With more Huntington’s disease clinical trials, volunteers need help with comparison shopping

After learning last month that some researchers believe the drug under study in the SIGNAL clinical trial might slow the progression of Huntington's disease, I was excited about the possibility of participating.

SIGNAL is open to asymptomatic carriers of the HD gene like me. I tested positive in 1999, and my mother succumbed to the disease in 2006.

This is a huge decision, so I have been weighing the risks and benefits with my wife and members of the HD community.

After posting an article about SIGNAL on November 1, I started to waver about whether I should take part in the trial of VX15/2503, a monoclonal antibody made by the small Rochester, NY-based biotech company Vaccinex.

I wondered: how safe is the drug? Why hadn’t I heard about SIGNAL before? With the trial based on just one recent paper about a test of the drug in transgenic HD mice, and with other trials typically based on more tests, I wanted to know more about the science behind it.

I contacted a number of people in the HD research community. Privately I received assurances about the safety of VX15/2503 and its potential for alleviating HD – but also recommendations against participation. One obvious major concern is that the compound is non-HD-specific, in contrast with the one currently under study in the historic Isis Pharmaceuticals, Inc., gene-silencing trial.

In a future article, I hope to interview Vaccinex scientists about why they think their compound can help HD patients and presymptomatic individuals like me.

Learning the background of clinical trials and deciding on participation can be challenging. In addition to consulting with physicians and clinical trial administrators, HD people and their families could benefit from better information about clinical trials. In this article I explore these issues and one (albeit partial) solution: the idea of a patient/caregiver advisory council to provide information and advice about HD trials.

No ranking system

Each year, more HD trials take place, each with unique drug mechanisms and participant selection criteria. Each volunteer must ask: which is best for me?

It’s possible that a good drug could be left out of the race because of the increase in the number of trials: the patient pool might be too small to furnish enough volunteers for every trial.

The Huntington’s Disease Society of America (HDSA), the leading patient organization in the U.S., recently launched an online search tool, HDTrialfinder. It’s a “clinical trial matching service” that provides information similar to that found on at Clinicaltrials.gov, but in a somewhat clearer format. It has HD-specific search tools and provides the opportunity to receive updates via email. It lists current HD trials.

However, it does not rank or recommend trials.

“HDSA does not endorse any interventional HD drug studies, but we do encourage individuals to talk with their physicians about the opportunities to participate in all types of clinical research that can help lead to treatments for HD,” said George Yohrling, Ph.D., HDSA’s Director of Medical & Scientific Affairs. “Additionally, we strongly recommend that patients do their own due diligence to better understand exactly what their involvement in a study would mean to them and their families.”

HDBuzz.net, podcasts such as Help4HD’s “The HD View,” and other online sources also provide easy-to-understand information about HD research and HD clinical trials, but don’t offer recommendations or rankings.

Cautions about new experimental drugs

To get a broader understanding of clinical trial planning and HD families’ part in the process, I conducted a 90-minute phone interview with LaVonne Goodman, M.D., on November 16. The founder of Huntington’s Disease Drug Works and physician to many HD patients, Dr. Goodman has provided the HD community with a constructively critical view of the process and its many related issues.

Dr. Goodman began with some general observations about clinical trials and volunteering for them.

“In general, I have problems with giving an experimental drug with unknown risks to individuals who have minor or no symptoms of HD,” she said. “Though it may sound maternalistic, it is my bias that, if you have a clinical trial for this group of people who aren’t very sick at all clinically, then a new experimental drug should not be tried in them first. The risks are unknown, and that’s different than giving the drug to a symptomatic individual who is already sick, because they have more at stake and are willing to take a greater risk.”

LaVonne Goodman, M.D. (photo by Gene Veritas)

Two key questions about trials

“We trust our beloved doctors,” Dr. Goodman continued. “When they do a clinical trial, we may assume incorrectly that they know all the background. But they aren’t given all the (scientific) background.”

Dr. Goodman referred to an article she posted in March about the drug laquinimod, currently under study in a clinical trial sponsored by the Israel-based pharmaceutical firm Teva. (Laquinimod has already undergone testing for multiple sclerosis and shown various benefits for the brain, making it a good compound, with fairly well known risks, for an HD trial.)

In the article, she noted that prominent cancer researcher and author Siddhartha Mukherjee, M.D., Ph.D., has suggested that patients ask two “vital” questions about clinical trials: “Why is the trial being done?[...] What were the data that led to the clinical trial in the first place?”

“This is particularly important as our clinical trials become more complicated, and several are recruiting concurrently,” Dr. Goodman wrote. “This information should be provided to the community in a format that is easily assessable and in language that potential participants can understand for every new trial.”

She warned: “Can sponsors or investigators expect participants to sign up when the rationale for testing the drug isn’t more available?”

A clinical trial rating scale

Dr. Goodman proposed that a rating scale – done with feedback from HD families – could help patients select trials and assure that the most important trials secure enough volunteers.

“I think there are some broad recommendations that could be done with a rating scale,” she said, adding that it could be created with an “independent” group made of patient advocates and representatives from the Huntington Study Group (administrator of SIGNAL and other HD trials), HDSA, and other organizations.

“Patients’ families are not part of the discussion when it comes to HD clinical trials,” Dr. Goodman said. “There are groups like cystic fibrosis and breast cancer where there is precedent for this. I think it would be helpful to our particularly vulnerable community.”

Dr. Goodman believes the establishment of such a council may be a “moral obligation” to HD families.

Indeed, behind the scenes, some HD researchers, advocates, and others in the community have begun discussing the formation of a patient/caregiver advisory council to furnish input to HSG and other groups involved in clinical trials regarding clinical trial design and selection. Such an initiative could include a rating scale.

However, a rating scale must be built in a positive and efficient way that would “not push drug company sponsors away,” Dr. Goodman added.

Dr. Goodman pointed out that drug companies may trial a new drug in HD that was originally developed for another disease.  This is true for drugs in the LEGATO (laquinimod), Amaryllis, and SIGNAL trials.  It remains to be seen whether this is a good approach for HD, she said.

Furthermore, HDSA Centers of Excellence and other HD clinics need greater funding to increase access to care and therefore the number of people potentially interested in clinical trials, she said. At best, just a quarter of individuals with HD are seen by research center neurologists. High costs prevent more HD people from seeing these neurologists, a situation unlikely if the U.S. had a national healthcare system, she noted.

The FDA and momentum for a council

Momentum for patient/caregiver advisory councils for HD and other diseases is building in the wake of the recent and historic set of “patient-focused drug development” hearings held by the U.S. Food and Drug Administration (FDA), including the September 22 meeting on Huntington’s (click here to read more).

In the words of one informed observer, the FDA is “not just doing this for show.” The agency will likely start requiring drug companies to include patients’ perspective in clinical trial design.

Despite its duty to safeguard the public, the FDA itself also does not rate or recommend drugs, although it does carefully examine the outcome of a clinical trial before approving a drug for the market.

Likewise, the FDA is concerned primarily about toxicity when allowing a company to go forward with a Phase I or II clinical trial (when safety is the primary concern). For instance, the agency does not look at whether a drug for HD actually gets into the brain, Dr. Goodman said.

“Their primary objective is to not let something that appears too unsafe get into a clinical trial,” she observed. “They don’t discourage drug companies from testing drugs. On the contrary, they want drugs to be tested.”

Comparing trials

We can imagine the idea of an HD clinical trial rating scale overseen by a patient/caregiver advisory council as giving us the same power people have when doing comparison shopping at sites such as Consumer Reports or CNET.com.

We need information that is succinct but relevant, scientifically rigorous but understandable.

We also need the capability to compare the different trials. For those council members who ask, the trial sponsors could furnish full scientific data.

In effect, the HD community has often acted as its own clinical trial guide.

The decision to participate in a clinical trial is ultimately a personal one best made in consultation with a physician.

Having the additional assistance of a rating scale can facilitate the process and potentially speed the search for effective treatments.

Might I finally take part in a Huntington’s disease clinical trial? An update on the latest research

In the 20 years of my family’s fight against Huntington’s disease – we discovered my mom had HD the day after Christmas of 1995 – I felt this past week for the first time that I might have a chance to avoid its inevitable, mind-destroying symptoms.

On October 26, I learned about a new clinical trial aimed at rescuing brain cells from the degeneration caused by Huntington’s.

Called “SIGNAL” (alternatively, VX15/2503 Treatment for Huntington’s Disease), the trial will include asymptomatic carriers of the HD gene like me who are close to predicted age of onset. Made by the Rochester, NY-based biotech company Vaccinex, VX15/2503 is a monoclonal antibody, a type of molecule essential in molecular biological research.

Monoclonal antibodies are used in various forms by companies such as Vaccinex to treat an increasing number of conditions such as cancer. Vaccinex is also enrolling volunteers in a VX15/2503 trial for multiple sclerosis. Vaccinex believes the very same compound might help alleviate a host of other neurodegenerative diseases.

“The thought is that if we could give this drug early enough we can actually slow the progression of Huntington’s, and that’s really exciting,” said Jody Corey-Bloom, M.D., Ph.D., the director of the Huntington’s Disease Society of America Center of Excellence for Family Services and Research at the University of California, San Diego. She spoke to more than 50 people attending her annual HD research update presentation at the San Diego support group on October 26.

Jody Corey-Bloom, M.D., Ph.D. (photo by Gene Veritas)

Aiming to halt progression, delay onset

Dr. Corey-Bloom, who's provided research updates to the support group since 2005, kicked off this year’s presentation with a review of the historic news on October 19 that HD patients in England had received the first dosing of an Isis Pharmaceuticals drug, ISIS-HTT_Rx, aimed at stopping the disease at its genetic roots. ISIS-HTT_Rx is an antisense oligonucleotide (ASO), an artificial strand of DNA (click here to read more).

SIGNAL, initiated in June, is the “biggest” news on the HD clinical trial field scene since the development of ASOs for use in HD, Dr. Corey-Bloom said. SIGNAL marks the first ever use of a monoclonal antibody in an HD clinical trial, she noted.

“So we’re not just treating motor signs,” she said of SIGNAL. “We’re actually trying to slow the progression. And the reason is that this also belongs to a class of drugs that blocks inflammation in the brain in animal models. And so the hope is that we could either delay the onset or slow the progression.”

VX15/2503 would help HD patients by reducing inflammation in the brain. Scientists primarily from the lab of world-renowned HD expert Michael Hayden, M.D., Ph.D., in collaboration with Vaccinex researchers, published a breakthrough study in April in the journal Neurobiology of Disease demonstrating how the use of a monoclonal antibody restored health in HD mice.

Vaccinex is one of a growing number of biotech and pharmaceutical companies that have delved into the search for HD treatments as research has greatly expanded.

As the scientist-written HD research site HDBuzz noted last February, other investigators are seeking ways to use other antibodies in the quest for treatments.

You can watch Dr. Corey-Bloom’s research update, which includes details on numerous other hopeful projects, in the video below.

Update on Huntington's Disease Research 2015: A Presentation by Dr. Jody Corey-Bloom from Gene Veritas on Vimeo.

Including presymptomatic volunteers

HD clinical trials have rarely included presymptomatic people because of ethical concerns and the inability of science to measure a meaningful effect.

However, SIGNAL includes presymptomatic individuals for several reasons, in part because ways of detecting and interpreting the symptoms have become ever more effective, Dr. Corey-Bloom explained.

