Tuesday, March 24, 2015

The precious participation of the Huntington’s disease community in the quest for treatments: a report on the 2015 HD Therapeutics Conference

As long-awaited clinical trials of new drug candidates for Huntington’s disease get underway, scientists have intensified collecting information from research study participants to quickly and accurately test the effectiveness of the potential remedies.

This was a major theme of the 10th Annual HD Therapeutics Conference, held February 23-26 at the Parker Palm Springs hotel in Palm Springs, CA. (Click here to read my initial report on science and solidarity, filed during the conference.)

The event was sponsored by CHDI Foundation, Inc., a nonprofit, virtual biotech focused solely on developing HD treatments and the largest source of private HD research funding. Backed by wealthy donors, CHDI has an annual budget of about $100 million.

“The thing that I’m keying on is what I would call human data,” Robert Pacifici, Ph.D., CHDI’s chief scientific officer, told me in an interview on February 26. “Obviously when we do drug discovery we think about a variety of model systems – everything from worms to flies to zebrafish to sheep and songbirds and everything in between.

“But we both know that the only organism that actually has Huntington’s disease unfortunately is the human. So for a long time I’ve been saying that there’s nothing more precious and valuable to a drug hunter than an observation that’s actually made in the population that they seek to treat, in our case Huntington’s patients.

Dr. Pacifici recalled how genetic data from hundreds of people from dozens of families led to the discovery of the huntingtin gene in 1993. Thanks to those efforts, treatments aimed at lowering the amount of mutant huntingtin RNA and protein in the brain cells of HD patients are on the verge of entering clinical trials, he added.

“Now what we’re asking for is to really start getting more specific about the observations [in humans] that we want to make and how we’re going to leverage them,” Dr. Pacifici explained.

You can watch my interview with Dr. Pacific in the video below.


Key role of modifier genes

Dr. Pacifici cited two major examples of new human data revealed at the conference that will a have profound impact on the quest for treatments.

“We’re literally at the precipice of identifying what are modifier genes,” he said, referring to the research presented by Jong-Min Lee, Ph.D., of Massachusetts General Hospital. “It’s just incredibly exciting to me.”

An abnormally expanded huntingtin gene is the principal cause of HD, but other so-called modifier genes also help determine the age of disease onset.

“Why is it that one person’s Huntington’s starts earlier than another?” Dr. Pacifici asked. “That’s tragic.” More positively, it also means the other person’s onset starts later. “Well, that’s exactly what we want a drug to do.”

Human data has played a major role, he pointed out. With thousands of HD-affected people participating, researchers have been able to examine their genetic composition, involving not just their Huntington’s gene, “but their entire genome, to do what’s called a Genome Wide Association Study, or GWAS, and figure out what it is that’s different about individuals that causes one person’s Huntington’s to start earlier than another,” Dr. Pacifici explained.

In his presentation titled “Medication of Huntington’s disease by genetic variations,” Dr. Lee reported how the large research team seeking modifier genes has narrowed its search to chromosomes 3, 8, and 15. (Located in all of a human’s cells, the 46 chromosomes are long, twined strands of DNA containing a person’s entire genetic heritage.) According to Dr. Lee, chromosome 15 has both a “bad” and “good” modifier, with a six-year difference in onset between individuals having one versus the other.

“If we can identify that [good] gene and figure out how it’s doing that, then what we have is a very specific set of instructions for drug hunters to make a compound that does that same thing,” Dr. Pacifici said.




Jong-Min Lee, Ph.D. (photo by Gene Veritas)

Cheating a little bit with biomarkers

The second example involves cerebrospinal fluid (CSF), the liquid that bathes the brain and circulates up and down the spine. Researchers have been searching for HD-related biomarkers in samples of CSF taken from volunteers afflicted with the disease as well as so-called premanifest people, individuals who (like me) carry the gene but have yet to show classic, easily notable symptoms such as involuntary movements (chorea and other types).

Dr. Pacifici defined biomarkers as “a way of cheating a little bit” to get signals without waiting for the more time-consuming and more expensive later phases of a clinical trial.

