Dr Eric BastingsEric Bastings, MD
The FDA has given the go-ahead to Kyowa Kirin for its istradefylline (Nourianz) tablets as an add-on therapy to levodopa/carbidopa in adults with Parkinson disease who are experiencing off episodes.1

Ultimately, the selective adenosine A 2A receptor antagonist’s approval was based on its success in 4 clinical studies which lasted 12 weeks and included more than 1100 participants in which statistically significant decreases from baseline in daily off time compared to placebo were observed.

The treatment was previously put before the FDA a decade ago, though Kyowa Kirin (then known as Kyowa Hakko Kogyo) received a not approvable letter in February 2008 for its submission, with the agency requesting additional clinical follow-up data as well as an overall summary of nonclinical mineralization findings.2 It has been approved for use in Japan as Nouriast since May 2013.

"Parkinson disease is a debilitating condition that profoundly impacts patients' lives," said Eric Bastings, MD, acting director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research, in a statement. "We are committed to helping make additional treatments for Parkinson disease available to patients."

This new submission to the FDA was supported in part by data including a phase 3 randomized, multicenter, placebo-controlled, double-blind study in patients with Parkinson disease who were taking a consistent dose of levodopa/carbidopa in combination with or without additional medications for their disease. The trial, announced in 2013, was developed under a Special Protocol Assessment (SPA) agreement with the FDA (NCT01968031).3

In 2016, the 12-week trial results showed a trend toward a greater decrease in daily off-time compared with placebo for both the 20-mg and 40-mg doses. Although, there was no statistically significant difference in the primary outcome measure—change from baseline in daily off-time—at week 12 compared with the placebo group. With regard to safety, istradefylline was deemed well-tolerated at both doses.4

In October 2018, data from an interim analysis of a post-marketing surveillance study conducted in Japan, which included 476 patients, showed that the drug was rated as effective in 61.3% of patients, as determined by physician’s global assessment, and the Unified PD Rating Scale (UPDRS) Part III score decreased from 33.7 to 30.3 from baseline. The treatment was again shown to  be generally well-tolerated, although dyskinesia and hallucinations were reported as the most common adverse drug reactions.5

As for efficacy, ultimately, off time was reduced in 38.2% of patients and off-time symptoms were reported as improved or markedly improved in 44.7% of patients. Additionally, motor dysfunction was improved or markedly improved in 48.5% of patients.  

In a 2008 study of the therapy which included 196 patients, the decrease of daily awake off time for istradefylline was a mean of −10.8 ±16.6% (95% CI, -13.46 to -7.52) from baseline, compared with -4.0 ±15.7% (95% CI, -7.73 to 0.31; P = .007) for placebo. The investigators noted that the treatment effect “corresponded to changes from baseline in total daily awake off time,” which were -1.8 ± 2.8 hours in the treatment group and -0.6 ± 2.7 hours for placebo (P = .005). Treatment‐emergent adverse events with istradefylline were considered mild in that trial.6

At the time of its NDA acceptance by the FDA in April 2019, Jeffrey S. Humphrey, MD, president and chief medical officer, Kyowa Kirin Pharmaceutical Development, said in a statement that the company was “excited by the possibility of bringing a new medicine to people living with Parkinson disease” and that there is a “significant need for new treatments.”
REFERENCES
1. FDA approves new add-on drug to treat off episodes in adults with Parkinson’s disease [press release]. White Oak, MD: FDA; Published August 27, 2019. fda.gov/news-events/press-announcements/fda-approves-new-add-drug-treat-episodes-adults-parkinsons-disease. Accessed August 27, 2019.
2. Kyowa Hakko Receives Not Approvable Letter from FDA for Istradefylline (KW-6002) [press release]. New Jersey, US: Kyowa Hakko Kogyo; Published February 28, 2008. kyowa-kirin.com/news_releases/kyowa/2008/er080228_01.html. Accessed August 27, 2019.
3. Kyowa Hakko Kirin Initiates a Global Phase 3 Trial of Istradefylline (KW-6002) for Parkinson's Disease [press release]. Tokyo, Japan: Kyowa Hakko Kirin Co; Published November 21, 2013. kyowa-kirin.com/news_releases/2013/e20131121_01.html. Accessed August 27, 2019. 4. Kyowa Hakko Kirin Announces Top-Line Results of Global Phase 3 Trial of
KW-6002 (Istradefylline) for Parkinson's Disease [press release]. Tokyo, Japan: Kyowa Hakko Kirin Co; Published December 13, 2016. kyowa-kirin.com/news_releases/2016/pdf/e20161213_01.pdf. Accessed August 27, 2019.
5. Takahashi M, Fujita M, Asai N, Saki M, Mori A. Safety and effectiveness of istradefylline in patients with Parkinson's disease: interim analysis of a post-marketing surveillance study in Japan. Expert Opin Pharmacother. 2018;19(15):1635-1642. doi: 10.1080/14656566.2018.1518433.
6. LeWitt PA, Guttman M, Tetrud JW, et al. Adenosine A2A receptor antagonist istradefylline (KW‐6002) reduces “off” time in Parkinson's disease: A double‐blind, randomized, multicenter clinical trial. Ann Neurol. 2008;63(3):295-302. doi: 10.1002/ana.21315.