At Therapeutics Conference, landmark study of young gene carriers highlights how Huntington’s disease researchers seek to solve critical puzzles

Armed with ever more impressive data and a deeper understanding of Huntington’s disease, scientists and drug hunters convened at the 15th Annual HD Therapeutics Conference this week, facing the complex puzzles that still hinder the quest for treatments for this deadly neurological disorder.

One of those puzzles: how to not only treat symptoms, but to prevent them, especially in young presymptomatic carriers of the HD gene, so that they don’t have to spend their lives fearing the currently inevitable onset of this devastating disease.

On February 26, Sarah Tabrizi, FRCP, Ph.D., of University College London, answered key questions about what kinds of health consequences young presymptomatic gene carriers suffer decades before they’re likely to develop the disease in midlife.

Previous studies have demonstrated that brain shrinkage can occur as early as 15 to 18 years before predicted age of onset. Ranging in age from 18-40, the 64 gene carriers in Dr. Tabrizi’s HD Young Adult Study went through state-of-the art brain scans and cognitive testing, and also provided samples of blood and cerebrospinal fluid (CSF) for analysis. These at-risk volunteers are, on average, 24 years from estimated onset.

This study, in line with “The Path to Prevention” (one of five major themes of the 2020 conference), is aimed at helping identify the optimal time to treat gene carriers to slow or prevent their neurological decline.

“Comprehensive cognitive testing was normal,” as compared to 67 non-HD-affected individuals, reported Dr. Tabrizi in her presentation to the conference. “There were no significant psychiatric differences, which I found very interesting, because I would have predicted they would’ve been big differences.”

Dr. Tabrizi said that "there’s always been a thought that carrying the HD gene hard-wired you for psychiatric burden,” but the Young Adult Study suggests that such symptoms become more prominent closer to onset.

“I think that was – and I don’t say this lightly – a landmark presentation,” Robert Pacifici, Ph.D., the chief scientific officer for CHDI Foundation, Inc., the conference sponsor, told me today, adding that Dr. Tabrizi’s team carried out the study with “a high degree of rigor and granularity.”

“The participants seem to be remarkably well,” Dr. Pacifici observed. The absence of many of the neurological and other problems typical of HD is an encouraging prospect for developing safe and well-tolerated treatments that could “not just reverse, but actually prevent” HD, he said.

Dr. Pacifici lauded the study volunteers for their "unbelievably selfless participation," including submitting to the study's "incredibly rigorous battery."

Above, Dr. Sarah Tabrizi presenting her talk on the HD Young Adult Study at the 2020 HD Therapeutics Conference, February 26, 2020, and, below, a closeup of Dr. Tabrizi (photos by Gene Veritas, aka Kenneth P. Serbin)

Overall, ‘good news’ for young gene carriers

The young gene carriers in the study did appear to go through a small change in the area of the forebrain known as the striatum, consisting primarily of the putamen and the caudate, the deep brain regions that are most affected by HD. The striatum helps to control our movements and rewards system.

The study found a significant reduction in the size of the putamen, but an insignificant reduction in the caudate. Nevertheless, Dr. Tabrizi explained that, based on this study, these differences (in comparison with the normal subjects) were “not associated with predicted years to onset.”

“So what we now know, based on the data, is that the striatum never appears to be the same size as the control group,” she explained. 

The “very slightly smaller” striatum may suggest a “neurodevelopmental effect” (the way the brain develops) that is “well compensated for,” Dr. Tabrizi said, meaning that the brain adjusts without clear damage. She added that it “might be why the striatum is vulnerable later in life, because it has a double hit.” As mentioned by Dr. Tabrizi, this interpretation resonates with the research of Peg Nopoulos, M.D., who has studied the compromised development of the brains of people affected by juvenile HD.

Alternatively, neurodegeneration early on could be “too subtle and variable” to associate with predicated age of onset, Dr. Tabrizi noted.

Other imaging results showed no decrease in the white matter (the tissue in the brain made of nerve fibers and possibly involved in cognitive problems in HD) or any other aspect of the brain measured in the study, indicating that the subjects were still “very far from onset,” Dr. Tabrizi continued.

“This is really good news,” Dr. Tabrizi stated.

Douglas Langbehn, M.D., Ph.D., a psychiatrist and biostatistician at the University of Iowa who did the statistical analysis for the HD Young Adult Study, listens to Dr. Tabrizi at the Therapeutics Conference (photo by Gene Veritas).

The ongoing search for reliable biomarkers

The study also involved the ongoing search for reliable biomarkers (signs of disease and drug efficacy).

The study detected mutant huntingtin protein in the subjects’ cerebrospinal fluid. “CSF mutant huntingtin was higher in those closer to [predicted] onset, suggesting that some injury is releasing mutant huntingtin [from the brain], but very subtle,” Dr. Tabrizi said.

Several other biomarkers were elevated in the subjects’ CSF, again indicating an early, subtle injury, but most of those subjects had readings showing levels very close to those of the unaffected control subjects, Dr. Tabrizi continued. Furthermore, six other biomarkers were normal, she added.

The Young Adult Study points to the one CSF biomarker in particular, neurofilament light, a marker of brain damage, as potentially helpful in measuring disease progression and treatment response in people decades from onset, Dr. Tabrizi concluded.

A drug that kept neurofilament light at very low levels could prevent degeneration of the brain, she added.

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

A moving keynote address

With a record attendance of 380, the conference opened on February 24 with a moving keynote speech by Amy Merkel, a 45-year-old nurse from Wisconsin and the founder of Starfish Yoga.

A small company, Starfish focuses on encouraging constructive coping skills, primarily for people affected by past imprisonment, sexual abuse, and neurological disorders, including HD.

