Wednesday, September 03, 2014

Moving toward a potential treatment: Isis, CHDI researchers outline upcoming Huntington’s disease gene-silencing trial

Scientific research and clinical trials aren’t glamorous, but they are the meat and potatoes of effective treatments and perhaps ultimately a cure for Huntington’s disease. The gene-silencing approach like the Isis-Roche initiative reported here August 23 has great promise.

In a two-hour interview with me at company headquarters in Carlsbad, CA, on August 22, Isis Pharmaceuticals, Inc., officials and researchers provided details about the Phase I trial of the antisense oligonucleotide (ASO) ISIS-HTTRx. Isis and Roche, the Swiss drug maker, plan to start the trial in Canada and Europe by mid-2015. If successful, the trial could result in a drug in five or six years, by 2021.

By attacking the disease near its genetic roots, ISIS-HTTRx could potentially reduce, partly reverse, and even prevent the symptoms of Huntington’s. If it works as intended, this synthetic strand of DNA will turn off the huntingtin gene messenger RNA that contains the instructions to make the huntingtin protein in brain cells.

The huntingtin gene is essential for development very early in life, but some people inherit it with an expanded length, leading to the production of faulty huntingtin messenger RNA and huntingtin protein. Carriers of genes expanded beyond a certain length develop Huntington’s disease. The most recent evidence suggests that not only the faulty protein, but also the faulty messenger RNA damages the brain.

ISIS-HTTRx will later receive a generic scientific name and, if marketed, a trade name from Roche. HTT stands for huntingtin, and Rx for medical treatment. Founded in 1989, Isis based its name on the Egyptian goddess known for her healing powers.

“We have a drug that is going forward into clinical development,” said Frank Bennett, Ph.D., Isis’s senior vice president for research, who has led the development of the HD project. “Assuming all goes well, our plan is to start clinical trials towards the first half of next year…. We’re very enthusiastic about the drug.”

Dr. Bennett said that Isis is currently conducting standard toxicology studies of the drug primarily in non-human primates, but also in rodents, to assure that it will not cause harm to humans. A Phase I trial tests primarily for safety and tolerability.


Dr. Frank Bennett (photo by Dr. Ed Wild)

If the toxicology studies are successful, in the first quarter of 2015 Isis and Roche will request formal authorization to start the Phase I trial from the Canadian and European country equivalents of the U.S. Food and Drug Administration (FDA).

Asked about previous delays in the clinical trial timeline and the certainty of a 2015 start, Dr. Bennett affirmed that “we’re on track.”

“What’s really different is that we now have the drug,” he said. “The rest of this is really kind of operational where we have to do additional important work, but it’s not the necessarily the same kind of research we were doing before, where there were a lot of unknowns that impacted timelines. We have to do some experiments, but we … have a lot of experience doing these toxicology studies. We aren’t anticipating any major issues associated with them.”

“It’s never been more close,” said Douglas Macdonald, Ph.D., a long-time contributor to the project. The director of drug discovery and development for CHDI Management, Inc., which carries out the day-to-day mission of the non-profit, HD drug-discovery biotech CHDI Foundation, Inc., Dr. Macdonald was its point man during the foundation’s collaboration with Isis from 2007-2013 and, along with others from CHDI, continues to advise on the project.

With a $30 million investment in Isis’s preparations for the clinical trial and the prospect of additional future payments, Roche last year acquired the rights to the drug. The deal allowed CHDI to switch to an advisory role as intended and enabled Roche to bring to bear its expertise in developing drugs and bringing them to the market. Because of the high cost of drug development, a small biotech firm such as Isis must partner with a drug manufacturer to get its remedies to patients.


Gene Veritas (aka Kenneth Serbin) at Isis headquarters in Carlsbad, CA (photo by Alex Chambers, Isis intern)

Safety and tolerability

The trial of ISIS-HTTRx will involve approximately 36 early-stage Huntington’s patients at four to six clinical trial sites (institutions, clinics, and/or hospitals) in Canada and Europe, said Roger Lane, M.D., M.P.H., Isis vice president of clinical development and neurology and the company’s lead organizer of the HD trial. Isis will announce the sites next year after contract signings and approval from regulators. Isis and Roche are focusing on sites with considerable experience in clinical trials in Huntington’s disease.

Dr. Lane joined Isis in January 2014 in large part to help it ramp up the ISIS-HTTRx trial.

He explained that the site clinical trial investigators will seek to recruit individuals who have received a medical diagnosis of HD due to their high level of motor symptoms (involuntary movements) but still in the early stages of the illness. The trial will require people with a “very high level of functioning”  with Total Functional Capacity score of 11-13 (on a rising scale of 1-13).

The patients need to be “fully capable of informed consent and able to make a determination whether they want to be in the study or not,” he said.

Although it’s widely recognized that cognitive loss and/or mood and behavioral disorders can precede motor symptoms in HD, the ISIS-HTTRx Phase I criteria will hone to the classic definition of motor onset, Dr. Lane indicated. The patients without a lot of motor symptoms might qualify for the eventual Phases II and III, depending on the observations made in Phase I, he said.

Recruitment will take place through physicians, without public advertisements. Patients will receive reimbursement for expenses associated with the trial.


Dr. Roger Lane (photo by Dr. Gene Hung, Isis)

“We want patients that are going to be fairly local to the site, so we don’t want patients to come from a long way,” he explained. “If there’s any complication, obviously we want them to be admitted very rapidly to the clinical facility.”

Because a Phase I study focuses on safety and tolerability, patients will receive one of four ascending doses of ISIS-HTTRx over three months. Although ISIS-HTTRx might be able to reduce the amount of huntingtin messenger RNA and protein as much as 90%, the highest dose is anticipated to achieve a reduction of 50-70%, Dr. Lane explained.

