Huntington Study Group 2005 Annual Meeting Report

HD Lighthouse Contributing Editor's Comment:
--
Posted to the HDL: 09 Dec 2005

Jim Tretheway and Marsha Miller at the 2005 Huntington Study Group Meeting

Background

Most of us know that basic research in Huntington’s Disease has been truly outstanding. We have had some of the best researchers in the world working on the problem. In 1993 they found the gene that causes HD, and a genetic test was developed shortly thereafter. But now twelve years later we still don’t have a cure for HD patients. HD families know that all the research in the world on Huntington’s Disease doesn’t help them if it doesn’t lead to effective treatments for HD in a reasonable time period.

Huntington’s Disease families are interested in knowing the strategic plans for bringing treatments from the lab to the clinic. This fall, the HSG leadership and Barbara Boyle, national executive director of the Huntington’s Disease Society of America (HDSA), invited us, Jim Tretheway, family advocate on the SET-HD project and a member of the board of the Wisconsin HDSA chapter, and Marsha Miller, managing editor of the HD Lighthouse and the Huntington’s Disease Advocacy Center websites, to attend the Huntington Study Group (HSG) annual meeting in Philadelphia as representatives of HDSA. Local HDSA Delaware Valley chapter members were also invited to attend.

The Huntington Study Group

Since 1993, the Huntington Study Group (HSG), based in Rochester, New York, has been developing and carrying out clinical trials on HD at over 60 sites, mostly in the U.S., but also in Canada, Europe and Australia. A number of HD Lighthouse readers have participated in these trials. For more information on HSG, please see its web site at www.huntington-study-group.org.

Some of HSG’s trials have been observational, which means that a treatment is not being tested but rather the course or natural history of the disease is monitored to learn more about it. Some of you may be participating in PHAROS, an observational study in individuals at risk for HD, or PREDICT, an observational study of unaffected individuals who have been tested and are known to carry the HD gene. One goal of these observational trials is to identify the underlying measurable changes that occur as the disease progresses so that these biomarkers can be used to measure the efficacy of therapies earlier than can be done now.

HSG also has carried out a number of therapeutic trials, where a drug or other treatment is being tested for safety, tolerability, proper dosages and efficacy in treating HD. These have included Remacemide, Co-enzyme Q10, Riluzole, Creatine and Minocycline. Unfortunately, none of the compounds tested have to date proven to be effective at the dosages used during the time period of the trials.

Finding out more about the current and planned clinical trials sponsored by HSG was one of our goals for attending their 2005 annual meeting. Another was to contribute our perspective as HD family members wherever appropriate.

The 2005 HSG Annual Meeting

The 2005 Huntington Study Group Thirteenth Annual Meeting brought together 223 participants from the US, Canada, Europe and Australia. This included researchers who are neurologists, psychiatrists, psychologists, and study coordinators. These individuals have skills in such diverse fields as basic and translational research, drug development, clinical trial design and statistics, government regulations, trial administration, patient rights and ethics. Some care for HD patients and families in clinics worldwide.

A number of HD family members, primarily from the local Delaware Valley Chapter of HDSA, were invited to attend the general sessions as well. To give you some feel for the intensity of the meeting, approximately 90 individual meetings of working groups and general sessions were held in a four day period. Sessions started at 7:00am and went to 8:30pm.

Speakers at the meeting clearly articulated some of the problems we have faced in finding a cure for HD. They pointed out that there are many steps between basic research and an effective treatment. With HD, we’ve had lots of good basic research funded by HDSA, the Hereditary Disease Foundation (HDF), the High Q Foundation, the Huntington Society of Canada, the National Institutes of Health and others. We also have a great clinical trial group in HSG. But historically we have lacked strength in the important intermediate steps like translational research and drug optimization that could substantially improve the odds of finding a cure.

Of course, sometimes scientists get lucky and can bypass the intermediate steps, taking basic research, or even a good guess, directly into clinical trials. But it’s clear that HSG has had a difficult challenge in its efforts to identify and examine useful compounds for clinical trials.

Fortunately, the HSG meeting showed that the HD community is rapidly filling in the missing gaps so that we can maximize our potential for successful clinical trials. The following table outlines the steps now being undertaken to develop a treatment for HD and the primary HD organizations in each activity. Each organization listed often funds or otherwise supports activities in other areas, and we don’t mean to slight any organization’s efforts. The National Institutes of Health, especially its National Institute of Neurological Disorders and Stroke (NINDS), provides significant funding for all areas of Huntington’s research. The U.S. Food and Drug Administration’s (FDA’s) Office of Orphan Products Development provides additional grants and other assistance regarding HD clinical trials.

