Sorry if your getting this again, It errored the first time so I'm not sure if it sent or not.  Lynn

At the recent HDSA convention, representatives from the Huntington Study Group (HSG) announced plans for another large CoQ-10 trial (2CARE) testing its effectiveness in Huntington’s disease. We were told that recruiting would likely begin in late winter 2005-2006. 2CARE is to be a large (600 people), long (5 years), and expensive (more than ten million dollars) placebo controlled single drug trial. We were told that the primary funding source will be the National Institute of Neurologic Disorders and Stroke (NINDS) which is part of the National Institutes of Health (NIH) which is the part of the US Government that funds most health research.

There is however a discrepancy between this information from HSG and the NINDS website where it states that funding has not been approved and further review of the grant request won’t be addressed until September at the earliest.

Vitaline Corporation is set to supply the CoQ-10 product (FDA application pending). University of California at San Diego (UCSD) has rights (profit-sharing) in Enzymatic Therapy Inc., the company which in turn, owns Vitaline. There is information that Dr. Clifford Shults, a professor at UCSD and primary investigator in the ongoing Parkinson’s study which is using Vitaline CoQ-10, had (at least initially) involvement with this company. This is not unusual; it is common practice for universities to require that the scientific investigator share patent rights to any product developed at their institution.

However, because Dr. Shults is a close research associate of HSG leaders (who are also Parkinson’s research leaders) it would be wise for full disclosure of any financial interests of trial investigators (or close associates) in Vitaline Corp to avoid the appearance of conflict of interest. We wonder why HSG chose to go with Vitaline which will require 8 tablets per day as compared to the Tishcon Corporation product at 2 tablets per day for equivalent bioavailability.

Patient advocates, patient families were not involved in trial preparation at any point of the process. So we really know nothing about this trial. We suspect that trial participants will not be allowed to take other agents that have preliminary evidence of benefit (creatine or omega 3 fatty acids) for the five year duration of this trial. We don’t know that there is a process that allows them to switch to these agents if (for instance) benefit is shown in the upcoming Miraxion trial.

So to say the least, it has triggered a variety of mixed reactions from those of us at HD Lighthouse.

The Positive

On the positive side, it is good to see phase III action in the HD clinical trial arena. And CoQ-10 is a worthy candidate among the agents that need to be tested. At the end of five years this trial will answer the question of whether CoQ-10 definitively (with 95% significance) is useful for HD people with early disease. It will be good for scientists who will learn the specific biologic activity and whether that benefit lasts for five years. It will be very good for the owners of Vitaline who, with FDA approval, will gain rights to market and sell this over-the-counter agent as a drug for HD. Then, finally a good thing for patients, it may become a covered expense under some, probably not all, insurance plans.

The Negative

On the negative side, we wonder how many multi-million dollar clinical trials NIH will be able to fund for HD. Can we anticipate that this kind of money will be made available for HD again in the near future? Or, might lack of money delay (by years) large trials of creatine or other agents that may have greater benefit? Will 2CARE be the only large U.S. funded trial we will have for the next several years?

But by far, our greatest concern is that HSG’s large trial approach of single agents asks the wrong question and dooms timely completion of combination trials even though most HD experts believe combinations will give best treatment. Single drug trials address the question “will this one work in HD?” Combination drug trials address the question “what is the best treatment for HD people”. One drug results may be great for pure scientific interest: But it’s not greatest good for patients.

Conflicts OF Interest

When it comes to clinical trials for HD people (or any other disease population), there is natural conflict between patients, medical researchers, and drug companies. The patient has the desire and need for treatment (best treatment). The researcher has the scientific need to rigorously define biological activity and medical benefit of an individual agent (usually their own research favorite). The drug company needs a trial that maximizes the chance for (always their own) drug approval.

We believe this CoQ-10 or any other trial that tests safe drugs alone does not test predicted best treatment, which is undisputedly what patients want, need, and have right to. 2CARE doesn’t even lead into combination trials. This trial is not designed to lead to greatest benefit to people. This trial instead best suits the needs of researchers who want to know pure biological activity of a single compound, and the drug company who wants to sell it.

