Monday, May 21, 2018

Free from the threat of Huntington’s disease, our ‘miracle baby’ turns 18


I dedicate this article to my daughter Bianca Serbin.

In June, our “miracle baby,” who tested negative in the womb for Huntington’s disease in 2000, will graduate from high school and turn 18. In August, she will enter the University of Pennsylvania, to study in its College of Arts and Sciences.

It is a watershed moment, a milestone I once feared I would not reach, and a sign—though hardly a final one—that our daughter is on the road to adulthood with her family intact.

Because I inherited the HD gene from my mother, who died of the disease in 2006 at age 68, I will inevitably develop symptoms. At 58, I’m well beyond my mother’s age of onset. Each day of health is a blessing and a privilege, as I witness so many of my affected “HD brothers and sisters” struggle with the disabling symptoms.

Scientists strive to understand why people like my mother and me, with the same degree of genetic defect, become symptomatic at different ages. Although there is no scientific proof, doctors and scientists have told me that leading an enriching life – and treating my health carefully – has helped me stay healthy.

I agree. Watching HD rob my mother’s ability to walk, talk, and care for herself, I could not imagine reaching this point free of the disease’s classic symptoms. Joining my wife Regina in guiding Bianca to adulthood has provided me with a deep sense of purpose, enjoyment, and pride.

With Bianca, we have also faced crises: being HD-free is no guarantee of perfect health or a worry-free life for her. As a result, we have become closer as a family, and Bianca has matured.

Now, as Bianca prepares to enter the next stage of life, I am deeply relieved.

I had feared not being able to watch her graduate from high school. As educator parents valuing quality schooling, we sacrificed financially to put her in a top private high school to give her the best chance to succeed in life. I had worried that, if disabled by HD, I could not help pay the bills and save for college.

I also feel a deep sense of pride, satisfaction, and accomplishment: I have fulfilled some key responsibilities as a father, handing Bianca the baton of life.


Bianca Serbin (family photo)

Because of the psychological trauma of testing Bianca in the womb, Regina and I decided against further children. Raised as an only child, Bianca needed to overcome shyness and social isolation. Her high school’s strong emphasis on academics and leadership helped her blossom in these areas.

Bianca and her generation will face immense challenges beyond the first-order responsibilities of learning, growing, and finding their place in the world. They are bequeathed such daunting social problems as gun violence, inequality, anti-democratic political movements at home and abroad, global warming, and nuclear proliferation – challenges my generation has failed to adequately address. They will need to exercise great leadership and form new social movements.

I believe they will. I am impressed with, and proud of, young people such as the Parkland, Florida, shooting survivors who have organized politically, refusing to accept the tiresome and dangerous status quo on gun violence. Their movement has the potential to impact society the way the civil rights and anti-war movements of the 1960s did. Bianca and her schoolmates joined students around the country in the local-level protests against the violence.

Raising a daughter in the era of #MeToo produces great angst. Bianca will need to be strong and independent as she navigates new challenges and, as in the fight against HD, she will need to find allies.

I’m confident that, no matter what path she chooses, Bianca will help make the world a better place.


Gene Veritas (aka Kenneth P. Serbin) with daughter Bianca (family photo)

Previous generations did not have our options. After the discovery of the HD gene in 1993, Regina and I became part of the first wave of couples testing babies in the womb, and later using preimplantation genetic diagnosis, to safeguard our children from the disease.

Regina and I were especially adamant about testing because, in a cruel twist of HD, men can pass on an even greater level of genetic defect, leading some children to develop the juvenile form of the disease.

Our generation of HD families have also become more outspoken about HD, a disease so terribly hidden and stigmatized in the past. It’s still that way for many families here and around the world.

I’ve always answered Bianca’s questions about HD, wanting her to learn about the topic with full transparency, to prevent the harmful effects of denial. She was first exposed to HD at the age of two by learning that her grandmother was ill with a “boo-boo on her brain.” At age nine, she learned that I carried the gene – but also that she did not.