The study will help determine the frequency and size of dosages for eventual Phase II and Phase III trials. In line with the research done in animals, a successful ISIS-HTTRx drug in humans might require dosage only a few times per year, Dr. Lane said.

One in four patients will receive a placebo and therefore become a comparison group, a standard practice in clinical trials to allow for a more accurate understanding of the actual effect of a drug.

After the first dose, patients will undergo monitoring for at least 24 hours before heading home.

Participants will undergo periodic neurological and neuropsychiatric evaluation. The first evaluation will take place on the eve of the first dose. After the last dose, researchers will continue to evaluate the patients for six months. “We’ll be keeping a close eye on them,” Dr. Lane noted.

A spinal tap

Patients will receive the drug through a routine lumbar puncture, that is, a needle inserted into the lower spine. Experienced neurologists will first withdraw a small amount of cerebral spinal fluid (CSF), to be analyzed as part of the clinical trial research. (See more on this research below.)

Next, without withdrawing the needle, the doctors will inject a few milliliters of a solution containing ISIS-HTTRx.

In technical terms, introducing the drug into the spinal canal is known as an intrathecal injection. The CSF naturally travels to the brain. As in tests with rodents and non-human primates, the ISIS-HTTRx should flow with the CSF to the brain.

As Isis and Roche prepare for the trial, they will decide on the best position for the patients – lying on their side or drooped over a chair, for instance – to get as much of the drug as possible into the brain and minimizing complications such as post-procedure headaches.

Dr. Lane explained that the doctors will use a so-called atraumatic needle, which has a slightly more blunt point than other types of needles and produces fewer post-procedural headaches.

In all, the actual procedure will last several minutes, with patients spending no more than half an hour on this part of the trial, Dr. Lane said. A local anesthetic can be used but is avoided by doctors because it can cause swelling and make it harder to see under the skin, he added. Each trial participant will undergo the procedure five times over the course of the treatment period.

“I’ve had lumbar punctures myself, and I’ve given many lumbar punctures to other people,” Dr. Lane continued. “If you’re in the hands of a very experienced clinician who’s done them many times and who does not impart any anxiety to the patient, then it’s not an inconvenient or painful procedure. You feel a little bit of pressure perhaps in the back. If you do not have any headache after the procedure, then it’s not really that inconvenient. There is a psychological component to the thought of having a needle put into your back. It’s not an agreeable thought to people. But it’s not a painful procedure.”

Children undergoing spinal taps in an Isis clinical trial for a drug to treat spinal muscular atrophy have not suffered any serious consequences, Dr. Bennett pointed out.

For more on spinal taps and Huntington’s disease research, see Dr. Ed Wild’s account of his own lumbar puncture by clicking here.

Isis and Roche are conducting joint research on the latter’s so-called brain shuttle technology, which in the future might allow patients to take a drug such as ISIS-HTTRx via an intravenous or subcutaneous (under the skin) injection, Dr. Bennett said. The companies are not currently offering public comment on that research, he added.

Timeline and study sites

Depending on the pace of recruitment, Phase I most likely will end in 2017, Dr. Lane said. If Phase I is successful, Phase II could follow no sooner than nine months later. All three phases of a clinical trial program typically take at least five years.

With its large HD population and high-level medical facilities, why won’t the U.S. host the Phase I trial?

“This trial is very small,” explained Dr. Lane. “So we only need a few sites. We could have run the study in the U.S., but it didn’t make sense to run it in both the U.S. and Europe. We chose Europe.”

Dr. Lane said that the FDA’s clinical trial guidelines did not lead to the decision to conduct the experiment abroad.

Aimed at demonstrating the efficacy of ISIS-HTTRx, Phase II would recruit a much larger number of people and will certainly include the U.S., Dr. Lane said.

Measuring the results

The trial investigators will check for the safety and tolerability of ISIS-HTTRx by putting the patients through several tests and measurements, including clinical observations, behavioral and neuropsychiatric testing, cognitive testing, a motor function examination, and neuroimaging (putting the participants in a structural MRI machine and taking measures of brain volume).

The measurements will also allow the researchers to make “assessments of the disease itself,” Dr. Lane said.

“On the flip side, we can actually explore if we’re actually improving those parameters [the patients’ condition],” he added.

However, Dr. Lane warned that the short duration of the study would limit the use of such observations.

“We might not see much change, even if the drug was capable of inducing change,” he said.

Key biomarkers: CSF and PET-ligands

A key set of observations on the disease will come from the CSF. Researchers will also measure the ASO concentration in the fluid to determine the amount of drug remaining in the brain.

They will also seek to identify and study biomarkers, that is, markers of the disease and disease progression. Biomarkers can also indicate the effect of a drug.

Because ISIS-HTTRx  should reduce or “knock down” the huntingtin messenger RNA and protein, the scientists want to measure and interpret the amount of both normal and mutant huntingtin in the CSF. (Both types exist in HD patients because they inherit a copy of the huntingtin gene from each parent, one healthy, the other HD-affected.)

“There’s good news on that front in that we can measure huntingtin in the CSF, but we don’t know yet what that means,” Dr. Lane explained. “Where is it coming from? Is it coming from the blood? Is it coming from the brain? If it’s coming from the brain, where in the brain is it coming from?”

(For a recent scientific discussion of mutant huntingtin in the CSF and other bodily fluids, please click here.)

Isis and CHDI are collaborating to help answer these and other questions about the CSF, said Holly Kordasiewicz, Ph.D., an Isis HD team member. By studying rodents genetically modified to develop HD-like symptoms and treated with ASOs, they aim to establish a correlation between the amount of both normal and mutant huntingtin in the CSF and the brain. That will help the researchers determine the frequency and quantity of the drug’s dosage.


