Overflow audience at 13th annual Huntington's Disease Therapeutics Conference

With more than 350 Huntington’s disease researchers and pharmaceutical executives in attendance, the 13th annual HD Therapeutics Conference got underway last night in anticipation of key presentations on progress towards treatments, including the successful Phase 1/2a Ionis Pharmaceuticals gene-silencing clinical trial completed late last year.

Sponsored by CHDI Foundation, Inc., the nonprofit virtual biotech focused on the search for HD treatments, the conference runs through March 1 at the Parker Palm Springs hotel (which is less than three hours’ drive from my San Diego home). In the last presentation, Ionis clinical trial administrators will present the results of the Phase 1/2a study of the company’s HD, drug IONIS-HTT_Rx.

“The first day we opened up the registration, we were almost full at the Parker immediately,” Robert Pacifici, Ph.D., CHDI’s chief scientific officer, said in his opening remarks in the main conference room, which holds 300 people. “We actually ended up allowing 365 participants to register. Not everybody can fit in this room.” So, for the first time at the Parker, CHDI arranged for an overflow room, with a screen projecting the proceedings.

After cancellations, a total of some 350 are expected to attend, one of the largest audiences in the history of the conference.

Dr. Pacifici also presented a check for $38,000 to Louise Vetter, the CEO of the Huntington’s Disease Society of America (HDSA).

As a research organization, CHDI provides no family services such as support groups and care centers. Demonstrating their commitment to HDSA’s mission in these areas – essential for developing treatments – Dr. Pacifici and five other riders (mainly from CHDI) raised the funds in a recent 100-mile biking competition in the Southern California desert.

You can watch Dr. Pacifici’s introduction in the video below.

CHDI Conference Opens with Overflow Crowd from Gene Veritas on Vimeo.

‘Huntingtin lowering’ and other main themes

Scientists and patient advocates eagerly await the March 1 presentation of the Ionis Phase 1/2a clinical trial, in which IONIS-HTT_Rx successfully lowered the amount of the mutant huntingtin protein in participants’ cerebrospinal fluid.

The trial aimed not to study efficacy but safety and tolerability. The next phases of the trial remain a major hurdle: to test whether the drug can actually alleviate or reverse symptoms.

The Ionis contingent at the conference includes Frank Bennett, Ph.D., Ionis senior vice president of research and the franchise leader for the company’s neurology programs, and Anne Smith, Ph.D., the Ionis director of clinical development and the individual responsible for the day-to-day management of the trial.

Dr. Smith will present the Ionis results along with Sarah Tabrizi, FRCP, Ph.D., of University College of London, the lead clinical trial site.

In addition to so-called “huntingtin lowering” strategies such as the Ionis drug, the main conference themes include potential therapies for fixing brain circuitry; the use of stem cells to better understand HD and develop treatments; the interplay of the huntingtin gene and DNA dynamics; and huntingtin protein structure and function.

The opening day also featured a resource fair, with research tools and databases available for HD research and developed by CHDI, partner organizations, and contract research organizations.

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

Jen Ware, Ph.D., CHDI's director for experimental design (right), explains a new CHDI research resource, the Independent Statistical Standing Committee, intended to provide independent, unbiased evaluation and expert advice regarding experimental design and statistics (photo by Gene Veritas).

CHDI's 13th conference promises some good news for the Huntington's disease community

With potential Huntington’s disease treatments on the horizon, I am looking forward to the 13th Annual HD Therapeutics Conference with great anticipation.

Although a powerful reminder of my gene-carrier status, the opportunity to watch world-class academic and pharmaceutical researchers present their latest findings always leaves me with increased hope that I won’t die from HD like my mother.

Sponsored by CHDI Foundation, Inc., the conference takes place at the Parker Palm Springs hotel in Palm Springs, CA, February 26-March 1. It will be my seventh, including an appearance as the keynote speaker in 2011.

The conference will assess progress towards HD treatments and point to future paths for research and clinical trials.

Gene Veritas (aka Kenneth P. Serbin) before the CHDI logo in 2012 (photo by Lev Blumenstein)

A report on the Ionis trial

I’m especially eager to learn about the latest data from the highly successful Ionis Pharmaceuticals Phase 1/2a gene-silencing clinical trial, aimed at reducing the amount of harmful huntingtin protein in brain cells. The project received an initial infusion of about $10 million from CHDI, later repaid by Ionis.