Since childhood, Bianca has participated in HD fundraisers and other events. Recently, she has also volunteered for the local chapter of the Huntington’s Disease Society of America.

Bianca reads this blog regularly, a way for her to deepen her understanding of HD and to tighten her bond with me. I know that she loves me and is deeply concerned about my risk for HD.


Bianca, San Diego Chargers tight end Antonio Gates, and Gene Veritas at an HDSA-San Diego fundraiser, 2008 (family photo)

Throughout Bianca’s senior year, Regina and I have begun to brace ourselves for the empty nest syndrome.

At the same time, we’re very excited for Bianca. I’m looking forward to our family trip to Philadelphia to install her at Penn and help her transition to this new phase in her life.

Meanwhile, on the HD front, much work remains to be done: along with thousands of other Americans, I still face the threat of HD. We need to realize the dream of effective treatments – perhaps even a cure – that would allow me to live to a ripe old age and, with Regina, continue to enjoy the next stages of Bianca’s life.


Kenneth, Bianca, and Regina Serbin after Bianca's induction into the Cum Laude Society (family photo)

Thursday, April 26, 2018

New Ionis data show positive trends in clinical measures of Huntington’s disease drug trial volunteers


Exploratory analysis of new data showed positive trends in several clinical signs of Huntington’s disease in the recently concluded Ionis Pharmaceuticals, Inc., gene-silencing Phase 1/2a clinical trial, the company announced April 24.

“Results from exploratory analyses of data from the study demonstrated correlations between reductions in mutant huntingtin (mHTT), the disease-causing protein, and improvements in clinical measures of Huntington's disease,” an Ionis press release stated about its drug IONIS-HTTRx.

Initiated in September 2015 and completed in December 2017, the trial tested the drug in 46 symptomatic volunteers at nine sites in Canada, Germany, and the United Kingdom.

Because of the very limited size, duration, and scope of the Phase 1/2a trial, the newly studied clinical signals have only statistical importance. They do not demonstrate whether an individual patient got better, or by how much a person did better on a particular test.

However, they provide hope for the HD community because they showed an association between reducing, or lowering, mHTT, and the improved scores. The new data will help pave the way for the planned Phase 3 trial to test efficacy.

“These important clinical results further demonstrate that targeting the reduction of the toxic mutant huntingtin protein with IONIS-HTTRx has the potential to be disease-modifying,” Frank Bennett, Ph.D., Ionis senior vice president of research and franchise leader for neurological programs, stated in the release.

Sarah Tabrizi, FRCP, Ph.D., of University College London, the lead investigator of the Phase 1/2a trial, also presented the new information on April 24 at the annual meeting of the American Academy of Neurology (AAN) in Los Angeles. Out of more than 3,000 submissions, the talk was one of four selected for the top-featured session at the meeting, which drew more than 12,000 professionals.

Checking movements and cognitive loss

On March 1, at the 13th Annual HD Therapeutics Conference in Palm Springs, CA, Dr. Tabrizi revealed that the drop of 40-60 percent in mutant protein observed in the cerebral spinal fluid (CSF). Based on numerous animal studies done by Ionis, that corresponds to to a decrease of 55-85 percent in the cortex of the brain. The cortex is the most developed area of the brain and the source of thought and language, abilities severely hampered by HD. In the caudate – which helps control movement, another critical problem in HD – the corresponding decrease (based on animal data) ranged from 20-50 percent.

The new data demonstrate associations between reduction in mHTT (measured in CSF) and improvement on two clinical tests commonly used in HD clinical studies: the total motor score test (measuring impairments in movements) and the symbol digit modalities test (measuring cognitive loss).

The press release further noted a significant correlation between huntingtin reduction and an improved score on the Composite Unified Huntington's Disease Rating Scale (cUHDRS), which measures decline in patients.

Two tests showed neutral results: the stroop word reading (checking for cognitive loss) and the total functional capacity (assessing ability to perform daily tasks).