The human brain can only be studied directly only after a person has died, as pointed out in a talk on CSF by Ed Wild, M.D., Ph.D., of the University College of London. Imaging methods such as MRI are helpful but very limited. So scientists are putting ever greater emphasis on finding signals in the CSF such as mutant huntingtin protein and other biomarkers.

CSF provides a “snapshot of what’s going on in the human brain,” Dr. Pacifici observed, adding that it might indicate in a clinical trial whether a huntingtin-lowering drug is having the desired effect.

Clinical trial administrators would still need to wait many months to get meaningful observations about actual effects on symptoms, but seeing what the drug does at the molecular level is a key first step.

“In other words, we don’t want to give the drug [. . .] and hope that after three years of waiting that we’re going to have an effect,” he said. “We want to know right away that that drug was doing the job that it was charged to do, in this case lowering huntingtin levels.”

A CSF study

Describing the analysis of CSF from HD patients in a research study of twelve individuals that he helped direct, Dr. Wild observed that the closer a premanifest individual was to probable onset, the higher the level of mutant huntingtin found in the CSF. Similarly, among affected individuals higher levels of the mutant protein correlated with worse symptoms.

Dr. Wild and other scientists are still striving to determine the specific origin of the mutant huntingtin found in the CSF. At this point they hypothesize that it comes from neurons, a specific type of brain cell.

Scientists aim to improve CSF collection efforts and obtain a clearer understanding of what occurs in the CSF through a new, CHDI-funded project called HDClarity. The initial research sites are at University College of London, the University of British Columbia, and the University of Ulm, Germany.

You can watch Dr. Wild’s presentation in the video below.


The rise of clinical trials

The need for clinical trial volunteers will increase dramatically as the number of trials grows rapidly.

With a total of nine active trials, 2014 had an “unprecedented amount of activity in clinical trials in Huntington’s disease,” Ray Dorsey, M.D., a professor of medicine at the University of Rochester and the president of the Huntington Study Group, stated in an overview of recent HD trials.

These trials included the two largest-ever regarding HD: a study of coenzyme Q10 with 609 participants and a study of creatine with 553 participants. Both were halted because of lack of efficacy, but helped scientists understand the need for better evaluation of substances before taking them into a trial, Dr. Dorsey noted.

Last year brought one of the few successes in HD clinical trial history: the highly favorable results of Auspex Pharmaceuticals’ testing of its compound SD-809, which reduces chorea substantially and with fewer and milder side effects than its predecessor drug, tetrabenazine.

Presenting a chart of clinical trial trends, Dr. Dorsey demonstrated that the number of HD trials is growing exponentially: from four trials in 1999-2002 to 28 trials in the period 2011-2014.

“I think we’re poised for success,” he concluded.


10th Annual HD Therapeutics Conference participants watch a presentation (photo by Gene Veritas)

Assessing the potential of gene-silencing

In reviewing the clinical trial outlook for 2015, CHDI’s consulting medical director, Bernhard Landwehrmeyer, M.D., Ph.D., noted the continued upward trend, with six active trials.

Dr. Landwehrmeyer described the plans for a Phase I gene-silencing clinical trial by Isis Pharmaceuticals, Inc., and Roche. This approach seeks to attack the causes of the disease at its roots (click here to read more).

Isis’s senior vice president for research, Frank Bennett, Ph.D., stated in his conference presentation that the trial would begin by the end of the second quarter, but Dr. Landwehrmeyer predicted it would start later in the year. It is only the very first step in gene-silencing treatments for HD, he stressed.

Nevertheless, he observed that many other companies and labs are working on their own versions of gene-silencing treatments for HD. The chart he displayed showed 14 other entities in addition to Roche and Isis.

“It’s important that we have such a rich toolbox in attempts to make gene-silencing a therapeutic reality,” Dr. Landwehrmeyer said.

He noted that the Isis/Roche trial is unusual because it must include symptomatic patients, who will receive the gene-silencing drug via a spinal tap. Typically a Phase I trial accepts only healthy volunteers because it is testing for safety and tolerability, not for efficacy.

