Combatting the pandemic, Roche also forges ahead with critical Phase 3 Huntington’s disease clinical trial

Using its expertise to combat a coronavirus pandemic that has left more than 180,000 people dead worldwide and a third of the earth’s people on lockdown, pharmaceutical giant Roche is also forging ahead with its Phase 3 clinical trial for the Huntington’s disease gene silencing drug RG6042, now known by the generic name tominersen.

The final step in a clinical trial program, Phase 3 tests the efficacy of a drug. A successful Phase 3 allows a pharmaceutical company to apply to regulatory agencies for permission to market the drug. In a time of “social distancing” and a shutdown of normal life, Roche and HD clinical trial administrators are seeking to mitigate the risks associated with the spread of COVID-19, the disease caused by the coronavirus.

In an April 20 letter to the global HD community, Roche announced that it had completed recruitment for the trial, GENERATION HD1. A total of 791 symptomatic volunteers across 18 countries have been enrolled, just ten fewer people than Roche projected after the trial got under way last year – almost 99 percent of the target.

“This achievement is a result of the HD community’s commitment from the beginning, and we are very grateful to all trial participants, their families, the clinical trial sites and staff, and the broader HD community who have supported the design, initiation and recruitment phases of the study,” Roche global patient partnership directors David West and Mai-Lise Nguyen stated in the letter.

West and Nguyen reassured the community that “tominersen studies are ongoing at clinical trial sites around the world,” and, in collaboration with local health authorities, “ensuring patient safety and data integrity throughout the studies given the ongoing impact of COVID-19.”

On February 27, Roche announced the generic name for its HD gene-silencing drug candidate RG6042, formerly known as IONIS-HTT_Rx, developed by Ionis Pharmaceuticals, Inc. With assistance from Roche, Ionis ran the successful Phase 1/2a trial for the compound, shown to be safe and tolerable in trial participants. It also lowered the amount of mutant huntingtin protein, a major suspect in the disease, in volunteers’ cerebrospinal fluid. (Slide courtesy of Roche.) 

Aiming to analyze data in 2022

“Given the dynamic situation with COVID-19, we decided to close recruitment at 791 participants globally in order to avoid additional pressure on clinical trial sites who were screening potential participants,” they added, noting that the number of participants is “sufficient” to assess tominersen’s efficacy.

Roche is “working closely with the research teams, trial sites and local authorities to reduce any new risks posed by COVID-19 and ensure the trial can continue as long as it is safe to do so,” the letter stated. Roche advises participants to “discuss individual circumstances with their respective study sites.”

“Where patients and families can no longer go into [the] hospital to receive treatment or assessments, research teams will be in close contact over the phone to monitor their health and discuss any potential adverse events or any other issues,” the letter added.

Roche expects to complete the trial and start analyzing data by 2022, after each of the volunteers has completed the 25-month program involving intrathecal (spinal) injections of tominersen or a placebo, tests, medical evaluations, and digital monitoring, West and Nguyen stated.

If tominersen demonstrates efficacy and safety, Roche will submit applications to national health authorities to obtain approval as a treatment.

“During these exceptional times, we continue to consider how we can best support the community and welcome any suggestions,” the letter concluded.

In an April 21 e-mail to me, West noted that GENERATION HD1 recruitment was “completed within expected timelines,” unaffected by the COVID-19 crisis. In line with plans announced last October, Roche will also extend the study to China “as soon as possible,” West added.

Combatting COVID-19

The April 20 statement on GENERATION HD1 followed a general statement by Roche on March 19 discussing the March 11 announcement of the pandemic by the World Health Organization and the company’s efforts to combat it.

“We recognise that the public and private sectors across the globe need to work together to help effectively manage this developing situation,” said the statement, noting that Roche was engaged in developing a COVID-19 “diagnostics test which was granted Emergency Use Authorization by the U.S. Food and Drug Administration.”

Scientists, physicians, and public officials have stated repeatedly that vastly increased testing for the virus is needed in the battle against the pandemic.

Roche also confirmed initiation of COVACTA, a global Phase 3 clinical trial to evaluate the safety and efficacy of its rheumatoid arthritis drug Actemra/RoActemra in treating patients with severe COVID-19 pneumonia. The study started to enroll patients on April 3, with a target of 330 globally, including the U.S., Canada, and Europe.

Roche is also examining other drugs in its portfolio for potential testing to treat COVID-19.

(Click here to read more on Roche’s efforts against the coronavirus.)

