Epilepsy: The Pipeline, Part II

Bench Research Lacerta Bio

In our previous article, we presented a general overview of the epilepsy pipeline, noting that there are over two hundred drug candidates in various stages of development.

In this article, we take a closer look at some of the more interesting mechanisms of action.

As we go through these candidates, we need to keep in mind a point made in the previous article, namely, that epilepsy does not lend itself to target-based, rational drug discovery. So while drugs such as levetiracetam are highly effective for many patients, their complex pharmacology and multiple mechanisms of action leads to side effect issues.

Is Epilepsy an Inflammatory Condition?

Approximately one third of epilepsy patients do not respond, or respond poorly, to standard anti-epileptic therapies. For many of these patients, viewing epilepsy as an inflammatory condition may open up new approaches to treating this condition.

For some patients, prednisone and other steroids are effective, especially in severe cases. However, their well-known side effect makes their long-term usage prohibitive, especially in children.

One novel anti-inflammatory, VX-765 (Vertex) was under development for the treatment of both drug-resistant partial epilepsy and chronic plaque psoriasis. The drug worked by inhibiting caspase-1, a key enzyme in the activation of pro-inflammatory interleukin-1. Vertex terminated this program in 2014 due to a lack of efficacy in a Phase IIa trial.

Regardless of this clinical failure, there remain many physicians who recommend an anti-inflammatory “lifestyle” for managing epilepsy via exercise, fish oil supplements, and reduced consumption of unprocessed foods.

Is Marijuana the Answer?

A number of states across the US are now making marijuana readily available for both recreational and medical purposes. For many epileptics, this is welcome news, but does it have merit?

Cannabinoid derivatives are in development for the treatment of a variety of seizures. For example, cannabidiol (INSYS Therapeutics) is in development for a variety of conditions, including treatment-resistant seizures. Interestingly, an oral solution is being studies in a Phase I/II trial in pediatric patients with treatment-resistant seizures. Other cannabinoid receptor agonists in development for epilepsy include GWP-42006 (GW Pharmaceuticals, Phase II), NB-23R1 (Nemus Bioscience, Discovery), and ZYN-002 (Zynerba, Phase I).

Mechanistically, targeting cannabinoid receptors makes a great deal of sense. It is believed that compounds like cannabidiol block excitatory neurotransmitter release, thereby reducing the transmission of impulses from one nerve to another. However, recent events in France clearly demonstrate that we have a lot to learn about this mechanism of action.

Old Dogs & New Tricks

As we discussed in our previous article, a number of product candidates are reformulations of drugs already on the market, especially benzodiazepines. On the surface, this makes a great deal of sense. These drugs, such as diazepam, have been used for decades for epilepsy. Their efficacy and pharmacokinetics are well known.

Their pharmacology (GABA A receptor agonists) is proven in epilepsy via other drug classes. And, given the difficulty in discovering new compounds in epilepsy, leveraging existing knowledge and existing compounds makes a great deal of sense, especially when a rapid 505(b)(2) regulatory path can be followed.

For example, Upsher-Smith is developing an intranasal formulation of midazolam, a short acting benzodiazepine, for the treatment of cluster seizures. Similarly, Alkermes was developing an intranasal formulation of lorazepam for the treatment of status epilepticus and acute repetitive seizures. This program is currently Inactive.

Lastly, Jazz Pharmaceuticals was developing an intranasal formulation of clonazepam, also for acute repetitive seizures. This program also appears to be inactive. It is unknown to us why the latter two programs are inactive.

Mind The Gap

Gap Junctions are channels which form between cells for cell-cell communication. These channels are used to exchange a variety of ions and small molecules, especially calcium. In many diseases, including epilepsy, it is believed or known that the propagation of a negative cellular message, such as hyperactivity, is propagated via gap junctions.

Can blockade of gap junctions in the brain prevent epileptic seizures?

Budapest-based Vichem is exploring this very concept. VID-45110 is in Preclinical testing for both the treatment and prevention of epilepsy. The precise mechanism of action is not known, but it is believed to act by blocking the proteins (“connexins”) which come together to form gap junctions.

Where Are We Going?

Overall, the epilepsy pipeline appears to be limited, especially in terms of mechanism of action. There remain a disproportionate number of compounds chasing the same mechanisms of action, especially GABA A agonists/antagonists, reformulated benzodiazepines, and ion channel blockers (not discussed here).

What about non-pharmacologic approaches to the treatment of epilepsy, such as cell or gene therapy, or the use of electrodes into the brain? We’ll take a look at those approaches in our next article.

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