Tuesday, November 22, 2016

This Thanksgiving, let’s show gratitude for disease researchers and drug hunters

This Thanksgiving, lets pause to show gratitude for the many researchers and drug developers in America and around the world who strive to treat diseases and improve the quality of health for all.

As we await the first effective treatment for one of the worlds cruelest maladies, we in the Huntingtons disease community feel especially grateful for the efforts of the scientific, medical, and biotech communities to bring relief from HDs devastating cognitive, motor, and behavioral symptoms.

Our cause is urgent: HD strikes in the prime of life and is ultimately fatal. Stopping HD would mark a historic step in the quest to conquer brain diseases.

As a presymptomatic carrier of the HD gene, I found inspiration for Thanksgiving 2016 in the powerful speech last February by HD advocates Astri Arnesen and Svein Olaf Olsen at the 11th Annual HD Therapeutics Conference, sponsored by CHDI Foundation, Inc.

Leaders of the HD cause in their native Norway and in the European Huntington Association (EHA), this indomitable couple bared their souls about marital commitment, denial, genetic testing, and raising a family.

Their goal: to motivate and demonstrate appreciation for the audience of more than 200 world-class HD researchers, physicians, and drug company executives.

Svein Olaf Olsen (left) and Asti Arnesen at the 11 Annual HD Therapeutics Conference. Astri is president of the EHA and Svein Olaf a member at large of its board (photo by Gene Veritas, aka Kenneth P. Serbin)

No questions asked

Astri and Svein Olaf titled their presentation HD more than a disease!

HD is much more than a disease, Astri said leading off. It affects every part of your life, and its really a part of who you are.

Astris family traced back HD to a maternal great-grandmother. Her maternal grandfather and her mother also developed the disease.

However, as is so often the case in HD, nobody in Astris family discussed the condition, even though they witnessed relatives debilitating symptoms each day.

You just sensed: no questions should be asked, Astri explained. My mother grew up in this family.

A special education teacher, Astri in the 1980s fell in love with a co-worker, Svein Olaf. She divorced her husband a brief marriage she had entered to escape caring for her HD-stricken mother and started a relationship with Svein Olaf.

The greatest gift of all

Svein Olaf knew of Astris 50-50 chance of carrying the HD gene. However, the young couple didnt discuss HD much. Without Astri getting tested, they had two daughters in the early 1990s, before the discovery of the huntingtin gene in 1993 and the development of a definitive genetic test.

After their older daughter Jannike turned 18 in 2009, she wanted to get tested for HD.

I said to her, Thats not possible,’” Astri said. “‘I could not by any means let you go through that. I will do the test [first]. So the day before Christmas, I called the doctor.

The process took weeks. The waiting and uncertainty were so traumatic, Svein Olaf told the audience, that afterwards he could not remember anything about the tests. Nothing.

When the couple visited the clinic to obtain the results, the doctor practically came running to Astri. You dont have the gene! she exclaimed.

Svein Olaf crashed his hand on a table. At that moment, he vowed to marry Astri, something they had planned for years but always put off.

It was really the most amazing thing to come home and tell our daughters that there is no risk anymore, Astri remembered. That was really for me the most important thing. You can handle your own situation, but knowing that I hadnt passed it on to them was really the greatest gift of all.

The hope of science

Since then the couple have dedicated themselves to the HD cause in part because Astris youngest sibling, Arne Dag, was stricken with HD.

He was a brilliant young man, Astri said. He was really teaching my father, an engineer, how to fix the car when he was six years old. So he was a future engineer coming up. But in his early 20s, hes starting to have trouble. He doesnt manage to finish his studies.

In a typical symptom of HD, Arne Dag became deeply depressed. He was formally diagnosed in 2005.

At the 2010 meeting of the European Medicines Agency (the counterpart of the U.S. Food and Drug Administration) in London, Astri showed a video of a short interview she did with her brother.

In the clip, Arne Dag struggles to speak, and his body twists and turns because of chorea, the involuntary movements caused by HD.

Arne Dag tells Astri that he wants to participate in a clinical trial as soon as possible. She asks him about his hopes for the future.

