After setback, Roche to run new clinical trial with Huntington’s disease gene silencing drug

 

After halting dosing in the historic Phase 3 clinical trial for its Huntington’s disease gene silencing drug tominersen last March, pharmaceutical giant Roche announced today that it will start a new, less ambitious Phase 2 trial, limited to younger adult patients with “less disease burden.” The goal is to measure tominersen’s efficacy against the progression of HD.

 

Disease burden is calculated using a person’s age and degree of genetic mutation: the higher the sum of those two factors, the higher the burden. Roche, after initial testing of the drug, skipped Phase 2, which typically tests safety and efficacy of different doses, to pursue a Phase 3 trial, which confirms safety and efficacy in a larger population. Now it is proceeding in a more typical manner.

 

Roche informed the global HD community about the new trial in a letter released today. Roche’s partner Ionis Pharmaceuticals, Inc., the original developer of tominersen, also issued a press release.

 

“New exploratory post hoc analyses of GENERATION HD1 suggest that low exposure (less frequent dosing) tominersen may benefit younger adult patients with lower disease burden,” the Roche letter stated.

 

 

Low dosing meant volunteers received the drug every 16 weeks, while high dosing was every eight weeks.

 

“These findings, together with safety data of low exposure tominersen, support the continuation of the development program with a new Phase II clinical trial in younger adult patients with lower disease burden,” the letter continued. “While the findings are encouraging, confirmation in a randomised, placebo-controlled study is important.”

 

Post hoc analyses involve criteria set after data is seen, and “therefore they are not definitive,” the letter said. Because the trial was not specifically designed to run these analyses, the number of patients in the subgroups are small and the differences to placebo are not "statistically significant" and "could represent a chance result."

 

Even so, “these findings are promising and warrant a new study designed to test tominersen in this specific patient group,” stated Frank Bennett, Ph.D., Ionis' executive vice president, chief

scientific officer and franchise leader for neurological programs, in the press release. “This is an encouraging development for the HD community. We and Roche are grateful to the HD community's continued partnership, which has led to these important insights and a new scientific hypothesis [about tominersen].”

 

Maximizing benefits for HD patients

 

“It’s very exciting,” said Jody Corey-Bloom, M.D., Ph.D., the director of the Huntington’s Disease Society of America (HDSA) Center of Excellence at the University of California San Diego.

 

One of the GENERATION HD1 trial investigators, Dr. Corey-Bloom participated in a Roche-sponsored videoconference about the GENERATION HD1 findings that are serving as the basis for plans for a Phase 2 trial.

 

“They’ve analyzed the data in a very thoughtful manner,” Dr. Corey-Bloom said. “They’re hoping to really maximize benefits for at least a specific group of patients with HD, based on the results of their post hoc analysis.”

 

Roche is still planning the new trial. Therefore, it has not yet announced a timeline, sites, eligibility criteria, or information about dosing.

 

“This is just the news that should instill hope – a clear demonstration of the researchers’ commitment to regroup, redirect, and bravely move forward with its work on tominersen even after the challenges of 2021,” Martha Nance, M.D., the Center of Excellence director at Hennepin Health Care in Minneapolis, MN, commented by e-mail. “HD families, research scientists, and clinicians will need to work together in the coming years to determine when, whether, and how this drug can be delivered safely, effectively, and ethically to people in the earliest stages of HD.”

 

Representatives of Roche will present public updates on tominersen in previously scheduled webinars on January 20 for the European Huntington’s Disease Network (click here to register) and HDSA (click here to register). Another webinar, hosted by the European Huntington Association, will take place on January 24 (click here to register).

 

Roche is “resurrecting” tominersen in the “right way,” wrote Evaluate Vantage biopharma analyst Madeleine Armstrong. “Instead of running another phase 3, or indeed seeking approval, Roche is now going back to phase 2, although details are scant.”

 

With “no approved therapies for Huntington’s,” Roche “looks justified in trying again,” she added.

 

More results at upcoming conference

 

In an initial trial completed in 2017, Ionis had demonstrated that tominersen had successfully lowered the amount of the mutant, purportedly toxic huntingtin protein in the cerebral spinal fluid of a small group of volunteers.

 

Those impressive results led Roche to skip the standard Phase 2 trial and enter directly into Phase 3 (click here to read more). The GENERATION HD1 trial started in early 2019, enrolled a total of around 800 participants globally, and was to end in 2022.

 

However, in March 2021 a monitoring board conducting a standard review of trial data recommended that all dosing of tominersen in GENERATION HD1 be stopped. Roche decided to also stop dosing in a supporting trial. The following month Roche confirmed that trial data indicated that tominersen was ineffective and, in some cases, actually caused volunteers to worsen.

 

Roche is expected to present a detailed scientific update on tominersen at the 17th Annual HD Therapeutics Conference February 28-March 3 in Palm Springs, CA.

 

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

Annual Huntington Study Group meeting reveals an HD community energized to aid families, develop treatments

Moved online because of the COVID-19 pandemic, the 27th Annual Huntington Study Group Meeting nevertheless revealed an HD community committed to aiding affected families and developing cutting-edge treatments.

