Rationale:
Levetiracetam (LEV) has been a blockbuster drug and drew attention to a unique mechanism of action. The history of antiseizure medication (ASM) discovery provides lessons for new drug development.
Methods:
We reviewed literature and conducted interviews with the investigators involved.
Results:
Piracetam was synthesized in 1964 by Giurgea in a project attempting to develop GABA analogues for use in sleep induction. Piracetam did not successfully affect GABA or sleep but showed possible cognitive benefits in rodents. While it was used in countries outside the USA for cognition and myoclonus (first noted by Terwinghe in 1978), the weight of scientific evidence since has cast doubt on cognitive benefits in humans.
UCB became interested in further exploring this family of drugs as nootropics. Etiracetam was synthesized in 1966 and LEV (the S enantiomer) in 1977. LEV was studied as a cognitive enhancer but was ineffective. As a matter of routine, the new drug was screened in ASM models, primarily intended to exclude adverse proconvulsant effects. Gower noted that while LEV was only weakly effective in the more common maximal electric shock (MES) and pentylenetetrazole (PTZ) models, it was surprisingly effective as an anticonvulsant in an audiogenic mouse model. Gower consulted with Löscher who discovered that LEV was effective in blocking seizures induced by electrical kindling.
These discoveries and Gower’s subsequent finding of efficacy in an absence seizure model justified the clinical studies that would demonstrate the effectiveness of LEV leading to eventual FDA approval in 1999.
It was only as clinical trials were being conducted that the mechanisms of antiseizure action were understood. Noyer discovered a brain specific binding site and Klitgaard showed this was important to the anticonvulsant effect. Synaptic vesicle protein 2A was identified in 2005.
The success of LEV led to major investment in attempts to build a drug with higher affinity and selectivity. Seletracetam and brivaracetam (BRV) were both synthesized and BRV was chosen as more promising for clinical development based on effectiveness in MES and PTX models as well as the audiogenic mouse model. BRV is more selective and much more potent than LEV and its higher lipophilicity improved blood brain barrier permeability. Clinical trials have shown BRV is also an effective ASM. Whether these differences lead to clinical superiority remains unclear, but there is some data that BRV has less psychiatric adverse effects presumably from its selectivity.
Conclusions:
LEV would not have been discovered if only standard screening models were used. New screening methods may help identify new ASMs.
New mechanisms of action may be potential avenues for improved efficacy.
Analogs of existing or potential ASMs should be further explored, as they can show substantial improvements.
Funding: None