A slide from Dr. Tabrizi's talk at the AAN meeting illustrating improved scores in two clinical tests (top two graphs) and neutral scores in two others (bottom graphs) (slide courtesy of Ionis)

Larger, longer studies needed

At the AAN meeting, Dr. Tabrizi emphasized that the three-month Phase 1/2a trial was not designed to measure a true clinical benefit from IONIS-HTTRx. It sought primarily to gauge safety and tolerability of the drug.

The researchers used so-called “exploratory post-hoc analysis.”

As explained by Ionis officials in an e-mail, post-hoc means that Ionis did not predefine the analyses in the clinical trial protocol. Such analyses cannot provide conclusive proof of a drug effect. These analyses are common in early-stage clinical trials, where drug companies look for interesting signals worthy of careful evaluation in later-stage trials.

The officials also pointed out that, in analyzing the data using the gold-standard technique for demonstrating effect - comparing clinical test results of drug-treated participants with those on placebo - no improvements were found. This was not a surprise, given the limited scope of a Phase 1/2a trial.

In fact, they added, the trial planners included the clinical tests primarily to monitor for unexpected worsening.

The Ionis officials described the relationship between mHTT-lowering and potential clinical benefit as "subtle."

They emphasized the need for larger and longer trials to demonstrate efficacy.

A 'hint of clinical benefits'

“The measurements were done during the trial, but these statistical analyses were not pre-specified, and so we say that they are post-hoc and exploratory,” Jody Corey-Bloom, M.D., Ph.D., the director of the Huntington’s Disease Society of America (HDSA) Center of Excellence for Family Services and Research (COE) in San Diego, explained in an e-mail.

Dr. Corey-Bloom described the correlations between the clinical measurements and the reduction in the huntingtin protein as “positive but weak. This is very welcome news and clearly in the right direction! We will obviously need larger and longer studies to really confirm a potential clinical benefit, though.”

Swiss pharmaceutical giant Roche, which now holds the license to the Ionis drug, has confirmed that it will take the unusual step of skipping a Phase 2 trial and going directly to Phase 3. Phases 2 and 3 measure a drug’s efficacy. Roche, which renamed the drug RG6042, does not yet have a timeline. (Click here to read more about Roche’s plans.)

"Though press releases and post-hoc analysis can be problematic, the reported improvement in clinical measures in this early clinical trial, if borne out by subsequent study, is a ‘wow’ for the HD community,” LaVonne Goodman, M.D., the founder of Huntington’s Disease Drug Works, commented in an e-mail. “So I look forward to seeing the full data set in a peer-reviewed article. If results from this first trial are borne out in the larger Phase 3 trial, this drug is a game changer for HD. And also great, if results are similar to the present trial, it might take less than the earlier predicted three years to show it.”

“It is quite exciting to see any hint of clinical benefits,” Martha Nance, M.D., the director of the Minneapolis COE, wrote via e-mail. “It is important to know that these clinical results are not definitive, but this report adds to the growing list of favorable results from this groundbreaking trial of gene silencing in HD. The HD community has every right to be excited about these results!”

* * *

For additional coverage of the Ionis news, click here and here.

For HDSA's Q & A on the news, click here.

For background on the development of clinical tests for HD, click here.

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

(This article was updated on April 27, 2018, to include additional comments on the clinical trial analyses by Ionis officials.)

Friday, April 13, 2018

Nora Guthrie: we’re all ‘hoping machines’ in the fight against Huntington’s disease


The cause to defeat Huntington’s disease came full circle at the recent HD Therapeutics Conference, where keynote speaker Nora Guthrie recalled the brave struggle against the disease by her father, iconic folk singer Woody Guthrie, and the groundbreaking advocacy of her mother Marjorie, the founder of the Huntington’s Disease Society of America (HDSA).

“We are the hopers and the changers,” said Nora, 68, quoting her father, to the audience of 350 scientists, drug company representatives, and family advocates gathered at the 13th annual meeting in Palm Springs, CA, in late February. “The note of hope is the only note that keeps us from falling to the bottom of the heap of evolution, because about all a human being is anyway is just a hoping machine.”

