FDA Accepts Updated NDA for Parkinson Disease Off Episodes Treatment

Jeffrey S. Humphrey, MD, president and chief medical officer of Kyowa Kirin Pharmaceutical Development

Jeffrey S. Humphrey, MD

The FDA has accepted a new drug application (NDA) resubmission for istradefylline (KQ-6002, Kyowa Kirin) as an adjunctive treatment to levodopa/carbidopa for adults with Parkinson disease during off episodes.¹

According to the company, the investigational selective adenosine A 2A receptor antagonist has had its prescription drug user fee act (PDUFA) action date has been set for August 27, 2019.

“People living with Parkinson disease have difficulty moving that often worsens during 'off' periods, and there is a significant need for new treatments,” said Jeffrey S. Humphrey, MD, president and chief medical officer of Kyowa Kirin Pharmaceutical Development, in a statement. “We are excited by the possibility of bringing a new medicine to people living with Parkinson's Disease and look forward to working closely with FDA during the review process.”

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.

“Istradefylline, is an A2A receptor antagonist, and if approved by FDA, may provide a novel non-dopaminergic pharmacologic approach to treating off episodes for people living with [Parkinson],” said Stuart Isaacson, MD, from the Parkinson’s Disease and Movement Disorders Center of Boca Raton, Florida, in a statement.

This new submission is supported by data from 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

The top-line findings of that trial were not representative of success. In 2016, the 12-week trial results did show a trend toward a greater decrease in daily off-time compared with placebo for the 20-mg and 40-mg doses, but no statistically significant difference in the primary outcome measure—change from baseline in daily off-time—at week 12 was noted compared with the placebo group. With regard to safety, istradefylline was well tolerated at both doses.⁴

At the time, Yoichi Sato, managing executive officer, vice president, and head of Research and Development Division had stated that the trial’s results were “not what we expected.”

“We need to fully understand the study results and will present further findings including those from the secondary outcome measures at upcoming scientific congresses and/or in scientific journals,” he added.

However, last October, 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 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

REFERENCES

1. Kyowa Kirin Announces FDA Acceptance of Istradefylline (KW-6002) New Drug Application Resubmission in the US [press release]. Tokyo, Japan: Kyowa Hakko Kirin Co; Published April 4, 2019. businesswire.com/news/home/20190404005252/en. Accessed April 4, 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 April 4, 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 April 4, 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 April 4, 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.

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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.

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