I hope that science is on my side, he says, laughing.

Participants at the 11th Annual HD Therapeutics Conference, Palm Springs, CA, February 2016 (photo by Gene Veritas)

Thanking the researchers

Arne Dag died in April 2015 at the age of 46.

But he hoped, Astri told the conference attendees. And that was really important in his life. He hoped for the hard work you [scientists] are doing to give results for him and for us.

As a slide showing infants appeared in the background, she added: And thats what we are fighting for, and thats why we are so involved in this work. Because now, its not about him. Its not about me. Its about all these lovely children and grown-ups living with a risk, living with the gene, and who really put their hope on you and your work.

And no matter how long it takes, that is so important in our daily lives. Knowing that you go to work really makes our day easier. For me, hope has really been my way of coping and dealing with it, and it is for a lot of us. We are many, many out there who support you, who need you, and who are waiting for results.

So we want to thank you so much. Its amazing to see how many fantastic, brilliant researchers that are in this field. We are so grateful for that.

Happy Thanksgiving!

You can watch Astri and Svein Olafs presentation in the video below.


Wednesday, November 09, 2016

‘Crying a few million tears’ for the fallen victims of Huntington’s disease

Huntington’s disease relentlessly attacks the brains of its victims and in other ways wearies many of us involved: advocates, caregivers, gene carriers like myself awaiting onset, young people pondering genetic testing.

Knowing at 56 how fortunate I am to have remained healthy beyond my deceased mother’s age of onset, I took a “break” from advocacy over the summer. (Click here to read more [September 15 blog article]).

However, on October 24 the hard reality of HD hit home once again.

Responding to a request from the Huntington’s Disease Society of America (HDSA) for information on this blog’s impact in the “landscape of HD communication,” that morning I wrote a long e-mail detailing how At Risk for Huntington’s Disease has reached thousands of people via both the web and Facebook.

Since I began writing in January 2005, the blog’s 230 articles have garnered more than 650,000 page views. More than 3,200 Facebook friends also have access to the blog in 60 HD-related groups.

“I think one of the most important aspects of the blog has been the wide range of topics it has covered: my family's struggles with the disease (mother dying, me testing positive, [my daughter] testing negative, etc.), the many social implications of the disease, advocacy issues, and the search for treatments,” I observed.

Reviewing the blog’s history reminded me of many painful moments in my struggle and of the HD community's collective suffering.

A nervous stumble

That afternoon, I had my annual HD checkup with a neurologist.

As with past checkups, in the hours before the visit, I became apprehensive about my performance on the various neurological tests.

One involves walking heel-to-toe along a straight line. This year I began that test with a bit of a nervous stumble. I wondered if that might be an early sign of onset.

I regained my balance and successfully completed the walk. I was going to suggest to the doctor that I repeat it, but she told me that I had done fine.

The other tests also went well.

Fortunately, she once again declared me symptom-free.

Tensing up at support group

Naturally, I felt greatly relieved.

However, I faced yet another challenging HD moment that evening: the annual research update at our local support group, from Jody Corey-Bloom, M.D., Ph.D., the director of the HDSA Center of Excellence for Family Services and Research at the University of California, San Diego.

Each year I record Dr. Corey-Bloom’s talk, later posted here and on Facebook. Striving to produce a video of good quality, I tensed up as I focused in and out and turned the camera to follow Dr. Corey-Bloom’s movements. This was vital information for the HD community.

With the rest of the audience, I intently listened to her presentation of the latest research breakthroughs and news of the crucial clinical trials that provide hope for effective treatments and perhaps even a cure. The update included a detailed discussion of the historic gene-silencing Phase I trial by Ionis Pharmaceuticals, Inc. (Click here to read more about the Ionis trial.)

Given the many projects in progress, Dr. Corey-Bloom spoke for 90 minutes, her longest update ever.

Seeing HD-affected support group attendees reminded me of my good fortune but also of the inevitability of my own onset, if a treatment isn’t found.

You can watch Dr. Corey-Bloom’s update in the video below.

Update on Huntington’s Disease Research 2016: A Presentation by Dr. Jody Corey-Bloom from Gene Veritas on Vimeo.