The conference was sponsored by CHDI Foundation, Inc., the nonprofit virtual biotech dedicated to developing HD treatments. Like a number of past keynoters, Nora preferred not to have her presentation recorded. She interweaved her father’s music – he wrote “This Land is Your Land” – with the family’s struggles against HD.

However, Nora agreed to an interview with me in which she reflected on the early days of HDSA – started in 1967, the year her father succumbed to HD, when she was 17 – and the progress towards treatments.


Nora Guthrie (right) being greeted by Sarah Tabrizi, FRCP, Ph.D., with Blair Leavitt, MDCM, FRCP (left) and Gregory Suter looking on (photo by Gene Veritas, aka Kenneth P. Serbin)

A vast HD ‘tribe’

I was thrilled to meet Nora. Watching and interacting with her helped me connect with a giant of American history as well as with what she called the vast HD “tribe” that Marjorie had started.

Before our formal interview, in conversations with Nora, I also relived key moments in my personal journey with HD.

After her keynote, filled with emotion, I hugged Nora, telling her that my mother had died of HD.

Nora was at first befuddled by my pseudonym, “Gene Veritas.” I explained to her that it meant “the truth in my genes,” a reflection of my condition as an HD gene carrier.

During one dinner, I told how, in the late 1990s, my efforts to get background on the disease and the cause led me to study Woody’s life and watch the 1976 film Bound for Glory, based on his autobiography and portraying his early phase as a drifting folk singer. Nora recalled her personal impressions while on the set.

“I feel a spiritual connection with you and your family,” I told Nora at the outset of our interview. “Thank you for being here, and thank you for speaking out for us, just as your father spoke out for so many people.”

Impressed with the research progress

As I proceeded to my first question, Nora interjected: “Not just speak out, but speak up.”

In that comment, and many of her other responses during the interview, Nora quoted her father or echoed his singular eloquence with her own plays on words and unique phrasing.

I asked Nora what it was like to speak to the scientists.

“For me, it was like a sci-fi movie, because coming from my early years with Huntington’s with my father in the late 1940s and early fifties, when there wasn’t one person you could talk to, not one doctor that knew anything about Huntington’s, not one social worker to help you get through it, not one support group,” she said. “Our family was kind of inventing how to deal with Huntington’s in those days. There were no pamphlets. There were no guidelines. So, we were going day to day, day by day, inventing – trying to be creative, trying to be helpful, trying to figure out even what the symptoms were.”

Nora recalled the first HD benefit concert Majorie organized at Carnegie Hall in New York City in 1968, with Woody’s musician friends

Today, Nora said, just at events like the CHDI conference, hundreds of “young, energetic, and smart” people are focused on developing treatments – all descendants of Marjorie, the “Eve” of the HD movement. To Nora, they represent hope for the community. 

Devoted to preserving her father’s legacy, Nora still seeks to combine music with HD advocacy. She described the concert she organized last summer in Berlin, gathering musicians and HD families and organizations.

“For me, the music and the art and the sciences are one group,” she said.

You can watch the interview in the video below.


A cure: when, not if 

Like all children of an HD-afflicted parent, Nora was born with a 50-50 chance of having inherited the genetic defect. In her talk, she did not broach the issue of genetic testing. We also did not discuss it in our interview. For many in the HD community, that is a private matter. 

At age 68, Nora has passed the age of typical onset. She looks to be in excellent health. According to Woody biographer Ed Cray, Nora declined testing. So did her famous brother Arlo, a musician born three years earlier. Their brother Joady tested negative for HD in the early 2000s. (Two half-siblings died of HD.)

I wished Nora and her extended family the best of health.

Finally, I wanted to know what her parents would say about the advances in HD science, if they were alive today.

"I think the most impressive thing for them is an affirmation of their belief in humanity," Nora said. "That people are interested. That people do care. That a cure is down the road. It's just a question of when, not if."

Wednesday, March 28, 2018

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-HTTRx, 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-HTTRx 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-HTTRx 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-HTTRx. 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-HTTRx 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-HTTRx 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.)