With the end of Phase 1/2a last December, Ionis officials commented only briefly on the demonstrated safety and tolerability of its gene-silencing drug IONIS-HTT_Rx, reserving a more thorough update for scientific meetings.

In the final talk – perhaps saving the best for last – IONIS-HTT_Rx trial administrators Anne Smith, Ph.D. (Ionis) and Sarah Tabrizi, FRCP, Ph.D. (University College of London) will present “Development of IONIS-HTT_Rx: From first principles to the first successful HTT-lowering drug trial.”

I’m hoping that Drs. Smith and Tabrizi will elaborate on the brief report from Ionis scientists in December that the drug did indeed safely and substantially lower the amount of mutant huntingtin protein, as measured in trial volunteers’ cerebrospinal fluid. That was only a first step, but an important one.

As a result, the Ionis scientists stated, clinical trial partner Roche, now the license-holder for IONIS-HTT_Rx, could skip the usual Phase 2 of the clinical trial program, going directly to a full-blown Phase 3. Phases 2 and 3 measure a drug’s efficacy. In consultation with the Food and Drug Administration (FDA) (and regulatory agencies in other countries), a drug company can shape the trial program as it sees fit.

I plan to interview Roche officials in Palm Springs, including Thomas Wiese, M.D., the Patient Partnership Director for the firm’s HD program.

‘The more the merrier’

"Wow, this is truly big news and very exciting news for the whole HD community since it tells us that the drug can do what it is designed to do!” HD specialist Jody Corey-Bloom, M.D., Ph.D., commented via e-mail in mid-December regarding the trial. “Now the hard part – can it make HD better?”

Also impressed, Martha A. Nance, M.D. pointed to the need for deeper clinical research: “Will people taking this treatment stabilize clinically, or improve?  And what about the long-term safety?  Will there be any unanticipated problems six months or five years later?  These are the questions that will require additional larger studies to answer, before the drug is understood well enough to use as a treatment in the clinic.”

“The IONIS results are ushering in a new and more hopeful era,” remarked LaVonne Goodman, M.D., the founder of HDDrugWorks.  “With the demonstrated safety (thus far) of the drug, and the urgency of our Huntington’s family needs, it makes a lot of sense to be going next to a Phase 3 trial.  Let’s hope the regulators think so too.”

Dr. Goodman added that the Cambridge, MA-based Wave Life Sciences is also currently enrolling patients in clinical trials of two gene-silencing drugs that, like Ionis’s effort, use strands of artificial DNA known as antisense oligonucleotides (ASOs) to decrease the huntingtin protein.

She reflected on the fact that, the greater the number of clinical trials, the greater the chances of finding effective treatments for this still untreatable condition.

“Competition is good,” Dr. Goodman said. “The more the merrier.”

Wave's unique approach

Just as the Ionis trial has made history, so might the Wave program. Whereas IONIS-HTT_Rx reduces both the mutant and normal huntingtin that all HD patients have, Wave’s ASOs attack just the mutant by targeting two specific genetic variations found in 70 percent of the HD population.

“We’re able to use the Wave technology to selectively lower the mutant huntingtin, while leaving the wild type, or healthy, huntingtin relatively alone,” explained Wave HD researcher Serena Hung, M.D., in a February 7 webinar sponsored by the Huntington’s Disease Society of America (HDSA) (click here to view). “This is a very unique approach, and this is probably the main difference between the Wave approach and other approaches.”

So far, the trial is enrolling participants in Canada and Poland. During the webinar, Dr. Hung indicated that other countries could be included, but did not mention the U.S. (Recruitment information for clinical trials worldwide is available at https://clinicaltrials.gov/).

For years, researchers have studied and debated the benefits and drawbacks of these different approaches. The distinctive IONIS and Wave trials could provide valuable answers.

At the CHDI conference, Wave’s Michael Panzara, M.D., MPH, will give a presentation on the firm’s program immediately before the talk on the Ionis effort.

Landmarks and a lucky year

In his welcome letter to conference participants, CHDI Chief Scientific Officer Robert Pacifici, Ph.D., notes that 2017 marked HDSA’s 50th anniversary.

