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Anticonvulsant Screening Program

Mission Statement

The Anticonvulsant Screening Program (ASP) is a government sponsored effort designed to provide early incentives that encourage and facilitate the discovery of new therapeutic agents. One of the major goals of the ASP has been the establishment of worldwide collaborative relationships among government, academia, and industry focused on the search for therapeutic interventions and cures for the epilepsies and other related disorders. This international network includes over 460 different suppliers from 30 countries and four continents. It is utilized to effectively link independent researchers and small pharma and biotech groups in ways that maximize the required expertise and financial support necessary to bring new discoveries through the various stages of testing required for regulatory approval. The ASP has succeeded in creating a structurally diverse, CNS focused chemical and biological library which is utilized to help predict early human efficacy and late stage toxicity of candidate compounds. The ASP strives to provide other discovery incentives such as characterization, optimization and profiling of novel antiseizure/anticonvulsant agents. These efforts are undertaken by offering a series of multilevel pharmacological assessments of candidate compounds that lead to safer and more effective therapies. The biological information generated and consultations afforded to participants provide insight concerning the pharmacokinetic and pharmacodynamic properties of submitted compounds. Since the mid 1970s these confidential services have proven invaluable to hundreds of academic and industrial researchers. The ASP has provided essential development support for many of the currently marketed treatments.

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Background

In 1966 the Neurology Institute at the NIH launched a program in epilepsy. A survey of the pharmaceutical industry revealed that there was very little research in the development of anticonvulsant drugs. In 1968, in view of the fact that no new therapeutic candidates were available in the U.S., NINDS conducted a series of six controlled clinical trials on anticonvulsants being used primarily in Europe. NINDS's support of these trials acted as an incentive for industry to initiate clinical efforts in drug development of some of these agents in the United States. An equally important outcome of this support was the development of expertise, new methodologies, and trial designs for future investigations of anticonvulsant drugs. Three of these drugs-carbamazepine (1974), clonazepam (1975) and valproic acid (1978)-received FDA approval and were later marketed to patients in the U.S. In 1975, to fill the void in preclinical anticonvulsant research and establish a drug pipeline for viable clinical candidate drugs, the Anticonvulsant Screening Program (ASP) was initiated. For the past 33 years the ASP has been a model for preclinical discovery and evaluation for new drugs in epilepsy, neuropathic pain, migraine and other neurological disorders. The Program annually screens an average of 800 new chemical entities using a series of in vivo/in vitro models. Candidate compounds are competitively evaluated against standard marketed antiepileptic drugs (AEDs), new agents undergoing development, as well as the ASP's rich collection of similarly tested candidate drugs representing a specific chemical class under investigation. Such evaluations have proved invaluable to researchers, saving them years in development as well as human resource effort used in optimizing lead compounds.

The chemical structures and other specified information obtained on submitted compounds are considered intellectual property and thus protected by the ASP's confidentiality agreement with each participant. This agreement has proven critical to facilitating scientific cooperation between the government via the ASP and the hundreds of participants in the Program. By assuring each of our participant's protection from premature disclosure of their research discoveries, we assure that new drug candidates remain protected for patenting and eventual marketing. These procedures have aided in bringing new drugs to market. A number of others are currently undergoing clinical evaluation.

Since 1975, screening has been performed via contract at one site, the University of Utah. The ASP's principle investigator at the Utah site is Dr. Steven White who has been with the program for over two decades. He along with several other highly experienced research scientists operates under the direction of the ASP staff at the NINDS. All testing is carried out in a blinded manner to assure the confidentiality of the source and structure of compounds being evaluated. Early on, the ASP recognized the value in having biological data generated by a single test facility with consistent methodologies. This has provided a high level of reproducibility and has helped build the reputation of the ASP as a world class center for drug screening. This consistency has also provided a unique added value making the database a highly useful tool that allows NINDS staff to aid participants in their decision-making processes.

The Institute is currently exploring avenues to use the ASP screening model for creation of translational research incentives in targeting other neurological diseases.

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Program Highlights

Through the establishment of hundreds of public/private partnerships, both nationally and internationally, the ASP has succeeded in encouraging hundreds of researchers at universities, biotech companies, and traditional pharmaceutical companies. For over three decades the ASP has strategically engaged in efforts directed at improving the quality of life of patients afflicted with the burden of disease. Through model development and drug screening of thousands of potential anticonvulsant drugs the ASP has aided in the identification and discovery of new mechanisms of drug action and design of clinical trials resulting in the eventual approval of several new therapies in epilepsy and other related indications. The ASP has provided direct preclinical support for nine new drugs currently in various stages of clinical development. These new agents, as well as others under development, are providing much needed hope for the thousands of people suffering from side effects of current therapies and those afflicted with poorly controlled or resistant seizures.

The ASP played a pivotal role in the identification and helped in the subsequent development of several new anticonvulsant drugs, e.g., felbamate (Felbatol) and topirimate (Topamax). Other drugs currently in late development that had significant ASP support include lacosamide and retigabine. These may well be the next marketed anticonvulsants. In addition, over twenty other compounds have entered clinical trials, were screened preclinically or otherwise partially supported by the NINDS.

The technical and financial assistance from the ASP affords academic and other researchers an opportunity to make significant contributions in the development of better treatments and ultimately in the discovery of a cure for this devastating disease.

Many compounds found active in the battery of models employed by the ASP have been found useful against other diseases such as pain, migraine, bi-polar and anxiety. Numerous other indications are under evaluation both in animals and in current medical practice.

In summary, the ASP provides the right mix of incentives and expertise to individual scientists and smaller companies to evaluate novel candidates in highly predictive and standardized assays. The ASP decreases development risks and delivers other critical motivation necessary to convince pharma to participate in a disease area that may not otherwise be economically viable to their business models. The preliminary data and confidential structural diversity comparisons provided by the ASP can act as a valuable optimization tool for larger pharmaceutical companies assisting in selection of lead compounds derived from their own high throughput drug development programs. But most importantly, the ASP provides hope to patients and their families assuring them that there is an ongoing effort to make their lives better.

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Last updated April 7, 2014