Dr. Holly Kordasiewicz (photo by Dr. Gene Hung, Isis)

They are also gathering data on these questions from the above-mentioned toxicology studies.

In addition to huntingtin protein, the researchers will observe other markers in the CSF such as markers of neuronal damage, inflammation, and transcriptional dysfunction (incorrect formation of proteins), Dr. Lane added.

In collaboration with Dr. Macdonald and others at CHDI, the Isis HD team is working to validate huntingtin lowering biomarkers. Beside the development of assays (investigative procedures) to measure the huntingtin protein in CSF, CHDI is also looking at PET-ligands to measure the effects of ISIS-HTTRx in the brain. The ligand, sometimes called a PET tracer, binds to a target or receptor in the brain, which can be measured in people using PET scan imaging.  The team has selected ligands to targets that are altered in HD; the hope is that when huntingtin is lowered the level of these targets will be restored, indicating that ISIS-HTTRx has a desired effect.

Dr. Macdonald offered the example of dopamine receptors. “It is well established that there is less of a receptor called the dopamine subtype 2 receptor in the brains of HD patients and animal models.  This can be measured using a specific PET tracer and we will look to see if that signal is increased after huntingin-lowering with ISIS-HTTRx. If that occurs this would be an indication that the drug is having the expected effect in the brain.” The procedure is non-invasive, he added.

Dr. Lane said that the PET-ligand most likely will be ready only for Phase II.

From these observations of the CSF and the PET-ligand signals, the researchers hope to draw conclusions about the effectiveness of the drug, if not in Phase I, certainly in Phases II and III.

“Biomarkers are an important aspect of any drug development program,” said Dr. Macdonald. “The fact that the Isis and Roche teams are seriously looking at what biomarkers they can use in the clinic is a very positive sign”.

Of course, the ultimate biomarker will be a healthy patient.


Dr. Douglas Macdonald (photo by Gene Veritas)

Completing the missile: ISIS-HTTRx  

Isis’s choice of ISIS-HTTRx in the first quarter of this year came after seven years of engineering and the testing of some 2,000 ASOs.

As Dr. Bennett put it in 2008, Isis technology is like a “laser-guided missile” that targets a specific, disease-causing messenger RNA and destroys it or takes it out of the body “so that you don’t produce that messenger RNA.”

In 2012, Dr. Kordasiewicz, Dr. Bennett, and other researchers published an article in the important journal Neuron demonstrating how the experimental ASOs produced stunning improvement in the health of HD-affected mice.

Some researchers referred to the improvements in symptoms and signs that persisted for a long time after the ASO treatment had finished working in the affected animals as a “Huntington’s holiday.”

Throughout 2013 and into 2014, Isis has tweaked the drug formula, aiming to improve safety and efficacy.

“It’s like you’re turning two different knobs, safety and efficacy, and sometimes they go in different directions,” Dr. Bennett explained. “You have to sort of adjust both knobs by screening a lot of different drugs that ultimately give you what you’re hoping is the candidate.

“We’re very pleased that screening shows that it’s potentially a well-tolerated drug. We wanted to make sure that it’s the most potent, most efficacious and safest drug that we could identify. This candidate fits that description.”

Isis designed ISIS-HTTRx to knock down both the mutant form of the huntingtin gene messenger RNA and the normal form. So far, research has not shown any negative effects of knocking down the normal gene in animals. Isis also has the technology to make mutant-gene messenger-RNA-specific ASOs, that is, types that reduce only the bad huntingtin protein.

“One of the big challenges for us was to decide whether we only inhibited the mutant gene that expresses the expanded CAG repeat or we targeted both the wild type [normal] as well as the mutant gene,” Dr. Bennett said. “There are a lot of pros and cons for doing both. Ultimately we decided that the technology with the mutant-specific compound wasn’t ready to go.”

The HD team “felt it was important to get a drug into clinical trials as quickly as we are comfortable with” in order to start evaluating the effects on the disease of knocking down the huntingtin messenger RNA and protein, he continued.

If ISIS-HTTRx works, the company may develop the mutant-specific ASOs as second-generation drugs. As Dr. Bennett explained, this version would require at least five different ASOs because of variations on the huntingtin gene among individuals.

(You can learn more about mutant-specific ASOs by participating in a Huntington’s Disease Society of America webinar 12-1 p.m. EDT on September 24 with Amber Southwell, Ph.D., of the University of British Columbia.)

The million-dollar question

At the close of the interview the Isis scientists assessed the clinical trial’s potential impact on patients.

“That’s the million-dollar question,” said Dr. Kordasiewicz. “We’re all very hopeful that it will work, but you just don’t know until you try it.”

“We’re going into the unknown territory now, because nobody’s really developed a therapy to treat Huntington’s disease that’s really targeting the huntingtin gene,” said Dr. Bennett. The hope is to stop disease progression and potentially reverse some symptoms. “The science would suggest we minimally could prevent the disease from progressing any further.”

Dr. Lane said that ASO technology “has a lower likelihood of failing” than traditional pharmaceutical products (so-called small molecules).

“With small molecules it’s not always clear exactly how they’re working,” he explained. “The mechanism here [ASOs targeting the messenger RNA of a specific gene] is so clear and so tied into the pathogenesis [cause] of the disorder that there’s more chance at being successful.”

(Small molecule drugs make up 90 percent of the drugs currently on the market. They are traditional, chemically manufactured drugs. Large molecules, also called biologics, are a new class of drug that is becoming increasingly important. They are proteins. ASOs represent another new technology distinct from these other two classes of drugs.)

Dr. Lane added that even though HD has been well studied, not all of the pathways of the disease – that is, the downstream biological processes flowing from the mutant gene – have been described and understood. Researchers still don’t “know for certain which are the important pathways of the disease.”