Originally scheduled for Atlanta, GA, the virtual conference took place from October 29-31, with more than 800 scientific and medical participants from around the world. The meeting featured two days of presentations concerning care of HD-afflicted individuals, as well as updates on key clinical trial programs, aimed at producing drugs.

 

On Family Day, which drew an estimated 180 additional people, the affected, caregivers, and advocates heard both expert presentations on coping with HD and highlights regarding research.

 

Research moving full steam ahead

 

Martha Nance, M.D., a long-time member of the Huntington Study Group (HSG) and the director of Family Day organizing committee, kicked off that event with a reflection on the “highlights and lowlights” of 2020 so far. A neurologist and frequent sounding board for this blog, Dr. Nance is also the medical director of the Huntington’s Disease Society of America (HDSA) Center of Excellence at Hennepin County Medical Center in Minneapolis, MN.

 

We all know the lowlights, Dr. Nance said: the COVID-19 pandemic, the death of George Floyd in Minneapolis, the 2020 election with its uncertainty, and climate change.

 

“For me, a highlight of this entire year was this meeting,” Dr. Nance said, referring to the great progress in HD research. “The last two days we heard about more things than you can shake a stick at.”

 

Dr. Nance listed the important developments detailed in the scientific talks, including several innovative ways to potentially block the harmful effects of the mutant huntingtin gene. Both the scientists and family members got updates on GENERATION HD1, the historic, in-progress gene silencing clinical trial by Roche aimed at reducing the amount of toxic huntingtin protein in the brain.

 

At the conference, several speakers referred to temporary slowdowns in research programs because of the new safety protocols resulting from COVID-19. Dr. Nance also noted difficulties in accessing some HD community members because of the pandemic in the U.S. and abroad, although she also has observed a helpful “explosion” in telemedicine.

 

However, despite the uncertainty about overall scientific research funding because of the COVID-19 crisis, “research is alive and well in Huntington’s disease,” Dr. Nance stated. “If what happened at this meeting continues, research in Huntington’s disease is moving full steam ahead.”

 

“I found the meeting to be energizing,” Dr. Nance concluded in an e-mail to me on October 31.

 

For detailed reports of the research presentations, see HDBuzz’s coverage by clicking here and here.

 

For the next year, HSG is providing access to on-demand recordings of the conference talks and other events. Click here to register for access.

 

‘Heroes,’ and a thank-you for me

 

Dr. Nance devoted most of her Family Day introduction to counterpoising the difficulties of 2020 with the stories of “heroes” who have stepped up to assist others in the HD community by exercising their unique skills.

 

“We need to hear about some people who’ve done good things,” she explained. “I hope that you can emboldened, empowered by some of these heroes.”

 

Dr. Nance – to my surprise and appreciation – began with the example of me, Gene Veritas (aka Kenneth P. Serbin), the author of this blog, now in its sixteenth year. Dr. Nance recalled how she and I had worked together on our college newspaper (click here to read more). She said that I use my journalistic skills to help inform the HD community, and to be “very up front about my struggles and fears” as a carrier of the HD mutation.

 

I write in this article about myself because Dr. Nance stressed how important it is for the HD community to be informed about its social ramifications.

 

‘I can’t breathe’

 

Dr. Nance recalled my September 2014 report on Jeffrey Bane, a West Virginia man arrested because the police misunderstood his HD symptoms to be the result of narcotics abuse (click here to read more).

 

Dr. Nance replayed the video of a bystander who had filmed Jeff suffering injuries as the police held him to the ground, thinking that, with his involuntary, HD-caused movements, he was resisting arrest. “I can’t breathe,” Jeff said desperately as he asked the officers for help.

 

Jeff only received the help of paramedics after the police had held him to the ground for almost ten minutes, Dr. Nance pointed out. 

 

Then she asked the attendees “to just take a deep breath, pause, and think for a minute.”

 

After 54 seconds elapsed, she resumed her presentation. “Hopefully you took a deep breath,” she said. “I think probably you felt anger, hate, sorrow, sadness, fear, anxiety.”

 

She continued: “We can’t change something that happened six years ago. What we can do is try as hard as we can to keep events like this from happening against in the HD community.”

 

Dr. Nance noted that HDSA has a toolkit for educating first responders, police officers, and fire personnel about HD. The organization provides other resources (such as a special HD ID card) to help HD-affected individuals and their families prepare for potential encounters with the police, she added.

 

(I have explored these crucial themes in other articles. Click here to read more.)

 

‘Your life matters’

 

In examples surely moving to the audience, Dr. Nance presented the stories of several other HD “heroes.” 

 

Inducted into the Minnesota Auctioneers’ Hall of Fame in 2005, Joe, whose wife and daughter died of HD, took “his grief, his sadness, his sorrow” and raised money and bought electric toothbrushes for hundreds of HD-afflicted people, Dr. Nance recalled.

 

As a ten-year-old watching his mother face HD, B. J. Viau started an annual basketball hoop-a-thon that over the years raised some $750,000 for HD research. Among other things, B. J. went on to become one of the founders of the highly active international Huntington’s Disease Youth Organization. 

 

Diagnosed at ten with juvenile HD, Elli started kickball tournaments to support the cause. She became an internationally recognized HD advocate.

