The Parkinson disease agent showed a safe and tolerable profile, with significantly greater improvements in MDS-UPDRS-III scores and OFF time per day.
In a phase 2b randomized, placebo-controlled study (NCT03703570), KW-6356, a selective antagonist of adenosine A2A receptors developed by Kyowa Hakko Kirin, demonstrated a favorable efficacy and safety profile as an adjunct treatment to levodopa in patients with Parkinson disease (PD). Presented at the 2022 International Parkinson and Movement Disorders Society (MDS) Congress, September 15-18, in Madrid, Spain, the findings support further development of the agent as a new antiparkinsonian treatment.1
After a 2-week single-blind placebo run-in period, 503 enrolled patients with PD were randomly assigned to treatment with either once-daily oral placebo (n = 168), or KW-6356 3 mg (n = 168) or 6 mg (n = 167), and were treated for 24 weeks. While the efficacy and safety of KW-6356 as a monotherapy had been previously demonstrated in a phase 2a study (NCT02939391), this trial, which spanned across 66 sites in Japan, was the first to evaluate the agent in patients with PD as an adjunct therapy.
Senior investigator Nobutaka Hattori, MD, PhD, FAAN, dean, Faculty of Medicine and Graduate School of Medicine, Juntendo University, and colleagues evaluated patients on change from baseline in the MDS-Unified Parkinson’s Disease Rating Scale (UPDRS)-III total score during the ON state as the primary end point. Change in mean OFF time per day, MDS-UPDRS subitem scores, Parkinson’s Disease Sleep Scale-2 (PDSS-2) and Epworth Sleepiness Scale (ESS) all served as secondary end points.
At week 26, patients in the KW-6356 3-mg and 6-mg groups demonstrated least square (LS) mean changes in MDS-UPDRS-III total score of –7.8 (95% CI, –9.0 to –6.5) and –7.0 (95% CI, –8.3 to –5.8), respectively, compared with changes of –5.2 (95% CI, –6.5 to –3.9) for those on placebo. Change from baseline in OFF time per day also favored KW-6356, with patients in the 3-mg and 6-mg groups demonstrating LS mean changes of –0.89 (95% CI, –1.37 to –0.42) and –0.65 (95% CI, –1.12 to –0.18) hour, respectively, compared with changes of –0.05 (95% CI, –0.53 to 0.42) in the placebo group.
The agent was found to be safe as well, with 67.3% and 58.1% of patients in each dosed group experiencing at least 1 treatment-emergent adverse event (TEAE) vs 55.7% of those on placebo. Notably, no deaths occurred during the study. Drug related TEAEs occurred in 7.2%, 20.8%, and 16.8% of the placebo, 3-mg, and 6-mg KW-6356 groups, respectively. The most common TEAE reported was nasopharyngitis, which was found in 7.8% of patients on placebo, 7.7% of those in the 3-mg group, and 4.2% of those in the 6-mg group. There were no clinically meaningful changes in vital signs, body weight, laboratory results, or ECGs.
The LS mean changes from baseline in PDSS-2 total score at week 26 were 0.9 for the 3-mg group and 1.1 for those on placebo; however, investigators did observe a LS mean change of –0.6 for the 6-mg group, which was statistically significant (P = .018 vs placebo). For individuals with sleep problems at baseline, the LS mean changes in PDSS-2 total score at week 26 were –1.3, –0.1, and –3.5 in the placebo, 3-mg, and 6-mg groups, respectively, stratified by PDSS-2, and 1.4, 1.6, and –2.7, when stratified by ESS. The difference between placebo and the KW-6356 6-mg group were statistically significant when stratified by ESS (P = .013 vs placebo).
In 2018, Kyowa Hakko Kirin released results from its phase 2a trial evaluating KW-6356 as a monotherapy. All told, investigators reported changes in MDS-UPDRS-III scores of –4.76 (95% CI, –6.55 to –2.96) in the high-dose KW-6356 group, –5.37 (95% CI, –7.25 to –3.48), and –3.14 (95% CI, –4.97 to –1.30) in the placebo group, with both KW-6356 groups showing a greater reduction in score compared with those on placebo. Additionally, no safety issues were observed in any of the groups.2