With ASOs, the downstream pathways are irrelevant, he said. “We go so early in the pathway that we should help everything.”

Asymptomatic gene carriers cannot participate in the ISIS-HTTRx trial.

“Obviously this mechanism has great potential to be used in individuals who have the mutant gene and are not yet symptomatic,” said Dr. Lane said.


Members of the Isis team: (from left to right) Alex Chambers, intern; Kristina Bowyer, director of communications and advocacy relations; Dr. Roger Lane; Dr. Gene Hung; and Dr. Holly Kordasiewicz (photo by Gene Veritas)

A transformation of medicine?

Isis has been making medical history.

In January 2013, the FDA approved Kynamro, a drug developed by Isis to treat a rare type of extremely high cholesterol. It was the very first systemic ASO drug to reach the market.

Shortly before that, Isis also made history with a clinical trial for an ASO drug to treat amyotrophic lateral sclerosis (ALS). The program was paused after Phase I because Isis is improving the drug for its ongoing development program using the latest ASO technology.

“The ALS trial was the first time that anybody had put an oligonucleotide drug into the intrathecal space [spinal cord], and so there were a lot of safety concerns,” Dr. Bennett said. “The ALS experience showed that intrathecal administration was very well tolerated.”

ISIS-HTTRx is an even more advanced ASO than the one used in the ALS trial, he added.

A gene-silencing HD treatment would not only make history but could transform medicine as the world prepares to care for tens of millions of people affected by Alzheimer’s, Parkinson’s, dementia, and other neurological conditions.

Said Gene Hung, Ph.D., a long-time member of the Isis HD team: “To date I don’t think there are any disease-modifying drugs out there in CNS [central nervous system] and neurodegenerative diseases, period.”

ISIS-HTTRx could be the first. But it will take several years before progress can be assessed.

See below links to previous reports on Isis.

Saturday, August 23, 2014

News flash: Isis and Roche hope to start Huntington’s gene-silencing trial in first half of 2015

The long-anticipated clinical trial of a drug that could potentially stop Huntington’s disease at its genetic roots and perhaps someday even prevent the disorder in presymptomatic HD gene carriers like me could start by the middle of 2015.

If successful, the trial could result in a drug in five or six years.

Officials at Carlsbad, CA-based Isis Pharmaceuticals, Inc., in an interview with me on August 22, said that the Phase I trial for their drug, ISIS-HTTRx, likely will start by the second quarter of 2015, as long as the company receives regulatory approvals and fulfills other standard requirements for trials.

ISIS-HTTRx is an antisense oligonucleotide (ASO), a synthetic strand of DNA that silences, or turns off, the messenger RNA that makes proteins as coded by the DNA. If ISIS-HTTRx works as intended, it would reduce the production of the huntingtin protein in brain cells, reduce damage to the brain, and reduce or even eliminate HD symptoms.

ISIS-HTTRx is the company’s internal name for the drug, which will later receive a generic scientific name and, if it reaches the market, a commercial name. HTT is scientific shorthand for the huntingtin gene, messenger RNA, and protein. Rx is shorthand for a medical prescription.

Isis is also conducting standard toxicological studies of the drug in non-human primates to assure that it will not cause harm to humans. A Phase I trial tests for safety and tolerability. Researchers can make observations about the drug’s efficacy but must then conduct Phase II and Phase III trials, which involve more people, to demonstrate whether the drug really works.

Isis is planning the trial with the Swiss pharmaceutical giant Roche, vastly experienced in clinical trials and staffed with specialists in neurological disorders. Last year the two entered a partnership that included a $30 million infusion of funds into the Isis preparations for the clinical trial.

The trial will involve 36 early-stage Huntington’s patients at four to six sites in Canada and Europe. If Phase II occurs, the companies would extend the study to the U.S.

Only recently did Isis, a world leader in ASO science and technology, settle on ISIS-HTTRx.

You can watch my brief report from Isis headquarters in the video below. Soon I will provide a detailed report on the ISIS-HTTRx clinical trial project.


Ramping up

I have tracked the Isis project since 2008 and, with the rest of the HD community, anxiously awaited the start of the ASO trial.

I became excited when I recently saw ISIS-HTTRx listed on the Isis website. It reminded me of the need to get an update on the project. This last visit to the company was my fifth.

At my first visit in 2008, I had learned that Isis hoped to start a Phase I trial in 2010. However, each time I obtained an update on the project, I learned that the researchers had postponed the start of the trial to account for new scientific discoveries, advances in HD research, improved ASO technology developed by Isis itself, and the desire to engineer the safest and most effective drug possible.

The postponements always disappointed me, but I also understood that scientific research and drug discovery are slow and painstaking processes.

However, during the August 22 meeting, it became abundantly clear that Isis and Roche are ramping up for the clinical trial. They are making necessary final arrangements such as the selection of sites, to be announced in early 2015. Significantly, with the selection of ISIS-HTTRx – the culmination of nearly a decade-long search for an efficacious drug in which the company tested some 2,000 ASOs – the engineering is complete.

Optimism and realism

Later that day, I pondered the likelihood of the Isis-Roche trial and how much of a change that meant for me, and for those in my situation.

After so many years of research and millions of dollars in investments, a clinical trial was becoming a reality. 

Reviewing the Isis visit with my wife Regina during a late-afternoon walk, I mentioned how a future, improved version of ISIS-HTTRx might prevent HD symptoms.

At 54, I am now well past my mother’s age of HD onset. Each day without HD is a gift. I felt simultaneously hopeful and concerned, optimistic and realistic, as Regina and I calculated when ISIS-HTTRx might reach the market: Phase I would likely end in 2017, and Phases II and III would likely take the project beyond 2020. A second generation of drugs for asymptomatic gene carriers would come even later.

