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.)

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

With preliminary data in hand, the pharmaceutical firm Roche has announced that it will reduce the frequency of dosing in its historic Phase 3 Huntington’s disease gene-silencing clinical trial, thus easing the burden on the participants, their families, and clinics.

In the recently initiated trial, GENERATION HD1, volunteers will now undergo a bi-monthly instead of a monthly spinal tap (lumbar puncture), Roche announced in a letter to the HD community on March 21, 2019. Lumbar punctures are routine and generally safe procedures, although they can cause side effects such as headaches and bleeding. In GENERATION HD1 it will be a 20-minute outpatient procedure.

Roche based the change on new data taken from 46 volunteers after nine months into the 15-month, so-called open-label extension trial (OLE) that it started for its drug RG6042. Those individuals previously participated in the successful Phase 1/2a clinical trial of RG6042, originally developed by Ionis Pharmaceuticals, Inc. The drug substantially lowered the amount of mutant huntingtin protein, the purported cause of the disease, in the patients’ cerebrospinal fluid. All OLE participants received the drug (as opposed to 25 percent getting the placebo in the 1/2a trial).

“The 15-month open-label extension of the Phase1/2a study is evaluating RG6042 treatment in doses every month (every four weeks) and every two months (every eight weeks),” the Roche announcement stated. “Review of nine-month data showed effects on lowering mutant huntingtin protein levels in the cerebral spinal fluid that support the exploration of less frequent dosing. Based on the totality of the data, including safety and tolerability, there appears to be no overall advantage to treatment monthly versus every two months.”

GENERATION HD1 has three cohorts of clinical trial volunteers, known as “arms.” The planned 660 participants at 80-90 sites around the world are randomly assigned to one of the arms. The study is double-blinded: neither the volunteers nor the trial physicians and their staff know which arm the volunteers are assigned to.

As a result of the update to the trial, all participants will undergo bi-monthly punctures over 25 months. In “arm 1” of the study, the dosing schedule will switch from a monthly puncture and administering the drug bi-monthly (with a placebo in between) to a bi-monthly puncture with no placebo at all. Arm 3 will go from getting a monthly puncture with placebo to a bi-monthly puncture with placebo. 

To test the possibility of reducing potential future drug dosing even further, arm 2 will go from a monthly puncture with the drug to a bi-monthly puncture but with the drug given only every four months (with a placebo in between).

“I am delighted by today’s news that the Generation HD1 protocol will be amended to be less burdensome to trial participants, families and HD clinics around the globe,” George Yohrling, Ph.D., the senior director of mission and scientific affairs for the Huntington’s Disease Society of America, commented in an e-mail. “We are all indebted to the 46 trailblazing research heroes participating in the Phase 1/2a and open-label extension studies that showed us we could not only lower huntingtin in humans, but could do so without monthly infusions of RG6042. Their contributions have forever changed the landscape of HD drug development.”

“The amended trial is good news for the HD community,” LaVonne Goodman, M.D., the founder of Huntington’s Disease Drug Works and a physician to many HD patents, wrote in an e-mail. “For the shorter term, it will make for fewer visits and spinal taps for all involved in the trial. And for the longer term, if the trial at completion is successful by clinical measures, it may further establish whether quarterly dosing is adequate and effective. If so, that would make it easier on the larger number of patients who would need to receive this drug life-long.”

Simplifying the study

Dr. Goodman added: “It was fortunate that the Roche analysis and amendment came at the very beginning of the GENERATION HD1 trial, so that changes could be made without a major time disruption.”

A statement on the Ionis website observed that the new trial design “will greatly simplify the operation of the study.”

Although amending the trial will cause a “slight delay” as Roche seeks regulatory approvals, “we don’t expect this delay will change the timing of study completion, and may even accelerate time to study completion,” the Ionis statement concluded.

“Our team is working to rapidly activate the updated study protocol around the world,” the Roche statement said.

Individuals who had already started GENERATION HD1, which began in January, will be eligible to switch to GEN-EXTEND, an OLE study in which everybody receives RG6042 (no placebo). Participants will receive drug every two or four months.

Great news for the HD community

As the Roche statement noted, the data from the Phase 1/2a OLE do not address the efficacy and long-term safety of the RG6042. That is the purpose of GENERATION HD1.

The update from Roche came in the wake of remarks by GENERATION HD1 scientific coordinator Scott Schobel, M.D., that the company is “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. That includes asymptomatic gene carriers like me and sufferers of juvenile HD (click here to read more).