Huntington's is not a Game, but…

The One Drug Analogy: At the recent HDSA convention in Atlanta, the HSG presenter compared clinical trials in HD to a soccer game. In this analogy, one ball (drug) is passed cooperatively between players, and if successful the ball makes it all the way to the goal (treatment). After heartfelt celebration, HSG clinical trial teams will energetically start down the field again, because they know that one goal is not going to win this game against the formidable opponent called Huntington’s. But unlike the researchers and drug companies, HD people will be less vigorous for the next run: some will be dead, others disabled, and all will have lost years of quality life.

The Multiple Drug Analogy: A better analogy is a game of pool. We start with many balls (drugs) on the table. To score the most points, we don’t aim for just one drug, because there are several ways (molecular targets) to score points. And yet further, if the player is skilled, several points can be scored with the first strike (clinical trial). If we do pool-style clinical trials instead of HSG’s soccer-style trials, more drugs will get to more HD people sooner, and more of us will have something to cheer for.

A New Era

Huntington’s has ushered in a new era. HD is different from diseases that have gone before because we are starting with many drugs to test, while other diseases had only one. In the old era, the reason to test one drug at a time was simple: there was no other choice. 2CARE is an obsolete, old fashioned trial system stuck in the previous era. By ignoring the many agents ready for trial, 2CARE is, at best, a waste of money, and, at worst, a diversion that will doom another generation of HD people to years of suffering.

It’s important to remember that the agents available now, including CoQ-10, are probably only a stopgap. HD people need these agents now, but they will fade into history when the drug development people at the High Q Foundation (Dr. Pacifici was the highlight of the convention) develop drugs that are truly effective. It is likely that it will take 7-10 years for High Q to find something that works modestly in HD people and 10-15 years to develop a drug that works well enough to be called a cure.

2CARE is spending 5 years and $10 million testing a treatment that everyone agrees is not the best, and which will probably be surpassed by drugs from High Q just about the time the study is published. Why is this being done? Does this make sense to you?

A Better Way: Combination Trials

Monotherapy is no one’s treatment goal. No one believes any one agent (available now) will work best alone. Then rationally, if the goal is aiming for best treatment, HSG should not be doing single agent trials. After determining best dosage, these agents and combinations should be tested in parallel. We realize this kind of trial is not exciting from the research perspective: it doesn’t advance a theory. But combination trials have a better chance of helping HD people.

How to do it? HSG is a huge and powerful organization. In 2CARE they are using only a small fraction of their clinical trial centers and member doctors. Given the chance, HD people will flock to centers for the chance to be in combination trials. And with NIH supplying the money, small drug companies would step forward (or be replaced). Go another step: Extend the trials to the extended HD family in Venezuela and let this gracious group of HD people come full circle from gene to first treatment. It is a good time to give them a chance to be in clinical trials for study of best treatment. This Venezuelan group could supply significant numbers of willing people who do not have access to agents available over the counter in the U.S.

We acknowledge that this kind of trial is not real exciting from a research perspective. HSG has chosen to pursue the more exciting science of single agents. We can hope that HSG leaders and federal supporting agencies will allow and consider the voice of patient advocates. If not, it is time to move towards a clinical trial system that addresses the treatment needs of the people. High Q has successfully created in CHDI (Cure Huntington’s Disease Initiative) an aggressive drug company for HD. Along side “in house” technology; CHDI has utilized smart outsourcing of appropriate work when it can be done faster and cheaper. This model might work better in the HD clinical trial arena. Another approach would be to have free standing clinical trial companies bid for NIH monies to run HD clinical trials. Miraxion has contracted with such a system in Europe.

Efficient clinical trials that ask the right question; (which admittedly isn’t the best question for single agent science) that test for best treatment is what the people need. This makes a lot of sense to people living with HD now and into the next decade. It should make sense to the doctors who care for them (within HSG and out). And we suspect it will make sense to Federal agencies whose mandate is to best serve the people.

This article was written by LaVonne Veatch Goodman, M.D. and endorsed by the following individuals: Malcolm Casale, Ph.D.; Nathan Goodman, Ph.D.; Linda Miller, M.S.; Marsha L. Miller, Ph.D.; Gayle Tinnerman, M.S.T.; Steve Ireland