Repurposing Approved Drugs Riluzole, Rotigotine, and Levetiracetam for Potential Treatment of Alzheimer Disease 

During a symposium at the Clinical Trials in Alzheimer Disease Conference, held in Boston, MA November 9-12, repurposing of 3 previously approved drugs for possible treatment of Alzheimer disease (AD) was discussed. The drugs being studied have been approved for treatment of amyotrophic lateral sclerosis (ALS), Parkinson disease (PD), and epilepsy. 

Riluzole, approved for treatment of ALS showed signs of improving cognitive measures in preclinical trials, leading to an exploratory clinical trial in people with AD funded by the Alzheimer's Drug Discovery Foundation (ADDF). In this trial people with AD treated with riluzole had less decline in cerebral glucose metabolism compared with those who received placebo. Cerebral glucose metabolism is known to be a biomarker for AD and a predictor of AD progression. A positive correlation with cognitive measures and riluzole treatment was also observed. Additional clinical trials are being planned.

Rotigotine is a dopaminergic agonist approved for treatment of PD. In phase 1 studies dopaminergic agonists have been shown to improve cognitive functions including memory, learning, attention, and decision making. Treatment with rotigotine in a phase 1b trial restored long-term potentiation (LTP), improved frontal lobe function, and reduced functional decline relative to placebo. 

A phase 3 trial of rotigotine with 4 treatment arms is now planned and funded by ADDF. This trial will compare the cholinesterase inhibitor rivastigmine alone and with rotigotine as well as rotigotine alone compared with placebo. The rationale for this approach is to evaluate the combined dopaminergic-cholinergic effects of rotigotine and rivastigmine to see if they may be additive or even synergistic. In addition, the approach allows for development of a unique drug that could be more easily commercialized. 

Finally, the potential use for treatment of AD with low-dose levetiracetam, a drug approved and widely used for treatment of epilepsy, was discussed. The proposed mechanism of action for levetiracetam in AD is through effects on hippocampal overactivity, which is pronounced in people with mild cognitive impairment (MCI) and amyloid pathology (ie, MCI due to AD). 
The investigators of low-dose levetiracetam developed a unique formulation of low-dose extended-release formulation of levetiracetam to provide a consistent concentration of the drug, again improving commercialization potential. A phase 3 trial, approved by the Food and Drug Administration (FDA) is fully enrolled and ongoing. 

Howard Fillit, MD, founding executive director and chief science officer noted, "Commercialization is critically important because if there is no commercial pathway, people are essentially unable to access the treatment. This is, in part, because without an indication from the FDA, no marketing can be done, making widespread dissemination of information about the new indication challenging. Additionally, without an indication, clinicians are put in a position of prescribing off-label, which has become much more difficult to do in the days of Medicare Part D and prior authorization."

Panelists discussed the advantages of repurposing drugs, including that the safety profile and pharmacokinetics are known and accepted and trials for those parameters are not required. However, because the return on investment for repurposed drugs is not as high as for new drugs, it can be difficult to interest companies in funding clinical trials for repurposing drugs. As a result, nonprofit and governmental funding is often needed.