Better Safety Profile Observed With Istradefylline Over Amantadine Extended-Release and COMT Inhibitors

Author(s):

Although the data used predated 2019, istradefylline was associated with a statistically significant lower odds of the overall incidence of treatment-emergent adverse events than other adjunctive therapies for Parkinson disease.

Fernando Pagan, MD

In a systematic literature review (SLR) and meta-analysis of randomized controlled trials (RCTs) assessing adjunctive therapies for Parkinson disease (PD), findings showed that istradefylline (Nourianz; Kyowa Kirin) was associated with a more generally favorable safety profile than other medications, including extended-release amantadine and catechol-O-methyltransferase (COMT) inhibitors. The study was limited by the fact that it was conducted in 2019, and this, there are more recent data that were not captured.

Led by Fernando Pagan, MD, director of the Movement Disorders Program and medical director of the MedStar Georgetown National Parkinson Foundation Center of Excellence, the SLR identified 1013 articles, of which 21 articles reporting on 20 unique RCTs were deemed eligible for inclusion. Of these studies, conducted from 2010 to 2019, 18 publications reporting on 17 unique RCRs were included in the meta-analysis. Currently, there is an ongoing network meta-analysis that will look to update these results using more robust methodology.

Presented at the 3rd Annual Therapeutics in Movement and Related Disorders (ATMRD) Congress, held by the PMD Alliance from June 22-25, 2024, the odds ratios (ORs) for treatment-emergent adverse events (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.

Against dopamine agonists (DAs), istradefylline showed slightly better ORs for both the 40 mg (1.22; 95% CI, 0.96-1.56) and 20 mg (1.20; 95% CI, 0.93-1.56) doses. In comparison with monoamine oxidase B (MAO-B) inhibitors, the therapy showed relatively similar rates of TEAEs (40 mg OR, 0.99 [95% CI, 0.76-1.30]; 20 mg OR, 0.98 [95% CI, 0.74-1.28]).

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 DAs 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.

At 20 mg, the odds of dyskinesia were significantly lower for istradefylline vs COMT inhibitors (1.52; 95% CI, 1.09-2.13) and DAs (1.61; 95% CI, 1.16-2.22). In comparison with istradefylline, amantadine ER had significantly increased odds of hallucinations (4.76; 95% CI, 1.64-14.29), and insomnia (8.33; 95% CI, 1.06-50.00), and withdrawals because of TEAEs (OR, 2.86; 95% CI, 1.18-6.67).

Approved in the US in August 2019, istradefylline was the first adenosine receptor antagonist labeled for use in PD. How the pathogenesis of PD is released to increased expression of these receptors in the striatum or SN is unknown. It is thought that antagonism of these receptors regulates GABAergic neurotransmission in the basal ganglia rather than affecting the dopaminergic system.

Istradefylline, administered as a once-daily tablet, was approved based on results from 4 randomized, double-blind, placebo-controlled trials. The studies, which included more than 1100 participants with PD, showed that the therapy was able to reduce daily awake “OFF” time, the primary end point, by approximately 1 to 2 hours. However, some placebo-controlled trials have failed to show efficacy of istradefylline in PD, including a phase 3 trial examining the agent as adjunctive therapy to levodopa/carbidopa in patients with PD with motor-response complications to reduce OFF time, as well as a trial that studied istradefylline as a monotherapy for improving motor symptoms in early PD. Notably, the FDA initially denied approval of istradefylline in 2008 owing to the relatively modest clinical benefit shown in trials involving the entire PD population.²

REFERENCES
1. 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.
2. Cummins L, Cates ME. Istradefylline: a novel agent in the treatment of “off” episodes associated with levodopa/carbidopa use in Parkinson disease. Ment Health Clin. 2022;12(1):32-36. doi:10.9740/mhc.2022.01.032