None of the newer antiepileptic drugs (AEDs) that have been introduced since 1993, including those that act on new targets, have become the “magic bullet” that can reliably make patients seizure free. When compared to the old AEDs the newer AEDs (developed since 1990) have provided significant improvements in safety, tolerability, and pharmacokinetics (Bialer & White, 2010). Equally important is the fact that the existence of >20 different AEDs offers a broader range of therapeutic options that may lead to better personalized medicine. Nonetheless, there is still a substantial unmet need for the 30% of patients with therapy-resistant epilepsy. Furthermore, the drugs that are currently available are still not completely without side effects, and thus the search for new therapies with a safer therapeutic index and better efficacy is clearly warranted.
All AEDs introduced after 1990 (with the exception of vigabatrin and tiagabine) were developed empirically utilizing mechanism-unbiased anticonvulsant animal models (Bialer & White, 2010; Bialer, 2012). The empirical nature of the discovery of these AEDs coupled with their multiple mechanisms of action explains their diverse clinical profiles. With 16 AEDs introduced in the last 22 years and the older AEDs still in use, the antiepileptic market is crowded. Consequently, treatment for epilepsy alone is not attractive in 2012 to the pharmaceutical industry, although the clinical needs of refractory epilepsy remains unmet. Therefore, future design of new AEDs must also have potential for treating nonepileptic central nervous system (CNS) disorders (e.g., bipolar disorder, neuropathic pain, migraine prophylaxis).
My opinion on the National Institutes of Health (NIH)–National Institute of Neurological Disorders and Stroke (NINDS) Anticonvulsant Screening Program (ASP)–anticonvulsant animal models is summarized by the following Pros and Cons:
- 1 Anticonvulsant animal models (in vivo) are effective in identifying new AEDs, mechanism-unbiased, and provide insight into the AEDs’ pharmacokinetic–pharmacodynamic relationship. Activity in a wide array of anticonvulsant models may indicate a wide antiepileptic spectrum of activity and a good clinical potential.
- 2 The maximal electroshock (MES) and subcutaneous pentylenetetrazol (Metrazol, scMet) tests remain the “gold standards.” New compounds active in the MES and scMet tests have been efficacious in clinical trials, although if approved it is impossible to predict a priori their annual sales or market volume.
- 3 Animal models with a similarly high predictive value do not exist in other CNS disorders (e.g., psychiatric disorders, migraine).
- 1 Animal models do not predict toxicity or side effects in patients or human tolerability.
My 25 years of working with the NINDS-ASP shows that activity in the MES and the scMet models, coupled with a broad anticonvulsant spectrum in other models, may lead to the identification of a new AED with activity against pharmacoresistent epilepsy. Therefore, concomitant with the continuous attempt to develop new compounds with antiepileptogenic disease-modifying properties, I am in favor of keeping the current ASP program while working toward the incorporation of additional screening that may help to differentiate the most promising AED. To this point, it is important to note that the ASP is not a static entity but extremely dynamic and takes advantage of the opportunity to incorporate new models into their screening protocol when it is appropriate to do so; for example, the 6-Hz acute seizure model and the lamotrigine-resistant kindled rat.
Target-based drug design or Targephilia’s mantra of: “one gene, one protein, one function” is useful in developing 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins), HIV protease inhibitors, or antibiotics but is not useful in the development of antiepileptic or CNS drugs (Enna & Williams, 2009; Bialer & White, 2010). This is because all successful AEDs have multiple mechanisms of action (MOAs) and the two single-mechanism AEDs developed by mechanism-based design are not widely used due to side effects related to their single MOA. In addition, CNS drugs with multiple MOAs have a better probability of being efficacious in refractory epilepsies and other CNS disorders.
I am fully aware of the current difficulties AEDs and CNS drug development present to the pharmaceutical industry, as reflected in a recent article entitled “Is pharma running out of brainy idea” (Miller, 2010). However, “putting all the eggs in the basket” of disease modifiers might be too risky, since currently we know that we do not know or at most know little how to develop and what are the correct animal models for antiepileptogenic activity. Therefore:
- 1 New AEDs must be better than existing drugs in terms of efficacy, safety, broad utilization, and, if possible, disease modification.
- 2 A nonteratogenic valproic acid derivate and/or an anti–status epilepticus drug that is superior to diazepam are attractive second-generation AEDs (White et al., 2012).
- 3 New AEDs should be active in refractory animal models where existing AEDs are inactive.
- 4 A new MOA is an incentive if it is the drug’s only (or major) MOA, which is usually not the case
- 5 New AEDs must be active in other CNS disorders, since use for epilepsy alone is not commercially attractive in 2012 but can serve as regulatory approval entry.