‘A life-long Holocaust’

Still pondering the exhausting moments of October 24, the next morning I was jolted by a powerful comment on my September 15 article "Dreams for a better future: an opportunity we Huntington’s disease people and our families are denied."

The words speak for themselves:

I am in nearly the same situation as the author of this blog. I am now 59 years old and will be 60 in February. Huntington's Disease killed my father & half my family. My sister is dying now in an extremely horrible case where she is burning so many calories that she looks like a skeleton. I have actually had continual muscle contractions all my life since I was about 25 years old, but nothing else. I've been able to live my life and work and function normally (although, I never married or had children). I've wondered my entire life when it would happen to me. Now, at almost 60, I wonder if this is it, and this is all that will happen, and I wonder why. Why did it kill so many people in my family and not me?

I can't really imagine a more horrible experience in a family. I had a doctor once tell me that he had never seen a single person come out of a Huntington's family who wasn't emotionally damaged for life. He described it as a kind of "life-long Holocaust" where you live your entire life watching one persona after another die the most horrible deaths, and unlike the Jews, you don't have anyone you can blame.

I have cried a few million tears in my life, but now approaching 60, I am able to see some things I could not have seen years ago. I look at myself and my family, and I realize that none of us are the people we would have been without this disease. We all became so much "more." We all learned to truly "see" people, to feel empathy with all people suffering, to appreciate all the small moments and the good things in life. We all embarked on a life-long journey to find meaning and to understand our place and purpose in this world. And, when I look around and see all the various kinds of suffering in this world, it makes me think that maybe this has always been the reason and the purpose for it – to cause us to become "more."

These words not only rekindled my desire to defeat HD; most importantly, they also inspired compassion.

Sarah falls to HD

A diagnosis for Huntington’s disease forever changes the lives of affected individuals and their families.

Without an effective treatment, thousands of people around the world continue to succumb to HD.

On October 17, Huntington’s took the life of 37-year-old Sarah Brook of Tamworth, England.

Many in the HD community became familiar with Sarah’s struggle on “Sarah’s Dream, a Facebook page run by her mother Gail and stepfather Jeff. “Sarah’s Dream” is also the name of a motorcycle the family used in the effort to raise funds and awareness. According to Gail, Sarah’s first symptoms appeared in her early twenties. Sarah's father died of HD at the age of 35.

“This is the saddest time of my life,” Gail wrote on Facebook. “Nothing could compare to the loss and heartbreak I feel. […] It's the wrong way round, this shouldn't be happening. I can't bear the thought that I'll never see her again. I want to hold her so much.”

Sarah’s funeral took place on November 3. Her body was cremated.

“We've put her near the TV,” Gail wrote of Sarah’s ashes, held in an urn. “She's always liked her telly, and [we] will scatter them in the place she chose, when we feel ready.

Despite their enormous loss, Gail and Jeff will continue in the fight against HD.

“We've been married for 33 years and he adopted Sarah, knowing that she was at risk of HD,” Gail wrote me in a Facebook message. “We have agreed to carry on with Sarah's Dream, in memory of Sarah.”

We need to find a way to wipe away the tears of HD. Perhaps we can be heartened by the profound dedication to the cause displayed by Sarah's family.

Above, a collage of photos of Sarah Brook. Below, Jeff Brook riding Sarah's Dream (family photos).

Wednesday, October 19, 2016

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

At its halfway mark, Ionis Pharmaceuticals' historic Huntington’s disease Phase 1 gene-silencing clinical trial is on track to finish as scheduled in late 2017, company officials said in an interview on September 26.

“What we can say is that the trial is going well,” said Frank Bennett, Ph.D., Ionis senior vice president of research and the franchise leader for the company’s neurology programs.

Dr. Bennett added that no “issues” have arisen so far in the Phase 1 safety and tolerability study of its drug IONIS-HTTRx in patients with early HD. IONIS-HTTRx aims to reduce the production of huntingtin protein in brain cells. This approach, if it advances to Phases 2 and 3, may have the potential to slow, halt or perhaps even reverse the progression of HD symptoms. The trial began in September 2015, with participants in England, Germany, and Canada.