The scientist-written site HDBuzz described the amended trial design as a “surprise” but also a “good thing.”

“Clearly Roche and their partners didn’t predict that we’d be able to deliver [the drug] only every four months when they started the GENERATION HD1 study,” its article on the Roche statement observed. “The fact that they’ve seen data convincing them that we can get away with it is great news for the future of this program, and for future HD community members receiving treatment.”

HDBuzz further noted that other companies using the Ionis-Roche approach (antisense oligonucleotides) can now “consider using longer intervals between treatments.”

As an HD gene carrier and also a sufferer of chronic back pain, I was relieved to learn that the number of lumbar punctures for a potential drug could be as few as three per year.

The Roche announcement coincided with the news that the U.S.-based biotech firm Biogen and its Japanese partner Eisai had announced that they were halting two phase 3 clinical trials for an Alzheimer’s disease drug because an interim analysis concluded that the compound was unlikely to benefit patients. The drug was given through intravenous infusions.

The results of that trial once again underscored the extreme difficulty of treating neurological disorders and the need to the need to have realistic expectations about RG6042 (click here to read more). Not just Alzheimer’s and Huntington’s, but also Parkinson’s, Lou Gehrig’s, and other neurological disorders lack effective treatments.

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

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.

Ionis Huntington’s disease drug a step closer to a critical Phase 2 study

Ionis Pharmaceuticals has made two positive announcements about the historic Phase 1 clinical trial of its gene-silencing drug for Huntington’s disease: trial enrollment is complete, and the company will extend the study for all patients who complete Phase 1.

These are key steps on a multi-year path to possible Phase 2 and 3 trials that, if successful, would bring the trial drug, IONIS-HTT_Rx, to market. Typically, all three phases of a clinical trial project take at least five years, although nobody can predict the actual course of a trial.

IONIS-HTT_Rx aims to alleviate HD symptoms by reducing production of the huntingtin protein in brain cells (click here to read more). Ionis launched the Phase 1 trial in September 2015. Three dozen patents are taking part in the trial, expected to be completed by the end of 2017, at sites in Canada, Germany, and England. This first phase aims not to assess success in combating HD but rather simply whether the drug is safe and tolerable.

It marks the first time HD patients are receiving a substance aimed to attack the genetic causes of the disease. It’s also the first time they’re getting a drug via spinal injection.

“The safety and tolerability profile of IONIS-HTT_Rx in the completed cohorts of the Phase 1/2a study supports its continued development,” a June 22 Ionis news release stated. “Patients who complete the Phase 1/2a study will be eligible to participate in an open-label extension (OLE) study that Ionis plans to initiate in the next several months.”

“Open label” means all participants take the drug, in contrast with a “double-blinded” clinical trial like the current Phase 1, where half the patients receive a placebo and neither patients nor doctors know who is receiving the actual drug.

This month’s news provided the strongest indication so far that Ionis and its partner Roche, a much larger multinational pharmaceutical firm with vast clinical trial experience, will take IONIS-HTT_Rx into a larger, critical Phase 2 study, as early as 2018, to measure efficacy.

“Upon completion and full analysis of this study, the next step for this program will be to conduct a study to investigate whether decreasing mutant huntingtin protein with IONIS-HTT_Rx can slow the progression of this terrible disease," Frank Bennett, Ph.D., the Ionis senior vice president of research, said in the release.

Ionis has repeatedly indicated that a Phase 2 study would include U.S. trial sites.

Frank Bennett, Ph.D. (photo by Kristina Bowyer, Ionis)

‘Cautiously optimistic news’

The double-blinded protocol of the Phase 1 HTT_Rx trial insures that bias and other external factors don’t affect the trial results.

As noted, in an OLE each participant receives the actual drug, and usually at the highest dose tried in Phase 1. An OLE allows researchers to gather more data, examine the drug’s effects over a longer period of time, and better prepare for an eventual Phase 2. Patients also potentially benefit by receiving the drug longer.

The HD research website HDBuzz, which is produced by clinicians and scientists, described the Ionis announcements as “cautiously optimistic news.”

“News that the trial is fully recruited and the final patients are going through the procedures is a strong suggestion that even at the highest doses, the drug’s safety looks good,” the HDBuzz report observed. “Despite exhaustive safety testing before going into patients, any drug can produce unwanted effects, so that’s really the best news we could be hoping to hear at this stage.”

