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.

An ‘electric,’ inspiring Thanksgiving for the Huntington’s disease community

Thanksgiving is my favorite holiday. I’ve reflected on it many times in this blog. For me, rather than the commercialism and stress associated with the holidays, it’s truly a day of relaxation, the warmth of friends and family, and gratitude.

This year, the Huntington’s disease community has bountiful reasons for thanks. Several clinical trials to test what might become the first effective treatments are in progress, and the community has demonstrated spirited participation.

The historic Roche gene-silencing program successfully started its crucial third and final phase, GENERATION HD1, earlier this year. The program includes an open-label extension of all 46 participants in the first phase, completed in December 2017, all of them receiving the drug RG6042 via a monthly injection into the cerebrospinal fluid (CSF).

“Two years ago, we showed for the first time – about 25 years after the discovery of the gene –the ability to lower CSF levels of mutant huntingtin [protein] in patients with HD, which was a very exciting first-in-human accomplishment, and that was really the springboard that allowed us to proceed to our global development program,” Scott Schobel, M.D., M.S., Roche’s associate group medical director and clinical science leader for RG6042, reported at the 26th annual Huntington Study Group (HSG) meeting on November 8. “So these heroic 46 volunteers were the foundation of that.”

GENERATION HD1 is “recruiting incredibly well,” Dr. Schobel said. “It’s been absolutely electric.” Total worldwide enrollment in GENERATION HD1 and related studies has surpassed 800. “It’s been a huge response from the community,” he added.

Several other programs provided updates at the HSG meeting.

Although much work remains to develop effective therapies, HD families and their supporters can feel proud for helping further the progress achieved in 2019.

Priscilla’s inspiring fight and peaceful paintings

An HD-stricken woman I know from Brazil, Priscilla Ferraz Fontes Santos, embodies the life-force of the HD cause. I saw Priscilla in 2013 at the sixth World Congress on Huntington’s Disease in Rio de Janeiro, and got to know her at #HDdennomore, Pope Francis’ special audience with the HD community in Rome in 2017.

Brazilians don’t celebrate Thanksgiving, but Priscilla’s words, paintings, and photos help us feel the peace and hope of our quintessentially American holiday.

Priscilla was stricken with juvenile HD as a teenager. She had played soccer, pursued acting, and completed her journalism degree, but the disease prevented her from finishing a second degree in tourism.

Many juvenile patients do not live past 30. Priscilla is 36. She takes no drugs to control her involuntary movements and other symptoms but instead relies on alternative and spiritual approaches, including yoga. However, she also follows HD clinical trials and hopes for a cure.

Starting November 22 and ending December 10, Priscilla and her art teacher are staging an exhibit of Priscilla’s paintings in Serra Grande, a town in the state of Bahia. They have called it “Colored Atmosphere.”

Priscilla with two of her paintings (family photo)

“The past two and a half years, I have been taking painting and art classes, and I have discovered for myself the pleasure and well-being that painting brings,” Priscilla wrote in an introduction to the exhibit. “As I await the cure, I have gained the courage to overcome many difficulties and meet challenges with the ever-present support of my family, friends, and health professionals who care for me.”

Priscilla ended with this wish: “I hope that you enjoy my paintings and that they awaken in you all of the strength, beauty, and joy with which I painted them.” (I translated the text from the original Portuguese.)

Priscilla is an “inspiration of strength and positive thinking” for all of us, Priscilla’s mother Lígia wrote in a message in Brazilian WhatsApp group dedicated to the HD cause.

Priscilla practicing yoga (family photo)

Symptom-free, but awaiting treatments

As always, I am profoundly grateful for not having yet developed any of the inevitable classic symptoms of HD, which struck my mother in her late 40s and ended her life at 68.

I turn 60 next month – an age at which my mother had full-blown HD and could no longer care for herself.

Last week, I presented my new book on Brazilian history to an audience at the University of San Diego. I had never imagined I would still be able to write at age 60.

