**2005 Report submitted by Benchmark Steward(s):**

H. Steve White, Ph.D. (University of Utah)

James Stables, M.S.A. (National Institute of Neurological Disorders and
Stroke)

**Background of the benchmark goal:** As with all classes of drugs, the
discovery and development of new AEDs rely heavily on the employment of
preclinical models to demonstrate efficacy and safety prior to their
introduction into human volunteers. Obviously, the more predictive an
animal model(s) for a particular seizure type or syndrome, the greater
the likelihood that the investigational AED will demonstrate efficacy in
human clinical trials. Herein lies one of the most often discussed
issues in the current-day AED discovery process; i.e., what is the most
appropriate in vivo/ in vitro model system(s) to employ when attempting
to find comparable efficacy in human epilepsy patients?

**Current status of field:** Since 1993, nine new AEDs have been
introduced for the management of partial epilepsy. Currently there are
also several new compounds in various stages of clinical development.
These discoveries and their subsequent development have predominately
been based on activity either the maximal electroshock, s.c. Metrazol,
or kindled rat models of generalized and partial seizures. Their
introduction into the treatment armamentarium has clearly had an impact
on the lives of patients with epilepsy through improved seizure control,
a lessening of adverse events, improved pharmacokinetics, and fewer
drug-drug interactions. Unfortunately, despite the availability of these
new therapeutic options, a significant fraction of the patients with
epilepsy continue to live with uncontrolled seizures, often at the
expense of significant drug-induced adverse events. Clearly, there is a
need for more efficacious therapies that will not infringe on a
patient's quality of life. The successful identification of more
effective drugs will depend on the identification and validation of
models that more closely resemble human epilepsy.

**Activities update:**

-   Planning for a Models Task Force Meeting to review progress/barriers
    in models for antiepileptogenesis (AEG) along with unique
    pharmacology in the pediatric and elderly systems.

-   Awarded 6 grants in the area of AEG and pharmacoresistance (PR).
    Also, people are now reporting numerous research activities in the
    area of AEG & PR.

**Top priorities for next 5-10 years:**

-   Develop a community-wide data base of pharmacological results
    forthcoming from RFA supported grants

-   Define a mechanism for selecting and testing investigational therapy
    in newly defined epilepsy model (Task Force topic)

-   Determine the feasibility for incorporation of newly identified and
    validated model systems of AEG & PR into NINDS sponsored screening
    program testing the most novel candidates to these new systems.

-   Continue to shepherd efforts to support model development for
    catastrophic pediatric epilepsies and geriatric epilepsy that can be
    incorporated into therapy screening programs.

-   Develop a consortium of investigators that have an expressed
    interest in characterizing novel therapeutics in a more diverse
    battery of the highly labor intensive, low throughput animal models

-   Develop collaboration with other Benchmark Stewards in an effort to
    incorporate novel findings into ongoing therapy discovery programs

**Roadblocks to progress:**

-   Low through-put associated with most chronic epilepsy animal models

-   Recognition that translational support will promote progress in both
    basic and clinical outcomes.

-   Lack of validated miniaturized video-telemetry recording units that
    can be employed in genetic mouse models. Need to develop and apply
    new technology in these areas.

-   Paucity of laboratories interested in conducting therapy screening
    and trained whole animal pharmacologists with expressed interest in
    translational research.

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47\. Stables J.P., Bertram E.H., White H.S., Coulter D.A., Dichter M.A.,
Jacobs M.P., Loscher W., Lowenstein D.H., Moshe S.L., Noebels J.L., and
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48\. Stables J.P., Bertram E., Dudek F.E., Holmes G., Mathern G.,
Pitkanen A., and White HS. Therapy discovery for pharmacoresistant
epilepsy and for disease-modifying therapeutics: Summary of the
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