Investigational small molecules in phase II clinical trials for the treatment of epilepsy

ABSTRACT

Introduction: Epilepsy is a neurological disorder that significantly impacts the quality of life of affected persons. Despite advances in research, nearly a third of patients have refractory or pharmacoresistant epilepsy. Even though numerous antiepileptic drugs (AEDs) have been approved over the past decade, there are no agents that halt the development of epilepsy. Thus, new and improved AEDs to prevent these conditions are necessary.

Areas covered: We highlight recent advances in new and innovative drugs for epilepsy disorders. We review three small molecule drugs in phase II clinical trials: Cannabidivarin, BGG492 (Selurampanel) and Ganaloxone.

Expert opinion: The full potential of Cannabidivarin will be realized by testing in other types of treatment-resistant seizures; if they are beneficial, larger phase III clinical trials would probably be undertaken in the same patient population. About BGG492, the challenge will be to find ‘superselective’ AMPAR antagonists targeting only calcium-permeable receptors, with specific mechanisms, that may be attractive partners for drugs in polytherapy. Moreover, there is anew interest surrounding Ganaloxone because of a new submicron formulation that improves its absorption and pharmacokinetic profile, but new studies are necessary before progressing. Further clinical innovations will define the future for these small molecule-type drugs in epilepsy therapeutics.

KEYWORDS:

• Epilepsy
• antiepileptic drugs
• AED
• seizures
• selurampanel
• cannabidivarin
• ganaxolone

Article Highlights

• Despite availability of several antiepileptic drugs (AEDs), one-third of patients still have the intolerable condition; they are inadequately treated with AEDs and this is linked to a relatively high mortality

• Small molecules are synthetic chemicals with a low molecular weight (<900 Da) and a size on the order of a nanometer. These organic compounds constitute the majority of current drugs in the market

• Results of preclinical investigations favored cannabidivarin as an efficient anticonvulsant, which has now entered clinical trials. The ultimate objective should be investigation of full antiepileptic potential of all investigational cannabinoids

• There are encouraging preclinical data from animal seizure models; BGG492 and other alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) may be broad-spectrum agents with usefulness beyond focal seizures

• Ganaxolone is the only neurosteroid that is effective and well tolerated for the treatment of refractory generalized or focal epilepsy both in adults and in children. Treatment with exogenously administered natural neurosteroids or synthetic analogs such as ganaxolone may be beneficial to treat partial seizures

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.