The trial will take place at HD centers in England, Canada, and Germany that have in-patient intensive care monitoring facilities, he noted.

Dr. Landwehrmeyer said it was important to set realistic expectations for the HD community, which anxiously awaits good news about gene-silencing because of its potential to significantly impact the disease.

“You are NOT missing the boat, if you do not participate in the Isis study,” he said, referring to HD-affected individuals. Establishing safe and effective gene-silencing therapies for HD will still take “decades.

Once trials prove them to be safe and effective, these drugs can reach the market and become available to all HD families.


Bernhard Landwehrmeyer, M.D., Ph.D. (photo by Gene Veritas)

Big challenges remain

Dr. Landwehrmeyer also commented on the other trials taking place this year: Pride-HD (to test pridopidine); APACHE and Amaryllis (to test “Viagra for the brain”); LEGATO-HD (to test laquinimod); and a forthcoming trial in deep brain stimulation.

In all, he noted, at least 1,500 HD patients are expected to take part in clinical trials this year.

“That’s on the one hand fantastic,” he said. “But timely recruitment into these studies has become an issue.”

Some HD study centers are underutilized, while others are overloaded, he noted. The number of trial participants is further restricted by inclusion/exclusion criteria (for example, the particular disease stage of the patient). Pharmaceutical companies should enhance a “culture of cooperation” regarding trials, he said, and regional and national patient advocacy organizations need to activate their networks.

Enroll-HD, the global platform, research project, and family registry aimed at facilitating clinical trials and the discovery of treatments, recently reached a milestone with its 5,000th registrant, but needs to grow to as many as 30,000, Dr. Landwehrmeyer observed.

Hoping for an end to conferences and HD

The 10th Annual HD Therapeutics Conference had numerous other compelling presentations on the search for treatments. Click here to visit my video album, where you can view many of the presentations.

The conference also featured some 90 posters detailing cutting-edge HD research projects.


Conference attendees view posters of Huntington's disease research projects (photo by Gene Veritas)

“Obviously we’re a time-motivated organization, and we know patients are waiting,” Dr. Pacifici said. “So the fact that it’s taken us ten years to get to this stage is not necessarily something to celebrate. That said, I think we should pay homage to the progress that’s been made over that period of time.”

Dr. Pacifici observed that with well-designed clinical trials, “it’s really an exciting time” in the quest for treatments.

He said that he was struck by the courage and collaborative spirit of the community, from academia to the private sector to the families. He also thanked HD families and their supporters for their participation in research studies, clinical trials, and other activities.

“This isn’t a competition,” he declared. “This is an opportunity for all of us to enable each other, which I don’t take for granted, because one of the potential downsides of getting to the endgame – which we are – is that’s when people start to be a little more secretive and a little bit more protective. We saw here time and again even multinational pharmaceutical and biotech companies standing up at our conference and presenting new, unpublished findings so that everybody could benefit from them.”

Along the way, failures will occur, because drug discovery is a very inefficient process, he emphasized. (Only one in ten clinical trials results in a marketable drug.)

“That’s frustrating,” he recognized. “Don’t be disheartened. Know that we have a large and deep portfolio [and] that we’re going to learn from each one of these failures. I think, and I have every confidence, that we’re going to start getting real positive signals that then we can build on. And that’s when the fun starts.

I hope we’re sitting here together again next year for the eleventh conference, but I also hope we’re not sitting down here for too many more. And I mean that in a positive way.”

* * *

For additional coverage of the conference, visit HDBuzz.net.

(Disclosure: I hold a small number of shares of stock in Isis Pharmaceuticals, Inc.)

Thursday, February 26, 2015

‘None of us are free until we are all free’: science and solidarity at the 10th Annual Huntington’s Disease Therapeutics Conference


Riding the emotion of a keynote speech by a young scientist at risk for Huntington’s disease, and seeking treatments with the immense help of a non-profit foundation, the participants at a historic research conference this week witnessed the fusion of science and human solidarity ultimately necessary for defeating HD.

