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.

Friday, June 27, 2014

New California stem cell chief stresses speed and efficiency in search for treatments

A major hope of those facing Huntington's disease (and numerous other diseases) resides in stem cell research.

The new president and CEO of the California Institute for Regenerative Medicine (CIRM), transferring from the pharmaceutical industry, has assumed the helm of the $3 billion organization stressing efficiency, including a pledge to prioritize speedier development of treatments for the many diseases falling within the agency’s scope.

“What I promise I will do is to bring stem cell therapies and treatments to the patients that need them,” C. Randal Mills, Ph.D., chosen to run CIRM by its board of directors on April 30, said in San Diego on June 24 at the third of three “Meet the New CIRM President” events. “That is quite sincerely what I have done my entire career, and the only thing I care about and the only reason I came to CIRM.”

Dr. Mills was introduced by CIRM board chair Jonathan Thomas, J.D., Ph.D. The meeting took place in conjunction with the 2014 BIO International Convention, June 23-26, which showcased the work of leading biotech firms and featured a keynote speech by British business magnate Sir Richard Branson and a moderated Q & A with former Secretary of State and potential 2016 presidential candidate Hillary Rodham Clinton. The convention attracted more than 15,000 participants from all 50 states and 70 countries.

Dr. Mills outlined four questions he said will guide him in decision-making at CIRM.

First, he said, "is whatever we're doing speeding up a treatment reaching a patient?"

Secondly, will CIRM’s activities increase the likelihood of a treatment reaching a patient? There are many “valleys of death,” or dead ends, in stem cell research, Dr. Mills noted.

Third, is CIRM meeting an unmet medical need, as opposed to a condition already successfully dealt with by other medical means?

Fourth, is CIRM doing all this efficiently?



Randy Mills speaks to disease advocates and stem cell industry representatives in San Diego (photo by Gene Veritas).

Taking care of patients

Dr. Mills said his patient-oriented outlook started during his undergraduate studies in microbiology and cell studies at the University of Florida, in Gainesville.

“During that time I worked as a medic in the emergency room,” he told the audience. “I saw and dealt with a lot of patients and got a pretty good sense of what patient care was like and delivery was like.”

Dr. Mills obtained his Ph.D. in drug development, also at the University of Florida. After that, he worked for the university as a specialist in orthopedic transplants. With a partner, Jamie Grooms, he started a company within the university specializing in spinal fusion, one of the most common of orthopedic procedures.

In 1995, the two “spun out” the company from the university, calling it University of Florida Tissue Bank. That year the company had $1 million in revenues, with only six employees. Five years later, when the firm went public, it had 550 employees and annual revenues of $120 million.

“More importantly, (we were) producing regenerative medicine solutions for patients all across the United States on the scale of hundreds of thousands of implants, and better implants, a year,” Dr. Mills explained.

“It was during that time that I really learned a lesson. And the key lesson is: if you take care of patients, then your business is going to follow. If you don’t take care of the patients, there is nothing you can do in order to get your business to come along.”

Randy Mills (Osiris photo)

Key achievements at Osiris

In 2004, at the age of 32, Dr. Mills was recruited to become the president and CEO of Osiris Therapeutics, Inc., a Columbia, Md.-based company that commercialized the world’s first stem cell product, Osteocel, for bone regeneration. According to Mills, that product has brought a total of $1.5 billion in revenue to Osiris.

Under his leadership, in May 2012 Osiris received approval to market the world’s first systemically infused stem cell drug, Prochymal, which it developed to combat pediatric acute graft-versus-host disease. (It was approved in Canada but is also available in the U.S.; click here to read more.)

This condition occurs in patients receiving bone marrow transplants that reject the person and attack the body.

“Patients will literally peel out of their skin,” Dr. Mills said, describing the horrors of the condition. Patients with the condition have a life expectancy of only 87 days, he added.

With Prochymal, patients got better two-thirds of the time, he said.

Dr. Mills attributed Osiris’s success to its intense focus on patients.

“The board room is covered with pictures of our patients,” he said.

“That’s my mission with CIRM,” he continued. “We’re going to focus on the patients, and everything else is going to come along. If you get a sense of urgency from me, it’s because, if a life expectancy of a disease is 87 days, missing a month or two months or three months are actually real patients dying.”