A key supplementary trial

The February 27 announcement of the generic name tominersen took place at the 15th Annual Huntington’s Disease Therapeutics Conference, sponsored by CHDI Foundation, Inc., in Palm Springs, CA. (For an overview of the conference, click here.)

Scott Schobel, M.D., M.Sc., Roche’s associate group medical director and medical leader of the GENERATION HD1 effort, introduced the name when presenting the preliminary results of the so-called open label extension study (OLE) study of the compound. For 15 months, Roche continued to give the drug to all of the 46 participants of the successful Ionis trial, completed in December 2017. That same day, Roche posted the slides of Dr. Schobel’s presentation on its website.

The OLE reinforced the findings of the Phase 1/2a trial, which showed tominersen to be safe and tolerable in trial participants. Tominersen also lowered the amount of mutant huntingtin protein, a major suspect in the disease, in volunteers’ cerebrospinal fluid.

Also, when still in progress in early 2019, the OLE led Roche to temporarily halt GENERATION HD1 to redesign it in line with the OLE’s promising early data. 

In the original GENERATION HD1 design, participants would undergo monthly spinal tap (lumbar puncture) procedures over 25 months. One-third of participants would receive tominersen each month and one-third every other month. Another third would get a placebo.

In the updated trial, which resumed in June 2019, Roche decreased lumbar punctures to once every other month over the same period of time. In this revised design, one-third of participants are receiving tominersen every other month and one-third every four months. Another third will receive a placebo every other month. (Click here to read more.)

Less frequent dosing eases the burden on participants, their families, and clinical trial administrators.

The OLE also investigated potential biomarkers (signs of the disease and drug efficacy) for use in GENERATION HD1.

The OLE formed part of Roche’s strategy for skipping the usual Phase 2 trial to test efficacy and entering directly into Phase 3 to confirm efficacy in a larger population (click here to read more).

Scott Schobel, M.D., M.Sc., presenting open label extension study data for tominersen at the 15th Annual HD Therapeutics Conference (photo by Gene Veritas)

The ‘ultimate’ question: efficacy

After his presentation, Dr. Schobel met briefly with HD advocates to discuss his presentation and GENERATION HD1.

For the HD community, the takeaway message was the OLE’s confirmation of a less frequent dosage, and its helpful data for GENERATION HD1. Except for one person who decided to drop out to take a trip around the world, all of the OLE participants had continued taking the drug, putting them now at 20 months of follow-up, he explained.

Roche has great “confidence” in the sufficiency of the less frequent dosing in GENERATION HD1, Dr. Schobel emphasized.

With the OLE, Roche has “been able to learn” and apply it directly to GENERATION HD1 “in a way that we couldn’t have done if did a more traditional drug development path, which we feel great about,” he said.

What remains is the “ultimate” question: will tominersen be an effective treatment?

“We’re well-positioned with GENERATION HD1 to answer that question,” Dr. Schobel concluded.

If the trial is successful, tominersen will become the first treatment to slow, halt, and perhaps even reverse the symptoms of Huntington’s disease. 

(I hope to report soon on other ways in which COVID-19 has impacted the HD community and research.)

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

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 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.

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

Pharmaceutical giant Roche’s September 16 announcement of the 2019 start of its Phase 3 Huntington’s disease clinical trial has raised great expectations about whether this drug could be the first effective treatment for this devastating disorder.

The short answer: it’s still too soon to tell.

During a September 26 Huntington’s Disease Society of America (HDSA) hour-long webinar on the trial, Roche representatives received hundreds of questions via chat from HD community members. They had time to answer only a few, with HDSA pledging to compile and post answers to unanswered questions on its website soon. (Click here to watch the webinar.)

Likewise, in response to my September 16 posting about the Roche announcement, many people in Facebook HD discussion groups have sought further information about the trial.

Roche plans to test the efficacy of RG6042, a gene-silencing drug aimed at slowing, halting, and perhaps even reversing HD symptoms, in 660 volunteers over 25 months. The test will take place at 80 to 90 sites in approximately 15 countries. Each month, participants will receive the drug or placebo through a lumbar puncture. Roche will announce the sites gradually in the coming months.

Roche has named the study GENERATION HD1 (short for Global EvaluatioN of Efficacy and safety of Roche/genentech AnTIsense OligoNucleotide for Huntington’s Disease).

Let me try to address some of the key questions about the trial from the HD community, as well as my own relationship to it as a presymptomatic HD gene carrier.

