Wednesday, March 14, 2018

In chronicling the quest to cure Huntington’s disease, a whirlwind of emotions

Covering the 13th Annual Huntington’s Disease Therapeutics Conference left me with immense hope about potential treatments but also, as in the past, a whirlwind of emotions regarding the disorder that killed my mother and threatens the lives of tens of thousands of HD patients and presymptomatic gene carriers like me.

The conference began on February 26 with a remarkable keynote speaker invited by sponsor CHDI Foundation, Inc.: Nora Guthrie, the daughter of iconic folk singer and activist Woody Guthrie, who died of HD in 1967, and his late wife Marjorie. In 1967, Marjorie founded what would become the Huntington’s Disease Society of America (HDSA).

“We are the hopers and the changers,” said Nora Guthrie, quoting her father, to the audience of 350 scientists, drug company representatives, and family advocates. “The note of hope is the only note than can help us or save us from falling to the bottom.”

CHDI keynoters, who always come from HD-affected families, aim to inspire researchers’ quest for treatments. (I led off the 2011 event.) Guthrie interweaved her father’s music – he wrote “This Land is Your Land,” performed at President Barack Obama’s 2009 inaugural celebration – with the family’s struggles with HD.

CHDI Chief Scientific Officer Robert Pacifici, Ph.D., with Nora Guthrie (photo by Gene Veritas)

As reported in my previous article, the conference closed with the “best news since the discovery of the gene” in 1993: the Ionis Pharmaceuticals drug IONIS-HTTRx lowered mutant huntingtin protein an average of 40 percent, with a maximum reduction of 60 percent, in patients’ cerebrospinal fluid in a Phase 1/2a clinical trial (testing mainly safety and tolerability).

Based on animal studies, that translates into reductions in the cerebral cortex ranging from 55-85 percent. Ionis partner Roche, a major pharmaceutical firm based in Switzerland, confirmed that it would take the unusual step of skipping a Phase 2 trial (testing efficacy for the first time) and going directly to a Phase 3 (test and confirming efficacy in hundreds of participants).

I was elated to meet Nora, hear the Phase 1/2a results, and interview Roche representatives about the next steps in the clinical trial program for RG6042, the drug’s new name. (Roche and HDSA will update the HD community on Phase 3 eligibility criteria and other details.)

Upcoming articles will feature my interviews with the Roche officials and Guthrie.

Eric Lundgren (left), lifecycle leader of the Roche HD program, Gene Veritas (aka Kenneth P. Serbin), Mai-Lise Nguyen, patient partnership director of the Roche HD program, and Lauren Boak, Ph.D., Roche global development team leader (selfie by Eric Lundgren, Roche)

How early does HD start?

With several dozen presentations over 72 hours, the conference was a barrage of information about HD. Despite the positive news, like the six previous CHDI conferences I’ve attended, this event brought a stark reminder of the devastation caused by HD and the community’s urgent need for treatments.

I tested positive for the HD gene in 1999 and will, unfortunately, inevitably develop symptoms – unless a treatment becomes available soon. Watching the scientists’ presentations – many referred to the havoc caused in HD-affected brains – felt like getting a preview of how I’ll decline and die.

Sandrine Humbert, Ph.D., of the Universit√© Grenoble Alpes (France), discussed the role of the huntingtin protein in the development of the cortex (the largest portion of the brain) of mice. Her research explores HD as a possible “developmental disorder,” that is, the progression of symptoms from the earliest stages of life, given that people like me are born with the genetic defect.

Dr. Humbert said that subtle signs of the disease appear “years before” the appearance of involuntary motor movements, which doctors until recent years used as the indicator of onset. Perhaps drugs targeting the “abnormal development” of the brain will be needed to “delay disease onset,” she concluded.

Further research is needed in this new area of HD science. Still, Dr. Humbert’s presentation and the subsequent Q & A with scientists made me wonder: as I push 60, are the memory lapses and other cognitive changes I’m experiencing because of ordinary aging – or HD?

In the video below you can watch the discussion of this point. For Dr. Humbert’s complete presentation, click here.

‘A bucket of cold water’

My interactions with physicians, scientists, and HD family members further reminded me of my “race against the genetic clock” and the challenges faced by HD families.

Despite the air of excitement about the Ionis Phase 1/2a results, one doctor familiar with my story cautioned me about the extensive time needed for Phase 3: “It’s a little bit naive to not consider that you might not be ready for the Ionis drug.”

“I feel like you’ve just thrown a bucket of cold water on me,” I told her.

The range of onset for someone with my mother’s and my level of mutation is between the late 40s and late 60s. She probably developed symptoms in her late 40s. She died at 68. At 58, I’m extremely lucky to have gotten this far without symptoms.

I can’t wait much longer for a drug. If successful, RG6042 probably won’t reach the market for five or six years – and that’s an optimistic scenario, since Phase 3 could fail.

The physician reminded me of the importance of planning carefully for the onset of symptoms, citing the case of one patient who was able to remain at work after some adjustments to his routine.