The Cure HD Initiative

The conference started with a presentation by Robert Pacifici, PhD, chief scientific officer of the Cure HD Initiative (CHDI), www.chdi-inc.org. He described the large gap that the HD community previously faced when attempting to directly apply basic research to treatments for people. For example, some of the compounds that extended the life of various animals used in HD research were really quite toxic to humans and were unlikely to have strong efficacy even at the dosage that was expected to be needed.

Many of these problems are often solvable, but these solutions require the expertise of translational researchers and drug developers, very few of whom were involved with HD until recently. Now that’s the work that CHDI does, in conjunction with specialized private companies that CHDI contracts with as needed. Dr. Pacifici provided extensive detail on what they are doing. It was impressive to see.

In the future this is expected to provide more effective drugs with fewer side effects to test in clinical trials. Unfortunately, the reality is that we probably can’t expect such optimized compounds to move into clinical trials much before 2008 or 2009. But our conclusion is that the resources are being put in place to see strong progress in the next five years.

Systematic Evaluation of Treatments - SET-HD

Dr. Collin Hovinga, a research neuropharmacologist, made the next presentation about the SET-HD Initiative. SET-HD stands for the Systematic Evaluation of Treatments for Huntington’s Disease. SET-HD has been coordinated by the National Institute of Neurological Disorders and Stoke. The SET-HD working group includes HD researchers and an HD family representative, one of the authors of this article. The Lighthouse welcomes the involvement of an HD family advocate on this project. It also encourages all HD organizations include qualified HD family advocates on their boards and working committees to make sure that this perspective is brought to all decisions that affect HD families.

SET-HD’s purpose is to identify and systematically assess experimental therapies for Huntington’s Disease by involving the entire HD community and other researchers. The goal is to make sure that no compound is overlooked. This project permits any person or group to nominate a compound they believe might be helpful. You can do this yourself on the Huntington Project web site, www.huntingtonproject.org. You can also find a list of all the compounds already nominated there as well.

Approximately twenty high priority compounds have already been evaluated in detail and the results are posted to the Huntington Project web site. Approximately twenty more reports are underway. You can read each of these yourself at www.huntingtonproject.org/Default.aspx?tabid=48. They are very detailed and identify the next steps required to test these trials in humans.

The result of SET-HD’s work is already noticeable. In 2002 Jerry Lampson, founder and then-editor of the HD Lighthouse, ran several articles on the research of Clifford J. Steer, MD, a researcher at the University of Minnesota. Dr Steer had shown that tauroursodeoxycholic acid (TUDCA) increased the life span of one mouse model for HD. There was good evidence that the compound prevented apoptosis (programmed cell death), which is implicated in HD. Some felt that Dr. Steer’s work wasn’t receiving appropriate attention and they nominated this compound for consideration by SET-HD.

The SET-HD screening committee felt that this compound was worthy of additional study and prepared a detailed evaluation. Based on this report, an HD researcher at Oregon Health and Science University, Penny Hogarth, PhD, prepared a research proposal using TUDCA that has now been funded. While it will be some time before we know the results of Dr. Hogarth’s work, we do know that one of the gaps between research and treatment for HD is being filled by SET-HD so that good ideas are not lost.

HSG Clinical Trial Plans

The good news is that HSG has new clinical trials that are currently enrolling participants. It is important for HD families to support these trials by volunteering to participate. Additional details of the compounds that are being tested and where these trials will be conducted are available on the HSG web site. See www.huntington-study-group.org/CLINICAL TRIALS IN PROGRESS.html. We have been told that more clinical trials and trial sites will be listed in the near future.

Creatine. Perhaps the most exciting thing we learned about at the meeting was new “unofficial” information about creatine. Creatine is a nutritional supplement that research has shown can help protect the mitochondria of the neurons affected by HD. These mitochondria are the key energy-producing parts of cells and when they don’t work properly the neurons can become damaged or die. Creatine can be purchased for a reasonable price without prescription in powdered form at any health food store, but the dosage and purity of these preparations may vary by supplier.

As the HD Lighthouse has earlier reported, creatine has shown efficacy in some animal models of HD and in various small open-label trials in humans. For example, in one small open-label clinical trial at 10 grams per day of creatine, HD was stabilized in the participants who finished the one-year trial. They didn’t get better, but they didn’t get worse. With HD, that’s pretty good.

Open-label trials are those where the patient and/or the doctor know whether they are taking the trial agent, so their results are viewed somewhat skeptically. And with HD, the clinical protocol currently used for measuring disease progression has limitations concerning small changes at some stages of disease progression.