The Ionis HD team explained that the Phase 1 trial is not assessing the drug’s efficacy. Each patient in the trial receives the drug for just three months – not long enough to gauge any impact on symptoms.

Furthermore, the trial is “double-blinded”: trial participants, trial administrators, and Ionis scientists do not know who is getting the drug or a placebo. This insures that bias and other external factors don’t affect the trial results.

Nevertheless, the absence of problems is good news.

No surprises have occurred to date, commented Anne Smith, Ph.D., the Ionis director of clinical development and the individual responsible for the day-to-day management of the trial.

“It’s blissfully quiet,” Dr. Smith said. “You don’t want surprises in clinical trials. Most surprises in safety trials are bad surprises. This one is surprise-free to date.”

Also, trial participants had no difficulties with the delivery of the drug via injections into the spine (so-called intrathecal injections), added Roger Lane, M.D., the Ionis vice president for neurology clinical development and one of the designers of the trial.

Watch my reaction after the interview at Ionis headquarters on September 27 in the video below.

Phase 2 could start in 2018

“We’re continuing to enroll patients in the study,” Dr. Bennett said. A total of 36 patients divided into four cohorts – each subsequent cohort taking a higher dose of IONIS-HTTRx – will participate in the trial.

Ed Wild, M.D., Ph.D., one of the administrators of the trial at University College London, announced in June at the annual convention of the Huntington’s Disease Society of America in Baltimore that the third cohort had received permission to receive the drug. (Click here to watch a video of Dr. Wild’s presentation.)

“This is a new therapy, and we want to make sure that we’re doing no harm,” Dr. Bennett emphasized. “Everything is geared towards the safety of the drug at this stage.”

If Phase 1 confirms safety and tolerability, a year-long Phase 2 trial to measure efficacy in a larger number of patients likely would start in 2018, Dr. Bennett said.

Infants on an Ionis SMA drug living longer

The update provided by the Ionis HD team came in the wake of further validation of the company’s scientific approach.

Ionis makes antisense oligonucleotides (ASOs, artificial strands of DNA) that alter the expression of genes and can therefore potentially serve as treatments for genetic diseases. On August 1, Ionis and its partner Biogen actually halted a Phase 3 trial of an Ionis ASO (nusinersen) in infants with spinal muscular atrophy (SMA) because the drug, which increases the level of a key protein, was working so well.

On September 27, Biogen announced that it had completed its application for priority review of nusinersen by the U.S. Food and Drug Administration (FDA).

Like HD, SMA is a genetic neurodegenerative disorder. It primarily affects children, who “end up becoming paralyzed over time,” Dr. Bennett explained, and become vulnerable to respiratory infections or other diseases. Children diagnosed with the most severe form of SMA generally live less than a year, he said. In a less severe form of SMA, children lose the ability to walk over time as they grow up, Dr. Bennett added.

“I think the surprising thing that we found – and this was evidence early in the program – was that we didn’t just stop the decline in these patients, but we actually reversed it,” Dr. Bennett said. “That was really unexpected. I should say that they’re not cured of the disease, but they’re doing much better now than expected. They are surviving longer based on the natural history of the disease.”

These results demonstrated the body’s capacity to mend once the cause of a disorder is removed, he observed.

“We’re hopeful that will also occur in Huntington’s,” Dr. Bennett affirmed. “We have to demonstrate it, but I think there’s a precedent now in these neurodegenerative diseases. If you remove the insult or the toxicity, you can recover function.”

Dr. Frank Bennett of Ionis makes a point during discussion of the company's Phase 1 clinical trial for a Huntington's disease treatment (photo by Kristina Bowyer, Ionis)

Preparing for the HD clinical study

In the Phase 1 IONIS-HTTRx trial, clinical trial investigators are collecting some information about the drug’s effect on biomarkers (indicators of a disease mechanism or drug impact) that may help the team design a potential Phase 2.

