Members of the Huntington Study Group held their quarterly press conference with Huntington’s Disease family reporters Steve Ireland from the Huntington’s Disease Advocacy Center, Don Lamont of the Huntington’s Society of Canada, and Marsha Miller from the HD Lighthouse. Representing the HSG were Ira Shoulson, M.D. (Chair, HSG Executive Committee), Leslie Briner, Ray Dorsey M.D. (Medical monitor for the TREND-HD study), Karl Kieburtz (Executive Committee Member), and Colleen McCollough.
Several topics and issues were on the agenda from HSG history to future plans, based on questions which were submitted in advance.
History of the HSG
Ira Shoulson spoke about the founding of the HSG. 1993 was the official start but the idea had been incubating for a number of years. Ten years before, Dr. Shoulson and a colleague started the Parkinson’s Study Group, bringing together clinical investigators who were interested in controlled clinical trials. Although some of the challenges were worked out with the PSG, there were still some to be met with Huntington’s. The HSG received support from the HDSA, the Huntington Society of Canada, and the Foundation for the Care and Cure of Huntington’s Disease. They convened a meeting of twenty people in Bethesda Maryland and discussed whether to meet again. By 1994, they were committed to continuing as an organization. Their first goal was to develop a tool to measure disease progression in research. The United Huntington’s Disease Rating Scale (UHDRS) was developed, went through several versions through 1996, and continues to be used.
The HSG started with ten research sites. Various sites were added over the years until today there are 80 to 90 sites in the U.S., Canada, Europe and Australia.
The first HSG study took place from 1995-6 and involved the antioxidant OPC-14117 which was not well tolerated. Although the compound was not successful, the members were successful in being able to work collaboratively.
The CARE-HD study was largest multicenter research effort to date and involved CoQ10 and remacemide. While remacemide was not effective there was a signal that CoQ10 might be, although the difference was not statistically significant.
Karl Kieburtz noted that organizations like the Study Groups are sociologically interesting. The HSG is not a legal entity and does not operate on a contractual basis. It is based on voluntary collaboration. Academic medicine attracts and rewards individuals who are independent, so the idea of institutional collaboration was new. The first meeting was really to decide whether to meet again, “Is there enough common work that we should meet again?” Between 1993 and 1996 we worked out the format of the HSG. The initial seed money which was less than $50,000 carried the group through the first two years and has paid dividends in getting trials going.
Choosing compounds for trials
Dr. Shoulson explained that review and approval is required by the HSG executive committee for it to be called a HSG trial. Prior to that, there are two major review groups which way in on the proposal, the Scientific Advisory Committee, which is chaired by Anne Young and includes basic and translational scientists, and the Bioethics Advisory Committee, chaired by Kimberly Quaid.
The exec committee is in touch formally every six to eight weeks. They meet in person twice a year and on conference call at other times. The principal researcher of a proposed study will join the conference call. Funding is needed for the study of course from NIH, foundations, or private sources. It’s a multiyear process that engages a variety of review groups, both internal and external.
Dr. Kieburtz pointed out that the HSG doesn’t choose compounds for clinical trials. The actual process is an interaction between individual effort and collaboration. The individual or small group who wants to do the research is the champion of the proposal. The projects which survive are those that make it through the reviews. The review committees aren’t in the mode of restricting projects but rather optimizing them, suggesting improvements, and making sure that the proposals are ethical, meaningful, and scientifically rational. It isn’t top down – it’s a grass roots effort.
If investigators don’t convince their colleagues in the HSG that they have a good idea, they can pursue it outside the HSG as well.
Asked about strategic planning, Dr. Shoulson pointed out that PHAROS, Predict-HD, and COHORT emerged out of a strategic planning effort which concluded that more needed to be learned about pre-manifest HD. The SET-HD project which solicited nominations of potential treatments from the community did as well. [See http://www.huntingtonproject.org/] Most recently, strategic planning has focused on therapies, training and research capacity.
He also mentioned that brainstorming meetings are held during the annual HSG meeting to involve members of the HD community in planning and input in new studies.
Asked about pharmaceutical companies which may want to have the HSG conduct their clinical testing, Dr. Shoulson said that there aren’t a lot of pharmaceutical companies calling the HSG. They may contact the pharmaceutical company about a compound that they are interested in such as they did with tetrabenazine. TREND with ethyl-EPA decided to work with the HSG on their second Phase III clinical trial.
Dr. Kieburtz talked about how the Dimebon study came about. Since he works with the FDA, people sometimes call him for advice. Medivation had called him to discuss their development plans for Alzheimber’s and then asked if there’s anything else they should be thinking about. Dr. Kieburtz suggested that their drug might be investigated for Huntington’s Disease. They called back six months later and said that they were interested. They did some preclinical work which looked promising and then they asked Dr. Kieburtz to bring the proposal to the HSG which he did, using the process described above.
