CHDI head scientist Pacifici: ‘hang on in the learning roller coaster ride of Huntington’s disease clinical trials’

With historic clinical trials now aiming for the first effective treatments for Huntington’s disease, affected individuals and their families need to clearly understand the news about these efforts and their implications.

That critical recommendation was offered by Robert Pacifici, Ph.D., the chief scientific officer of the nonprofit HD-treatment-seeking CHDI Foundation, Inc., during an interview on the last day of the organization’s 15th Annual HD Therapeutics Conference, held February 24-27 in Palm Springs, CA.

“Getting to this stage – which we’ve all so been hoping for – is still a bit of a roller coaster ride,” Dr. Pacifici told me. “You have to be able stay in our seats and weather the ups and downs. I think we’re well-poised for some great news, as some of these trials hopefully report out. Even a whisper of efficacy would be just amazing.”

However, there will also be “disappointments, where, despite our best attempts, some of the things that showed so much promise didn’t end up meeting their endpoints,” he cautioned. “But it’s going to be a learning roller coaster. So hang in there. Don’t lose hope.”

The HD-affected (and their caregivers) should keep informed about the trials by consulting their physicians, attending meetings of patient organizations such as the Huntington’s Disease Society of America (HDSA), and keeping abreast of developments in such sources as HDBuzz.net and this blog, Dr. Pacifici advised.

Become knowledgeable, he urged, “so that you are not disproportionately spooked or elated when these bits of information come out.”

Featured conference speaker Christopher Austin, M.D., the director of the National Center for Advancing Translational Sciences/National Institutes of Health, presents part of the Drug Discovery, Development and Deployment Map the research and pharmaceutical community must navigate in today's complex and challenging scientific world (photo by Gene Veritas, aka Kenneth P. Serbin).

‘Genuinely interested’ in treating HD

Dr. Pacifici began the interview noting the excitement generated by the conference and within the HD field, with a record 380 participants, overflow seating, and more than 100 people turned away. However, CHDI’s goal ultimate goal is not to host well-attended conferences, but to stop HD, he emphasized.

“There are that many people who are genuinely interested in presenting the results and learning about the incredible developments that are unfolding in Huntington’s disease drug discovery and development,” he said of the response to the conference.

Dr. Pacifici also noted the very high quality of the presentations, in comparison with the early years of the event. 

“We’re batting 1,000 this time – every single talk very relevant,” he observed.

Considered science fiction a decade ago, the new technologies applied in HD research are transforming the field and allowing for a more thorough analysis of cells in the quest to understand the disease, he added.

Dr. Pacifici cited the example of whole-genome sequencing on individual brain cells, which permits the reading of the DNA sequence of “every single gene in there, and doing that thousands of times.” 

You can watch my interview with Dr. Pacifici in the video below. For my video album of the conference, please click here (and check back in the coming days as I add videos).

Hang on in the 'learning roller coaster ride' of Huntington's disease clinical trials from Gene Veritas on Vimeo.

New understanding of the protein

Dr. Pacifici also discussed new research into the huntingtin protein presented at the conference. Such research suggests that the protein might have a key role in maintaining the integrity of the huntingtin gene and also in the way the gene expands over time (known as somatic expansion), which researchers now see as a key driver of the disease (click here to read more).

With this potential new finding, a single drug might be developed to counteract the mutant protein by both reducing its quantity and preventing it from causing somatic expansion, he speculated.

He pointed in particular to the presentation by Jeffrey Carroll, Ph.D.

A possible key biomarker

Dr. Pacifici also commented on the discussion around phosphodiesterase-10 (PDE-10). A PDE inhibitor was seen as a potential “Viagra for the brain” but ultimately showed no improvement in a clinical trial run by the drug giant Pfizer.

However, PDE-10 might still play a role for the HD community as a biomarker (sign of disease and/or effect of a treatment), Dr. Pacifici said.

“It is pretty uniquely expressed in the neurons that we know are affected by Huntington’s disease, the medium spiny neurons,” he explained. 

If PDE-10 decreases in HD because the gene is shut down or cells die or some combination of both, and “if you had a molecule that bound to PDE10 and sent out a signal, then you could know how much PDE10 was in that brain, and if it was declining, that would mean that the disease was progressing.” Similarly, with an effective therapy, “you would see PDE10 levels going up,” Dr. Pacifici added.

The U.S. Food and Drug Administration is unlikely to approve a drug based solely on evidence from a biomarker, because it needs to see actual clinical benefits in patients, Dr. Pacifici said. However, the biomarker could give a drug maker the “confidence” that the “intervention is doing its job biologically and now it’s worth waiting for the clinically meaning outcome.”

(The presentation by Steven A. McCarroll, Ph.D., of the Harvard Medical School, included discussion of the role of PDE-10.)