Amy, who titled her talk “Life is Good,” belongs to a family deeply affected by HD. She recounted her extended family’s decades-long struggles with HD. Amy received a standing ovation.

Stay tuned to this blog for additional reporting on the conference, including an overview provided in my interview with Dr. Pacifici.

Above, HD advocate Amy Merkel addresses the 15th Annual Therapeutics Conference, and, below, poses with researchers Dr. Sarah Tabrizi (far left), Leslie Thompson, Ph.D. (second from right), and Gillian Bates, Ph.D. (photos by Gene Veritas).

Planning a ‘Dancing at the Vatican’ screening to celebrate the global Huntington’s disease community’s journey

On February 19, the University of San Diego (USD) will host the world’s third screening of Dancing at the Vatican, the short documentary featuring South American Huntington’s disease-afflicted families’ historic 2017 encounter with Pope Francis at the Vatican.

As I noted in my preview before the July 2019 premiere of this 38-minute film in Los Angeles, Dancing at the Vatican captures key moments of those impoverished, disease-stricken families’ journey to their meeting with the Spanish-speaking Francis, the first Latin American pontiff in the Catholic Church’s 2000-year history. It was extraordinary: some had never ventured beyond their home towns; some even lacked birth certificates.

Now, as both an HD advocate and faculty member in USD’s Department of History, I’m helping organize the upcoming screening, and hope many more people will see it. 

Dancing at the Vatican also will be shown in London on February 5. Showings are also confirmed for Washington, D.C., in March (date and place TBA), and at the Huntington’s Disease Youth Organization conference in Glasgow, Scotland, in May. Screenings are under consideration for South America, too. Ultimately, the film will become available online.

In the words of producer and narrator Charles Sabine – like me, a presymptomatic HD gene carrier – coming together to view Dancing at the Vatican is an occasion of “extraordinary celebration” for the Huntington’s community.

An Emmy-award-winning former NBC-TV foreign correspondent, Sabine helped spearhead “HDdennomore: Pope Francis’ Special Audience with the Huntington’s Disease Community in Solidarity with South America.” Both Sabine's father and brother died from HD.

While Dancing at the Vatican captures what I called in my preview “the underside of the HD world” – families dealing simultaneously with one of humanity’s most devastating diseases and severe poverty and discrimination – it also portrays what Sabine described as “happy tales set against the dark canvas of our disease.”

At HDdennomore, and as the film recalls, Francis became the first world leader to recognize this horrible disease. And he declared that it should be “hidden no more.” 

Pope Francis with HD families in Rome, May 18, 2017 (photo by #HDdennomore)

Faith, reason, and advocacy

At USD, the primary sponsor of the screening is Frances G. Harpst Center for Catholic Thought and Culture (CCTC). Along with other USD units, the CCTC co-sponsored my trip to Rome for #HDdennomore, and also my public presentation on the event (click here to watch).

USD is a Catholic university where “faith and reason are compatible in education,” and it “welcomes students, faculty and staff of every faith tradition,” according to its statement on Catholic identity. Indeed, since my arrival in 1993, I’ve faced no restrictions on my research on abortion in Brazil, and have taught students from many religious backgrounds.

I have explored the nexus between faith and reason/science in this blog, including the in-depth article “God, Huntington’s disease and the meaning of life.”

After CCTC Director Jeffrey Burns, Ph.D., read my preview of Dancing at the Vatican last July, he e-mailed me to ask whether we could bring the film to USD. Sabine readily agreed to the idea; he’ll introduce the film and take questions afterwards.

Ignacio Muñoz-Sanjuán, Ph.D., a leading neuroscientist seeking HD treatments at the Los Angeles office of the nonprofit CHDI Foundation, Inc., also will speak. Dr. Muñoz helped organize #HDdennomore. He co-founded Factor-H, which aids Latin America’s poor HD-affected families. Both Sabine and Muñoz will also meet with students and faculty interested in their respective professional fields.

We selected the February 19 date because Sabine, based in London, will join Muñoz and several hundred researchers from around the globe the next week at the CHDI-sponsored 15th Annual HD Therapeutics Conference in nearby Palm Springs, CA. I will also attend.

In planning the screening, I’ve strengthened the bond between advocacy and academic work that USD values and that I began to establish after exiting the terrible and lonely “HD closet” in 2012 (click here to read more).

Dr. Ignacio Muñoz-Sanjuán entering the Vatican with Dilia Oviedo Guillén, a Colombian woman who lost her husband and five children to HD (photo by #HDdennomore)

A free event, with many sponsors

The screening will take place from 6:30-8:30 p.m. in USD’s Manchester Auditorium (located in Manchester Hall) and will be followed by a reception. The event is free and open to the USD community, the local HD and biomedical communities, and the public. Attendees must register at cctc@sandiego.edu or 619-260-7936.

To fund the event, we have secured support from Ionis Pharmaceuticals, Inc., the developer of the gene-silencing drug currently under study in a historic Phase 3 clinical trial by Roche. (Click here for a recent update on the trial.) Ionis is located in Carlsbad, CA, part of the San Diego-area biotech hub, one of the world’s most important. Ionis’ chief scientific officer and HD team leader, Frank Bennett, Ph.D., donated to #HDdennomore.

In addition, Roche’s U.S. subsidiary Genentech will also sponsor the screening. Headquartered in South San Francisco, CA, Genentech also has a facility in Oceanside, just north of San Diego. 

Another local company, Origami Therapeutics, Inc., is supporting the event. It also seeks to develop an HD treatment. It was founded by Beth Hoffman, Ph.D., the former president of the San Diego chapter of the Huntington’s Disease Society of America.

