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.”

Feeling the hope

(I dedicate this article to the dozens of people who joined or supported the “Serbin Family Team” on April 14 in the 2013 Team Hope Walk-San Diego of the Huntington’s Disease Society of America, HDSA.)

Lately, I’ve been feeling great hope – even as my genetic clock ticks ominously – that researchers will find an effective treatment for Huntington’s disease and save me from following in the footsteps of my mother, who struggled against this so-called “devil of all diseases” for nearly 20 years before succumbing at age 68 in 2006.

Because the underlying causes of HD are untreatable, I’ve rarely permitted myself to have all-out hope during my 15 years of advocacy and personal fight to avoid the inevitable symptoms. I’ve braced myself for the impact of onset, even as I keep advocating for the cause on full throttle until our community, together with the scientists working overtime for effective treatments, achieves victory.

Hope is a precious commodity to be savored when breakthroughs occur. I’ve saved a couple bottles of Hangtime Pinot Noir, the wine served at the Parker Palm Springs hotel in 2011 at a reception after my first major speech on HD, delivered at the Sixth Annual HD Therapeutics Conference, sponsored by the CHDI Foundation, Inc., in February 2011. I’m keeping at least one to celebrate on the day a treatment is announced.

Big news, a sense of relief – tempered by reality

In recent weeks, the science news and advocacy milestones have left me feeling particularly buoyant.

On April 2, I was thrilled with President Barack Obama’s announcement of the BRAIN (Brain Research through Advancing Innovative Neurotechnologies) initiative, which will spend hundreds of millions of dollars over the next decade to map the mysterious circuitry of the brain. Although HD researchers hope to find treatments before the potential benefits of BRAIN become available in a decade or more, the announcement of the project finally brings brain health and research to a long-overdue prominence in American politics.

The very next day, HDSA held a symposium at the U.S. Senate to mark the 20^th anniversary of the discovery of the HD gene. Dr. Francis Collins, the director of the National Institutes of Health and one of the scientists who helped find the gene, keynoted the meeting, which included presentations by key HD researchers about the prospects for treatments. As I watched the live streaming video of the event, I could feel the sweep of history as I reflected on the scientists’ words and my family’s odyssey with HD, beginning with my mother’s genetic test in 1995 and my own test in 1999.

Just a few days later, on April 8, the Swiss pharmaceutical giant Roche and Carlsbad, CA-based Isis Pharmaceuticals, Inc., announced a multi-million-dollar partnership to bring Isis’s potentially revolutionary HD gene-therapy drug into clinical trials, with a projected start date of the first half of 2014. I have followed the Isis project closely since 2008, visiting the company’s labs, interviewing its scientists, writing detailed articles about the research, and, in speeches to the HD community, citing the project as a great sign of hope.

As I prepared an article on this latest phase of the project, I felt a profound sense of comfort and elation as I pondered how the deal with Roche should accelerate the research, increase the potential for effective results for symptomatic HD people, and, for the very first time, allow scientists to envision ways of preventing presymptomatic people like me from ever developing the disease!

I let out a long sigh of relief – as I do again now in writing these words – and imagined a future without HD for me and the tens of thousands of families around the world devastated by the disorder.

However, since then I’ve tempered my enthusiasm with reality. Although scientists express genuine optimism about developing treatments, only one in ten clinical trials leads to a drug.

As I race against my genetic clock and past my mother’s age of onset, a treatment may not arrive in time to prevent my symptoms.

Nevertheless, the great feeling of hope lingers and brightens my days!

Our generous supporters

In the midst of these events, my wife, my daughter, and I sought fundraisers and walkers for the April 14 Team Hope Walk.

In the wake of my definitive exit from the “HD closet” (in an article in The Chronicle of Higher Education and an interview on the website of my employer, the University of San Diego), nearly 70  friends, colleagues, and other supporters donated more than $16,000 to the “Serbin Family Team” – more than three times our goal. (Overall, local HDSA board members expected the event to net more than $40,000 for the organization.)

Twelve volunteers joined us in the 5K walk at Tidewater Park in Coronado, CA, to help raise awareness about HD.

Members of "Serbin Family Team" at 2013 Hope Walk-San Diego (photo by Vince Margetta)

I felt enormous pride in my family, my friends and supporters, and the HD cause.

Love and humility

I was moved most by donations from individuals and families themselves hit with serious illnesses, all of them with at least a partial genetic basis: breast cancer, colon cancer, young onset Parkinson’s disease, fragile X syndrome, and multiple sclerosis.

My family and I learned of these other families’ struggles, including, in one case, a harrowing decision about genetic testing.

I was deeply moved by this outpouring of generosity and love.

For me, it was also a lesson in humility, a reminder that so many others suffer from disease, an opportunity to become more sensitive to others’ needs, including the need to support other causes.

Above all, the immense display of support for the “Serbin Family Team” stirred in me the same feeling of hope that I experienced in contemplating the Roche-Isis project.

Hope wins out

Sadly, just two days before the walk, I learned of the death of a fellow HD support group member, a 20-year Navy veteran and airline pilot whose career and life were cut short by Huntington’s disease. He was just 65.

“Damned disease finally won,” his mournful wife wrote me in an e-mail.

As on countless occasions in my battle against HD, I had to overcome a sense of hopelessness, which threatened to overpower all of the good feelings about the research and the Hope Walk.

At the Hope event, I hugged our departed friend’s wife. Everybody held a moment of silence for him.

Before setting out on the walk, I guided one of our team members, a ninth-grader with a passion for science and technology, over to the area where employees from walk co-sponsor Vertex Pharmaceuticals were congregating.

I introduced him to Paul Negulescu, the Vertex vice president of research, and mentioned that he aimed to become a researcher.

Paul invited him to visit the Vertex facility and, in the future, perhaps contribute as an intern.

“I want to cure diseases,” the budding scientist told me during the walk.

Our cause had lost a warrior, but the Hope Walk had helped prepare another to do battle.

(Below see other photos from the Hope Walk.)

"Serbin Family Team" members (left to right): friends Sofia, Jessica, Alejandro, and Victoria along with Ken Serbin, with San Diego skyline in background

"Serbin Family Team" members James Kohn (left), Ami Carpenter, and Ken Serbin at finish line

Vertex Vice President of Research Paul Negulescu (left), Ken Serbin, and Vertex Vice President, Biology, Beth Hoffman

"Team Vertex" and friends with San Diego-Coronado Bridge in background

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.)