Epilepsy: The Pipeline

Research II

According to GlobalData, there are 220 products in development for the treatment of various forms of epilepsy, of which 40% are in Preclinical testing. Approximately 40% are in various stages of clinical development, with 13 (5.9%) are in Phase III.

But what is in the pipeline? Are there real innovations in development for epilepsy, or are we looking at reformulations of previously approved drugs?

Now before we begin our discussion, keep in mind that no single database can capture every single product or drug candidate in development. Also, there is no guarantee that the information is up to date.

Lastly, there are bound to be compounds or even entire mechanisms of action which are missing. And if you know of anything which is missing, let us know via email!

Phase III

Half of the candidates in development for epilepsy are for partial seizures. The majority of these entries are for compounds which are already approved in one geography, but are still in development or regulatory processing in other geographies.

A few reformulations and new routes of administration, such as intranasal diazepam and intranasal midazolam. Of the NCEs, YKP-3089 (SK Biopharmaceuticals) is a next-generation carbamate in development for partial onset seizures.

These product candidates are important reminders of a few point. First, while the carbamate class is “old,” there is always a need and opportunity for new compounds to pursue established mechanisms of action.

Second, epilepsy is perhaps one of the few conditions where reformulations are both valuable and welcomed. While some of these reformulations may not be “blockbusters,” there are nevertheless potentially valuable opportunities.

Phase II

The database contains 12 candidates in Phase II. As mentioned earlier, there are a few reformulations of existing approved drugs, such as alprazolam and topiramate. Two of the Phase II candidates, GWP-42006 (GW Pharmaceuticals) and cannabidiol (INSYS Therapeutics) are derived or extracted from marijuana cannabinoids.

Both are delivered orally, and clinical trial results are currently unavailable.

Phase I

The database contains 16 candidates in Phase I development, again with a few reformulations and repurposing candidates, such as diazepam, histamine, lamotrigine, and, interestingly, simvastatin.

Impressions…and Complications

Our impression from a very cursory overview of the pipeline is that it is not very diverse. We see some reformulations, some repurposing, and a number of compounds chasing the same mechanism of action.

For example, the pipeline lists 40 entries targeting GABAA Receptors, and most of these are benzodiazepines (i.e., diazepam, alprazolam, and midazolam). Even phenytoin, which was used in epilepsy beginning in the 1930s, is experiencing a bit of a renaissance with a few prodrugs in development.

In fact, it could be the overall understanding of the voltage-gate sodium channel which phenytoin targets that explains the number of drugs in development which are also targeting these channels, i.e., eslicarbazepine (Phase III), brivaracetam (Registration), YKP-3089 (Phase III), and others.

This point is made by GlobalData analysis, who note that >40% of today’s epilepsy pipeline is targeting traditional targets, such as GABA, glutamate, and sodium and calcium channels.

Part of the problem here is that epilepsy generally makes it difficult to execute a target-based drug design approach. That is, many of the effective anti-epileptics actually have multiple mechanisms of action. For example, levetiracetam, arguably one of the most effective and successful products ever discovered for the treatment of epilepsy, has two mechanisms of action.

First, it binds to synaptic vesicle protein 2A in neurons, inhibiting neurotransmitter release. But, levetiracetam also blocks calcium channels. Thus, the disease itself may simply lend itself to complex mechanisms of action, making novel drug discovery all the more complicated.

Interestingly, a derivative of levetiracetam, known as brivaracetam, has less ability to block sodium channels, and is expected to be superior to levetiracetam from a side effect profile perspective.

Anytime a patient is taking one or more drugs with different mechanisms of action, the probability of experiencing side effects increases. Such is the case in epilepsy, where side effects for many of these drugs are problematic, and will continue to be so as long as the same mechanisms of action are being pursued.

Our next article will examine other approaches to treat epilepsy, such as cell and gene therapies.

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