RELEVANCE OF ISTRADEFYLLINE
Istradefylline (Nourianz) is an add-on medication to treat off episodes in Parkinson’s disease.
The oral therapy, developed and marketed by Kyowa Hakko Kirin Pharma, is approved by the U.S. Food and Drugs Administration (FDA) to treat Parkinson’s patients who are on a carbidopa/levodopa treatment regimen.
Istradefylline is the first selective adenosine A2A receptor antagonist which has recently been approved in Japan for Parkinson’s disease therapy. Its launch followed a journey through drug development over a period of more than 20 years. Initially, istradefylline was shown to be a highly selective antagonist for adenosine A2A receptors and to have a highly localised site of action linked to the indirect output pathway from the striatum. Subsequently, it was found to be effective at reversing motor impairments in rodent and primate models of Parkinson’s disease without provoking dyskinesia in primates. In clinical trials, istradefylline (as an adjunct to L-DOPA therapy) decreased ‘OFF’ time without increasing troublesome dyskinesia. The latter findings were the basis for its registration as a treatment for ‘wearing off’ in Parkinson’s disease. However, this sequence of apparently logical events was interrupted by many challenges that had to be overcome—the topic of a still unfolding story. At this time, the development of istradefylline in Parkinson’s disease is still incomplete and under further clinical investigation. Recently, the drug has shown effectiveness in experimental models of non-motor features of Parkinson’s disease. The latter findings and further experience from the clinical use of istradefylline in Parkinson’s disease will provide future scope for the development of A2A antagonists in treating human disorders.
How Nourianz works
Parkinson’s is a neurodegenerative disease marked by a loss of mobility and coordination, among other symptoms. The disease results from progressive damage to nerve cells in the brain, although its exact cause is not known. The loss of these neurons leads to lower quantities of important neurotransmitters (molecules that signal between brain cells) being produced. Dopamine, in particular, is found in low levels in Parkinson’s patients, and this decrease is thought to be partly responsible for the disease’s motor symptoms.
A mainstay Parkinson’s treatment is a combination of carbidopa/levodopa. Levodopa can be metabolized in the brain to form dopamine, while carbidopa inhibits the enzyme that breaks down dopamine. The combination increases dopamine levels in the brain. But many patients, particularly as their disease progresses, experience off episodes — times between medication doses in which symptoms return as dopamine levels drop.
The active ingredient in Nourianz, istradefylline, is a small molecule that binds to a receptor called the adenosine A2A receptor on brain cells. By binding to this receptor and blocking it, istradefylline increases the release of a neurotransmitter called gamma amino-butyric acid (GABA), which is involved in nerve signaling that controls movement.
By increasing the amount of GABA produced by the brain, istradefylline works to ease off episodes in people using carbidopa/levodopa.
Nourianz in clinical trials
FDA approval of Nourianz was based on data from four 12-week, placebo-controlled Phase 2 and Phase 3 clinical trials (NCT00955526, NCT00455507, NCT01968031, and NCT00250393). The trials assessed the safety and effectiveness of two doses of istradefylline (20 mg and 40 mg) in reducing the hours each day spent in the off-state. Motor symptoms were also evaluated.
The four trials enrolled a total 1,143 patients already being treated with levodopa/carbidopa, levodopa/benserazide, or levodopa and any other medication that inhibits the breakdown of dopamine. Results showed that the addition of istradefylline significantly lessened the duration of off-episodes during the day compared to patients given a placebo.
In one of the Phase 3 trials (NCT01968031), which evaluated the efficacy of Nourianz administered orally as a 20 mg or 40 mg once-daily treatment for 12 weeks in addition to a levodopa regimen, the difference in daily off time did not reach statistical significance against placebo, although a trend was shown.
An interim analysis of 476 patients treated in Japan demonstrated that istradefylline was effective in increasing muscle function in 61.3% of study participants as assessed by the Unified Parkinson’s Disease Rating Scale (UPDRS) Part 3 (motor assessment) scores. Daily off-episode times were reduced in 38.2% of patients, and off-episode symptoms eased in 44.7% of patients.
Other information
The most common side effects of Nourianz include involuntary muscle movement (dyskinesia), dizziness, constipation, nausea, hallucinations, and insomnia. The FDA recommends that patients prescribed Nourianz be monitored for dyskinesia, a side effect reported to cause 1% of treated patients in the trials to stop its use.
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