Other USD co-sponsors include the International Center, the Enhanced Student Faculty Interaction Fund, the Humanities Center, the above-mentioned Department of History, the Program in Latin American Studies, and the Department of Communication Studies. The College of Arts and Sciences also has lent its support.

Charles Sabine dancing at the Vatican with #HDdennomore participants (photo by #HDdennomore)

‘All of us standing together’

On January 10, I had a long lunch with George Essig, a well-connected veteran radio ad salesman and former HDSA-San Diego president. Essig’s extended family is affected by HD. As I wrote in a 2014 article, Essig “epitomizes the dedication of the unaffected relative.” (Click here to read more.)

In discussing the screening, we noted that it will be a unique event for the San Diego HD community and its supporters. Over the years, most events – such as galas, marathons, and walks – have focused on raising funds and awareness.

Echoing Sabine, I stressed that this event would be a celebration.

We brainstormed on the meaning of “celebration” for the local HD community – and for the many donors Essig has brought into the cause.

Their support had helped HD “become hidden no more,” he said. 

The screening also will be about “the evolution of the cause,” he added. 

With that in mind, Essig said he would tell supporters that he would be “remiss not to invite you to this celebration.”

The Dancing at the Vatican screening will also celebrate the progress in research, which has advanced thanks to the donors and broad collaboration in the HD community, he noted.

Essig summed it up: the Dancing at the Vatican event will be “all of us standing together and saying: I helped bring a cure to an incurable disease, even if it’s just $10 that I gave.”

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

Are we failing to stop Huntington’s disease by ignoring ‘natural’ remedies, alternative therapies, and repurposed drugs?

This article is Part 2 of a two-part series.

Because Huntington’s disease is so devastating and intractable, many affected individuals and presymptomatic gene carriers like me have chosen to take substances outside the pharmaceutical mainstream to try to forestall the inevitable onset or worsening of symptoms.

The reason: 26 years after the discovery of the huntingtin gene, despite significant progress in understanding the disease, there is no effective therapy or cure. 

In Part 1 of this series, Robert Pacifici, Ph.D., the chief scientific officer for CHDI Foundation, Inc., discussed the immense progress made in HD research and the optimistic prospects for developing therapies. CHDI is the largest nonprofit effort aimed at defeating HD.

Only two drugs addressing symptoms of HD have been approved by the U.S. Food and Drug Administration (FDA) – Xenazine in 2008 and the similar, improved drug Austedo in 2017. Both treat the involuntary movements in HD (chorea) but do not attack the causes or halt progression of this fatal disorder. (Click here to read more.) 

Physicians also prescribe medications – nonspecific for HD – to alleviate the difficult behavioral and psychiatric symptoms. Those drugs also have no effect on progression.

Trying supplements

My mother died of HD in 2006 at age 68. As I desperately witnessed the disease’s inexorable onslaught on her mind and body, I embarked on a controversial “treatment now” program of unproven but certainly not quackish supplements, the Huntington’s Disease Drug Works (HDDW) regimen developed by veteran HD physician LaVonne Goodman, M.D. 

Starting in 2005, I introduced the supplements into my diet in steps. I worked up to a daily routine in which I took 75 grams of trehalose, a sugar that seems to help the brain clear cellular debris; 600 mg of medical-grade coenzyme Q-10 (which I had taken on and off since 1996); two g of omega-3 oil; two g of blueberry extract; and ten g of medical-grade creatine. (Click here to read more.)

For several years I participated as a subject in an HDDW online observational study, performing cognitive tests on a home computer. In this very small study, several early or midstage HD-affected people showed stabilization or improvement. Late-stage patients did less well, continuing to progress with the disease. The study was too small for its results to be applicable to the general HD population. (Click here to read more.)

I was the only presymptomatic gene carrier in the trial. Afterwards, I continued the regimen on my own, but regularly consulted with Dr. Goodman.

In 2014, I stopped coenzyme Q-10 and creatine after clinical trials proved them ineffective. Recently, in place of expensive high-grade omega-3 pills, I’m eating more fish. Annually, I’ve spent thousands of dollars on supplements – none covered by health insurance.

I have also sought to lead a healthy lifestyle, including intellectual and social enrichment. Doctors and researchers encourage this and have pointed out that it could be part of why I have long passed my mother’s age of onset, although there is no scientific proof  (Click here to read more).

The HDDW program and the clinical trials for coenzyme Q-10 and creatine were the most formal testing of supplements. HD-affected individuals have tried and/or discussed a range of other substances, including injections of live fetal shark cells, the amino acid cysteine, medical marijuana, and the highly popular – but potentially harmful – marijuana and hemp extract cannabidiol (CBD), usually by drinking an oil.

Above, CBD products in a Los Angeles, CA, grocery store (photo by Deceptitom [CC BY-SA 4.0 {https://creativecommons..org/licenses/by-sa/4.0}]). Below, the supplements I have taken (photo by Gene Veritas, aka Kenneth P. Serbin)

One group of advocates has also pushed for a clinical trial of methylene blue, a dye under study as a possible way to alleviate a variety of medical conditions.

In our recent interview, Dr. Pacifici and I delved into whether CHDI and the HD community are failing to defeat the disease by ignoring these types of alternative approaches, including so-called “natural” remedies and repurposed drugs. The video of our interview is posted at the end of this article.

HD-specific drugs needed

Citing the increased interest in HD in the pharmaceutical industry (discussed in Part 1), Dr. Pacifici said that CHDI would assist any company aiming to test an HD drug, as long as it’s safe, tolerable, and backed with enough resources to do a careful clinical trial.