“This year [2018] also marks the 25th anniversary of the identification of the huntingtin gene, a landmark accomplishment (for biology generally, not just HD) that of course could not have been achieved without the generous participation of HD families who volunteered their family history and donated their DNA.”

Dr. Robert Pacifici (photo by Gene Veritas)

The participation of thousands of HD family members in genetic research and other projects has helped shape CHDI and the HD field’s focus in the quest for treatments. That includes the “exciting new area” of DNA repair and handling, a theme of this year’s conference.

In addition to the popular, ever-expanding conference poster session, this year’s conference will include a resource fair, an innovation introduced at the 2017 conference in Malta. (Every fourth year, the conference is held in Europe.) The fair will display scientific tools and technologies useful in HD research.

“We are delighted to return to our ‘home’ here at the Parker Hotel in Palm Springs for lucky number 13!” Dr. Pacifici quips in his letter.

I officially became an advocate two decades ago this April by joining the board of HDSA-San Diego, where I served for twelve and a half years.

Blessed to have avoided symptoms so far, and observing the vast progress in HD research over these past two decades, I believe that 2018 could indeed be a lucky year for our community.

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

Faith in each other: sticking together through the challenges of Huntington's disease

This article is dedicated to my lovely wife Regina and to HD caregivers.

In 2017 my wife Regina and I marked 25 years of marriage with several celebrations, including a May dinner in Rome before meeting Pope Francis at #HDdennomore and then at one of our favorite San Diego restaurants on our anniversary, December 8.

Throughout last year, I relished the many triumphs of our life together: establishing successful careers, building important friendships, and raising our daughter Bianca, who will graduate from high school in June.

I have also reflected on how Regina and I have confronted the ordeals of Huntington’s disease, the debilitating, genetic neurological disorder that took my mother’s life twelve years ago this month. Because I too carry the HD gene, I will inevitably develop symptoms.

Last year, former San Diego Chargers PR director Bill Johnston exemplified the commitment to caregiving when, after 38 years with the team, he skipped its transfer to Los Angeles to keep his wife Ramona in an award-winning HD care facility.

“He didn’t run away from his marriage vows,” HD community member Dave Elliott reacted to the news in a Facebook comment. In HD families, those vows imply a heightened commitment.

Gene Veritas (aka Kenneth P. Serbin) and Regina Serbin at the Vatican Museums, with St. Peter's Basilica in the background, Rome, May 2017 (photo by Bianca Serbin)

Avoiding the HD shipwreck

Regina and I have faced the challenges of HD together.

The day after Christmas 1995, we received the terrible news that my mother had HD, that I had a 50-50 chance of inheriting the genetic defect, and that the children we planned for also faced a risk.

Many relationships shipwreck upon receiving such news (click here to read more).

However, Regina stood firmly by my side. One night, as I lay beside her gripped with fear, she hugged me tightly.

In 1999, Regina sat by my side as a geneticist revealed that I had tested positive for the HD gene.

Seven months later, we shared a tremendous sense of relief with the news that the baby in her womb, our daughter Bianca, had tested negative.

In 2011, Regina sat in the front row as I delivered the keynote address at the “Super Bowl” of HD research, the Sixth Annual HD Therapeutics Conference, sponsored by CHDI Foundation, Inc.

Each day, Regina lives with the fear that she could lose me to HD. Like my “HD warrior” father, who cared for my mother daily for more than a decade, she faces the prospect of watching (and tending) to my slow deterioration and loss of self.

However, not once has she blinked in her commitment.

With faith in each other, and also in the Creator, we have stared down the lion of HD. Striding side-by-side in annual Team Hope Walks, we yearn for an effective treatment.

A healthy relationship might delay onset

Like any long-term relationship, ours has had its ups and downs. Sometimes our different cultural backgrounds (Regina’s from Brazil) have led to disagreements. Overall, though, we have come to accept and appreciate each other’s foibles.

Ken and Regina in front of the Sugar Loaf Mountain in Rio de Janeiro, 1991 (family photo)

We’ve built a united front in running the household, helping Bianca prepare for college, and strengthening the family finances, preparing for the likelihood of my disability.

Whereas my mother’s HD symptoms started in her late 40s, at 58 I have fortunately avoided HD onset.