On the evening of February 23, I and the approximately 300 attendees at the 10th Annual HD Therapeutics Conference, sponsored by the CHDI Foundation, Inc., listened as Jeff Carroll, Ph.D., recounted his mother’s demise from HD, his positive test for the HD genetic mutation, and his decision to pursue a career in science to save himself and others from HD.

“He’s an interesting combination of things in terms of being an advocate in the community, in terms of being someone from an HD family, in terms of being a top-flight researcher in the HD community, in terms of being a great communicator – he and his partner Ed Wild – in establishing HDBuzz, which is just a tremendously useful model of how to communicate results out to the rest of the community,” Robert Pacifici, Ph.D., CHDI’s chief scientific officer, said in introducing Dr. Carroll at the conference in Palm Springs, CA.

As an HD researcher-advocate who has attended all ten therapeutics conferences since 2006, Dr. Carroll offered a uniquely qualified, candid assessment of the progress towards treatments and CHDI’s role in the process.

“Every year, I come home revitalized and energized by the site of so many smart people working so hard on this problem,” Dr. Carroll, 37, told the audience in the main ballroom at the Parker Palm Springs hotel. He expressed his profound gratitude to CHDI, which has funded his and numerous other scientists’ research.

Painful progress toward success

However, success depends on the “efficient and timely completion of well-designed Phase III trials with HD drugs,” Dr. Carroll continued.

“A few weeks ago I attended a meeting at the Princeton CHDI office that included attendees from major pharmaceutical companies currently running HD clinical trials,” he said. “They are deeply concerned about something that would never have occurred to me to worry about, which is poor recruitment for trials of Huntington’s disease drugs.

“On reflection, it makes sense that the HD community may be wary of the way we have been speaking to them. Participating in the first clinical trial of a new molecule might be exciting, but participants of the third could be excused for having some questions.”

Trial administrators put participants through a daunting number of tests, he observed, which may discourage people from participating in more than one trial. Because trials are extremely expensive, sponsors often try to maximize the findings in Phase II, but not enough trials are reaching Phase III, he added.

“It must be said the scale of what is possible here must be unique in human history,” Dr. Carroll said of the efforts by CHDI, which has put more than $700 million towards treatments. “Resources on the scale being deployed by CHDI have been spent on common diseases, but never before have they been spent on such a focused attempt to ameliorate a rare disease.”

The HD community will achieve “something never done before” or “fail majestically,” he quipped with irony.

He added: “We might actually be watching the painful progress toward success.”

You can watch Dr. Carroll’s speech in the video below.


Our brothers and sisters

After Dr. Carroll and his wife Meghan had HD-free twins, thanks to preimplantation genetic diagnosis (PGD), he believed that “HD is done killing people in my family until I am gone,” he recalled.

However, recently two at-risk babies were born in his extended family.

“For a brief window, my family was the last that had to face this awful threat,” Dr. Carroll said. “But the arrival of these children has reminded me that none of us are free until we are all free.”

We must “raise up those of our brothers and sisters still suffering,” he concluded.

Like me, Dr. Carroll is racing against the genetic clock.

Crying for our community

This conference, my fifth, has proved especially poignant for me personally – even more so than the 2011 meeting, which I keynoted. In terms of the quest for HD treatments, it has been a landmark event. (My next article will provide an overview of the conference’s scientific aspects.)

I was both deeply saddened and heartened by Dr. Carroll’s story. I relived my own mother’s death from HD in 2006, my positive test for the gene in 1999, and my daughter’s negative test for HD in the womb (PGD was unavailable) in 2000.

It was one of the best speeches I have heard in two decades of observing the HD movement. Dr. Carroll tempered his enthusiasm and compassion for the HD community with hard-nosed, no-nonsense scientific analysis.

For the evening of February 25, the conference organizers arranged for a surprise outdoor screening of the 28-minute documentary The Lion’s Mouth Opens, about actress, director, and producer Marianna Palka’s positive test for HD. The film made the 2015 Academy Awards shortlist for Best Documentary Short.

As part of the surprise, Marianna, whom I had met earlier in the day, took questions from the audience. She appeared at the edge of the crowd, next to me, just as the film was ending.