“It’s wonderful that there’s this diversity of folks that have assets and try and come into the field, as long as they’re credible and well-thought-out,” he said.

However, because of HD’s genetic cause and complexity, CHDI has stressed that drugs for halting disease progression must be “new chemical entities” and HD-specific.

Dr. Pacifici pointed to an example: difficulties with sleep, a serious symptom of HD. The HD field must consider: “What are the things that are probably going to happen out there anyway, because there’s a big market for sleep medications versus the things that are very specific to HD, that if we don’t do them, they’re not going to get done?”

Don’t expect to win the jackpot

The need for unique HD drugs, and the overall history of drug discovery, point to the fact that so-called “natural” approaches and repurposing of other drugs will not result in effective treatments, Dr. Pacifici asserted.

The alleviation of Dr. Pacifici’s own suffering from familial Mediterranean fever (FMF, discussed in Part 1) resulted from the discovery of the drug colchicine, “a natural thing from the crocus flower” already in use to treat gout. Such a scenario is atypical, he explained.

“Obviously, I didn’t just win the Lotto,” Dr. Pacifici said. “I won the Mega Millions with the fact that I happen to be treated by an existing drug. It’s pretty rare.”

The HD community should not expect such an outcome, he said.

“Obviously the thing that’s wonderful when that does happen is that there’s no path that’s shorter from a discovery to a treatment,” he continued. “But the effect has to be pretty overwhelming.”

Indeed, colchicine “completely stopped” the recurrent abdominal pain and fever of FMF. 

“You can imagine,” he said, “that observation’s a little harder to make in Huntington’s disease, given the slow progression of the disease, given the myriad of symptoms.”

Robert Pacifici, Ph.D. (photo by Gene Veritas)

Is ‘natural’ better?

The notion of “natural” products is a bit “artificial,” Dr. Pacifici pointed out.

“People, first of all, seem to think that something that’s ‘natural’ is better,” he said. “There are plenty of horrible poisons like ricin that are natural, and if you take them, they kill you. It’s ‘organic,’ and it’s ‘natural.’ That doesn’t mean it’s good for you!”

We discussed a clinical trial for an eye disease using liquid from the resin of the mastic tree from the Greek island of Chios, as reported by New York Times columnist Frank Bruni. For thousands of years, people have used the resin to address many types of health problems. The trial seeks to test whether the liquid can repair damaged nerves in the eye, with potentially positive implications for people with Alzheimer’s disease and other neurological conditions.

Dr. Pacifici said that, in such a study, scientists need to know the exact chemical makeup of the substance and, in the case of a possible HD treatment, determine whether that makeup is any different from other compounds CHDI has tested.

In the case of the mastic tree, scientists also need to ensure that weather conditions and the conditions of the tree do not alter the makeup of the resin. Also, the testing of the substance needs to be “reproducible,” he explained. 

That the compound in the liquid comes from a natural source is irrelevant, he added, because scientists can produce such compounds in a lab.

Clinical trials are expensive, costing hundreds of millions of dollars, Dr. Pacific observed. Ultimately, CHDI and HD researchers need to avoid “taking empty shots on goal that we could have predicted up front had no chance of working.”

Millions of experiments

Not long after its founding in 2003, CHDI did a project to ensure that the HD field did not miss a possible remedy among existing drugs and other substances, some of them natural. According to Dr. Pacifici, the foundation worked with a small firm that had a library of all FDA-approved drugs and also substances such as vitamins and other generally safe items, including some shown to be safe and tolerable in Phase 1 clinical trials.

“We tested all of those,” Dr. Pacifici recalled, referring to the entire library. “In fact, we tested all of those at multiple concentrations. In fact, we tested all of those at multiple concentrations with each other, in pairwise fashion [two drugs at a time].”

Carried out in cells, the tests ran into the millions, he said.

“But we found nothing that suggested, ‘Yeah, there’s the Mega Millions hit or combination of things that should go forward,'” he said.

The massive experiment confirmed the need for a unique, HD-specific type of medicine that could be delivered to the brain safely over a long period of time, thus attacking the specific problems caused by the disease, Dr. Pacifici observed.

Through Enroll-HD, the CHDI-sponsored global study of HD-affected individuals and their families, CHDI tracks unusual data from visits to HD clinics that might suggest follow-up to discover further clues for developing drugs.

The CBD ‘craze’

As a September 29 CNN documentary reported, in the United States production and use of CBD for health reasons has boomed in the last six years. The unregulated proliferation of CBD-containing products such as tinctures, foods, and oils has left the public with little reliable information on the risks, including items with harmful impurities.

“The CBD craze that we’re in, I think, is unprecedented really in the history of medicine,” Donald Abrams, M.D., a leading cannabis researcher, said in the broadcast. “It’s a compound that has gotten way ahead of any research to support the claims that are being made.”

Dr. Pacifici, who’s studied the issue closely, echoed these concerns. Tetrahydrocannabinol (THC), CBD, and other marijuana-based compounds are “enjoying their moment in the sun” because of legalization for recreational and medical use in some states, although not federally, he observed. “It’s kind of the flavor of the month, if you will.”

Only one approved CBD drug

CBD is a “real compound,” he explained.

However, there is only one FDA-approved drug made from CBD, Epidiolex, manufactured by the British firm GW Pharmaceuticals. Epidiolex was shown to be safe and efficacious in the treatment of two types of childhood epilepsy.

GW Pharmaceuticals had to run “through the same paces as any other drug substance,” Dr. Pacifici remarked. “They happened to get it out of the marijuana plant. That’s fine. I don’t care where it comes from. But it’s highly purified and highly quantified so that they know exactly what’s in there and what’s not in there and the purity of it.”