 

Dr. Nance also recognized the 791 “heroes” who are taking part in the GENERATION HD1 clinical trial.

 

With HD, she said, it’s easy to become angry, sad, and depressed. However, people can also “stand up tall” to help others. We need more everyday heroes, she added.

 

“Your life matters – not to take away from anybody else whose life matters,” Dr. Nance said in closing. “What you do makes a difference.”

 

Dr. Martha Nance (left) praises the advocacy of juvenile Huntington's disease-affected Elli Hofmeister (in images at right) at the virtual 2020 HSG Family Day (screenshot by Gene Veritas).

Striving to overcome the doom of Huntington’s disease

Usually, I experience a whirlwind of emotions during and especially immediately after the annual Huntington’s Disease Therapeutics Conference, held in Palm Springs, CA.

This year, however, intensifying my advocacy in what I call the “HD movement,” I feel that I’ve reached another level of engagement. Paradoxically, at the same time, I feel that I’ve attained greater calm and insight regarding the disease and its impact on the community.

After my last article – on the pathbreaking scientific evidence suggesting how and why the HD age of onset varies widely and how I’ve reached 60 healthy – I’ve read stories in Facebook HD groups confirming that variability.

Some pointed to extremely early, very tragic onset, but others resonated with my (very fortunate) situation of having gone more than a decade beyond the point of my mother’s first symptoms. Significantly, scientists are seeking ways to use the biological mechanisms behind delayed onset to produce treatments.

As I pondered those more optimistic scenarios, I thought: “Does HD have to be only a story of doom?”

Clearly, in many instances, it still is.

On February 19, at the packed, moving screening of the HD documentary Dancing at the Vatican at my university, one HD family member recalled how, out of ignorance, both a parent and a grandparent had been kept in a straightjacket.

However, the collective celebration of the film’s portrayal of Pope Francis’ historic audience with HD families in Rome also demonstrated how far the HD cause has come. Thanks to Francis – but also to thousands of family members and advocates around the world – HD is “hidden no more.”

A life-size stand-up poster of Pope Francis at the February 19 screening of Dancing at the Vatican at the University of San Diego (photo by Gene Veritas)

How far we've come

An illuminating panel discussion at the screening illustrated how awareness has grown on all fronts. The presence of representatives from four biotech sponsors underscored the growing commitment to discover effective treatments.

The evening of February 21, the mother of a young man who died of juvenile HD left me a voicemail. She spoke of how the near-20-year struggle to care for her son led her to develop bipolar disorder and PTSD.

That sounds devastating. However, she also reminded me of an important trend in the HD community, in which the affected are no longer referred to as “HD people” but as “people with HD.”

“You’re not Huntington’s disease,” she said. “How could I ever look at my son and think, ‘disease?’”

At this evening’s opening of the 15th Annual HD Therapeutics Conference, sponsored by CHDI Foundation, Inc., I will have renewed hope for the development of effective treatments. As understanding of the disease has evolved, so have the approaches to achieving those treatments.

On February 27, conference attendees will hear a report on a clinical study investigating RG6042, the gene-silencing drug also currently under evaluation in a Phase 3 clinical trial run by Roche.

If successful, that trial will have produced the first treatment to slow, halt, and perhaps even reverse HD.

That could signal the end of doom for tens of thousands of HD-affected families around the world.

What if we could turn off the cause of Huntington’s disease?

What if scientists could simply switch off a mutated gene causing a debilitating neurodegenerative disorder like Huntington’s disease?

Known as gene (or genome) editing, that approach is a current hot research topic, generating hope for sufferers of genetic diseases like HD.

Gene editing will be the focus of a symposium on September 4 sponsored by life science start-up incubator Johnson & Johnson Innovation, JLABS (hereafter simplified as JLABS) and the Janssen Pharmaceutical Companies, the drug-discovery arm of Johnson & Johnson, in San Diego, CA.

At the sponsors’ invitation, I will give a presentation, based on my two decades as an HD advocate, on the health and social challenges faced by HD-affected individuals and their families. The two firms have also invited seven leading scientists and biotech executives to speak at the symposium, titled “Science Alliance: Silencing Neurodegenerative Diseases and Sensory Disorders with Gene Editing.”

HD community members can watch the live webcast of the event for free by registering at the event website and entering the discount code “HDCOMMUNITY” at check out. Attendance in person is $35 for the general public and $20 for students and academics, at the JLABS facility at 3210 Merryfield Row, San Diego.

Recent milestones in gene therapy “have ignited interest” in the field and “especially its application to neurological disorders,” the website states. Gene editing has opened the door to innovation in the treatment of diseases like HD, spinal muscular atrophy, and ALS, according to the organizers.

The website points out that, as the technology progresses, key questions are emerging, such as how to effectively deliver gene editing drugs to the brain.

Owned by Johnson & Johnson, JLABS provides labs, offices, marketing, education, and events for early-stage life-science companies unaffiliated with Johnson & Johnson. In San Diego, one of the world’s leading biotech hubs, it offers services to 60 companies; globally, JLABS serves 580 companies.

The pharmaceutical arm of Johnson & Johnson, the Belgium-based Janssen was acquired in 1961.