I recalled that a clinical trial is an experiment with an unpredictable outcome.

More than ever I need to focus on maintaining my health in order to postpone the inevitable HD onset as long as possible.

In the meantime, I will cheer on the Isis-Roche team as it brings the hope of an HD-stopping drug.

See below links to previous reports on Isis.

Friday, August 15, 2014

Bidding farewell to CoQ10: a long-studied supplement proves ineffective in the fight against Huntington’s disease

One of the first and most-studied potential treatments for alleviating the symptoms of  Huntington’s disease has proved ineffective, leading researchers to halt a clinical trial of the substance.

Along with many others in the HD community, I have taken the readily available supplement coenzyme Q10 (CoQ10). As I wrote in a February article about the debate over unproven supplements, the lack of a treatment to slow HD’s devastation of the brain led me to take several of these substances in the hopes of staving off onset (click here to read more).

As reported August 13 by the HD science portal HDBuzz.net, the National Institute of Neurological Disorders and Stroke (NINDS) and the Huntington’s Study Group (HSG) stopped the CoQ10 clinical trial this week because of lack of significant results.

“It seems clear now that coenzyme Q10 does not work for HD,” the HDBuzz article stated. “Looking back, the body of evidence used to decide to test CoQ10 in human patients was fairly limited. In fact, recent efforts to repeat the observation that CoQ10 makes HD mice better have failed.”

According to HDBuzz, the trial known as 2Care, was the “largest ever therapeutic trial for Huntington’s disease.” It had enrolled 609 participants with early HD symptoms from 48 sites throughout North America and Australia. Half received a placebo, while the other half took 2,400 mg of CoQ per day – four times the amount that I have taken.


My supplements, including coenzyme Q10 at far left (photo by Gene Veritas)

A natural substance, CoQ10 is found in all of our cells and helps to turn food into chemical energy. Starting in the mid-1990s, scientists hypothesized that CoQ10 might help alleviate the serious energy deficits found in the brains of HD patients.

In another recent clinical trial, CoQ10 was also shown to have no benefit in stopping early Parkinson’s disease symptoms.

After consulting with several HD specialists, I have decided to stop taking CoQ10. Given the demonstrated lack of efficacy against HD, I see no reason to continue.

Also, although inexpensive over-the-counter varieties of CoQ10 exist, I have taken a medical-grade form that has cost me $1,000 per year. (Health plans do not cover supplements.) I can use that money to relieve strain on the family budget and/or spend it on services such as psychotherapy that help me cope with my situation as an HD gene carrier.

For now, I will continue to take other supplements as detailed in my February article: trehalose, creatine, omega-3 oil, and blueberry extract. However, I also plan to carefully rethink this strategy in consultation with my neurologist and HD specialists. (For a 2012 overview of key supplements and HD by Dr. LaVonne Goodman, please click here.)

A process of elimination

“While the results of this study are disappointing to all of us particularly the people with HD who faithfully took the drug …  every day for as long as five years, and subjected themselves to blood draws and neurologic exams and questionnaires and surveys as part of their participation in the study they are nonetheless very important,” Martha Nance, M.D., the director of the Huntington’s Disease Society of America (HDSA) Center of Excellence at Hennepin County Medical Center in Minneapolis wrote in an e-mail response to my request for comment. “Knowing that coenzyme Q10 DOESN’T work will spare the HD families of today and tomorrow the expense of the supplement, and the false hope that it created.”


Dr. Martha Nance: trial result ends "false hope" about CoQ10.

“Nobody said that finding a cure for HD would be easy, but I think that HD patients and families should be enormously proud of their efforts in this study a commitment that can only help us with the future trials and challenges ahead,” Jody Corey-Bloom, M.D., Ph.D., the director of the HDSA Center of Excellence at the University of California, San Diego, wrote in an e-mail.

The process of elimination in scientific and clinical research is a slow, meticulous, but necessary part of the quest for treatments. Only one in ten clinical trials results in an effective drug. Understanding what doesn’t work expands scientists’ knowledge of the disease.

We can now divert the resources that were going to be used for the 2CARE study to other studies with a better chance of working, the HDBuzz article pointed out. In fact, its likely that the next year or two will see the launch of several trials targeting specific mechanisms underlying HD, rather than generally beneficial compounds like CoQ10.

Added Dr. Nance: We are actively pursuing many other avenues in HD research, and hope that many people will share the wonderful attitude of my patient (I will call her Susan), who said: ‘So, Dr. Nance, I'm sorry that this one is over, but now can I enroll in another HD research study?!’”

Closing out a complex relationship

For me, the end of the 2Care trial closes out nearly two decades of a complex relationship with CoQ10.

I first started taking an over-the-counter variety in early 1996, just weeks after learning of my mother’s diagnosis for HD. With a 50-50 chance of inheriting the gene for a devastating, incurable brain disorder that was inexorably destroying my mother’s personality and ability to think and walk, I grasped for whatever might provide the slimmest of hope.

In the mid-2000s, I started taking a higher grade of CoQ10 along with other above-mentioned supplements in a study under the Huntingtons Disease Drug Works program, which at the time emphasized a “treatment now” approach for a community desperate for solutions. After the study ended, I continued to take the substances and paid for them out of pocket.

CoQ became part of my daily ritual. I broke up the 600 mg chalky, yellow, sweetened CoQ10 tablet into four parts, which I took methodically at breakfast, lunch, and before and after dinner.

Although I knew there was no evidence about CoQ10’s efficacy, I believe it may have had a placebo effect. At 54, I have passed my mother’s age of onset. Now whatever placebo effect might have existed will disappear. In my particular use of CoQ10 and the other supplements, however, an actual placebo effect is scientifically unproven. In addition, scientists are getting closer to understanding the factors (such as a modifier gene) that trigger HD onset.