Scientists are still seeking to explain the differences in onset in people with identical HD mutations like my mother and me. I’ve strived to lead a healthy life, as I’ve chronicled in this blog.

Though the data from studies is complex, science suggests that healthy relationships can help promote overall health.

I firmly believe that I remain asymptomatic in good part because of Regina’s love and support, and because of our shared mission to build a family and raise a thriving child, soon to turn 18.

Treasuring my family

In our frenetic society, and as my aging seems to make life move faster, it becomes easy to take Regina for granted in our daily routines.

I feel a deep need to stop time and savor every moment with Regina and Bianca.

As I've pondered the deeper meaning of our marital commitment, I've focused on what's essential: treasuring them fully.

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

After announcing December 11 that Ionis Pharmaceuticals’ gene-silencing drug for Huntington’s disease safely reduced the production of the toxic HD protein, company officials analyzed the firm’s successful Phase 1/2a clinical trial and discussed the next step: larger trials that are designed to test IONIS-HTT_Rx’s efficacy in alleviating symptoms by modifying the course of the disease.

I met with two lead scientists from Ionis’ HD team at company headquarters in Carlsbad, CA: Frank Bennett, Ph.D., Ionis senior vice president of research and the franchise leader for the company’s neurology programs, and Anne Smith, Ph.D., the Ionis director of clinical development and the individual responsible for the day-to-day management of the trial.

Drs. Bennett and Smith stressed that, because the two-year trial ended just last month, they could provide only an initial assessment of the results. The company plans to present detailed clinical trial findings at medical conferences in early 2018 and then publish the results in scientific journals.

Ionis will transfer administration of the next clinical trial phases to Roche, a key partner in the project since 2013. Roche now holds the license to IONIS-HTT_Rx, will lead further development, and handle all potential sales. Phase 1/2a took place in Canada, England, and Germany, but the next phase will have sites in the U.S. and other countries, to be determined next year by Roche. Ionis will continue to play an advisory role in the project.

“We are very appreciative of the community, and the patience that the community has exhibited,” Dr. Bennett said. “We understand how important this is for the HD community. We’re very pleased it’s going forward. The community has been very respectful towards the company and has allowed us to conduct this study in a way that was very robust.”

Drs. Bennett and Smith focused on how the trial revealed a reduction in the mutant huntingtin protein that “substantially exceeded our expectations,” according to the December 11 press release. The key, initial piece of trial data came from the measurement of the protein in the HD patients’ cerebrospinal fluid (CSF). Other trial data such as brain scans and blood samples will become available later.

IONIS-HTT_Rx and other Ionis drugs are antisense oligonucleotides (ASOs, artificial strands of DNA), which alter the expression of genes. In August 2016, Ionis and its partner Biogen actually halted a Phase 3 trial of an Ionis ASO in infants with spinal muscular atrophy (a motor neuron disease) because the drug was extending their lives. The FDA (Food and Drug Administration) approved the drug, with the commercial name SPINRAZA, in December 2016.

In October, Ionis and Biogen won a biotechnology prize for SPINRAZA (click here to read more). Ionis is also collaborating with Biogen to develop a drug for amyotrophic lateral sclerosis (Lou Gehrig’s disease).

Dr. Frank Bennett (left) with Gene Veritas (aka Kenneth P. Serbin) and Dr. Anne Smith (photo by Kristina Bowyer, Ionis)

Following are key excerpts from the interview.

Compelling changes in mutant huntingtin levels

GV: How did patients react to the intrathecal administration of the drug, that is, via a spinal tap?

AS: We didn’t hear from any of the physicians that there were any difficulties. There was probably some nervousness, but there were few side effects, and that ones they had were manageable. I think it’s telling that all 46 patients completed the trial.

GV: What was observed in the HD patients in this trial?

AS: We’re still in the process of getting these next waves of data in. That will come out over months. It’s important to recognize that the trial just ended in November. But at this stage we did see a promising safety profile, meaning that we didn’t have any clinical concerns with the drug.

We saw clear, compelling changes in mutant huntingtin levels in the CSF. It was sort of gravy in this study. It’s designed as a safety study. We didn’t know when we entered the study whether we’d be able to even measure mutant huntingtin in CSF. But it is the best evidence of target engagement that we have – meaning that it is evidence that the drug is doing what it ought to do.