Advances in gene editing

Gene editing is different from gene silencing, the technique used in the Phase 3 Roche clinical trial currently in progress in the U.S. and a projected 17 other countries (click here to read more). Roche’s RG6042 is an antisense oligonucleotide, an artificial strand of DNA designed block the production of the huntingtin protein in brain cells.

With gene editing, scientists make changes in the actual DNA – a revolution in biomedical research.

The gene-editing technology currently getting the most attention – one already used in the search for HD treatments – is known as CRISPR. Scientists first observed CRISPR occurring naturally in bacteria in the 1990s. In 2002, scientists discovered additional DNA instructions called “Cas.” The combination CRISPR/Cas actually comprises the bacterial immune system. (Click here to read more.)

“There’s no equivalent of word processing software to edit genes,” then Ph.D. candidate Leora Fox (now a Ph.D.) wrote in HDBuzz in 2017. “To fix genes on a microscopic scale, one cell at a time, the faulty code has to be located and physically cut – and that’s what CRISPR/Cas does.”

To alter a gene, scientists need to insert CRISPR/Cas into the cells.

(Image credit: Ernesto del Aguila III, National Human Genome Research Institute, and Wikimedia Commons)

In a disease like HD, the goal is to use this mechanism to cut directly (that is, shorten) the defective, elongated gene. Researchers are also looking at other ways to deploy gene editing.

In recent years, HD research groups have used this technology to edit the HD gene in the brains of genetically modified “HD mice”. One group developed a technique that led to beneficial effects in mice, including the recovery of older mice that had already developed symptoms. (Click here to read more.)

Chinese researchers have used gene editing in human embryos to fix the mutation behind the blood disease beta-thalassemia, which reduces the amount of red blood cells. However, the embryos were not implanted. 

Gene editing is still far from use in human clinical trials. Among the challenges, scientists need to find ways to effectively deliver such a treatment to the brain and avoid inadvertent editing of other genes. (Click here to read more.)

(Late last year a researcher in China claimed to have used CRISPR to alter the genomes of twin baby girls through in vitro fertilization to enable them to resist potential infection from HIV. The news of this development sparked renewed controversy over the use of biotechnology to intervene in human life.)

The symposium participants

To explore gene editing in neurodegenerative and sensory disorders (difficulties with the five senses), JLABS and Janssen have invited seven researchers and executives to the September 4 symposium, including at least two with experience with CRISPR. They include:

Leah Aluisio, Associate Director, Janssen Research and Development;

Alexis C. Komor, Ph.D., Assistant Professor, Department of Chemistry and Biochemistry, UCSD; 

Young Jik Kwon, Ph.D., Professor, Department of Pharmaceutical Sciences, University of California, Irvine, and co-founder, Responsive Polymers Therapeutics, Inc., and Jupiter Therapeutics, Inc.;

Sanjay Mistry, Ph.D., Head of JLABS @ San Diego, Johnson & Johnson Innovation, JLABS;

Gerry Rodrigues, Associate Vice President, Allergan;

Arthur Suckow, Ph.D., CEO, DTx Pharma; and

Gene Yeo, Ph.D., MBA, Professor, University of California, San Diego, and co-founder, Locana and Eclipse Bioinnovations.

Their bios are available on the event website.

Imagining a cure?

As a speaker, I hope to portray HD’s devastating impact and the urgent need for effective treatment.

In the HD world, scientists avoid the word “cure.” HD is so complex that many have said a cocktail of drugs will be needed to target the multiple problems in the brain and elsewhere in the body.

For the first time, actually switching off or completely removing a mutation might enable us to imagine the way to a cure.

Gene Veritas (aka Kenneth P. Serbin) (photo by Yi Sun, Ph.D.)

Roche gears up for pivotal Phase 3 Huntington’s disease gene-silencing clinical trial

Pharmaceutical giant Roche – currently without a timeline, but mindful of the urgency – is gearing up for the pivotal Phase 3 clinical trial of IONIS-HTT_Rx, the gene-silencing drug shown to dramatically reduce the amount of the toxic protein implicated in Huntington’s disease in Phase 1/2a trial results announced March 1.

The earlier study was aimed only to assess safety and tolerability, but also provided signals regarding the drug’s potential efficacy. IONIS-HTT_Rx lowered the mutant huntingtin protein an average of 40 percent, with a maximum reduction of 60 percent, in the cerebrospinal fluid (CSF) of participants in the Ionis Pharmaceuticals Phase 1/2a trial, completed in December 2017. Based on animal studies, that corresponds to reductions in the cerebral cortex of 55-85 percent. (Click here to read more.)

If Phase 3 is successful, that reduction in the cerebral cortex could mean alleviation or even reversal of HD symptoms. The source of thought and language, the cortex is the most developed area of the brain, and the most severely hampered by HD.

IONIS-HTT_Rx clinical trial leaders presented the results at the 13th Annual Huntington’s Disease Therapeutics Conference, sponsored by CHDI Foundation, Inc., and held at the Parker Palm Springs hotel in Palm Springs, CA. A nonprofit virtual biotech, CHDI has invested hundreds of millions of dollars in the quest for treatments, including a $10 million payment to Ionis, later repaid to the foundation. It has helped draw attention to HD in the pharmaceutical industry.

