Istradefylline Further Down But Still Not Quite Out In Parkinson’s?
Executive Summary
Despite the long and troubled history of the molecule, Kyowa Hakko Kirin has persisted with the development of istradefylline for Parkinson's disease, but a new Phase III failure might be the last straw for the A2a antagonist.
Japan's Kyowa Hakko Kirin Co. Ltd. announced the start of an additional international Phase III program for its first-in-class oral adenosine A2a receptor antagonist istradefylline just over three years ago, with an eye on trying again for a long-sought US approval for use in Parkinson's disease.
Fast forward to the present and disappointing new top-line results from the placebo-controlled trial might prove to be the final nail in the coffin of the drug in this indication, at least outside Japan, although its developer appears not to have completely given up yet.
Supported by positive local trials, istradefylline was launched in Japan as Nouriast in May 2013, for the improvement of wearing off in Parkinson's patients receiving concomitant levodopa-containing therapies. The product has so far not been launched in any other market, and does not appear to be in development outside the newly reported trial.
Missed Endpoint
The new top line results come from the eight-country Phase III study, conducted in around 600 patients with moderate to severe disease and wearing off symptoms on current therapy comprising levodopa plus either another dopamine agonist, MAO-B inhibitor or COMT inhibitor.
The trial design was agreed with the US FDA under a Special Protocol Assessment, with a primary endpoint of change from baseline in number of waking hours in the "off" state (period of decreased mobility) per day at week 12.
In patients given 20mg or 40mg istradefylline once daily for 12 weeks, while there was a trend towards greater reduction in daily awake off time compared with placebo throughout the evaluation period, there was no statistically significant difference in this primary outcome versus placebo.
The findings "are not what we expected," Kyowa Hakko Kirin’s R&D head Dr. Yoichi Sato said in a statement. "We need to fully understand the study results".
Drug treatment was well tolerated, however, and the company said it would release further detailed data - including on secondary outcome measures - at upcoming scientific congresses and/or in scientific journals.
Following the release of the findings, Kyowa Hakko Kirin’s shares closed down around 2% in morning trading in Tokyo on Dec. 14.
String Of Challenges
Kyowa Hakko Kirin originally made a US approval filing for istradefylline in Parkinson's back in April 2007, as an adjunctive therapy to levodopa/carbidopa for the improvement of motor function in patients with motor response complications.
However, this resulted in a non-approvable decision as only one of the supporting Phase III trials met its primary efficacy endpoint of reduction in waking off time.
A 2010 licensing deal with Biovail Laboratories International SRL (subsequently acquired by Valeant Pharmaceuticals International Inc.) for North American commercialization rights was terminated in 2011.
Despite these setbacks and the latest results, the Japanese firm still does not appear to have given up completely on its drug, Sato stating that it would "pursue a chance to work with FDA and discuss potential for successful submission."
A look at the study design shows a range of secondary outcome measures including total hours of "on" time per day without troublesome dyskinesia, sleep time, cognitive assessment, and motor function, activities of daily living and behavior scores. Positive results here may theoretically open the way to some form of use against specific symptoms.
Troubled Class
Adenosine A2a receptors, a form of G protein-coupled receptor, are found in the brain and particularly in the basal ganglia, a region of motor control where degeneration and abnormalities are typically found in Parkinson's patients.
While a number of other companies are conducting early stage work in the A2a antagonist area, the only other same-class drug to have entered Phase III trials for Parkinson's is Acorda Therapeutics Inc.'s (previously Biotie Therapies Corp.'s) tozadenant.
Previous notable Phase III A2a antagonist failures in Parkinson's include Merck & Co. Inc.'s preladenent back in 2013. (Also see "Merck hit with Phase III failure for Parkinson's drug" - Scrip, 24 May, 2013.)
From the editors of PharmAsia News.