Putting criticisms of CIRM in perspective

The stem cell board’s selection of a new CEO with long experience in the drug industry takes place a decade after California voters created CIRM by approving Proposition 71, the California Stem Cell Research and Cures Act.

According to CIRM’s statistics, so far four clinical trials directly funded by the organization have taken place – including an observational study of Huntington’s disease patients at the University of California, Davis, the basis for a potential CIRM-supported treatment trial envisioned by Dr. Vicki Wheelock and Dr. Jan Nolta (click here to read more).

Six additional trials for different conditions are based on “discoveries made by our grantees when they were carrying out CIRM-funded research,” CIRM reports (click here to read more).

According to Kevin McCormack, CIRM’s senior director for public communications and patient advocate outreach, five more directly funded trials for various diseases will start by the end of 2014.

CIRM’s efforts have not yet produced a drug, although one or more treatments could arise from the clinical trials.

Some in California have criticized CIRM’s performance. The San Francisco Chronicle, for instance, editorialized that CIRM “hasn’t lived up to its hype” and has compiled a “decidedly mixed” record, although it recognized that California voters had “outsize expectations when they passed Prop. 71.”

The Chronicle further noted that “it’s been a struggle to get the agency to use the best organizational practices. In 2012, a blue-ribbon committee of the National Academy of Sciences released a report after a yearlong review that found conflicts of interest on the CIRM board that threatened to ‘undermine respect for its decisions.’ It also found significant flaws in the agency’s grant-approval process.”

The editorial added: “Progress on stem cell research has been significant – but it’s been the progress of the tortoise rather than the hare.”

In general, news coverage of CIRM has been sporadic. After all, news outlets typically don’t report on the work of scientists in the trenches.

In this blog, I have provided frequent coverage of HD science as well as related stem cell research. In my 15 years writing about HD science, I’ve learned that scientific progress is slow by nature. It’s not just the CIRM projects that take a long time to produce results.

From my standpoint, stem cell science has produced a “growing array of possibilities” for treatments and the “potential for a new era in human health,” as I noted after attending the 2013 World Stem Cell Summit (click here to read more).

Producing treatments is also extremely expensive. According to Jim Greenwood, president and CEO of the Biotechnology Industry Association, which organized the Bio Convention, developing a new drug in the U.S. costs an average of $1.2 billion. CIRM and/or its affiliated researchers will need to partner with the pharmaceutical industry to bring treatments to market.

In the HD community, we earnestly hope for stem cell treatments, but we’re also aware that a “cocktail” of different approaches (like gene therapy) will likely be needed to deal with the complexities of the disease. We’re rooting for all the researchers to find keys to treatments.

Crucial experience with clinical trials

With the need to show results, it’s not surprising the CIRM board chose a new CEO from the business world.

As noted by David Jensen, author of the blog California Stem Cell Report, CIRM’s previous two presidents, Zach Hall, Ph.D., and Alan Trounson, Ph.D., came from “largely academic and non-business backgrounds…. Decisions are likely to come faster under Mills.”

In his introduction of Dr. Mills at the San Diego meeting, CIRM board chair Dr. Thomas said that the new CEO met the many qualifications sought by the organization, including familiarity with the process of running stem cell clinical trials and seeking approval of drugs from governmental agencies.

“Very few people can say they’ve had more experience in clinical trials in stem cells,” Dr. Thomas said. “Very few people can say they’ve had more experience with the regulators, not just from the U.S., but from other countries as well.”


Randy Mills (left) and CIRM board chair Jonathan Thomas (CIRM photo)

The board also sought someone familiar with CIRM. Dr. Mills has spent the last five years as a reviewer of proposals made to CIRM by stem cell researchers seeking funding. (Click here to read more.)

During the audience Q & A, one woman asked Dr. Mills what he would do to make the grant review process more “transparent.”

Recognizing that the process wasn’t “perfect,” Dr. Mills nevertheless said he believed it was “pretty good” and already “remarkably transparent,” with world experts involved in the reviews. He reminded the audience that no “divining rod” exists to pick perfect projects. He added that he will work for quicker approval of worthy applications.