Roche officials confirmed that the company would take the unusual step of skipping a Phase 2 trial (testing efficacy for the first time) and going directly to a Phase 3 (confirming efficacy in hundreds of participants).

The impressive Phase 1/2a results were the best news for the HD community since the discovery of the huntingtin gene in 1993. Forty-six early-stage HD patients took part at sites in England, Germany, and Canada.

A partner in the Ionis HD program since 2013, Roche now holds the license to IONIS-HTT_Rx. It is already conducting an open-label extension of the Phase 1/2a study, whereby all patients – including those who got placebo – will receive the drug. The extension allows researchers to gather critical additional data for planning Phase 3.

Roche now calls the drug RG6042. “R” is for Roche, and “G” for Genentech, a major U.S.-based biotech firm acquired by Roche in 2009. The number 6042 is a standard drug number assigned by the company. All U.S-based Roche personnel and products still use the name Genentech.

With a 120-year history and about 94,000 employees worldwide, Roche will bring considerable resources to bear in the Phase 3 trial. Hundreds will become involved in the project. It had a major presence at the CHDI meeting: twelve researchers and other personnel attended, including Scott Schobel, M.D., M.S., clinical science leader of product development.

“We’re all in,” Dr. Schobel told me, referring to the company’s commitment to the program.

To learn more about the plans for Phase 3, I interviewed three key members of the HD team, all based at Roche headquarters in Basel, Switzerland.

Lauren Boak, Ph.D., in her twelfth year at Roche, is the global development team leader, responsible for helping design, set up, and analyze clinical trials. Also in his twelfth year, Erik Lundgren, a Harvard University MBA, is the lifecycle leader of the HD team, involved in the manufacture and supply of the potential medicine, plus related matters such as regulatory approvals and educating the community about the drug. In her fifth year, Mai-Lise Nguyen is the patient partnership director for the HD program.

Members of the Roche HD clinical trial team watch the presentation of the IONIS-HTT_Rx Phase 1/2a data, March 1, 2018. From left to right, Scott Schobel, M.D., M.S., Lauren Boak, Ph.D., Erik Lundgren, and Mai-Lise Nguyen (photo by Gene Veritas).

Phase 3 ‘appropriate and reasonable’

The three representatives were excited about working with the HD community and passionate about their work on the Roche HD project.

GV: From Roche’s standpoint, what was observed in the HD patients in the Ionis-HTT_Rx Phase 1/2a trial?

LB: We’re very pleased to see that over a number of increasing doses, over four doses, the drug was safe and tolerable in HD patients and, also, that there was lowering of huntingtin, in a dose-dependent manner. As you increase the doses, the protein reduction was also increased. So, fantastic results from that study.

EL: It’s a step towards validating this hypothesis that we can target and reduce the causal protein, the root of this disease. It’s extraordinarily important to be able to demonstrate that that’s possible therapeutically. But it’s also important to remind everyone that this is an early, Phase 1 study. It’s 46 patients, and we certainly all owe a debt of thanks to those 46 people for being a part of early research. This trial also only studied four doses.  So while we are very encouraged about these early results, there are still extremely important questions that we need to address as we go forward.

GV: Will you go straight to Phase 3?

EL: Yes. We do think it’s appropriate and reasonable to go from here into larger studies that would support registration and filings for drug approval, so what would typically be referred to as Phase 3. In a rare disease, it’s not necessarily important to think about Phase 1, Phase 2, Phase 3. What we’re really focused on is: what are the requirements of regulators to ultimately look at the supporting evidence for this experimental medicine and make a determination that it’s acceptable for approval and, ultimately, to make accessible to the HD community? That is a registrational study, or a pivotal study.

However, an important caveat is: ultimately, we need to engage with – and we’re doing this work – FDA and global health authorities to understand what those requirements are, and to make sure that we’re building a clinical study program that addresses their questions.

Gene Veritas (right, aka Kenneth P. Serbin) interviews Lauren Boak, Ph.D., and Erik Lundgren (photo by Mai-Lise Nguyen, Roche).

Confidence in moving forward

GV: Was it the strong data from Phase 1/2a that led you to this conclusion? Ionis officials said that huntingtin was lowered “beyond expectations” in the CSF.

LB: Actually, it’s more related to the disease itself, and how much we know about the underlying cause of Huntington’s disease. It’s a monogenetic disease, and we know that it’s caused by a mutation in the gene that leads to the formation of a toxic protein, mutant huntingtin. Because of that knowledge, we have elevated confidence – versus, say, other neurodegenerative disorders – that if we target that mutant huntingtin and reduce it, it will lead to clinical benefit. That gives us confidence that we would be able to have a shorter path to demonstrate efficacy and therefore get to an approved medicine.

EL: But it’s not only about the monogenetic nature of the disease; it’s about the incredible commitment and selflessness of this community that’s dedicated to building a knowledge base that we can hopefully use to really accelerate from this point forward. The evidence that has been generated for Huntington’s disease and by the HD community is what gives us that scientific confidence. It’s the work of groups like CHDI and the rest of the HD community over years – of being a part of registry studies, of really being committed to and dedicated to research. We say “thank you” to the community for doing that.