No other CBD product has been tested in a clinical trial.

In Dr. Pacifici’s view, because of the lack of quality control and regulatory approval in the making of CBD products, a critical question remains: “Are people who are experimenting with it actually getting real, pure CBD?” In some cases, the products do not even contain CBD, or have an incorrect concentration.

CBD not yet tested for HD

Could CBD potentially treat Huntington’s disease?

 “The short answer is, we don’t know,” he asserted. “I can’t tell you of the number of fantastic ideas that I’ve had. Wonderful ideas, that I sit down, I think, ‘I’ve had this eureka moment.’ Until you test it, and you find out that biology is more complicated than you thought.”

Scientists, he said, know about CBD’s “pharmacology” – its function, effects, and where it gets into the body. “Is it something that could potentially have a beneficial effect? Sure. But has it been properly tested, especially in HD? Absolutely not.”

Many researchers are currently focusing on CBD for HD, and they have developed some very reasonable hypotheses, he said.

“To my mind, none of them, yet, have reached a level of evidence where somebody wants to go spend a hundred million dollars or more on a trial to see if it’s actually efficacious,” he said. “Maybe they will.”

Insufficient evidence on methylene blue

Regarding methylene blue, Dr. Pacifici observed that research is currently insufficient, “so I don’t think any of us can say definitively that it will work or it won’t work.”

“Isolated examples” show that it might be efficacious, but that’s not enough “evidence to actually run a full-blown human clinical trial,” he explained.

Produced by HD community members in 2016, The Blue Solution video suggests that families can consult their doctors about methylene blue.

However, Dr. Pacifici cautioned against this approach.

“A lot of times people have said things like, ‘Well, as long as it doesn’t do anything bad, why not take it,’” he remarked. “I think that’s a little bit dangerous. First of all, you never really know whether or not something is safe and well-tolerated until it’s tested.

“There are examples of opportunity costs. There are people who were on Co-Q 10 who were not allowed to participate in other, real trials because they were loaded up with Co-Q 10. So, the idea that ‘it’s probably safe, and I’ll take it in case it is good,’ I wouldn’t certainly advise somebody to go just based on that limited amount of evidence.”

Diet and lifestyle

I asked Dr. Pacifici why so little research has focused on HD and diet and whether it should.

“It doesn’t surprise me that people are curious about this,” he said, citing the example of Lorenzo’s Oil, a nutrition-based treatment developed for adrenoleukodystrophy, a deadly genetic brain disorder rarer than HD.

“In fact, we’re very careful,” he said of CHDI’s mission. “One of the reasons we say that we’re trying to accelerate ‘therapies’ for HD – we don’t say accelerate ‘drugs’ – is because we don’t know what shape that therapy could take. We want to be deliberately inclusive. In fact, I wouldn’t even limit it to diet. I would say ‘lifestyle.’”

He recalled the research of Jenny Morton, Ph.D., who works with transgenic HD mice and sheep. Dr. Morton observed in an experiment that HD mice had erratic sleep schedules – as do HD-affected people. She placed them with normal mice, giving them sleeping and wakeup pills, and gave them things only at night, a mouse’s normal time for activity.

“She was able to show that those mice now absolutely were back to their regular rhythm – they had no choice – and actually it was very beneficial for them,” Dr. Pacifici noted. “They actually even lived longer.”

Keeping our eye on the ball

With the advent of historic clinical trials such as the Roche Phase 3 gene-silencing program, “we’re at a stage now where there are some unbelievably compelling drug candidates,” Dr. Pacifici remarked.

“I guess the question we have to ask ourselves is: how much do we want to take our eye off the ball?” he asked. “Imagine how tragic it would be if there was something that collectively we, with CHDI’s involvement, could do to make those things successful and we were distracted with something else that had much lower probability of success.”

The HD community needs to “discipline” itself to focus on the “very best” possibilities for treatments and avoid “diluting our efforts the way we did in the old days” and “detracting resources.”

For a disease as complex and devasting as Huntington’s, there are no easy answers. The HD community – affected families, scientists, advocacy organizations, foundations, and our supporters – must continue the hard but brave march towards therapies.

CHDI: many 'irons in the fire' in quest for Huntington's disease therapies from Gene Veritas on Vimeo.

Roche ramps up Huntington’s disease clinical trial for early- to mid-stage stage patients, considers ways to expand research

Pharmaceutical giant Roche’s historic gene-silencing clinical trial for Huntington’s disease is now ramping up, with the firm’s scientists “actively thinking” about when and how to expand research to target groups beyond the current criterion of early- to mid-stage HD patients aged 25-65, said the program’s scientific coordinator.

“We’re excited to be moving forward with the Phase 3 program,” said Scott Schobel, M.D., M.S., Roche’s associate group medical director and clinical science leader for the HD drug RG6042. He spoke in a February 26 interview with me during the 14th Annual HD Therapeutics Conference in Palm Springs, CA.

In the Phase 3 clinical trial, called GENERATION HD1, some groups are excluded, such as presymptomatic gene carriers like me (also known as prodromal or premanifest individuals) and juvenile Huntington’s disease (JHD) sufferers, because of the need to first prove RG6042’s efficacy in people where measurements can best be made and, in Dr. Schobel’s words, “most likely to show an effect.”

“Though we do not have a planned prodromal trial, we are actively thinking about what that would look like, should the lead studies be supportive of pursuing that route,” Dr. Schobel said. Similarly, for expanding to JHD and other age groups, “we’re also having discussions.”

