Consulting and advising for preclinical epilepsy and neurological disease drug discovery

Phenotype-based drug discovery is one of the most effective solutions to uncover new molecular targets. Epilepsy is unique in the neurological disease space because the rodent seizure models are highly predictive of human response - drugs that block a seizure in a mouse are often likely to block a seizure in a person. This close correlation between animal and human response has led to several dozen antiseizure medicines being commercially marketed today. 

But new approach methods, or NAMs, are increasingly recognized as being useful to reduce the use of animal testing wherever feasible. NAMs have the potential to uncover new therapeutic options at validated molecular targets that are relevant to epilepsy. While phenotype-based screening has a higher likelihood of uncovering new therapeutic targets for any given disease state, target-based drug screening has a higher likelihood of uncovering new therapies for any given target of relevance to that disease state. To achieve this goal, we assessed the feasibility and utility of a multiorganismal compound library screening pipeline to assess whether we could identify a new therapeutic option for the GABA-A receptor. 

Our study demonstrates feasibility and confirms that the integration of non-mammalian models and NAMs in early antiseizure drug screening can successfully uncover new therapeutic hits, which can be further demonstrated as clinical lead candidates in targeted testing in a few rodent seizure models. This study provides compelling evidence that we will one day be able to better model epilepsy and discover new therapeutic options with minimal use of rodent models. 

The inhibitory neurotransmitter, GABA, is implicated in a number of seizure disorders. As a pentameric iontropic channel, GABA-A is a well-established therapeutic target to modulate inhibitory tone in the brain and provide seizure suppressive effects. However, many of the GABA-A modulators, such as benzodiazepines and barbiturates, are associated with significant sedative effects that reduce their suitability for chronic use in people with epilepsy. New treatments that can modulate the GABA-A receptor without sedating effects are thus in strong demand. 

ENX‑101 was designed to be more selective. Instead of acting broadly, it targets specific GABA receptor types (called α2, α3, and α5 subunits) that are linked to seizure control but avoids the α1 subtype often responsible for strong sedation.

Two of the most common questions I receive in any early preclinical program is "which rodent seizure or epilepsy model is most predictive of clinical efficacy in people?" or "How does each rodent seizure model translate to human seizures?"

These are understandably difficult questions to answer - there are SO many different approaches to assessing efficacy potential and a seemingly endless number of seizure models: maximal electroshock; subcutaneous pentylenetetrazol; amygdala kindling; hippocampal kindling; post-status epilepticus models; etc. Although various well-established models exist, their predictive validity across the spectrum of clinical epilepsies has been less clear.

So what is the best approach to screening new molecular entities?

The models with the highest clinical concordance were: maximal electroshock test and 6 Hz test, followed closely by the corneal kindled mouse.