MN: We’ve had relationships with the community. Now we’re at the point where we can build them further, by having discussions with the patient groups, with HD-Cope. We’re speaking with members of the community to make sure that we’re designing this next phase together.

CHDI’s role

GV: It’s evident that the investment CHDI has made in Huntington’s research is part of what you’re talking about.

EL: Yes.

GV: Have you consulted with CHDI as you move ahead?

LB: One of the great achievements that CHDI has spearheaded is the development of the Enroll-HD platform. Obviously, this built upon Registry and other efforts in the field. What the Enroll-HD platform gives – with over 16,000 patients worldwide enrolled – is a wealth of data available characterizing the natural history of patients (people living with HD over a period of time). We can learn a lot from this data.

The way CHDI has funded this, it’s an open source available for all researchers and industry. It’s just an incredible resource that is actually unique to Huntington’s. It’s such a rich resource, because of the number of years since the gene’s been discovered, and the countless efforts that have gone into it. From the standpoint of working together with CHDI, we’ll certainly be leveraging this along with a number of other groups such as HSG [Huntington Study Group], EHDN [European Huntington's Disease Network], and just the broader community.

GV: In the pharmaceutical industry, how common is it to go from a Phase 1 directly to a Phase 3?

EL: It’s not particularly common. You need confidence in the science. You need a medicine that shows promise. And there needs to be some urgency: the devastation of this disease, and the urgent needs of this community.  So, while it is not common, there is a well established regulatory pathway for us to follow.

LB: This is very well recognized by regulatory agencies. That’s why there is, as much as possible, flexibility within the pathways available for diseases such as this, with this type of potential medicine. Other areas that have this sort of Phase-1-to-Phase-3, seamless approach include oncology, where you have the obvious devastation of cancer and life-threatening nature of the disease.

EL: The ability to target is the other place where this overlaps with oncology – the ability to identify biologically a target and to develop a molecule that can effectively engage with that target and act on it.

Ionis’ comprehensive preparation

GV: Is the extreme care, amount of time, and extensive collaboration that Ionis used in developing its antisense oligonucleotide drug (ASO, an artificial strand of DNA blocking the production of the HD protein) one of the reasons for the jump to Phase 3?

LB: Ionis has developed a very comprehensive package for this medicine, and their expertise in ASOs is unparalleled. They have done a lot of work to develop a preclinical package – the preclinical animal data – to support the move into the clinic. That strength in the preclinical package gives us confidence in what we see in the clinic. We’ve got evidence that the drug is getting into the brain and is lowering mutant huntingtin.

Our confidence in whether this amount of mutant huntingtin would be enough to potentially lead to clinical benefit in humans is based on this solid animal, preclinical package. If we lower mutant huntingtin to a certain extent, based on the broad phenotypic [observable] changes and improvements in animals, in HD transgenic models, that will lead to a similar, broad effects in humans. Obviously, we need to do the next clinical study to prove that the lowering of the huntingtin protein leads to improved symptoms in patients with HD.

In addition, the Phase 1/2a study was designed and executed seamlessly. They chose very experienced scientific and collaborative investigators. It was a very solid and dedicated team, as is, we’re learning, the HD community in general.

Adding the U.S., other countries

GV: What are the key elements of the work you need to do as you head into Phase 3?

LB: We’re starting to think about what the next clinical trial will look like, and how it will be designed. We’re working with different stakeholders that will help guide this, such as patients, patient organizations and the regulators, to understand what the needs are to move this drug forward to approval. That’s a big effort and well underway. The medicine is moving into a global study. The Phase 1/2a was in Germany, the United Kingdom, and Canada. This next study will be across more countries, including the U.S. So we’re at the stage of exploring what additional countries the study will be conducted in and then identifying sites.

EL: The other group that’s really important here are payers, so insurers or national payers in European or other non-U.S. markets. The goal is to make this medicine available to people, and that means you have to address regulatory questions first, then you have to provide compelling data so that insurers will allow people to have access to the medicine.

GV: Do you know much you’ll have to spend to get this into Phase 3?

EL: No. And it’s not something that’s the driving force. Honestly, at this point, it’s about getting the answers right. We’ve made significant investments, and we’ll continue to do what needs to be done to answer the questions in front of us.

GV: How many participants are you estimating will take part in the next phase?

LB: We don’t know at this point. It’s dependent on the final design of the study, how many dose arms [dosages] we have, the particular endpoints [outcome measures], as examples. But likely in the hundreds.

A ‘small army’ at work

GV: How many people at Roche are working on the project?

EL: It’s a small army [laughter]. Obviously, the number is increasing as we’ve opted into move the program forward. It’s a team that is mostly based in Basel, but is global in scope. It’s an incredibly passionate group of people.

GV: Are we talking dozens of people on the HD team? Hundreds?

EL: It will be hundreds, for sure. It takes an unbelievable amount of effort to go from here to where we and the HD community need to be. The global aspect is extremely important. If you’re living with HD – whether you have the gene yourself or are symptomatic or are a caregiver or just an interested party – it’s a very individual issue. So we have to find a way to serve the individual nature of this problem, but also have an eye to the global nature of what we need to do to be able to serve every appropriate person that could potentially benefit, and that’s not only people that reside within the United States, for instance. It increases the complexity of the work that we have to do quite significantly.