“That desire [to expand access] comes from a place of having seen and interacted a lot with the community and understanding the severe unmet need of [treating] juvenile HD, on the one hand, and also the highly compelling nature of preventing the decline from occurring in the first place, the ultimate goal of a Huntington’s therapy,” Dr. Schobel explained. “Symptom reduction is great, and we hope to have great effects in manifest, but well recognize that the ultimate goal would be to help, let’s say, the ‘generation next’ that’s coming.”

At the moment, demonstrating RG6042’s effectiveness in GENERATION HD1 is Roche’s main goal. “For us to get to that expand strategy, we need to have confidence in evidence generation from the lead studies,” Dr. Schobel said. “I don’t think we’re there today, but I think we could hopefully get there in the course of the program.”

(The failure to discover effective Alzheimer’s disease treatments after hundreds of clinical trials has led researchers in that field to start including prodromal individuals in trials.)

Background on GENERATION HD1

Designed and tested in a successful Phase 1/2a clinical trial by Ionis Pharmaceuticals, Inc., RG6042 substantially lowered the amount of mutant huntingtin protein in the trial volunteers’ cerebrospinal fluid (CSF). Those impressive results prompted Roche, the drug’s license-holder, to accelerate the development of RG6042 and go directly to Phase 3.

In January, Roche announced that it had enrolled its first participant in GENERATION HD1. The trial is currently under way in Canada and the U.S., and Roche recently announced planned sites in Spain and the United Kingdom. It plans a total of approximately 660 participants at 80 to 90 sites in about 15 countries.

In addition to GENERATION HD1, all 46 participants in the Phase 1/2a study enrolled in a 15-month “open-label extension” (OLE) study that assesses the safety and tolerability of longer use of RG6042 and provides further data in support of GENERATION HD1. Those who got the placebo originally now get the medicine.

Roche is also conducting a 15-month observational study – without a drug – called The HD Natural History Study (NHS). It is gauging the natural progression of the disease in up to 100 participants with early-stage HD in Canada, Germany, the United Kingdom, and the U.S. This study seeks to deepen understanding of the role of the mutant huntingtin protein in the progression of HD.

RG6042 is a drug molecule known as an antisense oligonucleotide (ASO), an artificial strand of DNA. This particular ASO partially blocks the production of the huntingtin protein, the mutant form of which causes HD. RG6042 is a non-allele-specific ASO: it reduces, or lowers, both the mutant and normal (wild type) huntingtin protein. Researchers in other labs are working with allele-specific approaches to target only the defective huntingtin protein.

As in the Ionis trial, in GENERATION HD1 doctors inject the ASO into the CSF with a spinal tap (also called a lumbar puncture) into the so-called intrathecal space of the spine. Participants are receiving a monthly spinal tap over 25 months as part of a three-arm study (two with drug and one with placebo).

For details and background on GENERATION HD1 and the associated studies, click here, here, and here.

In late February, it was reported that Roche had agreed to pay $4.8 billion to acquire Spark Therapeutics, Inc., a Philadelphia-based biotech firm focusing on gene therapy approaches to genetic diseases, including HD. The potential significance of this pending deal is part of the discussion below.

Designing and executing the clinical trial program

Dr. Schobel, based at Roche’s headquarters in Basel, Switzerland, received his medical degree from the University of North Carolina at Chapel Hill. From 2001-2012, he was affiliated with Columbia University in New York City. He interned in medicine and neurology, did a residency in psychiatry, and was an assistant professor in both medicine and clinical psychiatry. 

In 2013, the year Ionis and Roche agreed on a partnership, Dr. Schobel joined Roche as a translational medicine leader - focusing on the discovery of potential treatments to go into clinical trials.

In December 2017, he became the associate medical group director and full-time clinical science leader for the RG6042 program. He oversees the scientific design and execution of GENERATION HD1 and the associated studies, including the selection of the target population, the length, dosing frequency and levels, clinical outcome measures, and selection and assessment of biomarkers (signs of a disease or a medicine’s effect on it).

Dr. Schobel’s team collaborates with Roche data scientists on the system of digital biomarkers. He is also supporting the regulatory efforts for seeking health authority approvals for the clinical studies to run in the various countries involved in the study. His team also addresses any adverse events (AEs) that clinical trial volunteers might experience in the program.

“Really in this field at this time, this is absolutely a dream job,” Dr. Schobel said. “I wake up every day with utter enthusiasm for the potential of this molecule and to make sure that we do the best by seeing if it works or not, because we still don’t know.”

At the HD Therapeutics conference, sponsored by CHDI Foundation, Inc., Dr. Schobel was the senior author of the scientific poster that won third place in a competition that involved a record 115 posters. The poster resulted from research based on electroencephalography (EEG) readings of brain waves taken from the participants in the Phase 1/2a trial.

The work confirmed the EEG readings as potential biomarkers for clinical studies. (Click here to watch a presentation of the poster by Lauren Boak, Ph.D., of Roche. For further background on EEG, click here.)

Just before our interview, Dr. Schobel participated in a CHDI panel discussion on the question: how should the HD community prepare to follow up on the results of the huntingtin-lowering clinical trials, whether positive or negative? We addressed that and other key themes.

Scott Schobel, Ph.D., M.S., of Roche, with Anne Smith, Ph.D., Ionis director of clinical development, at the 2019 HD Therapeutics Conference (photo by Gene Veritas)

Several years to complete the study

GV: How many participants have enrolled so far in GENERATION HD1?

I can say that there are several sites open already in the U.S., Canada, and, as we just announced, we’re imminently starting up in the United Kingdom and Spain. We’re essentially in a ramping up phase of the pivotal study.