We were pleased that the assay [lab test] was developed to the point that we could use it to measure mutant huntingtin. The test is relatively new and fortunately came online at about the right time that we needed it.

The label from the first vial of the Phase 1/2a clinical trial, administered in London, September 2015 (photo by Gene Veritas)

GV: The reductions of mutant huntingtin “substantially exceeded” your expectations. To what extent?

FB: When we began the program with Roche, we picked a target level of reduction of mutant huntingtin in CSF, and, based upon that, we would decide to go forward with the program [into the next phase].

We put the mutant huntingtin data at the top of the list, because it was the data that was going to drive a business decision from Roche, but also, importantly, it was the data that would help them design the next study. So we prioritized that as being the first thing we would look at. It’s the basis for telling us what are the doses that we should be using for the next study.

GV: So can you specify the amount of mutant huntingtin reduction?

FB: We’re going to save that for a medical meeting.

Phase 1/2a too early for improving symptoms

GV: You project from your pre-clinical animal studies that the level of reduction in the brain itself should be greater than what is seen in the CSF, correct?

FB: Yes. An important nuance for the community is that the level of reduction that we’re seeing in CSF is not a one-to-one correlation with the level in [brain] tissue, which is where you want the drug to be working. We haven’t proven it in patients, but we’re very confident that it will translate [into higher levels of reduction in the brain].

AS: We’ve tested this drug in several species and are able to understand that relationship between what you see in CSF versus what you see in [brain] tissue, which is why it was really important this assay [CSF measurement] was online. It really is a window into the brain.

To understand that relationship in animals, the animals have to be sacrificed, to measure the level in the [brain] tissue. So we won’t ever ‘prove’ it in humans, so to speak, but we have a good understanding of it through the animals. And that it’s consistent from species to species is comforting. We can draw a conclusion about what’s likely happening in the human.

GV: Many in the HD community want to know: in this trial, did you see any signs of disease modification? Were there any hints at all from the doctors or from the data?

AS: We get anecdotal reports from physicians, but this is a population with a high placebo effect. These are motivated and excited physicians and patients as well. So I wouldn’t read anything into that. It’ll be several months before we have an understanding, though I would really caution any expectations along those fronts, because this is a short-term study.

We’re not expecting to see any sort of disease modification, just because of the way the study was designed. We dosed for three months, but it wasn’t even full drug effect for three months, because you build up the effect. This is the precursor to what would be long-term dosing.

GV: Have you observed whether there was also a reduction in the wild type (normal) huntingtin protein that all HD patients also have?

FB: There isn’t a good assay [lab test] for measuring wild type at this point. We have the samples, and once the assay is robust enough, we’ll look at it. The team is working on it, as well as others.

GV: Were there any surprises in the data that you’ve seen so far?

FB: It’s only surprising that it’s worked as we predicted it would [laughter]. Oftentimes when you go from pre-clinical to clinical, things don’t quite work out as well. But the drug is doing what it should be doing, which is lowering mutant huntingtin in cerebrospinal fluid. I think it’s all very positive from that perspective.

Phase 2 versus Phase 3

GV: What have you learned that will be helpful in planning phase 2?

FB: We asked a lot of the sites and the patients – because we collected a tremendous amount of data from them – for data that will be useful in designing a Phase 3 trial. We wanted to figure out which of the clinical outcome measures, which of the imaging measures, is actually reproducible, robust, and sensitive, to make sure it’s not “noisy” data.

AS: Another important learning will be whether there are differences from site to site. In a multi-site, multi-country trial, if a particular test just doesn’t translate well to German, for example, then we’ll have learned that. We can spare Roche from collecting data that are difficult to interpret, because they’re difficult to operationalize across sites and countries.

GV: You said “Phase 3” and not Phase 2. Why?

FB: Yes. At this point, Roche has not made a final decision on the next step. One of the options being considered is going right to a Phase 3 study. There’s a trade-off. You can do a smaller Phase 2 study – get more data that make it more probable that you’ll be successful for the Phase 3 – or you can go directly to a Phase 3 study. Those are the decisions that Roche is looking at right now very carefully.

The plus side is: if they go right to Phase 3, it would accelerate getting the drug to market. When we’ve reviewed with them the size of the study and the time of the study, there’s not a big difference between doing a Phase 3 and doing a more traditional Phase 2 first. It’s more expensive to go right to Phase 3, but it would save a lot of time.