Keeping CIRM running

Jeanne Loring, Ph.D., a leading expert on stem cells and Parkinson’s disease at The Scripps Research Institute in San Diego, wanted to know how Dr. Mills would prioritize CIRM spending from now through 2017, when the last of the agency’s grants will be made and the original CIRM allocation of $3 billion might run out.

The agency still has about $600 million in uncommitted funds. In all, $1.5 billion of its $3 billion budget has yet to be spent, as many budgeted projects remain in progress.

“Let’s be careful on speculating on when CIRM is going to run out of money,” Dr. Mills said in response to Dr. Loring’s question. “That (2017) would be the absolute earliest. This is an important thing for people to understand: in order for that date to be true, things have gone incredibly well. Everything we funded, 100 percent of it, has worked. If that ‘17 date happens, I’m a happy guy, because we are rattling off diseases left and right.”

Dr. Mills explained that CIRM does “milestone-based funding.”

So we’ll fund your project, but if you don’t hit your milestone, if it’s not working, we stop funding,” he continued. “That seems like a pretty good idea. So the projections on these running out of money is assuming that everything is going along. Everything’s going along, and we can’t get California to say, ‘Let’s keep doing it’? In a more practical sense, we’re not going to run out of money by then, and everything’s not going to work perfect. My job is to run CIRM as efficiently as we possibly can to develop treatments.”

According to spokesperson McCormack, the CIRM board can still redirect funding from the $1.5 billion as yet unspent. If a project comes in under budget, CIRM can also redirect savings to other projects, he added.

Some stem cell advocates such as Don Reed, who served on the executive board for the Prop 71 campaign, are already advocating a second round of CIRM funding to be requested from the state by way of another ballot proposition to be put before the voters. (You can watch Reed, HD advocate Judy Roberson, and children’s neurological disorders advocate Alex Richmond speak about their experiences by clicking here.)

Dr. Thomas has also spoken publicly about seeking private sources of funding for CIRM. In this vein, Dr. Mills’ experience in capital markets – one of the sought-for qualities in a CEO noted by Dr. Thomas – could prove helpful.

"California (undertook) a very important task in creating a funding stream for stem cell research," Clinton, referring to CIRM, said during her Q & A at the Bio Convention. "Other states have followed suit, when it looked as though the federal government would not be doing that. States have a role to play, but we need a national framework."

Our urgency for cures

Huntington’s disease advocates participated in the “Meet the New CIRM President” events in San Diego as well as Los Angeles and San Francisco.

One of those participants, veteran advocate Frances Saldaña of Orange County, sees Dr. Mills’ appointment as a positive step.

“I really liked Randy Mills,” Saldaña, a mother of three children stricken with juvenile HD, told me in an e-mail about her encounter with Dr. Mills at the June 10 Los Angeles meeting. “I feel that he really understands our urgency to find cures.”

Saldaña’s daughter Margie Hayes – who became one of the very first HD patients to advocate for CIRM support for Huntington’s stem cell research when she spoke at a December 2007 CIRM board meeting – succumbed to the disease on February 7. Hayes had just turned 44. She is survived by her husband Craig and two teenaged children.

Saldaña’s husband also died of HD, which has afflicted several other members of her extended family. She was recently presented the 2014 Living Our Values Award by Michael Drake, the chancellor of the University of California, Irvine (UCI), for her work in HD community service. Saldaña is the founder of HD-CARE, an Orange County care organization affiliated with UCI’s Institute for Memory Impairments and Neurological Disorders.

Saldaña said of Dr. Mills: “In the case of HD families, he completely understands that we're in a race against time, as our families are dying.”


As mother Frances Saldaña (left) looks on, Margie Hayes tells about her struggle against HD at the CIRM Spotlight on Huntington's Disease, Los Angeles, December 12, 2007 (photo by Gene Veritas).

Tuesday, June 17, 2014

Fear of onset: the inescapable reality of the Huntington’s disease gene carrier

As a carrier of the devastating and ultimately deadly genetic mutation for Huntington’s disease, I have worked hard to live as normally as possible. This blog is replete with examples of coping strategies and ways in which I have strived to balance work, leisure, family, and HD advocacy.