Gene Veritas (left, aka Kenneth P. Serbin), Marianna Palka, and Louise Vetter, CEO of the Huntington's Disease Society of America (photo by Jerry Turner, CHDI)

It was a highly emotional experience for me. Filled with anger, frustration, and overwhelming sadness that a young person like Marianna should have to face HD, and once again reliving the trauma of my own HD test and the excruciating experience of testing our daughter, I hugged Marianna and cried uncontrollably for several minutes as she held and consoled me.

It’s so unjust that people have to face HD, I thought to myself.

I hardly ever let myself think that, trying to be strong, but at that moment I allowed myself to do so, and also to let loose all of the powerful emotions of the conference.

I told Marianna I was so sorry for her.

Marianna, who is just 33, was strong, telling me that we would all work together against HD.

After the film finished, Marianna talked with the audience about her experience of genetic testing, her strategies for staying healthy, and her work in film. She observed that The Lion’s Mouth Opens makes men cry.

You can watch Marianna’s exchange with the audience in the video below.


Enrolling families in the fight

At the start of the conference, I had lunched with Joe Giuliano, the CHDI director of clinical operations in Princeton, N.J., HD advocate Jimmy Pollard, and Chris Brown, a scientist from Evotec, a drug discovery company headquartered in Germany.

We pondered the same critical issue raised by Dr. Carroll, and that brave advocates like Marianna impel us to consider: how to inspire more families in the HD community to become involved in research studies and clinical trials.

I recalled my own speeches and blog articles about the terrible barriers to greater involvement: ignorance, fear, denial, stigma, and family tensions.

Giuliano is also the chief CHDI administrator for the Enroll-HD program, a global platform, research project, and HD patient and family registry aimed at facilitating clinical trials and the discovery of treatments. As Giulano and others have noted, it is not scientists who cure diseases, but the patients who participate in clinical trials.

That observation provides a fitting coda to Dr. Carroll’s speech.

And it underscores the absolute necessity to fuse science and solidarity in the fight against not just HD, but all diseases.

For an update on Enroll-HD, watch my interview with Giuliano below.


A personal landmark, and gratitude

With this article I have completed my own HD milestone: it is the 200th post in this blog.

I am grateful to so many: God, my wife and daughter, my HD-victimized mother Carol Serbin, my HD-warrior father Paul Serbin, who died with a broken heart in 2009, CHDI, and the entire HD community.

Although I worry that my overly emotional response to the conference could signal the mood swings characteristic of early HD onset, I am also grateful that I remain, according to my last neurological checkup, asymptomatic.

As I prepared to depart the conference, I pondered how the HD movement can reinforce human solidarity and our bond with the researchers.

Monday, February 23, 2015

‘Darkness replaced by hope and light’: taking stock of Huntington’s disease research

As the Huntington’s disease community in 2015 enters a promising phase of clinical trials for remedies that might slow or halt the progression of the disease, one of the world’s leading HD scientists recently took stock of the significant progress made over the past several decades.

“The horizons for therapy were very far away,” Michael Hayden, M.D., Ph.D., the President of Global Research and Development and Chief Scientific Officer of Israel-based Teva Pharmaceuticals, said during a February 10, 2015, presentation about his company’s latest efforts to defeat HD.

Dr. Hayden recalled how, 40 years ago, HD was virtually unknown in his native South Africa and many other countries. HD-afflicted people faced stigma and were left to cope with their disease “in isolation and despair,” Dr. Hayden remembered of his first contact with the disease as a young medical student.

“It was just a dream then that there would be pharmaceutical companies interested in Huntington disease,” he said. (In some countries HD is referred to as “Huntington,” not “Huntington’s.”)

However, as Teva and other companies work towards HD treatments, the outlook has changed dramatically.

“We are now in a place of really tremendous hope,” Dr. Hayden declared enthusiastically. “The darkness is replaced by hope and light. At the end of the tunnel we are seeing this light now, not only with this [Teva’s] drug but other trials you are hearing about.”