Scott Schobel, M.D., M.S. (left), Roche clinical science leader of product development, announces GENERATION HD1 at the European Huntington's Disease Network Meeting in Vienna, Austria, on September 16, 2018 (photo courtesy of HDBuzz.net).

‘How do I sign up?’

A frequent question from the community: “How do I sign up for the trial?”

During the webinar, Roche officials stressed that patients should consult with their HD doctors and families about eligibility for the trial, the pros and cons of participation, and logistics such as transportation or relocation to a trial site.

J. P. Sacksteder, of Genentech Advocacy Relations, said that Roche will announce the sites as each becomes ready to enroll patients. (Genentech, a major U.S.-based biotech firm, was acquired by the Swiss-based Roche in 2009. All U.S-based Roche personnel and products still use the name Genentech.)

“We ask for your patience and understanding as we share these trial sites,” Sacksteder said, noting that many factors influence site selection, including experience in conducting HD studies. “We understand that each of your situations is unique, so please continue to discuss your situation with your HD specialist.”

Erik Lundgren, lifecycle leader of the Roche HD program, recognized the great “desire” of HD-affected individuals to take part, but also pointed out the substantial “commitment” required in a rigorous, 25-month clinical research project.

Clinicaltrials.gov and HDTrialfinder.org will provide the latest information on GENERATION HD1.

Roche officials further noted that participants could continue taking most HD-related medications, including anti-depressants as well as drugs to control involuntary movements such as Austedo and Xenazine. Excluded drugs are memantine and riluzole. Participants must start any new regimen of medicines at least three months prior to the trial’s start. Individuals cannot participate in a concurrent trial, but are not barred if they had participated in past HD trials.

For those aged 25-65

Roche will recruit volunteers who are between the ages of 25 and 65 at the start of the trial, explained Scott Schobel, M.D., M.S., Roche clinical science leader of product development. 

Based on statistical studies of the HD population, people in the 25-65 age group have a more predictable progression of symptoms than younger or older groups, Dr. Schobel explained. Focusing on that cohort, he said, will furnish trial researchers with the best, most efficient way to measure whether RG6042 alleviates symptoms.

The later a person’s motor onset, the standard diagnosis of HD, the “potentially less of a progression of symptoms over time,” he added. Motor symptoms involve involuntary movements and imbalance.

Thus, including people over 65 in GENERATION HD1 would be less helpful to researchers trying to gauge the drug’s impact.

Dr. Schobel’s assertion about later motor onset reassured me a bit regarding my own potential disease progression as an HD gene carrier. At my latest HD checkup earlier this year, I had not shown such symptoms. My HD-stricken mother’s onset occurred probably in her late 40s, and by age 58 (my current age) she had full-blown HD. She died at 68.

I hope that the lack of motor symptoms at this stage means that, after my inevitable onset, I, too, will have a lesser progression of symptoms.

Healthy gene carriers excluded

However, I can’t participate in GENERATION HD1, because, at this time, presymptomatic gene carriers are ineligible. My question during the webinar requesting further details about this wasn’t answered.

In general, presymptomatic gene carriers haven’t been invited to participate in most HD clinical trials because it’s hard to measure a drug effect on an apparently healthy person.

There are also safety and ethical concerns in involving healthy individuals in a complex clinical trial like GENERATION HD1 – for example, exposing a healthy person to the potential side effects of the trial. 

Regarding presymptomatic individuals and also the excluded juvenile HD population, Roche stated in its September 16 announcement: “We recognize the critical medical need for a treatment for HD, especially for people living with severe forms like juvenile onset HD. In consultation with HD community experts, our team will explore the potential use of RG6042 in populations beyond manifest [symptomatic] HD once there is sufficient scientific and safety rationale.”

At the September 16 announcement of GENERATION HD1, Dr. Schobel pointed out that the drug might act differently in the still developing brains of children and young people.

The ultimate goal of researchers is to develop a preventive treatment.

Concerns about frequent spinal taps

Even if eligible, I would have to seriously consider the risks of undergoing the lumbar punctures. The punctures, also known as spinal taps, introduce the drug into an individual’s cerebral spinal fluid (CSF) and allow researchers to withdraw some CSF for analysis.

Lumbar punctures are routine and generally safe procedures, although they can cause side effects such as headaches and bleeding. The 46 subjects in the Phase 1/2a trial of RG6042, completed in December 2017, had few side effects. Ed Wild, M.D., Ph.D., who conducts research on the CSF in HD, underwent the procedure as a demonstration for the HD community

Still, I’m personally concerned about the lumbar puncture, which, if a medicine is approved, would likely be the initial pathway for it to be administered.