We’ll be communicating on sites and timing and all those sorts of issues later. I can confirm that U.S. clinical trial sites will definitely be included in for the next phase. The trial will be important, but the trial is not the vehicle for people to have access to the drug. Ultimately, approval by health authorities [in specific countries] is the path for people to have access.

Timeline pending

GV: When will the next phase will start?

EL: We can’t commit at this point to when the next phase will start. There’s just a lot of unknown factors. We understand that that’s a pressing question that everyone wants an answer to. What’s most important for us is doing the work to make sure that the pivotal study is going to address and answer all of the questions that need to be addressed. We cannot afford to cut corners.

GV: Do you have an estimate of how many years it will take?

EL: It depends on a lot of things. When do we get it started? How long do people need to be in a study for us to have confidence that, if there’s a benefit to be observed, we give ourselves the best chance to see it in that study? So is it a one-year, 18-month, two-year, three-year, or four-year study? We’re very data-driven in how we make those determinations.

Another huge factor is: how many patients will we need in the study? It’s going to go faster if it’s fewer patients. It’s going to take longer if it’s more patients. The other piece that’s really important is: how long does it take to recruit that number of patients for the study? We’ll be able to give you a better answer to these questions later in the year.

An HD patient (photo by Mike Nowak)

Roche’s interest in HD

GV: How and why did Roche get involved in this project? What is it about HD that has attracted the company?

LB: This project was of real high interest to [former Roche executive] Luca Santarelli and the neuroscience group at the time because of the incredible groundbreaking science that Ionis had done and the promise of this particular medicine and, clearly, what potential it had to transform the lives of those with Huntington’s disease.

EL: Our organization has two principal pillars. First and foremost, Roche and Genentech are science-based organizations. The first thing we look for is: is the science compelling? Is it innovative? Is there a hypothesis we have confidence in? Right next to that is the need of the community. We’ve got a really excellent track record of transforming diseases that needed transformation, and hard problems: oncology, multiple sclerosis, ophthalmology, immunology. From that perspective, Huntington’s disease is an area where the science is rich and the needs of the community very well-established.

We’re being flooded with people within Roche that want to be a part of the HD program, because it speaks so powerfully to those two central parts of really who we are as an organization.

Roche is known in the broader scope for the innovation and transformation we brought to oncology. A really great example of that would be in HER2-positive breast cancer. HER2-positive is the most aggressive form of breast cancer. It had significantly higher rates of mortality. But it’s now become what people would like to have because effective treatments are available.

It’s also a really good example of not resting on laurels. We brought a product called trastuzumab, or Herceptin, to that community in 1998. And then, within the past five or six years, we’ve brought two more therapies that have improved upon trastuzumab and led to even more radical improvements for those patients.

MN: That is probably our most famous medicine. Roche has 30 medicines on the World Health Organization’s essential medicines list. Roche’s legacy has continued to grow, including with the integration with Genentech, which was the first biotech company in the world.

A new era for neurodegenerative treatments?

GV: What other neurodegenerative diseases are you focusing on?

LB: In our late-stage portfolio, we have two monoclonal antibodies in development for Alzheimer’s disease, as well as a number of others in earlier stage development for Alzheimer’s, Parkinson’s and ALS. In neuroscience generally, we have Ocrevus, which was recently approved for multiple sclerosis. We also have a number of programs in development for neuromuscular disorders and autism.

GV: What would treating HD effectively with RG-6042 mean for the field of neurodegenerative diseases?

LB: It would be a historic moment obviously for Huntington’s disease patients, but for the neurodegenerative field in general. One of the achievements would be to get a targeted therapy to the brain. We’ve seen evidence of that already with this medicine. The next step is to show that reducing a causative protein leads to clinical benefit. If we can do this, the hope is that this will herald a new era for neurodegenerative diseases because of what we can learn from Huntington’s disease and then apply to Alzheimer’s disease, to Parkinson’s disease, to ALS.

GV: It seemed that the pharmaceutical industry was moving away from neurodegenerative diseases. The companies were frustrated because they couldn’t develop treatments. The scientists were frustrated because they nobody wanted to invest anymore. You have jumped into what appears to have been a difficult situation. Can you comment on this?

EL: Neurodegenerative diseases are hard, because the science is opaque in many cases. Getting medicines to the brain has been an incredibly difficult challenge. The endpoints – the way in which clinical trials measure a treatment effect – are complex. It’s hard to see and measure and be able to prove with statistics that you’re having an effect in neurodegenerative diseases. In some of these diseases, it can take a really long time for the disease course to run. It makes it hard to run these trials.

We’re not discouraged. We’re quite encouraged, because in this case we think we do understand the science. We have been able to demonstrate that RG6042 gets into the brain and that we’re able to affect this protein.

Rare-disease status not a problem

GV: How does the fact that HD is a “rare disease” factor into your plans for Phase 3 and the rest of the project?

LB: The fact that it’s rare from a clinical trial perspective is important. There aren’t as many patients to participate in a clinical trial as in other diseases. However, because of our confidence in our understanding the disease and the mechanism of the medicine, the actual clinical trial size doesn’t necessarily need to be that big.