I think we’ve had a good start, though. We've met our target to enroll either by the end of 2018 or early 2019. That’s a massive accomplishment, from only one year ago completing Phase 1. We’re happy and proud about that.

GV: For each participant, it’s a 25-month study. Can you project at this point how long the trial will last? 

SS: We don’t know exactly at this point. If you assume that recruitment’s not going to happen overnight, and we have a two-year treatment length, then we have to plan on it being at least a few years for the primary outcome from the trial [to be ascertained]. It’s always based on when that last person is enrolled.

We think that [the 25-month study] length is necessary. We don’t want to sell short the ability to judge drug effect. It may take some time to determine adequately benefit/risk ratio.

Considering the broad continuum of HD

GV: The CHDI panel in which you participated today (February 26) asked how the HD community should prepare for both positive and negative trial results. What is the takeaway message?

I think there was a call for collaboration for leveraging the strength of the biological pathway [lowering the huntingtin protein] to enable more rapid assessment whether drugs are effective or not. I think there was a focus on being sensitive to covering the [various] stages of disease with the interventions [treatments] and not just focus narrowly on one stage of disease, but try to broaden that out, to de-risk the possibility that therapies may be more or less effective along [certain points of] the continuum of HD.

I was very thankful actually that CHDI organized that, because I think that getting us as a community, including industry but also academics and the broader community, to start thinking of these questions together proactively is a really good thing.

GV: The trial drug is for people aged 25 to 65. If the drug is successful and approved, would that mean that only people between 25 and 65 could take the drug? Would it specify that range on the label? Or would it be something that doctors could prescribe as they saw fit?

SS: This is a complex question, because it involves what regulators do when they grant a label, depending on study results. But we should not speculate. 

Despite a scenario of regulatory approval, there’s still the issue of access to the medicine. For access, as I’ve learned from my colleagues who are focused on this area, this is about the evidence package in support of giving the medicine to a population who you know will benefit based upon the evidence.

We wanted to start with a target population we knew would be sensitive to decline over the observation period, so that if our drug works we can measure the effect.

The studies are designed to provide health authorities with the required data so that the benefit-risk of RG6042 can be determined as quickly as possible. The ultimate goal is that RG6042 can be approved by health authorities and made accessible to the broader HD community.

Because that’s our primary purpose: if we don’t set ourselves up for success on our trial, none of those issues will ever matter, because you haven’t even proved the main point in the population most likely to show an effect, in our best judgment. A little narrow by design, but with the ambition to go broader, with more evidence generation.

Building the evidence for RG6042

GV: What is your scientific assessment of RG6042 as a potential HD drug?

SS: I feel very good about the potential of RG6042,but there is more we need to learn to fully understand the benefits and risks of RG6042. I’m well aware of a truly exhaustive preclinical set of studies [in animals], which optimized this particular molecule for clinical development. That was done head-to-head versus allele-specific agents, other non-allele-specific ASO agents, and this candidate essentially proved that it was efficacious across multiple models and also safe and tolerated, including what is now a completed toxicology package, including a chronic nine-month study [the Phase 1/2a study, which involved four doses over three months, plus six months of observation]. I’m very confident that we have a good molecule in the clinic on that basis.

What’s now better still is that we’ve had our successful completion of the Phase 1/2a study. Though I can’t comment specifically on aspects of the ongoing OLE, because that will only be presented in organized forums like podium presentations, etc., I can say now that we’ve been in that study over a year, so that also gives me confidence that this is something that could be suitable for a chronic treatment paradigm.

I think the pieces that need to come in now are the things that are going to take a little longer, that might require some patience, importantly efficacy and long-term safety in a larger group of patients. We’ll await the randomized [Phase 3] trial result, as the ultimate confirmation of that.

The open-label extension is our most advanced study. We’re quite focused on learning about the drug from that study, comparing the two treatment regimens [different frequency of drug] and the associated safety/tolerability, PK of the drug [pharmacokinetics: absorption, distribution, and metabolism of a drug], PD [pharmacodynamics: effect and mechanism of a drug] and exploratory clinical outcomes over 15 months, although note this is in an open label/not placebo-controlled setting. That’s obviously going to finish before the end of the pivotal study.

We’re pairing that with a Natural History Study to understand what we can be most confident of measuring in the open-label study, which is measures on objective biomarkers like mutant huntingtin. We can compare that against this matched natural history cohort over a longer time frame to understand not only the longer term safety/tolerability from the OLE, but also then the putative efficacy on the biomarkers and the clinical outcomes and digital clinical outcomes that are in the OLE study.

We’re in a very good spot and moving forward.

Expanding access to other disease groups

GV: So, the people in OLE will stop at 15 months?

SS: No. There is another study, which actually has been drafted and planned, that is essentially an extension of the first OLE study. And that’s known as the GEN-EXTEND Study. That will be an extension study for all participants of Roche- or Genentech-sponsored studies: the OLE, NHS, and GENERATION HD1.

[In the U.S., Roche personnel and products still use the name Genentech, a major U.S.-based biotech firm acquired by Roche in 2009.]

GV: Let’s say GENERATION HD1 takes four years. So, the people from Phase 1 through GEN-EXTEND will be able to continue that entire time?

SS: Yes, that’s right – if they wish. We’re not going to leave anybody who’s been committing their precious time to be in a Roche study to not continue treatment while they wait.

GV: When you say “expand,” which you referred to at the CHDI panel, you’re thinking about including prodromal individuals at some point?  

SS: Exactly. We need to get information from the lead studies in manifest HD first. Though we do not have a planned prodromal trial, we are actively thinking about what that would look like, should the lead studies be supportive of pursuing that route. We have a strategic mindset, and we indeed want to fully test the lowering hypothesis. And we fully believe that HD is a spectrum, so those planning discussions are consistent with that philosophy.