Regarding the open-label extension, it added, “We don’t want to read too much into a brief announcement, but running an OLE isn’t cheap for a trial sponsor, so this announcement certainly gives us optimism about the whole HTT_Rx program.”

Signs of HD in the blood

A separate research study, with results published June 7, could help Ionis and Roche researchers evaluate the results of the Phase 1 trial and plan the potential Phase 2 trial.

In what was described as a “major advance in the field of Huntington's disease and neurodegeneration in general,” a team of researchers has identified a potential blood biomarker for HD.

Biomarkers indicate a disease mechanism or drug impact. They are common for many diseases, but the complexity and inaccessibility of the brain have made it extremely difficult for researchers to find them for neurological diseases.

HD scientists have most recently focused on obtaining biomarkers from the cerebral spinal fluid (CSF). However, obtaining CSF, which requires puncturing the spine, is far riskier than drawing blood, the technique used in the new biomarker research.

Led by Ed Wild, M.D., Ph.D., one of the administrators of the IONIS-HTT_Rx trial in England, the new biomarker study demonstrated that a brain protein known as neurofilament light chain (Nfl) appears in the blood of HD patients and presymptomatic gene carriers. (Click here and here to read more.)

Dr. Ed Wild (photo from EdWild.com)

A less invasive measurement

Dr. Bennett of Ionis previously described Nfl as a protein involved in the cytoskeleton, or internal “scaffold,” of neurons. HDBuzz likened it to “the ribs of an umbrella.”

Dr. Wild’s team discovered that, the more advanced the stage of HD, the greater the amount of Nfl in the blood.

“This suggests that a blood test might be able to provide consistent information about the brain, in place of an invasive spinal tap,” HDBuzz commented. “We hope [Nfl] will be added to the arsenal of resources that are helping us to monitor HD and to develop new therapies.”

Indeed, the IONIS-HTT_Rx researchers previously noted that Nfl is one potential biomarker in the Phase 1 trial.

Further research is underway to confirm the Wild team's results and to determine to what extent Nfl can be used as a biomarker.

Pope Francis, Ionis, and the hope for a cure

The Ionis announcements about the clinical trial came as the 32nd annual convention of the Huntington’s Disease Society of America got underway in Schaumberg, IL. In addition to the news release, Ionis issued a letter to the HD community.

“We can assure you our number one goal remains our commitment to advancing IONIS-HTT_Rx development, a drug that has the potential to transform the treatment of HD,” the letter stated.

The positive news also comes in the wake of HDdennomore, the historic audience of the Huntington’s disease community with Pope Francis in Rome on May 18.

Dr. Bennett made a substantial donation to HDdennomore. He and several Ionis officials attended the audience. Dr. Bennett and his wife Paula sat in the front row along with leading HD scientists and dignitaries. They were greeted by Francis.

In his address, the pope recognized the geneticists and scientists “present here, who, for some time, sparing no energy, have dedicated themselves to studying and researching a treatment for Huntington’s disease. Clearly, there is a great deal of expectation surrounding your work: resting on your efforts are the hopes of finding the way to a definitive cure for the disease, but also of improving the living conditions of these brothers and sisters, and of accompaniment, especially in the delicate phases of diagnosis, at the onset of the first symptoms.”

If it succeeds, IONIS-HTT_Rx could fulfill those hopes and show the way to curing other neurological diseases.

Frank Bennett (left), Paula Bennett, and Gene Veritas (aka Kenneth P. Serbin) in St. Peter’s Square just before the audience with Pope Francis, May 18, 2017 (photo by Bianca Serbin)

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

(Click on the links below for past coverage of the Ionis HD project.)

Ionis Phase I Huntington's disease clinical trial at halfway mark: 'No surprises so far' means good news

Chief Huntington's disease drug hunter: 'every confidence first treatments' in the works

Huntington's disease patients get first dosing in historic Isis Pharmaceuticals' gene-silencing drug trial 

Isis Pharmaceuticals launches historic clinical trial to silence Huntington's disease gene

Moving toward a potential treatment: Isis, CHDI researchers outline upcoming Huntington's disease clinical trial

A key new ally in the search for Huntington's disease treatments

Quickening the pace towards a Huntington's disease gene-silencing clinical trial: pharma giant Roche, Isis enter partnership

Designing the best drug possible to defeat Huntington's disease

Building a 'laser-guided missile' to attack Huntington's disease

Observing the cure in progress