Also, it’s a rare disease, but not very rare disease. It’s actually a high-prevalence rare disease. In the case of HD, we are blessed with clinical trial networks that already exist that we can leverage such as HSG and EHDN.

EL: I don’t like the term “rare disease.” It makes it feel small, something off to the side. What all of us are personally struck by is: if you’re an HD family or a gene carrier or affected with symptoms, it doesn’t feel small. We think of HD as a really big problem to address.

Spinal injections to continue

GV: In the Phase 1/2a trial, patients received the drug via an intrathecal (spinal) injection, with the medicine carried to the brain via the natural flow of the CSF. In 2013, Luca Santarelli spoke of a possible alternative: using “brain shuttle” technology to introduce the Ionis drug into the brain in the form of a pill. What is the status of this research? Will it be used in Phase 3?

EL: The brain shuttle is exciting. We continue to invest in understanding that technology better. For us, the most important thing right now is to demonstrate the safety and effectiveness of RG6042 in people living with HD. There is enough complexity with just that question that we need to be laser-focused on first addressing that one before we add in the additional uncertainty that would be introduced by the unproven brain shuttle. Longer-term, we understand the attractiveness of something like a brain shuttle in HD.

GV: So will Phase 3 use the spinal injection?

LB: Yes.

EL: An intrathecal injection is a way to get around the blood-brain barrier, one of the central problems of neurodegenerative diseases. It’s an effective and reasonably well-tolerated approach, especially in a disease like HD.

Participants to use special smartwatch

GV: What other new technologies, techniques, and approaches might be used in Phase 3?

LB: One thing that we are developing – building on recent experience in multiple sclerosis and Parkinson’s disease – is a Roche HD Digital Monitoring Platform. It’s a smartphone and watch for use in the clinical study. We’ve tailored it for Huntington’s disease to measure appropriate symptoms and activity in the disease. Instead of just irregular clinic visits – single-day data points on patients’ symptoms and how they’re feeling – we’ll have potentially daily, continuous monitoring of this.

This has potential to increase sensitivity to detect treatment effects. There are 365 days of the year, and imagine if there’s only twelve visits in that period. There’s a lot that happens over the course of a day, let alone a month. There’s an inherent problem also with being able to remember, for anybody, how you were feeling a day ago, let alone a week ago, etc. It’s your recall bias. We’re really excited about this. We’ve already started deploying it in the open-label extension study. We’re going to learn and perhaps adapt this for inclusion in the pivotal study, Phase 3.

GV: Will the participants wear electrodes?

LB: No, there is a smartwatch and smartphone and everything that’s already built in, like a gyrometer and accelerometer. These are sensors that will detect movement.

EL: We don’t want to miss any signals – good ones or bad ones – that our trial participants have. It gives us more confidence that we’ll be able to see something happening, measure it, quantify it, and, ultimately, prove it. This is obvious to the HD community, but it’s important for how we design our study. HD affects so many different domains. It’s not just walking speed and spasticity and motor symptoms; it’s cognition, too.

There are two aspects of this digital platform: active monitoring and passive monitoring. The active monitoring will have different tests for the individual to do on a given day, such as a walking or cognitive test. With the passive monitoring they can have the smartphone in their pocket or on a belt and be monitored on how much they move in the course of a day.

GV: Will it measure pulse or be connected to the blood in any way?

EL: No. It’s a smartphone like you buy off the shelf. The software is what’s special, and the analytics engine behind it. A tremendous amount of data comes in. The algorithms and how you make sense of that is what our team has been working hard on developing.

A graphic illustrating the Roche-HD Digital Monitoring Platform (source: Roche)

Earning the community’s trust

GV: For many people, including in the HD community, “big pharma” is just out for profits. I understand that these are business enterprises, and we don’t live in a socialist system. But then you have things like the opioid crisis, which is driven by a lot of bad actors in the business. There’s also the idea that some companies just want to go for blockbuster drugs while ignoring smaller disease communities. Would you like to comment on this?

EL: We’re all quite passionate about this issue.

MN: We can only speak to Roche. I personally think Roche is a very unique company. We’ve had the same name over the door for over 120 years. We are still a majority family-owned company. The Hoffman-Roche family’s descendants are still involved in the company. Our vice chairman, André Hoffmann, said a phrase when he was speaking with some students this past summer. He and the whole leadership team believe that Roche needs to be a “net-positive contributor” to society.

We are lucky already that our core business is about health care. We’re already a contribution to society. But how do you be that net-positive? It’s about serving healthcare solutions, but we do so many other things with the communities that we operate in and beyond, whether it’s with social programs and philanthropy.

EL: We owe it to the HD community to earn trust. So we’re here to listen and engage, and we hope to hear back from the HD community if we fail in that test. This is not transactional for us. This is about partnering to make a difference. We’ve all chosen to do this because we’re moved by it. On our life cycle team, we talk about what we care about. One of our core pillars is keeping people with HD in the center of every decision we make. At the end of every meeting, we go around the room and score ourselves on that. It is not lip service.

(For the slides from a March 2, 2018 conference call and webcast regarding the Ionis-Roche clinical trial program, click here.)

(For updates on the RG6042 program, stay tuned to this blog and also visit www.HDSA.org and HDSA's HD Trial Finder)

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