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Anticonvulsant Screening Program

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April 29, 2008
New Screening services are now available to the research community! Find out more...

The NIH Anticonvulsant Screening Program (ASP):

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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Description of Testing Services

Evaluation begins with a structural comparison within our database of over 27,000 compounds. The structural diversity of this database and the wealth of associated biological data provide a wide range of parameters for structure-activity evaluation. This database possibly holds the most structurally varied collection of compounds specifically tested for anticonvulsant activity and toxicity in the world. Testing is performed in a series of successive stages. Compounds are screened in a variety of widely accepted models. Employing a battery of validated in vivo/in vitro models rather than any one single assay has proven to be highly predictive of efficacy in human condition. Unless a specific mechanism is known, qualitative anticonvulsant profiles are determined for each submission using two to three different animal models. If deemed biologically active or chemically unique, a compound proceeds into a series of screens designed to establish quantitative, mechanistic, and differentiation profiles for both activity and toxicity. The evaluation of new chemical entities for biological activity is a dynamic process. New assays are continually designed, validated and when appropriate are incorporated into the Program. This process is driven by technological advances and recommendations from expert ASP advisors. The Program Review Article provides a general overview of some of the tests used and basic approach applied in screening. Since the publication of the article several new assays have been incorporated including: the formalin and sciatic nerve ligation models, lamotrigine resistant model, in vitro slice electrophysiology studies and the minimal clonic seizure test (see Model Listings). Each stage of evaluation occurs with direct consultation with the participant(s) and ASP staff. The ASP provides prompt feedback on results, interpretation of generated data, as well as an assessment of the potential success of each particular compound or compound class. The most successful compounds receive a comprehensive profile report detailing all generated biological and comparative data. This document, known as a "Red Book," is frequently used as the original source of publications of the participants as well as documentation for early discussions with the Food and Drug Administration (FDA) and supporting evidence in submissions of Investigational New Drug (IND) applications.

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Confidentiality

Confidentiality is one of the hallmarks of the Program's long success. The trust and confidence in ASP's handling of the originator's intellectual property have helped to establish the partnering necessary to facilitate successful development of new drugs. Participation in the ASP begins only after the appropriate representatives from both the participant's organization and the NINDS sign the confidentiality agreement. This document defines the legal parameters for the partnership. All screening and other communication activities are performed in strict confidence to help safeguard the participant's intellectual property. Chemical structures are considered proprietary unless otherwise specified by the supplier. The only testing undertaken by the ASP is that agreed upon by participants in collaboration with ASP personnel. To further assure confidentiality each newly submitted compound has a unique ASP number code assigned. This ADD number is used in future communications, tracking, and analysis. All laboratory site personnel are blinded to both the structure and the source of submitted compounds. The data generated through screening activities are provided exclusively to the participating supplier.

ASP databases that store the test results and other proprietary information are protected and secured through the NIH intrusion detection system, firewall, and the NIH password policy.

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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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New Screening Services - Now Open to the Research Community

Recently the ASP has expanded screening capabilities through an HHS funded effort designed to search for counter measures to protect the world's populations against potential threats from intentional or accidental exposure to nerve agents.

Thus with funding provided to the NIH through HHS and the CounterACT Program the ASP has undertaken the development and validation of models, along with initiating a screening effort intended to identify, characterize and provide incentive for development of therapeutic agents for the prevention and treatment of neuronal damage resultant from exposure to nerve agents. One of the early manifestations of exposure to such agents is resistant seizures resulting in life-threatening status. The lithium-pilocarpine status epilepticus (SE) model is thought to closely recapitulate the pathophysiology of nerve agents that target acetylcholinesterase, the enzyme responsible for the metabolism of the neurotransmitter acetylcholine. In this regard, the pilocarpine model shares many characteristics with nerve agent-induced seizures which initially involve an overactivation of cholinergic receptors (Turski et al., 1989 ; McDonough and Shih, 1997). The ASP has employed a series of models designed to arrest benzodiazepine resistant SE including: pilocarpine induced status, neuroprotection against excitotoxins such as Kainate or NMDA in in vitro hippocampal slice culture model, non-convulsive electrophysiology monitoring and isobolographic studies. These models were developed and incorporated into the ASP screening capabilities with the intent to find compounds useful against both convulsive and non-convulsive status. Active screening was initiated in February 2007 and already has resulted in several structurally novel preclinical leads. Although the NIH and the ASP do not screen against actual nerve agents we are uniquely positioned to facilitate potential linking of participants with successful compounds to other potentially interested parties that could provide further preclinical and even clinical development support.

All screening is undertaken in a blinded manner the same as compounds routinely submitted to the ASP. Data collection and distribution is confidential and otherwise handled the same as compounds traditionally submitted to the ASP Program.

* Researchers interested in these services should contact ASP personnel for more detailed information on how to participate.

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PANACHE Database

The ASP is in the process of developing a new web-based search tool called PANACHE (Public Access to Neuroactive & Anticonvulsant CHemical Evaluations) to provide access to years of previously protected nonproprietary data on hundreds of tested compounds. These include antiepileptic drugs (AEDs) as well as drugs used for other indications. The database will be useful to chemists, pharmacologists, and other investigators working with molecules of similar chemical structure. We eventually expect to provide baseline pharmacological data across several different models for most of the marketed AEDs. In addition, portions of the data will be released through PubChem to provide a quick reference to investigators.

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How to Participate

A signed confidentiality agreement between the NINDS and each potential participant is required before submission of compounds for evaluation. If interested in participating please contact an ASP staff member for additional information about the program. Based on your research goals, resources and timelines, we will determine how the ASP can best serve your specific needs. An agreement for submitting confidential material is provided for review. After you have contacted staff and submitted two original documents the NINDS will execute and return one of the originals retaining the other for our records. A registration form is also required for each sample submitted for evaluation. These are provided once the NINDS has approved the entity for program participation. Preliminary screening is normally performed using in vivo rodent models thus an initial sample size of approximately 350 to 500 mg is required unless prior knowledge of the compound's efficacy and toxicity are known. Directions for packaging and compound submission will also be provided prior to sample shipment.

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Additional Translational Links

Career Awards

Personnel Contacts

James Stables , MS Admin., R.Ph.
Program Director, Office Director
js131e@nih.gov

Tracy Chen, Ph.D., D.A.B.T.
Scientific Research Specialist
tracy.chen@nih.gov

Kevin C. Lee, Ph.D.
Scientific Research Specialist-Interdisciplinary Chemist
kl322w@nih.gov

Taek Oh
Information Technology Specialist
to73c@nih.gov

Liz Geiger
Program Assistant
eg17w@nih.gov

Tanya Moxley
Grants Clerk
moxleyt@mail.nih.gov

Program and Workshop Summaries

 

 

Last updated May 14, 2008