At the HSG meeting, Steven Hersch, MD, PhD, and Diana Rosas, MD, both from Massachusetts General Hospital, reported the preliminary results of their most recent controlled dosing study of creatine monohydrate. They are finding that there may be an optimal higher dosage of creatine that may stabilize or in certain cases improve some of the symptoms of HD. Their results have not been through the all-important peer review process as of yet, where other scientists critique and comment on the work before publication, so it wouldn’t be wise for anyone to act on them. However, they are very encouraging and are likely to lead to a new HSG trial on creatine in the future.

We know that many HD Lighthouse readers already take creatine and the results of recent trials worldwide suggest that this is worth continuing. The HD Lighthouse does not make treatment recommendations, but does suggest that anyone taking creatine should do so only under the direction of their doctor, who should monitor their dosage and clinical condition on a regular basis.

2CARE.The biggest official news at the meeting was the announcement that the National Institute for Neurological Disorders and Stroke will be funding HSG’s 2CARE placebo-controlled study of higher dosage Co-enzyme Q10 (CoQ10). This study will run for five years at 46 sites and cost more than $10 million. It will involve 608 patients at a very high CoQ10 dosage of 2400mg per day. A placebo-controlled clinical trial means that some participants receive only a sugar pill or other inert ingredient, called a placebo.

CoQ10 is a nutritional supplement that, like Creatine, has been shown to help protect the energy-producing mitochondria of the cells. Earlier in this report, we mentioned that CoQ10 had already been tested by HSG (at 600mg per day), and it was not found to be effective in accordance with the original trial design. Further analysis of the data did indicate some slowing of functional decline beginning during the second year of the trial. In addition, a later trial on this same compound for Parkinson’s Disease showed some benefits at higher dosages up to 1200mg per day. These findings provide part of the rationale for this new Phase III trial.

Family Concerns. We were given the opportunity to comment on some of the family concerns relating to this trial. With a budget of $10 million, this trial is very expensive and as HD family members we fear that it could limit the funding of future trials on perhaps more promising compounds. Fortunately, we learned that the 2CARE trial design has not yet been finalized and that it may be modified to add a second therapeutic compound. That will be very good news if it happens.

We were told that the 2CARE trial design would not prohibit participants from taking nutritional supplements at “non-therapeutic” dosages. However, trial subjects may be prohibited from taking these supplements at the higher dosages that animal and other data indicate may be effective in slowing the progression of HD. Participants may also be prohibited from taking drugs recommended and prescribed by their own physicians that may have potential therapeutic efficacy.

These restrictions might not be so onerous if the trial only was planned to last one year. However, from the HD family perspective, a five year trial on symptomatic individuals typically is a significant part of their expected post-diagnosis quality lifespan. We understand the complications that permitting other agents to be used in a trial causes HSG in terms of the validity of trial results. On the other hand, as HD family members we believe that many trial participants will silently use these other agents in any event. After all, our loved ones are trying to survive this disease, not just help with a research study.

While there is a chance that the 2CARE trial could end earlier if clear efficacy is shown, this may be less likely to occur because of the current trial design. A significant risk is that compounds that might otherwise be found to be of therapeutic benefit in HD may not show efficacy in the 2CARE trial due to participants in the placebo group taking other compounds that actually help treat the disease. In our opinion, a more robust clinical trial design should be created to deal with the reality of the somewhat different objectives of clinical trial researchers and trial participants…our beloved family members.

We believe that the 2CARE clinical trial results will be far more meaningful if the trial design permits, records and adjusts for the use of potentially therapeutic dosages of other nutritional supplements and the off-label use of other drugs as prescribed by the physicians of the trial participants. One possible alternative control method that has been proposed for other fatal diseases is to use historical controls to compare the progression of trial participants with the normal progression of the disease or with their own previous rate of decline. The results may even identify fortuitous combinations that may be worth testing on a larger scale.

We’ve been told that the 2CARE trial design has not yet been finalized, and we asked that further consideration be given to this matter. At the same time we recognize that significant changes in the trial control methodology may not be possible at this late stage. As a practical matter, we would be satisfied if it were to add a single additional therapeutic agent, particularly if it is creatine. Several researchers at the meeting told us that they felt creatine was the most promising candidate for clinical testing at the present time.

PHEND-HD. Phenylbutyrate is an experimental compound that is in a class known as histone deacetylase inhibitors (HDAC inhibitors). HDAC inhibitors have shown significant efficacy in preventing neurodegeneration in animal models of HD. This clinical trial is designed to assess and gather information on the safety and tolerability of phenylbutyrate. Site locations include the University of California San Diego, University of Kansas Medical Center, University of Iowa, Massachusetts General Hospital, Columbia University and the University of Rochester. Contact them to enroll. See HSG’s web site for details on this and other studies. www.huntington-study-group.org/CLINICAL TRIALS IN PROGRESS.html.