Throughout my journey with CoQ10, I always viewed it as peripheral at best. I believed that the best hopes lay with the potential remedies such as gene silencing aimed at the root causes of the disease.

Knowing the complexity of HD, I knew that a dietary supplement such as CoQ10 provided no more than a sliver of hope.

As I bid farewell to CoQ10 and the idea that it could delay onset, Im once again forced to rethink how to survive in the gray zone between my genetic test result and the inevitable onset of an incurable disease. With science as a guide, I'm adjusting what is essentially an attempt at self-treatment.

Saturday, August 09, 2014

Making the threat of Huntington’s disease ‘small stuff’

To reduce anxiety about the threat of Huntington’s disease, I start each day with a deep breathing exercise and meditation.

I started developing this practice in late 1997, two years after learning of my mother’s diagnosis for HD and the devastating fact that I had a 50-50 chance of inheriting the mutated gene. After many months struggling with worry and denial, I had hit rock bottom emotionally. (I eventually tested positive for the HD mutation.)

Browsing at titles in a bookstore – bookstores mattered a lot more before the e-book explosion – I came across Don’t Sweat the Small Stuff… and it’s all small stuff: Simple Ways to Keep the Little Things from Taking Over Your Life, a bestseller by the late Richard Carlson, Ph.D.

Over the next few months, I studied the book’s 100 brief chapters, each prescribing how to achieve calm in our harried world. Some might consider self-help books shallow, but I found this one to have a core of wisdom.

Chapter 1, “Don’t Sweat the Small Stuff,” lays out Dr. Carlson’s basic philosophy, a combination of Judeo-Christian fraternal love with a Buddhist de-emphasis of the desire for material success.

“Often we allow ourselves to get all worked up about things that, upon closer examination, aren’t really that big a deal,” Dr. Carlson wrote. “We focus on little problems and blow them way out of proportion…. So many people spend so much of their life energy ‘sweating the small stuff’ that they completely lose touch with the magic and beauty of life. When you commit to working toward this goal you will find that you will have far more energy to be kinder and gentler.”

Getting calm with deep inhalation

Chapter 63, “Count to Ten,” was pivotal for me.

“When you feel yourself getting angry, take a long, deep inhalation, and as you do so, say the number one to yourself,” Dr. Carlson suggested. “Then, relax your entire body as you breathe out. Repeat the same process with the number two, all the way through at least ten (if you’re really angry, continue to twenty-five).”

The deep breathing “clears your mind with a mini version of a meditation exercise,” he explained. It increases the oxygen in your lungs, reduces anger, and provides perspective, making “big stuff” look like “little stuff.

With time I settled on 20 deep breaths for every morning, followed by a few minutes of quiet relaxation. I usually sit in a lotus position on a carpet or on the edge of a chair or couch with my back arched forward to get the air as deeply into my lungs as possible.

When family or work obligations occasionally make it impossible to meditate at home, I do my breathing while driving or in airports.

When I don’t meditate, my day almost always becomes more stressful, sometimes even sad.

The breathing provides a powerfully calming effect. I feel that I’m doing something good for my brain by increasing the oxygen. By reducing my overall stress level, I hope, I can help delay the onset of HD symptoms.

In the video below, you can watch the demonstration of the technique I gave at the start of my keynote speech at the 2011 HD Therapeutics Conference, sponsored by the CHDI Foundation, Inc., in Palm Springs, CA. Other members of the HD community as well as caregivers and counselors engage in or recommend similar exercises, and a vast bibliography exists on yoga and meditation techniques. The principles here can apply for everybody in any aspect of life.


Increased anxiety, new insights

The past couple years I have included in my meditation a reading from Living Faith: Daily Catholic Devotions. Resonating with many of Dr. Carlson’s points, Living Faith helps me tap my spiritual dimension, longstanding since my childhood in the Catholic church, and contemplate the mysteries of suffering and the Creator’s love.

Over the past couple years, now well beyond the age at which my mother’s symptoms started, I’ve become more anxious about HD as well as things in general. So, early this year, I decided to add a daily reading from Don’t Sweat the Small Stuff to my morning meditation.

A couple weeks ago, I finished.

Rereading Don’t Sweat the Small Stuff brought back warm memories of how I had overcome difficult moments, including depression, in those early years after my mother’s diagnosis – including my own positive test for the HD mutation in 1999.

It also revealed how I’ve usually dealt successfully with the ongoing challenges of living at risk. Rereading the book reinforced the lessons I had learned. It also provided me with new insights.

Some of my favorites are: Chapter 6, “Remind Yourself that When You Die, Your ‘In Basket’ Won’t Be Empty”; Chapter 16, “Ask Yourself the Question, ‘Will This Matter a Year from Now?”; and Chapter 66, “Think of What You Have Instead of What You Want.”

Problems as teachers

Two chapters in particular have helped me reflect on HD: Chapter 17, “Surrender to the Fact that Life Isn’t Fair,” and Chapter 75, “Think of Your Problems as Potential Teachers.”

“One of the nice things about surrendering to the fact the life isn’t fair is that it keeps us from feeling sorry for ourselves by encouraging us to do the very best we can with what we have,” Dr. Carlson wrote. “We know it’s not ‘life’s job’ to make everything perfect, it’s our own challenge.”

Regarding problems, he wrote: “Rather than push away the problem and resist it, try to embrace it. Mentally, hold the problem near to your heart. Ask yourself what valuable lesson(s) this problem might be able to teach you.”

Humility, acceptance, and hope for treatments

This is solid advice. However, isn’t a deadly genetic brain disorder like HD truly “big stuff” that just can’t be meditated away?