“You have to be gene-positive, but you don’t even have to have a diagnosis, because they believe that the drug itself is not going to hurt you,” she said, adding that the current stage of the SIGNAL trial (Phase II) is primarily to confirm its safety. (Later a Phase III would test the drug’s efficacy.)

SIGNAL will evaluate changes in participants’ brains using “very unique, very high-level, high-quality imaging,” she said. “They’re doing very special PET studies, and they’re also doing very special MRI studies, DTI, diffusion tensor imaging, and so just a lot of very, very special techniques that are being orchestrated by the Massachusetts General Hospital and [researcher] Diana Rosas.”

Measuring the effects

One attendee asked specifically how a presymptomatic individual would know whether onset had been delayed.

“I think the imaging data is going to be really compelling,” Dr. Corey-Bloom said, noting that previous research has abundantly demonstrated changes in the brain a decade or more before onset, as well as precise measurements in those changes over time. “I think they’re going to be able to tell that it isn’t declining the way people who aren’t being treated is declining.[…] If you’re in the early stages and stay there, that would be pretty impressive, too.”

Involving 36 volunteers at 13 sites across the country, SIGNAL will deliver VX15/2503 intravenously once per month over twelve months in one group and over 18 months in a second group. Dr. Corey-Bloom, whose Center of Excellence enrolled the first patient in SIGNA, said that each infusion would last about an hour. (Click here for the official details of the trial, which will be administered by the Huntington Study Group [HSG]). The HSG just completed its 2015 meeting, held October 21-24 in Tampa, FL.

Further information about SIGNAL in the San Diego region is available at 858-246-1254.

Confidence, but….

I will call that number very soon to learn more about my eligibility and the risks involved.

I tested positive for HD in 1999, and my mother died of the disorder in 2006 at the age of 68 after a two-decade battle. I’m almost 56, a stage where my mother already had involuntary movements and suffered from cognitive loss.

After attending the HD support group and seeing symptomatic friends, I’m always worried about onset.

Dr. Corey-Bloom’s recap of the good news about the long-awaited Isis clinical trial left  me with a feeling of confidence that someday we will defeat HD – but perhaps not in time to stop my onset. The Isis trial does not include presymptomatic individuals, and, even if successful, it could take five, ten, perhaps even 20 years for the approach to have a significant impact on the disease.

Wishing for a ‘normal’ life

However, after hearing about SIGNAL for the first time, a flood of new emotions began to pour over me.

I immediately felt hope for my friend Sharon Shaffer, my HD sister, and other HD-affected individuals in the audience.

Sharon Shaffer and mother Fran Walker (photo by Gene Veritas)

I awoke at 3:45 the next morning full of energy. Unable to sleep again, I worked on processing the video of Dr. Corey-Bloom’s talk.

“My 20th year attending support group – what a difference!” I wrote in my notes. “Treatments and trials, people asking questions about real scenarios, not just long-off hypotheses. PLUS: I learned of a trial that I can maybe take part in and see symptoms prevented. What if my career can be ‘normal’ and my life ‘normal’?”

I’ve hardly ever had such positive thoughts, although I recognize that I am extremely lucky to have remained asymptomatic this long.

Risks vs. benefits

My wife, who has seen so many of her own plans dashed because of HD, was pleased to hear about SIGNAL.

She hopes every day for a treatment to save me, as well as others, from the devastation she witnessed in my mother.

As I gather more information in the coming weeks, and if I am eligible to participate in SIGNAL, I will weigh risks and benefits with her, my physicians, and members of the HD community.

My immediate concerns: could VX15/2503 cause harmful side effects or even trigger HD? Would participation somehow prevent me from taking part in other trials in the future?

‘Unimaginable scenarios’

Regardless of my participation, I will follow this project with keen interest – as surely will the rest of the HD community.

As with the Isis compound, there is no guarantee VX15/2503 will work.

However, it is yet another shot on goal in the search for effective treatments. The more shots, the better the chance of success.

The HD community can now envision scenarios unimaginable 20 years ago. That's significant progress.