Dr. Michael Hayden (photo by Gene Veritas)

Reexamining a promising drug candidate

Dr. Hayden offered these remarks during a Huntington’s Disease Society of America (HDSA) research webinar titled “Pride-HD: a dose finding, safety and efficacy study of pridopidine in HD patients.” (Click here to watch the webinar.)

Pridopidine was first tested in two clinical trials – in Europe and North America – by the Danish pharmaceutical company Neurosearch. The company, although it observed some interesting effects, did not achieve sufficiently positive results to bring the drug to market.

That’s because the chosen “endpoint” in the study, the way of measuring the drug’s effects, didn’t show a result significant enough for obtaining regulatory approval, Dr. Hayden explained. Neurosearch chose only a subset of motor symptoms as the study endpoint.

But some researchers still believed pridopidine had potential as an HD drug. Dr. Hayden and Teva studied the overall impact of pridopidine and, after obtaining the license for the drug from Neurosearch, have decided to run an additional clinical trial, called Pride-HD (Pridopidine Dose Escalation in HD). Teva is using a different endpoint, the so-called total motor score, a measurement of all the motor symptoms.

Dr. Hayden observed that patients in the earlier pridopidine studies actually showed improvement in motor symptoms caused by HD such as chorea, or involuntary movements. Pridopidine also improved eye movement substantially, he said. It also stabilized levels of dopamine, a neurotransmitter and hormone involved in movement control, mood, and motivation.

Patients’ depression, another telltale HD symptom, also did not worsen, Dr. Hayden noted.

Aiming for broader impact

“There may be some broader affect on other features of Huntington disease,” he added. Additional studies of pridopidine in animals have indicated that it brings about changes in the brain, might be “neuroprotective,” and might help with improving thinking and feeling, he explained.

Therefore, Teva will add other key endpoints to the Pride-HD study: cognition, mood, and quality of life. The study also will assess the effect of dosages of pridopidine higher than those given patients in the earlier trials.

Pridopidine “could theoretically have some effect to change the course of the illness,” Dr. Hayden observed. “And wouldn’t that be exciting?”

Pride-HD enrolled its first patient in April 2014 and will continue throughout 2015. Teva aims to enroll 400 patients at 54 sites in North America, Europe, and Australia. If the results are favorable, Teva could seek regulatory approval for the drug in late 2016, Dr. Hayden said.

As HD specialist Dr. LaVonne Goodman noted in her February 18 commentary on the potential of pridopidine, “recruitment is not going well for Pride-HD.[...] The bottom line is that finding new drugs for HD takes a lot of work, good trials and a long-term commitment from HD families and investigators. If we don't join this or other trials, we will never have new drugs for HD: not for ourselves or the next generation."

To learn more about Pride-HD and how to participate, refer to the above-mentioned link to the webinar or call HDSA at 800-345-4372.

Teva is also conducting a clinical trial of the drug laquinomod for use in HD, Dr. Hayden noted. Laquinomod is thought to reduce the inflammation of the brain in neurological disorders. Click here to learn more about the trial.

Another historic moment

As a carrier of the HD gene mutation, I listened to Dr. Hayden’s comments on the long-term progress of HD research with great hope.

Scientists have observed that managing HD effectively likely will require a cocktail of drugs. Pridopidine is yet another potential element in the mix. (I have reported on many of the elements in this blog over the past ten years. Click here and here to see recent examples.)

Having tracked the HD movement for nearly 20 years, I also appreciated Dr. Hayden’s important reminder that the quest for effective treatments is a lengthy process. Science and clinical trials require time and investments of money and intellect.

I wrote this article in Palm Springs, CA, just before the start of yet another historic mark in the HD movement: the 10th Annual HD Therapeutics Conference, sponsored by the CHDI Foundation, Inc., at the Parker Palm Springs hotel February 23-26. In the past I have referred to this event as the "Super Bowl" of HD research.

In Palm Springs, I will listen to other scientists take stock of the search for HD treatments.

I also expect to witness yet further examples of researchers replacing the darkness of Huntington’s disease with hope and light.

For yet more perspective, watch my interview with Dr. Hayden at the 2011 HD Therapeutics Conference in the video below.