Amantadine and phenytoin: patent protected cases of drug repositioning

Author(s): Jan M. Keppel Hesselink

Repositioning of old drugs in new indications is a hot topic. However, there are some hurdles to take, and one is related to financial attractiveness. We will discuss two examples to solve this problem based on patents: phenytoin cream for neuropathic pain and amantadine extended release for dyskinesia and other neurological disorders, and discuss amantadine, its history of repositioning and its patents in more detail. Both molecules are respectable old compounds, phenytoin was synthesized more than a century ago, and amantadine in the 50s of last century. Amantadine was first recognized as an antiviral compound in the 60s of last century, and was approved by the FDA for flu prophylaxes in 1966. Parkinson was its first repositioning indication, triggered by a case study in 1968. Subsequently a great variety of indications were explored, from fatigue in multiple sclerosis, enuresis nocturna, ADHD, up to pathological gambling and recovery after head injury. Amantadine is currently developed as an extended release formulation for levodopa-induced dyskinesia in Parkinson’s disease (preapproval phase). It is protected by a patent from 2009, claiming a special formulation and time of intake. While its antiviral mechanism of action has been clarified, the mechanisms of action in other indications are still quite enigmatic. At the end of last century, it was stipulated that amantadine and comparable drugs with unexplained mechanisms may deserve additional studies to enfold its full therapeutic potential. Based on an analysis of the clinical perspectives for amantadine at that time it was felt necessary to developing an infrastructure for funding research on new purposes for older drugs after they lose patent protection. Nearly 2 decades later such recommendation still remains valid.