In 1977, at age 17, I suffered two herniated disks in my lower spine while shoveling heavy snow in my hometown of Mentor, Ohio. Ever since, I have struggled with low back pain.

An MRI (magnetic resonance imaging) scan ten years ago revealed that the disks mainly healed, but I suffer daily with muscular pain, or myofascial pain syndrome. Occasionally, severe flareups prevent me from walking and performing some daily activities.

Since that MRI, I’ve consulted regularly with pain management specialists. I’ve also worked with physical therapists to incorporate other exercises into my morning stretching routine to strengthen my core and back.

Along with daily aerobic exercises, I want to stay strong and flexible to help forestall my inevitable HD onset and, later, to help ameliorate symptoms.

Alternative drug delivery methods?

In 2013, as a participant in the PREDICT-HD (Neurobiological Predictors of Huntington’s Disease)  research project at the University of Iowa, I considered a request to provide a sample of my CSF. 

After reviewing my lower spinal MRI, a doctor at Iowa concluded that a lumbar puncture was too risky.

Also, had I suffered any complications after the procedure, I would have had to obtain medical care not in Iowa, but only after returning to my current hometown of San Diego, where I have health coverage.

I wanted to assist with the research, but ultimately believed that the potential risks outweighed the benefits.

Given these concerns, during the webinar I posed two questions regarding the spinal taps. First, what will Roche due to minimize the impact of the 25 monthly procedures? Secondly, how will Roche address the fact that many people in the U.S. suffer from lower back problems?

I look forward to hearing Roche’s ideas, including the latest research on alternatives to spinal taps such as Roche’s “brain shuttle” technology and/or devices for delivering the drug.

If back pain is part the price for an effective HD treatment, I am willing to endure it.

Timeline and cost

Another major concern of the community: if GENERATION HD1 is successful, when might drug approval come?

“I can’t ultimately commit to what that timeline looks like,” Lundgren said. “We are doing everything we can to speed it up.”

First, Roche must enroll all 660 volunteers. “That’s a big variable,” he said. “We can’t complete the study until 25 months after the last patients receive their first dose.”

Then researchers must organize and analyze the data. If the latter appear promising, then Roche must seek regulatory approval from the U.S. Food and Drug Administration and similar agencies around the world.

According to a September 17 article on the scientist-produced site HDBuzz, “Not every patient enrolls on the first day of the trial, so a trial in which each participant is involved for 25 months will take around twice that long to run, and possibly longer.”

It’s also too early to project the cost of the potential drug, Lundgren said. He added that Roche is committed to providing access to those with inadequate insurance.

Working towards the best treatments

Dr. Schobel addressed concerns about the fact that RG6042, developed by Ionis Pharmaceuticals, Inc., is designed to reduce both the harmful mutant huntingtin protein involved in HD and normal huntingtin, essential in cell function. 

According to Dr. Schobel, the drug’s effect “fundamentally is partial and can reverse and is titratable [adjustable], versus those kinds of experiments that are in the scientific literature, which shut off the gene 100 percent. That is not what we’re doing, for either the mutant protein or the so-called normal or total levels of protein. We have the ability to find a sweet spot potentially where there’s benefit and less risk, or even pause dosing.”

The Roche-Ionis approach differs from the two current Phase 1b/2a clinical trials by Wave Life Sciences, whose drugs target only the harmful protein by using genetic markers present in most but not all people with HD. (Click here to watch a presentation on the trials by Wave’s Michael Panzara, M.D., MPH.) 

These and other clinical trials seek to find the best approach. Scientists have said that a combination of approaches, or an “HD cocktail,” may be needed to treat this complex disease.

(I hold a symbolic amount of Ionis shares.)

This article is dedicated to the many donors and walkers who supported the Serbin Family Team in the 2018 HDSA-San Diego Team Hope Walk, held today. See photos below. Thanks to you, we raised over $4,000 towards the care and cure of HD! You can still donate by clicking here.

The Serbin Family Team of the 2018 Hope Walk: above, from left to right, Lance Ramsey, Adi Drapkin, Alexandra Drapkin, Regina Serbin, Gene Veritas (aka Kenneth P. Serbin), Maria Ramos, Peter Kim, Yuka Kim, and Lily Kim (in stroller). Below, from left to right, Tom Johnson, Yuka Kim, Peter Kim, Lily Kim (in stroller), Judy Melville, Gene Veritas, Patrick Melville, Sean Naficy, and Sam Melville (personal photos).