TREND-HD. This clinical trial will study ethyl-EPA in persons 35 years of age or older who have mild to moderate HD. TREND-HD is designed to determine the effect of ethyl-EPA on the motor (movement) signs and symptoms of HD. Ethyl-EPA is an Omega-3 fatty acid that has shown some efficacy in animal models of HD and has had inconclusive results in an earlier human trial. TREND-HD is a 12-month placebo-controlled study. Forty-three sites in the United States and Canada will each enroll approximately 7-8 research subjects with early signs of HD who are independently ambulatory (walking) and self-sufficient in activities of daily living, such as eating, dressing, and bathing. Eligible research participants are being actively recruited to the TREND-HD study (www.huntington-study-group.org/CLINICAL TRIALS IN PROGRESS.html).

COHORT. This long-term observational study will initially take place at 45 North American and Australian Huntington Study Group (HSG) sites. The goal of COHORT is to collect information in order to learn more about HD, potential treatments, and to plan future research studies of experimental drugs aimed at postponing the onset or slowing the progression of HD. This study will recruit both adults and children who have clinically diagnosed HD and unaffected adults who are a part of an HD family. Individuals who choose to participate will have one study visit every year for as long as they are able and choose to participate. Specimens, including blood and urine samples, will be obtained with the permission of participants in order to define biological markers of HD progression.

Cysteamine. A clinical trial to determine safety, tolerability and dosing is being planned for this compound. An 18-month randomized controlled trial involving symptomatic individuals is being proposed.

Our Conclusions

It is a very positive step forward for HSG and HDSA to invite HD family members involved with family communications and advocacy to participate in the 2005 HSG annual meeting. HSG leadership made us feel welcome and they permitted us to attend every session we requested. We hope that HD family advocates will be invited to participate in future HSG meetings as well.

We learned a great deal about what HSG is doing and planning to do regarding clinical trials We had the opportunity to talk directly with the clinicians who will be performing the trials. It was clear to us that as better compounds are identified that offer potential treatments for HD, HSG has the organization and expertise to do the clinical trials that are needed. From our discussions we learned that we may be close to having more sensitive biomarkers available to measure disease progression so that clinical trials can be shorter, giving time for those on placebo to begin receiving treatment before it is too late.

We continue to have serious concerns and frustration about the limitations of the methodology of randomized, placebo-controlled clinical trials as it relates to a fatal disease like HD. These limitations became very apparent almost two decades ago during the search for a treatment for HIV/AIDS, yet a solution has not yet been adopted. The reality is that individuals getting placebo have to do significantly worse than those receiving the drug being tested in order for efficacy to be demonstrated.

We would like to challenge HD clinical trial researchers to take the leadership in developing and implementing alternative methodology for future HD clinical trials that overcome these problems. This will require that they convince both NIH and the FDA of the efficacy of the new methods, not an easy task. It’s a real challenge, but the results will not only benefit HD families, but also families dealing with other fatal diseases where such clinical trial protocols are later used.

We were pleased to learn that HSG is evaluating the possibility of modifying the upcoming 2CARE clinical trial to possibly include another trial agent. We also welcomed the opportunity to present our concerns and hope that HD family advocates will be able to participate in the planning process for future HSG trials at an earlier stage.

We also welcome the efforts being made by the Huntington Project, HSG, HDSA and others to take the initiative to put more information about their activities and plans on their web sites and to share them with the HD Lighthouse and other family groups. We know that this takes an extra effort since communications with families may not always be a priority with research organizations, nor do they typically have funding dedicated for this purpose. The HD Lighthouse stands ready to assist in this effort, mindful of its role in not only communicating HD research and treatment progress, but also independently interpreting and commenting on its relevance to the needs of HD families.

We’re also very impressed with the efforts made by the SET-HD group to independently assess HD treatment candidates and to provide detailed, standardized summaries that may be useful to CHDI, HSG and others in their translational research, drug development and clinical trials work. We believe that CHDI is adding important additional skills to the search for a cure to HD. Finally, although the organization and its leadership prefer to remain behind the scenes, we would like to acknowledge the strong contributions being made by the High Q Foundation to direct and fund HD research in general and translational research in particular. High Q has also actively helped improve communications of research plans and results with HD families.

Source:

printer friendly version

	Read the HDAC/HDLighthouse Forum. Post your comments