According to Dr. Lane, before a patient receives each of the four planned doses, the trial administrators collect samples of cerebrospinal fluid (CSF) that will be used to measure levels of huntingtin protein and a variety of other protein markers of neuronal injury and inflammation. Patients also undergo brain scans to look at the volumes of, and the connectivity between, different parts of the brain that are known to be affected in HD.

Another biomarker is neurofilament, described by Dr. Bennett as a protein involved in the cytoskeleton or internal “scaffold” of neurons.  “It’s something very specific to neurons,” said Holly Kordasiewicz, Ph.D., the Ionis director of neuroscience drug discovery, who participated in selecting the ASO, researched it in animals, and is developing biomarker tests for the Phase 1 study. “When the neurons are damaged, neurofilament is released. In a number of neurodegenerative diseases, neurons are dying and neurofilament levels go up.”

In HD, brain cells die. In a clinical study, a decrease in neurofilament would suggest that the drug is protecting neurons, Dr. Kordasiewicz added.

Ionis Huntington's disease clinical trial planners Dr. Anne Smith (left), Dr. Roger Lane, and Dr. Holly Kordasiewicz meet with Gene Veritas (in green shirt) on September 26, 2016, to provide an update on the company's Phase 1 HD trial (photo by Kristina Bowyer of Ionis)

Getting the design of Phase 2 right

The participants in the IONIS-HTTRx study undergo a battery of tests that assess memory, thinking, movement, behavior problems, and abilities to perform every-day activities. This is in preparation for use of such measures in a potential Phase 2.

“We’re trying to get the information to design the best efficacy study that we can,” said Dr. Kordasiewicz. “A really sad outcome would be failure of an efficacy study due to the wrong design, not because the drug’s not working. You have to be sure you’re picking the right dose and the right endpoints for the efficacy study.  That’s why all the extra stuff goes into these Phase 1 trials, so that you can get the design right and have the best shot at giving the drug the best chance at working.”

The large burden of work on patients and trial administrators in Phase 1will ultimately allow Ionis (and its partner Roche) to “simplify” potential Phase 2 and 3 trials, making them quicker and making it easier for patients to participate, Dr. Bennett added.

Seeking answers to key questions

This is the first time that an HD gene-silencing drug is going into the human brain. In animals such as mice and non-human primates, the drug gets into both the cortex (the outer, main part of the brain, linked to consciousness) and the striatum (a part of the brain deep under the surface that is involved in movement). Both areas are affected by HD.

A key question for researchers: must IONIS-HTTRx reach the striatum to help alleviate HD?

According to Dr. Kordasiewicz, the latest research in HD mice (conducted by William Yang, M.D., Ph.D., of the University of California, Los Angeles) demonstrates that silencing the huntingtin gene in the cortex was more effective than silencing the gene in the striatum, but that silencing in both cortex and striatum was the most effective approach.

Another concern of scientists and HD patients and their families involves the abilities of the ASO, or gene-silencing drug. Should the ASO be designed to reduce only the so-called “bad,”mutant huntingtin? Or is it okay to reduce both the bad and the normal version, which is inherited from the unaffected parent? The IONIS ASO is expected to do the latter.

According to the Ionis HD team, the controversy over this question is diminishing. Studies in animals support the safety of approaches that reduce both mutant and normal huntingtin.  Additionally, Dr. Guohao Wang’s work in mice showed that eliminating huntingtin completely in later life did not have any adverse consequences.

“That was good evidence to support our approach,” said Dr. Lane.

Involving the U.S., thanking patients and families

Many in the HD community have asked: why didn’t Ionis conduct Phase 1 in the United States? And would a potential Phase 2 include Americans?

“I’d be surprised if the U.S. wasn’t involved in a Phase 2 study, as well as additional countries, but I don’t think we are in a position to say specifically which countries are going to be involved,” Dr. Bennett commented. “There were strategic decisions that caused us to go to Europe and Canada first. It’s not that we want to ignore the U.S.” He explained that it was faster to start a trial in Canada and Europe.

The Ionis HD team thanked the Phase 1 participants and their families for their involvement in the Phase 1 study.

“It’s been a very good community and very supportive of our efforts,” said Dr. Bennett. “We also want to thank them for their patience.”