clinical trials,” Frank Bennett, Ph.D., the Isis senior vice president for research, said in a phone interview. “It should accelerate the program.”

The deal, which could bring Isis up to $362 million in payments for developing and licensing the drug plus royalties on sales should it prove successful, provides a key piece of the puzzle for the company’s HD program. As a dynamic mid-sized company focused on drug discovery but lacking the capital and infrastructure for large-scale clinical trials and drug commercialization, Isis has finally secured the partner necessary for bringing the potential HD drug to market.

“This is the best news,” said Don Cleveland, Ph.D., an Isis collaborator who helped envision the treatment of HD with the company’s gene-silencing antisense oligonucleotides (ASOs). “Running a clinical trial takes substantial dollars. Isis is a smaller company. Roche is one of the world’s largest and most successful pharmaceutical companies.”

The partnership gives Isis the “confidence” necessary to move from the early to later stages of the clinical trials, Dr. Bennett said. Roche, with its long experience in central nervous system drugs such as Valium, in use since the early 1960s, will not be “dropping the ball as a partner,” he added.

Dr. Frank Bennett (photo by Dr. Ed Wild)

                                                                                                                       

In line with earlier projections, Dr. Bennett stated that Isis still hopes to begin the clinical trial during the first half of 2014.

Shuttling drugs into the brain

The ASOs diminish the production of the huntingtin protein by eliminating huntingtin RNA in brain cells, which are destroyed in HD, producing motor, cognitive, and psychiatric difficulties in affected individuals. (Click here to read more about the efforts to design the drug and bring it to trial.)

Isis and Roche will experiment with the latter’s “brain shuttle” technology, which, if successful, would allow greater penetration of the drug into the brain and make it far easier for patients to take.

Isis first aimed to implant a pump in a patient’s abdomen and inject the drug directly into the brain. Then it moved to an injection into the cerebral spinal fluid (CSF) through a quarter-sized port implanted near the rib cage, with a catheter running to the area of the spinal cord.

However, as Dr. Bennett explained, with the brain shuttle technique, patients would simply need a subcutaneous injection (under the skin) similar to the kind taken by diabetes patients.

The brain shuttle would “allow us to use systemic dosing,” Dr. Bennett explained. (Systemic dosing means the drug enters the bloodstream and is thus more available in the body in comparison with an injection into the CSF.)

“It’s much more convenient,” he added. “It’s a better tolerated therapy. It could capture the symptoms earlier, maybe even prevent the development of the disease.”

Glimpsing the Holy Grail?

That convenience also makes it easier to administer the drug to gene-positive asymptomatic individuals, Dr. Bennett noted.

For ethical and scientific reasons, people in this group (including me) have rarely, if ever, participated in HD clinical trials. Basically, scientists haven’t yet figured out how to measure how a drug could benefit this group. In addition, its risk-benefit ratio is higher than it is for people with symptoms. Solving these problems, and thus completely preventing HD (as well as other neurological diseases such as Alzheimer’s), is what I have called the Holy Grail of the research community.

For the first time, the Isis-Roche partnership suggests how the grail might be found. With reduced risks, participation in trials becomes more attractive, and ethical barriers diminish. In addition, the very entry of asymptomatic people into a trial permits the collection of data about efficacy specific to that group.

However, Dr. Bennett cautioned that this approach would most likely be reserved for second-generation clinical trials. Until the initial trials are completed, it’s impossible to venture a guess about the timetable for a second generation.

“As a scientist, you can always make something better, but you have to be careful,” he said of the time needed to develop the brain shuttle for ASOs. “For a patient that’s suffering from the disease, you don’t want to over-engineer and delay getting it to the patient.”

Dr. Cleveland pointed out that the brain shuttle approach is new and has yet to be proven as a way to transport drugs into the brain.

“That’s precisely why you want to have partners like Roche,” he said. “They’ve been delivering things to the central nervous system for a long time. There’s tremendous promise. The challenge will be to bring that promise into real fruition.”

Isis and Roche will conduct joint research to discover whether they can attach the ASO to molecules that naturally shuttle other, necessary molecules into the brain across the blood brain barrier, which shields the brain from foreign substances that might cause harm and prevents the ASOs on their own from entering.

Key details and collaborators

“Huntington’s is a severely debilitating neurodegenerative disease and a large unmet medical need,” Luca Santarelli, Head of Neuroscience and Small Molecules Research at Roche, stated in the press release announcing the partnership. “Treatments are urgently needed, and we believe that the Isis approach in combination with Roche’s brain shuttle represents one of the most advanced programs targeting the cause of HD with the aim of slowing down or halting the progression of this disease.”

Under the deal, the $30 million investment from Roche will underwrite the project through Phase IIA of the three phases of the first-round clinical trial, with Isis retaining control of the project, Dr. Bennett said. If Phase IIA proves successful, Roche would conduct the more extensive Phase III trial, seek regulatory approval for the drug, and market it.

The agreement also stipulates that over time Isis will reimburse the CHDI Foundation, Inc., the multi-million-dollar non-profit virtual biotech firm that funded and advised the HD research at both Isis and Dr. Cleveland’s lab at the Ludwig Institute for Cancer Research at the University of California, San Diego. CHDI will initially receive $1.5 million, with additional reimbursements occurring as Isis receives project milestone payments from Roche. CHDI will continue to advise Isis and Roche on HD research.

“This is an exciting development for the HD community, and a testament to the excellent work that Isis has done to develop their oligonucleotide therapeutic for HD,” said Robi Blumenstein, the president of CHDI Management, Inc., the firm that carries out the goals of the CHDI Foundation. “It's very encouraging that Roche, a pharmaceutical company with a great track record in central nervous system disorders, has now entered into developing treatments for HD. CHDI looks forward to working with both companies to steer this novel approach to the clinic as soon as possible."

Isis, Dr. Cleveland, and CHDI are currently conducting a large experiment to find HD biomarkers (signs of disease) that will enable them to determine the proper dose of the ASO drug and to measure its impact during the clinical trial.

David Corey, Ph.D., of the University of Texas Southwestern also collaborated with Isis on the gene-silencing project.

(Next time: my personal thoughts on the Isis-Roche project as a powerful new sign of hope for the HD community.)