GV: For an entity such as the FDA, is it okay to go from a Phase 1/2a to a Phase 3?

FB: The FDA will pay a lot of attention to the safety of the drug which – so far, knock on wood – looks very good. And then they leave it to the sponsor whether they want to risk the program. They may advise – because they ultimately want the drug to be successful, too – that this isn’t the best thing to do, but ultimately that’s the drug company’s decision. Roche will engage with the FDA.

GV: What is leading Roche to think it could maybe go directly to a Phase 3?

FB: It’s safety and tolerability [shown in Phase 1/2a], and the fact that we now know what dose of the drug produces this level of huntingtin lowering. Without that, they wouldn’t be able to go to Phase 3, but with that data, you could say that “this dose” should then produce “this level” of huntingtin lowering.

GV: Going straight to Phase 3, how much shorter would the whole program be?

AS: It’s definitely in the years.

FB: Yes, because if they were to do a Phase 2 study first, it would probably take three years to enroll and run. Roche wants to get this drug to patients as quickly as possible, assuming it works. They understand the disease. They understand the need for the patients.

GV: Whether Phase 2 or 3, when would the next study begin?

FB: I would anticipate towards the end of next year.

An important milestone

GV: What is the historical significance of the Ionis breakthrough?

FB: It’s an important milestone for the Huntington’s community. The mutation in the huntingtin gene was described in 1993. This is the first drug to go into clinical trials that is directly on target. It addresses the cause of the disease. We’re extremely excited that we’re actually seeing this basic science and all the work that NIH and other agencies have funded over the last 25 years now being translated into something that could actually have an impact for Huntington’s patients.

This bodes well for other neurological diseases. It has potential to markedly change how we treat those diseases. Perhaps this technology platform [the Ionis gene-silencing approach] would be beneficial for them as well. For patients out there overall, this is extremely important.

(For additional information about next steps in the IONIS-HTT_Rx program, click here for a Q & A with Dr. Ed Wild, an advisor and investigator of the program. You can also read a FAQS from the Huntington's Disease Society of America by clicking here.)

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

(In the video below, watch my report on the December 11 Ionis announcement.)

News from Ionis: drug reduces toxic Huntington's protein, trial may jump straight to Phase 3! from Gene Veritas on Vimeo.

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

In an initial clinical trial that marks a significant step toward finding an effective Huntington’s disease treatment, the Ionis Pharmaceuticals gene-silencing drug safely reduced the production of the toxic mutant protein implicated in HD, the firm announced today.

Ionis has handed development of the expected Phase 2 trial to its partner in the project, the multinational pharmaceutical giant Roche, earning a $45 million license fee, today’s Ionis press release stated. The drug is called IONIS-HTT_Rx: “HTT” stands for both the huntingtin gene and the protein it produces, and “Rx” signifies a remedy.

The trial was officially classified as Phase 1/2a. A Phase 1 trial measure’s a drug’s safety and tolerability in a small number of participants, while a Phase 2 trial examines efficacy in a larger group of patients. Though mainly Phase 1, this trial had elements of a Phase 2: actual HD patients took part, and it sought to determine whether the drug’s basic mechanism worked.

“We are encouraged by the performance of IONIS-HTTRx in the Phase 1/2a clinical study,” Frank Bennett, Ph.D., Ionis senior vice president of research, stated in the release.

The reductions of the mutant protein “observed in the study substantially exceeded our expectations,” Dr. Bennett added. The study, which involved 46 participants with early HD symptoms, did not assess whether that reduction slowed disease progression.

Ionis stated that “dose-dependent reductions of mHTT were observed” in the trial: the higher the dosage, the greater the reduction in the amount of the mutant protein.

“We were equally encouraged by the safety profile of the drug,” Dr. Bennett stated.

“The results of this trial are of ground-breaking importance for Huntington’s disease patients and families,” stated Dr. Sarah Tabrizi, professor of clinical neurology, director of the University College London’s Huntington Centre, and the global lead investigator on the Phase 1/2a study. “For the first time, a drug has lowered the level of the toxic disease-causing protein in the nervous system, and the drug was safe and well tolerated. The key now is to move quickly to a larger trial to test whether IONIS-HTT_Rx slows disease progression.”