I’ve thought a lot about this question as I reread Don’t Sweat the Small Stuff and corresponded with HD-affected friends. They are struggling with the loss of their mental and physical abilities; they can no longer work or drive and need help from others for the simple tasks of daily living.

Recently I also attended the wake for an old friend who died in his early 60s of pancreatic cancer, a mainly incurable condition. I didn’t know he was ill, so his death came as a shock.

I imagine my own HD symptoms, watching myself quietly fade away, losing the ability to write, teach, and engage with my family as we guide our daughter through high school and start thinking of retirement.

That is big stuff!

However, I try to make it as small as possible. When I’m not resorting to my old friend denial – which becomes harder as I approach the inevitable onset – I reflect on two of the key lessons taught by Dr. Carlson and the authors of Living Faith: the need for humility and acceptance.

I will die. As I witnessed with my mother, HD is a horrible way to go.

However, until onset I will adhere to Dr. Carlson’s Chapter 100: “Live This Day as if It Were Your Last. It Might Be!” 

As both Dr. Carlson and Living Faith's authors would agree, living life in that manner includes making the world a better place and engaging with family, friends, and many others. I may die of HD, but the collective work of advocates like me, together with the scientific community and friends and supporters, may help make HD "little stuff" in the future by furnishing effective treatments.

Tuesday, July 22, 2014

Can we afford the costs of orphan disease treatments?

Millions of people in America suffer from rare, or “orphan,” diseases, conditions defined by the government as affecting fewer than 200,000 people. With an estimated 30,000 affected individuals, Huntington’s disease is one of the more common of these disorders.

The pharmaceutical industry has largely ignored these diseases, which number several thousand, because each disease promises too few customers/patients to enable companies to recoup investments in drug research and development and therefore generate a profit. The market usually doesn’t work for people with these diseases.

News about a lawsuit by Arkansas cystic fibrosis (CF) patients against the state’s Medicaid program for its refusal to pay for a highly effective but extremely expensive drug – Vertex Pharmaceutical’s Kalydeco – shined light on this predicament.

In an article titled “The $300,000 Drug,” New York Times columnist Joe Nocera recognized Kalydeco as a “wonder drug” but questioned whether the country can afford the personalized medicine approach that enables scientists to design specialized treatments for very small and specific groups of patients.

With an annual wholesale cost of $311,000, Kalydeco was developed for a subgroup of about 1,100 CF patients with specific genetic mutations. The subgroup numbers about 2,150 patients worldwide in an overall CF population of 70,000 individuals.

“Because patients will likely be taking the drug for the rest of their lives, it could cost millions of dollars to keep just one patient on Kalydeco,” Nocera speculated. “That raises another important question about the coming of personalized medicine. How are we, as a society, going to pay for it?”

Same question for the HD community

The HD community could face this very same question. Because the U.S. has only 30,000 HD patients and 150,000 to 250,000 people at risk of carrying the gene, a potential treatment could cost a lot.

Boston-headquartered Vertex has sought to develop HD treatments since mid-2008. Though the company has made a substantial effort, it doesn’t yet have plans for a clinical trial. (Click here to read more.) Isis Pharmaceuticals, Inc., of Carlsbad, CA, has also worked about as long and is planning to launch a clinical trial in the next year or two.

It’s still too early to project the costs of treatments that have yet to be tested or even fully designed. Other potential remedies are in trials but at best likely remain years from reaching the market.

Furthermore, an HD treatment regimen will likely involve a cocktail of remedies, meaning that patients – via their insurers – will probably have to pay for more than one drug.


Vertex vice president of research Paul Negulescu (left), Gene Veritas (aka Kenneth P. Serbin), and Vertex vice president of biology Beth Hoffman at the company's San Diego facility, September 2010 (photo by Heather Farr, Vertex)

Patient assistance programs

The HD community must remain vigilant regarding the cost of potential treatments. However, failing to consider a number of factors, the coverage of the Kalydeco costs was perhaps too pessimistic about the future.

First, as I commented regarding the impatience with California’s stem cell institute after ten years of operation without a drug, biomedical research is slow by nature. And it’s expensive, with the average cost of developing a new drug in the U.S. at $1.2 billion. Only one in ten clinical trials results in a marketable drug, although the research from the unsuccessful projects provides highly valuable information on what does not work.

In the case of CF, Vertex is at work on another treatment that would reach thousands more patients with different kinds of mutations.

As Nocera himself noted, Vertex provides Kalydeco for free to patients without insurance.

Lundbeck, the pharmaceutical firm that markets Xenazine, which diminishes some of the involuntary movements caused by HD (chorea), provides financial assistance to patients who qualify. Depending on the dosage, the annual wholesale cost of this treatment can reach $50,000 or more, but, according to the Lundbeck website, “85 percent of U.S. patients taking Xenazine have a monthly co-pay of $50 or less before requesting co-pay assistance.”

It’s highly conceivable that the developers of future HD treatments will provide similar kinds of assistance – especially because these firms will have relied on the good will and extensive cooperation of HD families who participate in research studies and clinical trials. However, it’s not clear what the drug companies will charge insurers.

CHDI and pharma giants

After the founding in 2003 of the CHDI Foundation, Inc., a non-profit virtual biotech firm backed by wealthy donors who wish to remain anonymous, pharmaceutical firms small and large started to gain interest in developing Huntington’s treatments.

As a result, the network of firms working on HD now includes pharmaceutical giants such as Pfizer, Roche, and Medtronic.

As a non-profit with the sole purpose of finding HD treatments, CHDI promotes research on Huntington’s and the diffusion of scientific knowledge about the disease. With more researchers and firms involved, the chances for treatments have grown. Having more options could very well mean that treatments would cost less.

By pouring hundreds of millions of dollars into HD drug research, CHDI has created an incentive to produce cheaper drugs.