Dimebon has two promising two mechanisms. It is an acetylcholinesterase inhibitor like other drugs which have been shown to be effective in Alzheimer’s disease and it also blocks glutamate receptors, much like memantine. Those mechanisms may address cognitive and behavioral problems in Huntington’s Disease.
The study is underway. There are two phases, the early dose finding phase and then a larger placebo controlled and double blinded to look for signs of efficacy. Phase I and II are bundled together. If Phase I and II look promising, a larger phase III study will be needed.
Dr. Shoulson pointed out that when drug companies come to the HSG it is usually for symptomatic treatments that they could get to market quickly. Drugs to postpone onset and slow progression cost much more money and it is hard to interest pharmaceutical companies in doing them. The Ethyl - EPA and the Dimebon studies are symptomatic treatments.
Dr. Kieburtz stressed that care for individuals is also important.
Dr. Ray Dorsey said that while they are studying ethyl-EPA for effectiveness in dealing with symptoms, it could later be studying to see if it is disease modifying.
Dr. Kieburtz also suggested that although the Dimebon study is not designed to tell us whether it will delay progression there are reasons to think that it might do so. It’s desirable to study a drug with that potential.
Dr. Shoulson pointed out that the original Phase III Ethy-EPA study was designed to look at progression over a six month period, which was a short of time. They did get the results they hoped for but they did notice that some individuals had a beneficial reduction in involuntary movement. TREND-HD is designed to see if that finding can be confirmed, but they will also look to see if there are signals about effectiveness in disease modifications.
Signals that lead to clinical trials may also come from Alzheimer’s research.
European Huntington’s Disease Network (EHDN)
The HSG has a good relationship with their European counterpart. And we know each other from working together. The HSG is more established; EHDN is two years old. The HSG has more diverse funding while the EHDN are primarily funded by the High-Q foundation. They attend each other’s meetings but most contacts are email and conference calls. Right now EHDN is more focused on methods and biomarkers. [See http://www.euro-hd.net/html/network]
FDA and clinical trials in the light of problems in recent non-hd drug studies
Huntington’s Disease patients and their families are willing to accept more risk than research subjects in a study of a new pain reliever. There is a concern among HD families that clinical trials will be unnecessarily delayed by overly restrictive oversight that might come about as a result of the Vioxx and other problem drug studies.
Dr. Shoulson said that he shared the concern. The 2-CARE study (CoQ10) has been delayed because the FDA wants more animal toxicology information.
There is already a great deal of oversight when compounds go into an HSG clinical trial. There is the FDA, the Institutional Review Boards of the participating institutions, and also an independent committee of people who are not in the study who examine data.
Dr. Kieburtz agreed that more flexibility is needed for a serious disease like Huntington’s and commented that flexibility depends on strong leadership at the FDA which is matter for advocacy with Congress. You don’t want the FDA to let dangerous drugs get by and you don’t want them to stifle innovation, which always comes with some risk.
The need for more family advocacy was discussed. Dr Shoulson cited as a model the example of the National Breast Cancer Coalition’s training program to prepare and encourage activists to participate in research and public policy. The program is called LEAD for leadership, education and advocacy development. http://www.natlbcc.org/bin/index2.asp?strid=482&btnid=3&depid=7
Dr. Kieburtz pointed out that HD families can communicate with the Secretary of Health and Human Services – a top down approach. From the grass roots up, we can attend an FDA advisory committee meeting. There should be on coming up on Huntington’s Disease and there’s a time for public testimony.
In 2005, the HSG decided to sponsor a young investigator to do an early study of a promising compound. Dr. Penny Hogarth’s proposal to study Tauroursodeoxycholic acid (TUDCA) was selected. [see the SET-HD review of this compound http://www.huntingtonproject.org/Portals/0/TUDAC.pdf] The study is taking some time, There were problems in getting the drug and in assaying the concentration in the blood. It has been slow in terms of developing. “We’ve made an effort to light some fire under this and hopefully it will move forward.”
Dr. Kieburtz noted that drug supply is always a challenge. The three most limiting aspects of the clinical trial process are:
- regulatory review
- trained researchers
- adequate supply of pharmaceutical grade test compounds and placebos.
Communication of clinical trial results with participants and the community
Dr. Dorsey commented that one of the communication challenges they face is that in most cases, participants hear about the study when the public does, often in the press release from the commercial sponsor. In TREND we want to communicate personally with each study participant about the results by phone on the same day they are released. Leslie will develop a press release for the HSG website [http://www.huntington-study-group.org] and the HD community websites. The IRBS have to approve these communications.