She did note that my advocacy and coverage of the CHDI meetings might be delaying onset: they provide me with purpose and intellectual enrichment.

Reliving the shock

At one lunch, I briefly recounted my family’s HD story to a group of researchers and the Swiss neurologist Jean-Marc Burgunder, M.D., who chairs the executive committee of the European Huntington’s Disease Network, a CHDI-supported nonprofit network for advancing research, facilitating clinical trials, and improving patient care.

I explained that, with no prior knowledge of HD, I received a bombshell in a phone call the day after Christmas 1995. In the space of a few minutes, I learned of my mother’s genetic test and diagnosis; my 50-50 chance of inheriting the gene; and the potential risk for any child I might father.

Dr. Burgunder observed that HD testing centers now have a protocol that includes notifying potentially at-risk family members about genetic testing and counseling by geneticists and psychologists.

Back then, however, all I could do was to call my mother’s geneticist to get more information about HD and genetic testing.

To relive the emotional pain of that day and look back on the improved genetic testing process made me feel as if I were going through an out-of-body experience.

Sadly, learning about HD for the first time remains a shocking experience that won’t be eliminated until we have effective treatments.

Listening to other HD family members recall their stories of genetic testing of their children, I also remembered the months-long, anxiety-ridden process of having our daughter tested in the womb for HD. Luckily, she tested negative.

Research: ‘It’s for you guys’

Despite my renewed fears about HD, the final, upbeat session on “huntingtin lowering”  (reducing the amount of huntingtin protein in brain cells) lifted my spirits. In addition to the Ionis news, it included an update on another, recently started Phase 1b/2a gene-silencing clinical trial, PRECISION-HD, run by Wave Life Sciences. (Click here to watch a video of the presentation.)

During that session, I sat next to Scott Zeitlin, Ph.D., of the University of Virginia, whose presentation concerned his research in transgenic HD mice, a common tool of researchers, to measure the effects of lowering huntingtin. He described the types of changes in the animals’ brains that also compromise the human brain.

I was heartened to hear his conclusion.

“Many of these earlier changes that we see can be reversed fairly quickly,” he said of the experiment. “So I’m enthusiastic about this.”

Though the presentation was based on unpublished research – scientists don’t like to get “scooped” – Dr. Zeitlin gave permission to post it online (click here to watch).

“It’s for you guys,” he said, referring to the HD community and echoing the ethos of the quest for treatments.

Scott Zeitlin, Ph.D., with Sarah Tabrizi, FRCP, Ph.D., lead investigator of the Ionis Phase 1/2a trial (photo by Gene Veritas)

Personal and community milestones

I left the conference at 10:45 p.m. on March 1, as the farewell banquet wound down. I had drunk a couple of cups of strong black tea – normally something an HD gene carrier should avoid but which I needed for the 140-mile drive to my home in San Diego.

I arrived at 1:10 a.m. the next morning and, wired from the tea and the conference, started work on my article about the event. I finally went to bed at 5 a.m. – also not good for an HD gene carrier but perhaps understandable given the circumstances.

It was titled: “The best news for the Huntington's disease community since the discovery of the gene: Ionis trial data revealed, Roche confirms jump to Phase 3” (click here to read more).

Appropriately, it was entry number 250 in this blog: a personal milestone symbolic of my avoidance of symptoms, of my advocacy, and of the hope for treatments or even a cure.

(Visit my Vimeo album for other presentations and interviews at the conference.)

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

Friday, March 02, 2018

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

Researchers revealed impressive, if not conclusive, additional information at CHDI Foundation's 13th Annual Huntington’s Disease Therapeutics Conference yesterday regarding the historic Ionis HD clinical trial: the drop in mutant protein observed in the cerebral spinal fluid (CSF) of participants corresponds to as much as an 85 percent decrease in the cortex of the brain, head physician Dr. Sarah Tabrizi announced.

It’s the best news the HD community has received since the publication of the research confirming the discovery of the gene 25 years ago this month. As scientists have observed, it’s also a major step for disease and drug research in general.

“The magnitude of mutant huntingtin [protein] reduction observed exceeds the effect needed for disease modification in animal models,” Dr. Tabrizi, of University College of London (the lead clinical trial site), told an audience of some 350 scientists, drug company representatives, and HD advocates at the conference in Palm Springs, CA.

Dr. Sarah Tabrizi presenting the IONIS-HTTRx trial data on March 1, 2018 (photo by Gene Veritas, aka Kenneth P. Serbin)

Ionis officials announced in December that the Phase 1/2a trial for the gene-silencing drug IONIS-HTTRx “substantially exceeded our expectations” in safely reducing the mutant huntingtin in the CSF.

For the first time, Dr. Tabrizi’s presentation (plus an Ionis press release) specified the level of huntingtin reduction.

During the clinical trial, participants received the drug via spinal injections, and doctors measured the drug’s ability to reduce the protein by extracting CSF samples.

IONIS-HTTRx lowered mutant huntingtin an average of 40 percent, with a maximum reduction of 60 percent. As Dr. Tabrizi explained, projecting from the numerous, painstaking animal studies done by Ionis, the reductions in the cortex range from 55-85 percent.