As it states on its website, CHDI seeks to connect academic research, drug discovery, and clinical development in order to avoid “costly delays to therapeutic development” and make potential treatments a “good investment” that will result in “full clinical development, including licensure and marketing to get drugs to HD patients.”

Similarly, the Hereditary Disease Foundation and the Huntington’s Disease Society of America (HDSA) have supported research that could yield yet additional drugs.

Patient-driven medicine

Thanks to this level of support for HD research, the HD community stands in perhaps a better position than those facing even more rare diseases.

Nevertheless, orphan disease communities in general have reason to feel optimistic about both the development of treatments and their cost, if the vision of one key medical leader becomes reality.

Lee Hood, M.D., Ph.D., one of the scientific giants behind the Genome Project and the recipient in 1987 of the Lasker Basic Medical Research Award (the American equivalent of the Nobel Prize), has developed a plan for more effective and affordable medicine. In 2000, Dr. Hood founded the Institute for Systems Biology (ISB). Located in Seattle, the non-profit ISB teams scientists and technologists from many disciplines to pioneer the future of research in biology, biotechnology, medicine, environmental science, and science education.

In a 2012 speech at the Seventh Annual HD Therapeutics Conference, sponsored by CHDI, Dr. Hood outlined the importance of systems biology – what I think of as the “big picture” of disease – for HD research. Dr. Hood also advocated for the adoption of P4 medicine: predictive, preventive, personalized, and participatory. (Click here to read more.)

“Patients and consumers will be a major driver in the realization of P4 medicine through their participation in medically oriented social networks directed at improving their own healthcare,” Dr. Hood and Mauricio Flores, J.D., wrote in the March 2012 issue of the journal New Biotechnology.

ISB and several collaborating organizations have run some pilot programs in P4. If it is implemented on a wide scale, Dr. Hood predicts that it will revolutionize our healthcare system. Everybody will carry a health-monitoring device, and diseases will be predicted and prevented long before onset as the result of tiny blood samples taken from a pin prick, the article states.

Predicting falling medical costs

Significantly, costs could plummet.

“P4 medicine will require that all healthcare companies rewrite their business plans in the next 10 years or so,” Dr. Hood and Flores wrote. “Many will not be able to do so and will become ‘industrial dinosaurs.’ There will be enormous economic opportunities for the emergence of new companies tailored to the needs and opportunities of P4 medicine.”

The authors projected that savings will result from a series of factors, including earlier and more effective diagnosis of disease; better matching of drugs with diseases and their subtypes; better identification of genetically based adverse reactions to drugs; the ability to “re-engineer” disease-affected biological networks within people in order to reduce the cost of drug development; an increasing ability to deal effectively with cancer; the use of stem cells for replacement therapy and diagnostics; the routine extension of effective mental and physical health into people’s 80s and 90s; an improved understanding of microbes in the body; a deeper understanding of neurodegeneration (the cause of HD, Alzheimer’s, Parkinson’s, and other disorders); and the digitalization of medical and genetic information.

“On another tact, our prediction is that there will be a ‘wellness industry’ that will emerge over the next 10-15 years that will in time far exceed the size of the healthcare industry,” Dr. Hood and Flores affirmed. “P4 medicine is an area replete with economic opportunities.”

Dr. Hood and Flores believe that P4 medicine will “democratize” healthcare.

“The patient (consumer), through social networks, will drive the emergence of P4 medicine,” they wrote. “Because of intrinsic conservatism and sclerotic bureaucratic systems, physicians, healthcare specialists and the healthcare industry will take a back seat to the power of patient-driven social networks in bringing change to the healthcare system. Indeed, patients may be the only driving force capable of truly changing our contemporary healthcare system to the proactive P4 mode.”

This scenario serves as a serious alternative to the dim view that orphan disease communities will remain relegated to high-cost solutions.

Guaranteeing proper care standards

Indeed, a “revolution” has occurred over the past two decades in how patients have related to their doctors and the pharmaceutical industry (click here to read more).

Nowadays, people enter the healthcare system as both patients and advocates for their well-being.

This outlook led the Arkansas patients to sue for the right to have their Kalydeco costs covered.

Their lawsuit offers a striking similarity with the HD community’s pressure on the Social Security Administration and Congress to update the decades-old, inaccurate government criteria for determining disability benefits for Huntington’s patients (click here to read more). The Arkansas plaintiffs in effect have demanded that the state recognize Kalydeco as the standard treatment for their type of CF.

Negotiating the price

The competition of the marketplace, greater efficiency in drug development, and the revolution in medicine outlined by Dr. Hood should put downward pressure on the cost of drugs.

Patient advocates must play a crucial role in this process.

As the late San Diego biotech leader Duane Roth had told me during a dinner with California stem cell leaders in 2008, patient advocates must find ways to appeal to pharmaceutical companies’ primary interest in profits. Advocates need to lobby and court these business leaders.

At the same time, disease organizations such as HDSA and its network of advocates can pressure pharmaceutical companies and government agencies to assure new drugs’ accessibility and affordability.

In some circumstances, government can join in the process of persuasion and even play hardball, as the Brazilian Ministry of Health did in the 1990s in order to convince multinational pharmaceutical firms to dramatically reduce the price of HIV/AIDS medications. The Brazilian government provides HIV/AIDS drugs for free.

“Local production of generics, the possibility of breaking patents, and the offer of technology transfer became instruments for price negotiations with other countries and the pharmaceutical industry, leading to a real reduction in prices on the Brazilian and international markets,” wrote the coordinator of the country’s National STD/AIDS Program.

The marketplace exists, but it is susceptible to politics.

The rhetoric about the $300,000 drug can scare a lot of people. But in the long run, such a cost is not a foregone conclusion.