At 54, my HD-stricken mother was rapidly declining, heading towards a troubling and terrible death at the age of 68. Today, at 54, I continue to enjoy the gift of good health – the major reason I can often feel “normal.” Scientists are searching to discover the reasons for the wide variability in the age of onset observed in people, like my mother and me, who have the same level of mutation.

Yet my fear of onset often creeps back in.

Recalling a time of innocence

The past few weeks I’ve been so busy with the “normal” that I’ve had no time to write in this blog.

At work, I’m transitioning from five-and-a-half years as departmental chair to a year-long sabbatical, during which I aim to write a long-gestating book on the history of former Brazilian radicals now in positions of power. I’m also teaching an intensive, three-week summer session course on the history of Mexico. The next year promises to be an engaging, challenging time.

The transition has required an understandably disruptive move to a new office, but also allowed me to dispose of unneeded books and papers.

As I rummaged through old files and letters, I found myself reminiscing about the seemingly innocent period of my life before Huntington’s struck my mother.

It would be great, I thought, not to have to worry about onset. Without the threat of HD, which led me to expand my scholarly endeavors into the history of science, technology, and medicine, I could once again focus exclusively on the history of Brazil.

Watching for early symptoms

I’m also working out the logistics for my upcoming trip to the University of Iowa in Iowa City for my follow-up participation in PREDICT-HD.

An “observational study of the earliest signs of Huntington’s disease,” PREDICT-HD has aimed at creating key standards for predicting onset and measuring the rate of disease progression.

I’ll be staring onset in the face – and wondering about my performance on the battery of tests.

A visit to Auspex

I discussed my fear of onset and reiterated our community’s urgent need for effective treatments in an intense, 80-minute get-acquainted conversation last week with Pratik Shah, Ph.D., the president and CEO of Auspex Pharmaceuticals.

An investor-funded San Diego firm focused exclusively on central nervous system disorders and orphan diseases, Auspex struck me as made-to-order for the fight against HD. It is currently conducting clinical trials for a drug called SD-809, aimed at treating chorea, the involuntary abnormal movements produced by HD.

SD-809 (dutetrabenazine) is a potentially improved version of tetrabenazine, a chorea treatment currently marketed by the pharmaceutical company Lundbeck under the name Xenazine. If SD-809 works as intended, it will require fewer dosages and produce fewer side effects than tetrabenazine.

However, tetrabenazine does not affect the root causes of HD, nor is SD-809 expected to.

Auspex seeks to use SD-809 as a platform to research and develop drugs that would attack those causes.

Dr. Shah and I agreed to schedule soon an interview so that I can write an in-depth article on Auspex’s efforts.

I told Dr. Shah about a middle-aged, HD-afflicted man I had met who had maintained much of his cognitive abilities but suffered from strong chorea. However, tetrabenazine controlled the chorea, enabling him to keep driving, something most HD patients have to give up.

Tetrabenazine’s approval by the Food and Drug Administration had come too late to benefit my mother, who died of HD in 2006. I told Dr. Shah that she had taken another medication to control her chorea, which was relatively mild, although she had initially had strong chorea in her legs at night. In general, chorea was the least of my mother’s problems with HD, which devastated her cognitive abilities and caused serious psychiatric difficulties.

I also related my recent conversation with a former HD support group colleague who has had symptoms for a number of years.

Speaking to a symptomatic individual, I pointed out, provides me a terrifying glimpse of my own future.

A powerful HD dream

As I processed these latest events in my journey with HD, my unconscious mind produced a powerful dream.

I awoke from the dream at 5 o’clock on Sunday morning. Afraid that I would forget its content, I went to my home office to type out the details on my computer, and to outline this article.

In the dream, where I am meeting with other asymptomatic HD gene carriers, I encountered the same HD-affected man whom I had mentioned to Dr. Shah.

The people in our dreams often represent aspects of ourselves. In my interpretation, thinking of a symptomatic man in the context of a group for the asymptomatic meant that I was wrestling with the inevitable reality of my onset.

Tapping into the soul

As the dream continues, I fly to New York City on HD advocacy business.