Even more importantly, I’m able to continue supporting and loving my wife Regina and daughter Bianca. A sophomore at the University of Pennsylvania and HD-free, Bianca will spend Thanksgiving with friends in Connecticut. However, in a few weeks she will be home for winter break.

I am crossing my fingers that GENERATION HD1 and other trials can produce an effective treatment – and that I can hold on long enough to benefit and share more precious time with my family.

Roche restarts redesigned Phase 3 Huntington’s disease trial

Three months after announcing it would reduce dosing in its historic Phase 3 Huntington’s disease clinical trial – and pausing for a reset – pharma giant Roche announced on June 20 that it has reopened recruitment for the study, known as GENERATION HD1.

GENERATION HD1 aims to measure whether Roche’s gene-silencing drug, RG6042, will slow, halt, or perhaps even reverse HD symptoms. In late January, Roche announced that it had enrolled the first participant in the trial, which will include a total of 660 volunteers at more than 90 sites in at least 18 countries around the world.

In the original trial design, participants would undergo monthly spinal tap (lumbar puncture) procedures over 25 months. One third of participants would receive RG6042 each month and one third every other month. A third would get a placebo.

However, with new, promising data in hand from an open-label extension (OLE) of the Phase 1/2a trial, on March 21 Roche announced that it would decrease lumbar punctures to once every other month over the same period of time (click here to read more). In this revised design, one third of participants will receive RG6042 every other month and one third every four months. One third will receive a placebo every other month.

The change in dosing required Roche to stop the trial to obtain updated approval from regulatory agencies in the respective countries where the program is operating. Recruitment had to start from scratch, with all new volunteers. Roche completed the necessary details for resuming the trial in just a few months, as it had hoped.

“In March we announced our plan to amend the dosing frequency and study design, which will make study participation less demanding for patients, their families and HD centers,” Mai-Lise Nguyen, Roche’s HD patient partnership director, wrote to the HD community in a June 20 e-mail update on the trial. “Since then, our team has been working to implement study changes and obtain approvals from clinical trial review boards and authorities around the world. Today I am pleased to share that we have reopened the study for recruitment of new patients.”

Mai-Lise Nguyen (photo by Gene Veritas)

Initial authorizations received

With the lumbar punctures, GENERATION HD1 clinicians introduce RG6042 into the cerebrospinal fluid (CSF), which circulates along the spine and bathes the brain. The researchers hope that the drug will penetrate the brain sufficiently and, as a result, stop progression of HD. 

Lumbar punctures are routine and generally safe procedures, although they can sometimes cause side effects such as headaches and bleeding. In GENERATION HD1, the dosing will be a 20-minute outpatient procedure.

Roche changed the dosing based on new data taken from the OLE of the Phase 1/2a clinical trial of RG6042. Phase 1/2a was run by Ionis Pharmaceuticals, Inc., the original developer of the drug. Involving 46 volunteers in Canada, Germany, and the United Kingdom, that trial ended successfully in December 2017: the drug substantially lowered the amount of mutant huntingtin protein, the purported cause of the disease, in the patients’ CSF, which could be an indication of what’s happening in the brain – again, something to be studied in Phase 3.

All 46 participants took part in the 15-month OLE, which is run in support of the overall RG6042 research program. Nine months into the OLE, Roche had data indicating that it could reduce dosing in the larger Phase 3 study. Whereas 25 percent of the Phase 1/2a volunteers got a placebo, all 46 received the drug in the OLE.

“Initial clinical trial authorizations to start the amended GENERATION HD1 study have been received, and we expect to receive the remaining approvals soon,” Nguyen stated. “Recruitment timing will be different at each participating HD clinic/center, because the protocol amendment must be fully approved and in place at each study site before local recruitment may open. Our team is working to rapidly activate the updated study protocol at each site.”

