SET-HD is a program designed to identify and systematically assess experimental therapies for Huntington’s disease (HD) by involving the entire HD community and other neuroscience researchers.
Objectives:
1) To survey the Huntington’s disease (HD) community about potential experimental therapeutics for treating HD. Nominate compounds here for consideration.
2) To evaluate compounds for further research and clinical trials.
3) To disseminate this information to the HD and broader neuroscience research communities so that it may be used to inform the planning of clinical and pre-clinical research.
Why SET-HD was established:
Clinical trials require enormous resources. For rare diseases like HD, only a small number of interventions can be studied in clinical trials at any given time, making it imperative that the most promising interventions be given priority for clinical testing.
Selection of agents to be evaluated in clinical trials has, in the past, often been determined by the influence of researchers who support the agent or by timely hypotheses, rather than by the weight of the available evidence. SET-HD aims to provide an objective and systematic evaluation of available pre-clinical and clinic data so that researchers can select the most promising agents for further study.
The agents that come out of the SET-HD project may not be novel, but will be sound candidates for trials. Additionally, these assessments should highlight holes in the pre-clinical data and lead to more relevant, efficient animal studies. This approach has recently been used in Parkinson’s disease to inform NINDS-sponsored clinical trials (Ravina, 2003).
Why now?
Now is the time for a comprehensive survey of potential pharmacologic agents to treat HD for several reasons:
· Potential targets have been identified
· Several good rodent models of HD are available
· Investigators are actively screening compounds with encouraging results.
· An active clinical research community has emerged, which can rapidly implement high quality clinical trials for promising interventions.
This effort to identify and characterize interventions for HD is a key component of the Huntington Project (huntingtonproject.org ), a broad-based effort to bring clinicians, scientists, voluntary groups, families, and others together to develop treatments for HD.
A Four-Part Research Plan:
A four-part intervention assessment process is designed to inform pre-clinical and clinical research:.
Identify compounds
In order to collect the most relevant results, SET-HD will cast a wide net by seeking suggestions about compounds, biologics, and devices from the, academic, industry, and lay communities, including:
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All NINDS investigators working on HD
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HD foundations such as the Hereditary Disease Foundation, Huntington’s Disease Society of America, the High Q Foundation, and participants in the Huntington Project
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Biotechnology and pharmaceutical companies selectively contacted about relevant investigational agents that may or may not be in development for HD. These companies could be identified through the investigators as well as through the pharmaceutical manufactures and biotechnology trade associations
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Relevant professional organizations, such as the World Federation of Neurology
- Through literature searches of the PubMed and Medline databases to assure that all potential agents have been included
Individuals nominating compounds will be asked to provide information that fulfills the criteria below and to comment on these criteria. If data are unpublished, a brief summary of findings, including negative results should be provided.
Establish Criteria
In order to make comparisons among various compounds, criteria for evaluation must be explicitly stated and easy to rate and operationalize. Common pre-clinical and clinical study designs and measures will facilitate this process. Since criteria such as safety in humans an drug interactions tend to favor older compounds for which more information may be known, this bias should be factored into the weighting of criteria and prioritization of compounds. Criteria currently under consideration include the characteristics listed below. However, we seek to identify other criteria that would allow more efficient and appropriate prioritization:
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Rationale and mechanism
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Data from animal models: behavioral, motor function, weight change, neuropathology, and survival.
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Consistency and magnitude of effect across labs and models (full length and fragment)
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Administration and dosing: route of administration and schedule, kinetics, BBB penetration and target tissue concentrations, drug interactions
- Human data as available: safety and tolerability, preliminary efficacy data including observational
Characterize interventions
Using the information about compounds gathered from investigators and from the relevant literature, approximately 25 of the highest priority compounds will be selected in the first cycle for in-depth evaluation. Clinical pharmacologists will complete the initial evaluations. Drafts will be circulated to other members of the SET-HD steering committee, investigators known to have experience with the compound, as well as the person who initially suggested the agent, for comment. Final editorial comment will rest with the steering committee.
Disseminate information
The evaluations will be summarized and submitted for publication to a peer-reviewed journal. Individual drug summaries may be posted on the Huntington Project web site as well as the web sites of the publishing journal, NINDS, and/or the participating foundations for those interested in more detailed information. The Huntington Project will continue to accept electronic submission of nominations in the future. This information can then be used, as it has been in Parkinson’s disease, to inform the selection of drugs for further pre-clinical and clinical testing.
Round 1 Timeline:
Sept-Oct 2003: Establish committee, drug evaluation criteria, and working policies (committee meet in person)
Dec 2003-March 31, 2004: Initial solicitations
April-May 2004: Evaluations of compounds nominated between January 1 to March 31, 2004
June 2004: SET-HD working group to meet in person
June 2004-March 2005: Finalize compound review summaries
March 2005 - December 2006: Manuscript preparation and submission
Ongoing: We invite you to nominate compounds for future rounds of evaluations
Personnel
Core Group:
NINDS: Bernard Ravina, MD, Jill Heemskerk, PhD, Diane Murphy, PhD, Kenneth Fischbeck, MD, Nicholas DiProspero, MD, PhD, Robert Hart, MD
Academic Investigators: Susan Fagan, PharmD, Collin Hovinga, PharmD, Louis Profenno, MD, PhD, Madaline Harrison, MD
Patient Advocate: James A. Tretheway, MBA
Nomination form of agent(s) with therapeutic potential in HD: