Istradefylline Shows Promising Effects as Treatment for Tremor in Parkinson Disease

Interim data from a 6-month, open-label, single arm exploratory pilot study showed that istradefylline (Nourianz; Kyowa Kirin), an FDA-approved adjunctive treatment for OFF episodes in Parkinson disease (PD), may have positive benefits on treating tremor in this patient population. Additional findings and final analysis will be incoming for all patients who completed the study, including tremor amplitude scores utilizing the MindSquare app.¹

Presented at the 3rd Annual Therapeutics in Movement and Related Disorders (ATMRD) Congress, held by the PMD Alliance from June 22-25, 2024, 27 patients with tremor-dominant PD with levodopa resistant tremor were included in the trial. Each patient underwent 20 mg of daily istradefylline, followed by dose increase to 40 mg daily, for a total of 6 months. At the time of abstract submission, 2 participants withdrew from the study, resulting in 10 participants with available data to be analyzed.

Led by Fernando Pagan, MD, director of the Movement Disorders Program and medical director of the MedStar Georgetown National Parkinson Foundation Center of Excellence, treatment with istradefylline led to a mean reduction of 0.74 points on the tremor subcomponent of the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III from baseline to 8 weeks. These effects were sustained, as demonstrated by a 0.76-point difference between week 24 and baseline (P <10-6).

The therapy showed pronounced effects on motor symptoms as well, with treated patients showing an average decrease of 25.6 points on MDS-UPDRS Part III at week 8 (P <.02). At week 24, scores decreased by an average of 23.7 points (P <.001). On MDS-UPDRS Part IV, scores decreased between baseline and 24 weeks by an average of 4.5 points (P <.04).

Tremor amplitude data was measured through the MindSquare mobile application at baseline, 4, 8, and 24 weeks. Measurements were collected for both left and right arms in 3 different positions: at rest, arms extended, and in the wing beating position. Because of errors in data collection, data from 5 participants was unusable. In addition, because of the high variation in data among the remaining 5 participants, more in-detailed analysis is currently underway as all patients complete the study.

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Istradefylline, a selective adenosine A 2A receptor antagonist, resulted in no significant change on UPDRS Parts I and II, Montreal Cognitive Assessment, Geriatric depression scale, EQ5D, and RightEye Dynamic Testing. The therapy, approved as an add-on medication to levodopa/carbidopa in adults with PD experiencing OFF episodes, has been on market in the US since 2019 and available in Japan since 2013. Investigators of the study concluded that future direction will include a larger-scale, double-blind, randomized, placebo-controlled trial.

Pagan and colleagues presented an additional systematic literature review and meta-analysis at ATMRD 2024 assessing the safety of istradefylline in comparison with other adjunctive PD medications. Using 20 unique randomized controlled trials, istradefylline resulted in lower overall incidence of treatment-emergent adverse events (TEAEs) in comparison with extended-release amantadine and catechol-O-methyltransferase (COMT) inhibitors.²

All told, the odds ratios (ORs) for TEAEs for istradefylline vs COMT inhibitors was 1.33 (95% CI, 1.03-1.75) at 40 mg doses and 1.32 (95% CI, 1.01-1.72) for 20 mg doses. In comparison with amantadine ER, the 40 and 20 mg doses showed ORs of 3.45 (95% CI, 1.85-6.25) and 3.33 (95% CI, 1.82-6.25), respectively. At 40 mg, istradefylline demonstrated significantly lower odds of dyskinesia (1.30; 95% CI, 1.01-1.69) and somnolence (2.50; 95% CI, 1.28-5.00) compared with dopamine agonists and lowered odds of hypotension (8.33; 95% CI, 1.67-50.00) compared with MAO-B inhibitors. Using the same dosage, the therapy demonstrated significantly lower odds of somnolence (3.33; 95% CI, 1.49-7.69) vs COMT inhibitors and hallucination (3.57; 95% CI, 1.30-10.00) and orthostatic hypotension (12.50; 95% CI, 1.33-100.00) vs amantadine ER.

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REFERENCES
1. Ozay G, Zhang I, Umali M, et al. Interim analysis of istradefylline effects on tremor in Parkinson’s disease patients-promising benefits on tremor control. Presented at ATMRD Congress; June 22-25, 2024; Washington, DC.
2. Torres-Yaghi Y, Qian J, Cummings H, et al. Comparative safety of istradefylline among Parkinson’s disease adjunctive therapies: a systematic review and meta-analysis of randomized controlled studies. Presented at: ATMRD Congress; June 22-25, 2024; Washington, DC.