There are other aspects. As a part of drug development requirements, in the European Medicines Agency [the equivalent of the U.S. Food and Drug Administration] you’re required to come up with a pediatric investigational plan in juvenile HD, which we care about greatly as well.

That desire comes from a place of having seen and interacted a lot with the community and understanding the severe unmet need of [treating] juvenile HD on the one hand and also the highly compelling nature of preventing the decline from occurring in the first place, the ultimate goal of a Huntington’s therapy. Symptom reduction is great, and we hope to have great effects in manifest, but well recognize that the ultimate goal would be to help, let’s say, the “generation next” that’s coming.

Gaining confidence in the drug

GV: Since the confirmation of Phase 3 at the 2018 CHDI meeting, what new insights have you gained about the drug and HD, including from the open-label extension of Phase 1/2a? Can you elaborate on anything beyond what we’ve already discussed?

SS: I can just say that, broadly speaking, we’re very happy to be in the position where we have an open-label extension study that’s generating information on a regular basis. That gives us more confidence in the chronic therapy paradigm. We weren’t there a year ago. We just had had a four-dose study. Now we’ve had an OLE study running over a year. Further details from that will need to await our organized planned presentations, but we fully intend to share on that experience as this year progresses. The details of that are pending an ongoing set of analyses that we have.

GV: Have there been any adverse events in the OLE?

SS: Well, every drug program has AEs. There are nuances and details of what kinds of AEs. I’m just not at liberty to talk about those at this time, mainly because we don’t have the analysis on our full data set and we will be presenting at a later date during the course of the year. 

GV: But if something severe happened, you’d have to stop.

SS: Exactly. A really critical aspect of that is that we’re required by regulatory authorities to give any update of new safety signals, and we do that, if it comes up. Similarly, we have regular feedback from our network of investigators. So, it’s this sort of constant triad of communication that we do. We’re watching this with a magnifying glass.

GV: Are there any new findings that you can report regarding biomarkers?

SS: Clearly this is of high interest to everyone. We fully intend to communicate this type of information as it becomes available and as the program matures. I think we’re well-positioned with this drug to anticipate more biomarker findings.

The Spark acquisition and broadening the drug playing field

GV: What does Roche’s pending acquisition of Spark Therapeutics mean for GENERATION HD1? 

SS: Just a disclaimer: I’m not allowed to speak of any details. The short answer is: absolutely no effect on GENERATION HD1. We’re fully committed to developing this ASO, RG6042.

GV: I meant in a positive sense, not that it’s going to interrupt GENERATION HD1. But, with Spark’s knowledge and technology entering into the mix, what other possibilities does it open up for Roche in terms of tackling HD?

SS: I think it does, broadly speaking, open up possibilities. I think it’s premature, even for our program, to give a specific answer about how that might take shape other than to give the general message that it’s a positive. Broadening the playing field of therapeutic options that lower huntingtin is a good thing. I think that should be rightfully recognized by the HD community as well.

GV: They and other people work with viruses to deliver drugs. Is there any way RG6042 could be delivered via a virus?

SS: I don’t know the answer to that question. ASOs don’t need vectors, because basically they freely diffuse into cells and tissues. I don’t know that you’d even want to go to the trouble of putting it into a virus. As long as you’re getting an ASO into the CNS [central nervous system], to the intrathecal space, that in principle could be up high through the ventricles [the center of the brain] or anywhere along the neural axis [CNS]. It’s never come up as a strategic priority or focus.

What we are focused on is exploring alternate modes of delivery for the ASO. We like the idea that ASO therapy generally is periodic, dose titratable [adjustable], reversible. The thing we hope to do over time is to be able to learn and optimize a frequency of administration and dose of administration, to limit the burden of repeated lumbar punctures. Maybe through a device you don’t have to always access the intrathecal space. These are things we actually think about, because we well recognize that if this therapy works, it will be a chronic therapy.

Alternative drug delivery methods

GV: Is there any update you can give on brain shuttle research at Roche? As a technology that could get a drug past the blood-brain barrier, the brain shuttle might allow for a drug in the form of a pill.

SS: The brain shuttle technology is generally being pursued at Roche aggressively. It is not our lead strategy with this molecule, which is already having such promise through the intrathecal route. Could that still be a future possibility? I can’t really speculate on that, because it’s right now not in our core focus. What we need to do now with this ASO is test the hypothesis: does it work for HD? We know that that we can do that successfully with confidence through the intrathecal route. Once we do that, then we open up all kinds of possibilities for delivery modalities, including, in principle, technologies like the brain shuttle.

GV: You mentioned the word device. Would that be a pump?

SS: You must give ASOs by bolus injection [a single, large administration of a drug], generally. That promotes distribution. If there were a lumbar intrathecal device, it could help you access that bolus through a subcutaneous route and a port rather than needing to always go with the spinal needle into the intrathecal space. That kind of innovation is an example of what we’re actively thinking about. 

I can say that the intrathecal procedure, having now been steeped in it – and I’ve done a lot of lumbar punctures in my past role as a medical doctor before joining Roche, I’ve never done intrathecal dosing, but I’ve seen a lot now, talked a lot, and we know how it’s going in our studies – this is essentially a 20-minute procedure that’s outpatient.

We collaborate very closely with our investigator network that does intrathecal. This is the big focus: to educate. I helped co-produce a video of best practice that we’re using in our investigator network. I think those are the kinds of efforts that we need to be doing as a community, to promote best practices and the ability to receive the drug, if it works.