Friday, March 22, 2019

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.)

Thursday, March 14, 2019

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.

Tuesday, March 05, 2019

‘We can now fear Huntington’s disease less’: reflections on the 14th Therapeutics Conference


As in past years, covering CHDI’s Foundation’s recent Annual Huntington’s Disease Therapeutics Conference in Palm Springs, CA, produced a whirlwind of emotions about the devastating disorder that took my mother’s life and looms over the lives of tens of thousands of HD patients and presymptomatic gene carriers like me.

Last year, I left the conference during the Thursday night farewell dinner to drive 120 miles to my home in San Diego, arriving after 1 a.m. Wired from strong black tea and that evening’s news that the initial Ionis-Roche clinical trial had reduced the amount of the mutant huntingtin protein in trial participants’ cerebrospinal fluid, I worked until 5 a.m. on an article about the “best news for the Huntington's disease community since the discovery of the gene” in 1993.

This year I planned for a calmer post-conference moment by spending the last night in Palm Springs. That allowed me to enjoy and socialize at the dinner, get a good night’s rest after the long, adrenalin-filled four-day meeting, and drive back to San Diego leisurely the next day. I believe that such self-care is important in avoiding disease onset.

The smoother transition back home has helped me reflect on the progress towards HD treatments and solidarity among affected families, advocates, scientists, and drug companies.

‘Rod Man’ and his family’s fight

This was my eighth Therapeutics Conference since 2010.

This year’s event, the 14th annual conference, opened on February 25 with the unusual and deeply moving keynote address by comedian Rod “Rod Man” Thompson, the winner of season 8 (2014) of NBC’s Last Comic Standing reality TV talent competition. Rod was the first African-American CHDI keynoter.

Raw and humorous, Rod’s presentation contrasted sharply with the serious, more formal speeches of most previous keynoters, including mine in 2011.

Rod described the terrible physical, cognitive, and psychiatric decline that HD has wrought in his 66-year-old mother Shirley, who lives in the small Georgia town of Villa Rica.

“I see depression and sadness about stuff that can be a misunderstanding to most people, and they’ll let it go, but she still holds on to it and harbors it,” Rod said.

Because of Shirley’s involuntary movements, the family also keeps kitchen utensils away from her to prevent her from injuring herself or others.

“Now it’s better for her to eat with her hands, because she’s a little shaky,” Rod explained. “Her body’s not the same.”

I cried as I remembered my own mother’s depression and inability to care for herself. She died at age 68 after a two-decade struggle with HD.

Untested, Rod and his two daughters – a college graduate and a high school student – are also at risk.

Rod received a standing ovation.

“What a presentation,” CHDI Chief Scientific Officer Robert Pacifici, Ph.D., observed in his closing remarks on February 28. “It was heartfelt. It was pretty amazing to see, in his own quirky way, how he touched on so many of the things that are so important to families, how important our work is, how difficult it is for the caregivers, how much they’re counting on us to deliver something, how complicated the science is for people who are trying to struggle through with what it means in their lives, the information that needs to get to places, the difficulty of visiting the clinics, and the challenges of participating in some of the clinical trials.”

A future article will feature Rod’s speech.


Huntington's Disease Society of America CEO Louise Vetter with 2019 CHDI keynote speaker Rod "Rod Man" Thompson (photo by Gene Veritas)

Collaboration toward a common goal

I felt especially in sync this year with the scientists and fellow advocates. In our ultra-competitive society, facing HD has helped teach me the value of collaboration. At the conference, we all focused intensely on the common goal of developing treatments.

The HD community is known for the close cooperation between scientists and affected families. As one neurologist wrote me last year, when the scientific and medical leaders of the cause “get together, they by and large have tended to check their egos at the door and just try to do what needs to be done.”

At the conference, I paid special attention to the February 28 talk by Marcy MacDonald, Ph.D., a pioneer in HD research and a member of the team that discovered the huntingtin gene in 1993. Dr. MacDonald presented the latest data on so-called modifier genes, which can affect disease onset by decades.

In the past, I’ve only ever been able to just say hello to Dr. MacDonald. However, during a free moment after her talk, I told of the research’s importance for my own life: it may explain why, with the same level of defect in my HD gene as my mother, I have gone a decade without symptoms beyond her apparent age of onset.