An updated country list

Nguyen provided an updated list of countries currently hosting the GENERATION HD1 sites: Argentina, Australia, Austria, Canada, Chile, Denmark, France, Germany, Italy, Japan, The Netherlands, New Zealand, Poland, Russia, Spain, Switzerland, United Kingdom, and the United States.

Roche recommends that those interested in participating contact their local HD specialists. Individual site information will also be posted at ClinicalTrials.gov and ForPatients.Roche.com.

Individuals who had already started GENERATION HD1 before the announcement of the changes in dosing will be eligible to switch to GEN-EXTEND, an OLE study in which everybody receives RG6042 (no placebo).

Publication of the first data

The resumption of GENERATION HD1 comes in the wake of the first official publication of Phase 1/2a data. That article underscores the impressive results of the trial but also the need for careful study of RG6042 in Phase 3.

Co-authored by 22 scientists, including leaders of the Roche and Ionis HD teams, the article “Targeting Huntingtin Expression in Patients with Huntington’s Disease” appeared in the online edition of The New England Journal of Medicine (NEJM) on May 6 and in print on June 13.

The article confirmed that Phase 1/2a met its primary goal of demonstrating no serious adverse effects of RG6042.

The article also provided details demonstrating the extent to which RG6042 reduced the mutant protein in the CSF. However, it added that researchers still do not yet know whether that reduction in the CSF corresponds to a reduction in the human brain.

A ‘big leap forward,’ but with a critical need for Phase 3

The NEJM article also revealed that two tests showed results that could prove worrisome: temporary increases in the size of the ventricles (fluid-filled spaces) of the brain and in a biomarker (sign of disease) known as neurofilament light.

“Getting to the bottom of these potentially concerning lab tests requires a larger group of people, followed for a longer time,” commented HD researcher Jeff Carroll, Ph.D., in a May 7 HDBuzz.net article. 

In Huntington’s, the ventricles “appear to grow, as the [brain] tissue around them shrinks,” Dr. Carroll explained. This is “the opposite effect one would hope for if the drug was slowing brain shrinkage,” he added.

Regarding neurofilament light, Dr. Carroll observed that “this marker is released by sick and damaged brain cells called neurons, and researchers have previously demonstrated that it increases slowly and predictably in HD mutation carriers.”

The need to understand these test results is “exactly why Roche and Ionis are conducting a new, larger, study called the GENERATION-HD1 study,” Dr. Carroll continued.

Dr. Carroll concluded that “the now published results of the first study with a drug targeting the root cause of HD are a big leap forward for the community. They point towards refinements and cautions we should consider as we test the drug in larger groups of HD patients over a longer time.”

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

Click on the links below for previous articles on RG6042.

"Roche: less frequent dosing for Phase 3 Huntington's clinical trial, easing burden on patients"

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

"Roche announces U.S., Canada sites for Phase 3 clinical trial for Huntington's disease drug"

"Roche announces first sites for key Huntington's disease observational study"

"Unpacking GENERATION HD1, the Roche Phase 3 Huntington's disease clinical trial"

"Roche Phase 3 clinical trial for Huntington's disease gene-silencing drug to enroll volunteers in early 2019" 

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

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

"The best news for the Huntington's disease community since the discovery of the gene: Ionis data revealed, Roche confirms jump to Phase 3"

"Ionis scientists provide initial assessment of successful Phase 1/2a Huntington's disease trial and discuss next steps"

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

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

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

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

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

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

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

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

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

Background on GENERATION HD1

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

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

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

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

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

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

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

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

Designing and executing the clinical trial program

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

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

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

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

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

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

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

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

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

Several years to complete the study

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

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

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

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

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

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

Considering the broad continuum of HD

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

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

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

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

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

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

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

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

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

Building the evidence for RG6042

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

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

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

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

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

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

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

Expanding access to other disease groups

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

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

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

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

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

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

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

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

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

Gaining confidence in the drug

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

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

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

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

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

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

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

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

The Spark acquisition and broadening the drug playing field

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

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

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

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

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

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

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

Alternative drug delivery methods

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

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

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

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

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

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