Above, Dr. Steven McCarroll answers a question from the audience after his presentation on single-cell analysis of HD biology. Below, McCarroll lab researchers Nora Reed (left) and Christopher Mullally with the lab's poster on single-cell analysis, which took second prize in the poster competition (photos by Gene Veritas).

The terrifying truth about drug development

Dr. Pacifici reflected on the in-depth talk by the conference’s featured speaker, Christopher Austin, M.D., the director of the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health. NCATS, founded in 2011, aims to speed the development of treatments and cures.

I asked Dr. Pacifici to comment on the phrase that struck me from Dr. Austin’s presentation: “The hard work that nobody else wants to do.”

Scientific research is “unsexy” and “difficult to understand,” but Dr. Austin challenged the field to forge ahead, I observed.

“He painted a pretty bleak picture of how we’re sadly finding diminishing returns on our investment,” Dr. Pacifici said regarding drug investigation in general. “In other words, he kind of flipped around Moore’s law. Instead of things getting better and faster, the more money we spend, the fewer treatments we see coming out, especially for the harder neurological diseases.”

Dr. Austin presented to the audience what he called a “truly terrifying fact”: “The number of new drugs approved per billion dollars spent, inflation-adjusted, has gone down by half every nine years, since 1950.”

You can learn why this is so – and its very serious implications for HD – by watching Dr. Austin’s presentation by clicking here.

The HD field hopes to be the exception and the model

Dr. Pacifici pointed to the difficult and complex challenges involved in drug discovery, as illustrated by Dr. Austin.

Everybody wants to be the “star” that “made the compound that turned out to be the cure,” Dr. Pacifici said. But imagine: the compound is there, but no patients are available to do the clinical trial. Or patients participate, but researchers lacked the “outcome measures to see whether people were actually getting better.” Or, antibodies and assays needed to measure the samples derived from patients weren’t there.

Those things are the not-so “sexy” but need to get done, he said.

The HD field will need to overcome the inertia of diminishing returns, Dr. Austin emphasized. Deeply familiar with HD science, he believes that HD as a monogenetic disease has the potential to do so and could serve as the model for treating other, more common neurological disorders.

Dr. Pacifici agreed. He praised the HD research and biotech community not only for its commitment to make sure that key elements of the drug-hunting process are “proactively put in place,” but the “selflessness with which they are shared, so that those don’t represent competitive advantages for one company or another. I think everybody has come to the realization that this is a really hard problem. It’s no use competing with each other. We’re going to have to help each other.”

At the start of his talk on huntingtin-lowering strategies, Ignacio Muñoz-Sanjuán, Ph.D., a CHDI scientist and the co-founder of Factor-H, reminded the audience of the goal of the HD cause: to help individuals like Anyervi (in cap) and Brenda, two youths from South America with juvenile HD (photo by Gene Veritas).

Ionis drug successfully reduces toxic Huntington’s disease protein, paving way for Phase 2 trial of effect on patients

In an initial clinical trial that marks a significant step toward finding an effective Huntington’s disease treatment, the Ionis Pharmaceuticals gene-silencing drug safely reduced the production of the toxic mutant protein implicated in HD, the firm announced today.

Ionis has handed development of the expected Phase 2 trial to its partner in the project, the multinational pharmaceutical giant Roche, earning a $45 million license fee, today’s Ionis press release stated. The drug is called IONIS-HTT_Rx: “HTT” stands for both the huntingtin gene and the protein it produces, and “Rx” signifies a remedy.

The trial was officially classified as Phase 1/2a. A Phase 1 trial measure’s a drug’s safety and tolerability in a small number of participants, while a Phase 2 trial examines efficacy in a larger group of patients. Though mainly Phase 1, this trial had elements of a Phase 2: actual HD patients took part, and it sought to determine whether the drug’s basic mechanism worked.

“We are encouraged by the performance of IONIS-HTTRx in the Phase 1/2a clinical study,” Frank Bennett, Ph.D., Ionis senior vice president of research, stated in the release.

The reductions of the mutant protein “observed in the study substantially exceeded our expectations,” Dr. Bennett added. The study, which involved 46 participants with early HD symptoms, did not assess whether that reduction slowed disease progression.

Ionis stated that “dose-dependent reductions of mHTT were observed” in the trial: the higher the dosage, the greater the reduction in the amount of the mutant protein.

“We were equally encouraged by the safety profile of the drug,” Dr. Bennett stated.

“The results of this trial are of ground-breaking importance for Huntington’s disease patients and families,” stated Dr. Sarah Tabrizi, professor of clinical neurology, director of the University College London’s Huntington Centre, and the global lead investigator on the Phase 1/2a study. “For the first time, a drug has lowered the level of the toxic disease-causing protein in the nervous system, and the drug was safe and well tolerated. The key now is to move quickly to a larger trial to test whether IONIS-HTT_Rx slows disease progression.”