I told Dr. MacDonald that the discovery of modifier genes – and the more precise prediction of onset – might open up a new round of genetic testing for the HD community, although I added that I wasn’t sure I wanted to go through the difficult experience of testing again.

Later, at the farewell dinner, I hugged and thanked Dr. MacDonald for her work, which, as Dr. Pacifici noted, could lead to drugs mimicking the actions of the modifier genes. (Also click here to read more.)

Making a difference

I also interacted with a dozen advocates and family members. We discussed numerous HD-related matters.

For an upcoming article, I interviewed Scott Schobel, M.D., M.S., Roche’s clinical science leader of product development and leader of its HD scientific team, for an update on the company’s historic Phase 3 clinical trial to test the Ionis-Roche gene-silencing drug, which, if successful, could slow, halt, and perhaps even reverse HD symptoms. In the words of Roche personnel, they politely “turned the tables on me” by interviewing me on video about my advocacy and family’s struggle against HD for a forthcoming awareness-building campaign.

Together, I feel we are making a difference in the fight against Huntington’s disease!

The nonprofit CHDI is assisting immensely by providing funding, tools, guidance, and open-source data.


Above, HD advocates Jeff and Debbie Mulligan (seated) with (from left to right, standing) Frances Saldaña, HDSA CEO Louise Vetter and Gene Veritas (aka Kenneth P. Serbin) (photo by David Saldaña). Below, Janet Rafferty (in pink blouse), Roche's international communications leader for neuroscience and rare diseases, interviews Gene Veritas (photo by Charlotte Peterson, Edelman agency).



CHDI’s ‘Oscars’ ceremony

As he does each year, HD global advocate and former NBC News foreign correspondent Charles Sabine – also a presymptomatic gene carrier – added his own dose of humor with his mini-version of the conference Oscars, “The Charles’.” Presented on the last evening, they’re a hit with the audience after three days of nonstop scientific panels.

A notable, quite appropriate honor resulted from the incorrect medical instructions given to keynoter Rod and his family prohibiting his mother from consuming pork, one of her favorite dishes. Thus, Charles stated, the “medical intervention of the conference award” went to man “who told our keynote speaker, Rod Man, that his mom can eat as much pork as she likes.”

The awardee was long-time HD specialist Mark Guttman, a neurologist at the Centre for Movement Disorders in Toronto, ON. (Click here to watch the awards program.)

A certain path ahead

Minutes later, on a more serious note during his closing remarks, Charles displayed the same eloquence exhibited during his introductory statement at the HD community’ historic meeting with Pope Francis at the Vatican in 2017.

In Palm Springs, Charles noted that, thanks to the advances of the scientists, the future path for patients and gene carriers is “no longer unremittingly downward.” This absolutely marks the existence of hope, he added. 

To illustrate his point, Charles recounted his first experience at a recent Huntington’s Disease Youth Organization (known simply as HDYO) summer camp in the United Kingdom, with 65 young people.

“It was the hardest HD event of my life,” Charles said. He recalled how one distraught teen asked him: “Tell me something that you know for certain.”

In his ten years of travels around the world to meet with HD families, Charles had never heard a question so difficult to answer.

“A platitude wouldn’t suffice, nor a statement of which I was not one hundred percent certain,” Charles continued. “After a nod and a big breath, I replied: ‘No generation, yours included, will ever need to fear this disease as much as mine did.’ And the reason that I could say those words with such confidence was the tireless work and commitment of all of you in this room.

“So on behalf of all of those young people around the world, thank you.”

(Click here to watch Charles. Click here for my video album of the 14th Therapeutics Conference.)


Charles Sabine at the HD Therapeutics Conference podium (photo by Gene Veritas)

Thursday, February 28, 2019

CHDI’s chief scientist: ‘Not a time for the Huntington’s community to rest on its laurels’


Given the unprecedented interest from biopharmaceutical firms and broadening range of approaches to attacking the disease, the need for the Huntington’s disease community to participate in research studies and clinical trials is “exploding,” CHDI’s head scientist said at the organization’s 14th Annual HD Therapeutics Conference yesterday.