Frank Bennett, Ph.D. (above, photo by Kristina Bowyer, Ionis) and Dr. Sarah Tabrizi (below, photo by Gene Veritas)

Pharma giant Roche steps in

Ionis officials stated in June that a Phase 2 study could start as soon as 2018. Typically, all three phases of a clinical trial project take at least five years, although nobody can predict the actual course of a trial.

In 2013, Ionis, a mid-sized drug-discovery firm that does not produce or sell drugs or conduct clinical trials on its own, partnered with Roche, one of the world’s largest and most successful pharmaceutical companies (click here and here to read more). Roche’s expertise includes neurodegenerative brain diseases.

Roche will now take over the development of IONIS-HTT_Rx, including the Phase 2 and potential Phase 3 trials and bringing the drug to market. It will hold the license to the drug.

Roche also will administer the open-label extension of the Phase 1/2a study, announced in June, whereby all patients – including those who got a placebo – will continue to receive the drug. The extension allows researchers to gather more data, examine the drug’s effects over a longer period of time, and better prepare for Phase 2. Patients also potentially benefit by receiving the drug longer.

Phase 2 to include United States

By attacking Huntington’s disease near its genetic roots, IONIS-HTT_Rx could potentially reduce, partly reverse, and even prevent symptoms. Ionis drugs are antisense oligonucleotides, artificial strands of DNA. The drug aims to turn off the huntingtin gene messenger RNA that contains the instructions to make the huntingtin protein in brain cells.

Forty-six patients took part in the Phase 1/2a trial at sites in Canada, Germany, and England.

“Today is an exciting day for the Huntington’s disease community,” a joint Ionis-Roche letter to the HD community stated. “Future studies for the program will be conducted globally, including in the U.S. Roche will announce details about future studies, including eligibility criteria and planned start dates, as this information becomes available.”

More than a decade of research

IONIS-HTT_Rx resulted from more than a decade of research involving Ionis, Roche, the lab of neurobiologist Donald Cleveland, Ph.D., at the University of California, San Diego, and CHDI Foundation, Inc., the nonprofit virtual biotech firm aimed solely at finding (and funding) HD treatments.

On December 3, Dr. Cleveland received the $3 million Breakthrough Prize, the world’s richest science award, sponsored by Google, Facebook, and other entities. It is twice the value of the Nobel Prize. Dr. Cleveland received recognition for his career contributions to the life sciences, including work on a cause of Alzheimer’s disease. (Click here to read more.)

Dr. Cleveland was honored at the 2012 gala of the San Diego Chapter of the Huntington’s Disease Society of America. For a recent article explaining the Dr. Cleveland’s role in the Ionis project, click here.

In interviews today, I hope to obtain further details about the progress regarding IONIS-HTT_Rx.

HDBuzz’s take: a historic breakthrough

The HD research site HDBuzz, produced by scientists, stated that today’s announcement is “likely to stand as one of the biggest breakthroughs in Huntington’s disease since the discovery of the HD gene in 1993.”

The site’s article, written by Jeff Carroll, Ph.D. – an HD-gene carrier like me and a scientist dedicating his career to finding HD treatments – asserted that the “most exciting” part of today’s news is that “dose-dependent reductions of mutant huntingtin were observed.”

The clinical trial administrators know this because they examined samples of participants’ cerebrospinal fluid, which runs along the spine and into the brain. Participants received injections of the drug via a spinal tap.

“This means that patients treated with IONIS-HTTRx have reductions in the huntingtin protein in their cerebrospinal fluid,” Dr. Carroll wrote. “Based on this result, it looks like the drug is doing what it’s meant to do, and that huntingtin lowering has been achieved!”

Dr. Wild concluded: “This is a great day in the HD community, and it sets us on the path to even more exciting work in 2018. For the first time in history, HD patients are being treated with drugs known to reduce the amount of huntingtin protein in their brain. Until we conduct the next trial, we won’t know if this reduces the impact of HD. And while we know the drug is safe in the short term, we will also have to watch carefully for any long-term adverse effects. But we’re facing this problem with renewed excitement and hope. It’s the best early Christmas present we could have hoped for.”

Jeff Carroll, Ph.D., at the 2012 CHDI-sponsored HD therapeutics conference (photo by Gene Veritas)

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