Frank Bennett, Ph.D., Ionis senior vice president of research and the franchise leader for neurology programs (left) and Anne Smith, Ph.D., Ionis director of clinical development (middle), confer with Dr. Tabrizi moments before the two women's historic presentation of the IONIS-HTTRx trial data. Dr. Bennett led the Ionis efforts to develop the drug (photo by Gene Veritas).

The cortex – along with the striatum, which is critical to motor control and managing the reward system – is the area of the brain most affected by HD. It is the most developed area of the brain, the source of thought and language, abilities severely hampered by HD.

Watch Dr. Tabrizi in the short video excerpts below explain this data and thank the 46 brave clinical trial volunteers and the many others involved in the effort. I also recommend watching the full video – which includes further trial data and a helpful overview of the project by Anne Smith, Ph.D., of Ionis – by clicking here.
The plans for RG6042, the drug’s new name

The presentation by Drs. Smith and Tabrizi – the first public presentation of the trial data – can perhaps help inspire the HD community and researchers to become engaged in the next, crucial step: testing the drug’s efficacy.

Based on its partnership agreement with Ionis, Swiss pharmaceutical giant Roche, which now holds the license to the drug, will carry out a longer trial with hundreds of participants, including sites in the U.S.

The main question: will symptoms of this progressive, deadly disease stabilize, or even be reversed?

In an interview at the conference, Roche officials told me that – as Ionis had indicated – the company would take the unusual step of skipping a Phase 2 trial (testing efficacy for the first time) and going directly to a Phase 3 (confirming efficacy in hundreds, or more, participants).

They pointed to the excellent results of the Phase 1/2a trial; Ionis’ superb development of the drug; the nonprofit CHDI’s expertise and leadership; and the enthusiasm from – and urgent need of – the HD community.

Roche has officially changed the name of IONIS-HTTRx to RG6042. “R” stands for Roche, and “G” for Genentech, a major U.S.-based pharmaceutical company acquired by Roche in 2009 for $46.8 billion. The number 6042 is a standard drug number assigned by the company. If Phase 3 is successful, a drug issued for commercial sale will get a brand name.

All U.S-based Roche personnel and products still use the name Genentech.

Roche has not yet determined a start date or timeline for Phase 3. I will provide a detailed report on the interview and Roche’s plans, and also my personal reactions to the conference, in upcoming articles.

Members of the Roche HD clinical trial team watch Dr. Tabrizi's presentation. From left to right, Scott Schobel, M.D., M.S., clinical science leader of product development; Lauren Boak, Ph.D., global development team leader; Eric Lundgren, lifecycle leader of the HD program; and Mai-Lise Nguyen, the patient partnership director for the HD program (photo by Gene Veritas). 

Time for excitement, but also caution

CHDI Chief Scientific Officer Robert Pacifici, Ph.D., called the results of the Ionis trial “incredibly exciting.”

However, he also cautioned the HD community.

“Drug discovery is a really time-consuming and inefficient process, and, sadly, fraught with many failures,” Dr. Pacifici said. “The first time you put something into people, no matter how prepared, you never know whether it’s going to be safe and well-tolerated. What the initial trial showed was that at those doses, with the route of delivery, with that population of folks, it is indeed safe and well-tolerated. (If it wasn’t, it would stop in its tracks.) Once you get to this stage, a lot of the uncertainty about timelines goes away.

“This is really the time to be incredibly careful and incredibly deliberate. It’s going to take a while now to orchestrate the Phase 3 trial. That’s the pivotal trial that tells you whether or not the drug works.”

Everything needs to be done “by the book” to get a really “conclusive result,” he added.

If the trial fails, it will still provide scientists and physicians with guideposts for future research and trials, he said.

“We owe a huge debt of gratitude to those patients who signed up for that initial trial,” Dr. Pacifici concluded. “It’s going to require not only more of that type of participation, but a lot of patience.”

You can watch my interview with Dr. Pacifici about the conference and the Ionis trial in the video below.

* * *

Ionis hosted a live webcast at 11 a.m. Eastern Time today. A webcast replay, including slides with clinical trial data, are available by clicking here.

For detailed coverage of the HD conference presentations, visit

Visit my Vimeo album, to be periodically updated in the coming weeks, for other presentations and interviews at the conference.

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

Tuesday, February 27, 2018

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-HTTRx.

“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.

‘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-HTTRx 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).

Wednesday, February 21, 2018

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-HTTRx, reserving a more thorough update for scientific meetings.

In the final talk – perhaps saving the best for last – IONIS-HTTRx trial administrators Anne Smith, Ph.D. (Ionis) and Sarah Tabrizi, FRCP, Ph.D. (University College of London) will present “Development of IONIS-HTTRx: 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-HTTRx, 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-HTTRx 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

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.)

Saturday, February 03, 2018

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.

Saturday, December 16, 2017

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-HTTRx’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-HTTRx, 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-HTTRx 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-HTTRx 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.)