“This is not a time to rest on our laurels,” said Robert Pacifici, Ph.D., the chief scientific officer for CHDI Foundation, Inc., the nonprofit virtual biotech dedicated to finding HD treatments. “Trials won’t go forward without people willing to take the risk of taking a drug never taken before.”

Dr. Pacifici’s comments came in an interview with me at the conference venue, the Parker Palm Springs hotel in Palm Springs, CA. The gathering of scientists, pharma executives, and advocates ends today.

Critical new research studies

The conference comes just after news of the start of Roche’s historic Phase 3 gene-silencing clinical trial and other clinical trial programs (click here to read more).

“It’s exciting times,” Dr. Pacifici observed. “Now more than ever we need to make sure that these channels of communication between patients and caregivers and researchers remain open and clear so that everybody knows what’s going on.”

With the advent of more trials, both the pace and number of research projects requiring volunteers is growing rapidly, he explained. One involves a forthcoming brain imaging study (using a PET-ligand).

To help understand the disease and measure the effect of potential drugs in clinical trials, scientists need to find more biomarkers (signals of the disease) in humans. For years, they have collected samples of blood. More recently, they started examining the cerebrospinal fluid and saliva.

Now CHDI wants to collect semen, Dr. Pacifici said. “There are certain things that happen only in those cell types that are going tell us what happens to Huntington’s DNA, and that’s going to be really critical for our efforts as well,” he explained.

CHDI will also establish a “Brains for HD” initiative to request donations of that organ from deceased individuals, Dr. Pacifici added. “Invaluable,” he said of the importance of brains in HD research. “Especially the rare young brain, if somebody happens to pass away from something else, and we can harvest the brain before it experiences the ravages of Huntington’s disease.”

You can watch my interview with Dr. Pacifici in the video below.

‘Huntington’s homework’

Dr. Pacifici outlined the conference’s three major areas of focus.

He described the first as “Huntington’s homework.”

“We might not like it, and it might be tough, and it requires some dedication, but we still have basic research to do to understand the underlying pathophysiology of Huntington’s,” he explained. “There are still some fundamental questions about what’s broken in HD that we need to understand, because until you understand what’s broken, it’s hard to fix it.”

To that end, this year’s conference talks have included topics such as HD’s hampering of the brain’s ability to repair itself and the loss of white matter in presymptomatic gene carriers like me.

Modifier genes: a key discovery

A second area involves the discovery of so-called modifier genes – a major advance only made possible with the participation in the research of 9,000 HD family members.

“We now know there are other genetic factors that influence, for any given CAG [the length of the genetic coding for the huntingtin gene], whether you’ll get the disease sooner or later,” Dr. Pacifici noted. 

People with same gene length can get the disease decades earlier or later, he said. “That’s a really big range, and what we’ve found is that the propensity to get it earlier or later is also heritable.”

The modifier genes affect onset by as much as a dozen years or more, he added.

“Imagine if we could make a drug that did the same thing – or did it even better,” Dr. Pacifici said. CHDI and HD scientists are at work on this task.

‘A wonderful time for HD research’

A third major aspect of the conference concerns “genetically identified targets” that are changed in people because of HD. This type of lab research is still in the early stages, Dr. Pacifici observed. However, these targets might also serve as models for drug design.

Dr. Pacifici noted that in the relatively mature field of “huntingtin lowering” – the approach of the Roche drug and of several other companies present at the conference – something “unthinkable” five years ago has occurred: the possibility of a “small molecule” drug. Such a drug would be taken orally, thus avoiding the spinal taps and other highly invasive procedures currently envisioned for these drugs. 

On February 26, Anuradha Bhattacharyya, Ph.D., of Ireland- and U.S.-based PTC Therapeutics presented a paper on the company’s efforts to develop such a drug.

As a nonprofit, CHDI’s job is to provide all firms access to the necessary biotechnological tools they need and to potential volunteers for studies and trials, Dr. Pacifici said. CHDI has spent hundreds of millions of dollars in the effort to treat HD, including grants to scientists and companies.

He concluded: “It’s a wonderful time to be a researcher in the area of Huntington’s drug discovery and it will soon be an opportune time to engage the broader patient community, because we really need your help.”

(Future articles will discuss other aspects of the meeting. For additional coverage, visit HDBuzz.net.)