In my hotel room, I start to write a blog article describing the recent HD-related aspects of my life. I have my trusty laptop with me but am oblivious to it. Instead, I write in longhand on a white legal pad. It’s the way I sometimes wrote in college or now write on airplanes or when I’m revising a draft I’ve printed out.

There’s something pure and primal about this form of writing. It’s the way I first learned to write. I’m crossing things out, jotting down ideas, and flipping back and forth through the pages to read and make adjustments. At one point I think that, because I don’t have much time before my evening HD meetings, I’ll switch to the computer. But I want to first eke out some more lines on the pad.

The dream was compelling me to practice the craft I have enjoyed since childhood, to tap into the soul that defines me.

I later recalled the photograph that an HD-affected man posted of himself illustrating his superb kickboxing skills before the disease struck. He wanted to remember himself at the height of his powers.

The dream, I think, reflected my fear that HD will rob me of my writing skills.

A metaphor for facing HD

Later in the dream, I go to a restaurant along with two other asymptomatic gene carriers and my friend, blog editor, and HD alter ego, Norman. One of the gene carriers, I recognize, is the symptomatic man I’d encountered earlier in the dream, only transformed into a healthy individual. On the way there, I give each gene-positive man a bear hug. I feel deep brotherly love towards these men.

A native New Yorker, Norman describes the restaurant as a very different and unique place. He says it’s called Pub Med.

We seem to be on the Upper West Side of Manhattan. Evening is approaching.

The restaurant is made of recently hewn, unpainted pieces of wood, which are also used as furniture: benches and small, round tables. It’s outdoors, located in the middle of a square where I can hear kids playing on swings and moms walking their kids. There are small stores on the edges of the square, too.

But there’s something very strange: the benches and tables are stacked on top of one another in a pyramid-like fashion. They rise about 30 feet. We climb up and look for a place to sit. Norman is sitting with the first gene-positive person while, at another table, the second gene carrier continues to explain to me the nature of this restaurant-structure and how to sit on it without falling.

I'm still standing. However, as I try to sit down, some of the tables and benches near me shift down or fall off suddenly and unpredictably. I’m afraid that I’ll fall off. The second gene carrier seems to know well how to deal with it. He’s experienced and seems to take it all in stride.

As I strive to keep my balance on the structure, I gaze at a different kind of Manhattan skyline. On the horizon, I see some burning buildings. Referring to the restaurant-structure and the buildings ablaze in the distance, I tell the second gene carrier: “I can think of no better metaphor to describe living at risk for Huntington’s disease.”

Building hope, pondering onset

The dream, I think, represented my fight to continue advocating for the HD cause.

Manhattan is headquarters for three key HD organizations: the CHDI Foundation, Inc., the Hereditary Disease Foundation, and the Huntington’s Disease Society of America. Along with other organizations and scientists around the world, they hold the key to finding treatments.

Norman has taken my family and me on a walking tour of Manhattan. He urged me to start this blog. In both the dream and real life, he has acted as a kind of guardian angel in my fight against HD. I believe that the Norman of the dream also symbolizes my own internal editor, who, like the real-life Norman, the author of a richly detailed and public-spirited watchdog blog on Brooklyn's Atlantic Yards project, strives to produce in-depth and understandable reports.

Along those lines, I had told Dr. Shah I would read scientific articles about SD-809 before our planned interview. I believe that the Pub Med restaurant represents my desire to prepare thoroughly for an interview regarding the potentially life-saving work done at Auspex. In reality, PubMed, a well-known research tool, has more than 23 million citations from biomedical literature, life science journals, and online books.

I explained to Dr. Shah that in this blog I seek to provide the HD community with information about potential treatments, breakthroughs, and challenges.

My goal is to provide the community with hope, and advocate for change.

The dream, I believe, also reflected my continued striving for internal equilibrium as I ponder the kind of onset I will experience.

Will I falter like an HD person who can no longer control movements and mind? Will I continue to work and drive? Will I be able to help support my daughter as she studies in college? Will effective treatments arrive in time to at least reduce the severity of symptoms – and prolong my life?

These are the inescapable questions of my reality as a Huntington’s disease gene carrier.