Frank Bennett, Ph.D. (above, photo by Kristina Bowyer, Ionis) and Dr. Sarah Tabrizi (below, photo by Gene Veritas)

Pharma giant Roche steps in

Ionis officials stated in June that a Phase 2 study could start as soon as 2018. Typically, all three phases of a clinical trial project take at least five years, although nobody can predict the actual course of a trial.

In 2013, Ionis, a mid-sized drug-discovery firm that does not produce or sell drugs or conduct clinical trials on its own, partnered with Roche, one of the world’s largest and most successful pharmaceutical companies (click here and here to read more). Roche’s expertise includes neurodegenerative brain diseases.

Roche will now take over the development of IONIS-HTT_Rx, including the Phase 2 and potential Phase 3 trials and bringing the drug to market. It will hold the license to the drug.

Roche also will administer the open-label extension of the Phase 1/2a study, announced in June, whereby all patients – including those who got a placebo – will continue to receive the drug. The extension allows researchers to gather more data, examine the drug’s effects over a longer period of time, and better prepare for Phase 2. Patients also potentially benefit by receiving the drug longer.

Phase 2 to include United States

By attacking Huntington’s disease near its genetic roots, IONIS-HTT_Rx could potentially reduce, partly reverse, and even prevent symptoms. Ionis drugs are antisense oligonucleotides, artificial strands of DNA. The drug aims to turn off the huntingtin gene messenger RNA that contains the instructions to make the huntingtin protein in brain cells.

Forty-six patients took part in the Phase 1/2a trial at sites in Canada, Germany, and England.

“Today is an exciting day for the Huntington’s disease community,” a joint Ionis-Roche letter to the HD community stated. “Future studies for the program will be conducted globally, including in the U.S. Roche will announce details about future studies, including eligibility criteria and planned start dates, as this information becomes available.”

More than a decade of research

IONIS-HTT_Rx resulted from more than a decade of research involving Ionis, Roche, the lab of neurobiologist Donald Cleveland, Ph.D., at the University of California, San Diego, and CHDI Foundation, Inc., the nonprofit virtual biotech firm aimed solely at finding (and funding) HD treatments.

On December 3, Dr. Cleveland received the $3 million Breakthrough Prize, the world’s richest science award, sponsored by Google, Facebook, and other entities. It is twice the value of the Nobel Prize. Dr. Cleveland received recognition for his career contributions to the life sciences, including work on a cause of Alzheimer’s disease. (Click here to read more.)

Dr. Cleveland was honored at the 2012 gala of the San Diego Chapter of the Huntington’s Disease Society of America. For a recent article explaining the Dr. Cleveland’s role in the Ionis project, click here.

In interviews today, I hope to obtain further details about the progress regarding IONIS-HTT_Rx.

HDBuzz’s take: a historic breakthrough

The HD research site HDBuzz, produced by scientists, stated that today’s announcement is “likely to stand as one of the biggest breakthroughs in Huntington’s disease since the discovery of the HD gene in 1993.”

The site’s article, written by Jeff Carroll, Ph.D. – an HD-gene carrier like me and a scientist dedicating his career to finding HD treatments – asserted that the “most exciting” part of today’s news is that “dose-dependent reductions of mutant huntingtin were observed.”

The clinical trial administrators know this because they examined samples of participants’ cerebrospinal fluid, which runs along the spine and into the brain. Participants received injections of the drug via a spinal tap.

“This means that patients treated with IONIS-HTTRx have reductions in the huntingtin protein in their cerebrospinal fluid,” Dr. Carroll wrote. “Based on this result, it looks like the drug is doing what it’s meant to do, and that huntingtin lowering has been achieved!”

Dr. Wild concluded: “This is a great day in the HD community, and it sets us on the path to even more exciting work in 2018. For the first time in history, HD patients are being treated with drugs known to reduce the amount of huntingtin protein in their brain. Until we conduct the next trial, we won’t know if this reduces the impact of HD. And while we know the drug is safe in the short term, we will also have to watch carefully for any long-term adverse effects. But we’re facing this problem with renewed excitement and hope. It’s the best early Christmas present we could have hoped for.”

Jeff Carroll, Ph.D., at the 2012 CHDI-sponsored HD therapeutics conference (photo by Gene Veritas)

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

‘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.

None of Us Are Free Until We Are All Free: A Keynote Speech on Huntington's Disease by Dr. Jeff Carroll from Gene Veritas on Vimeo.

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.

'The Lion's Mouth Opens' and Marianna Palka on Huntington's disease from Gene Veritas on Vimeo.

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.

An Update on Enroll-HD from Gene Veritas on Vimeo.

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.