Objective: Our primary objective was to test the novel adenosine A_2A/A₁ receptor antagonist IDAA-338 in alleviating Parkinsonian symptoms when given as a mono or as a combination with L-DOPA to MPTP-lesioned macaques. Our secondary objective was to investigate IDAA-338’s efficacy in improving cognitive deficits in chronic low dose (CLD) MPTP-treated macaques.

Background: Long-term use of dopaminergic drugs prescribed to Parkinson’s disease (PD) patients are known to cause levodopa-induced dyskinesia (LID). PD also results in cognitive impairment. IDAA-338 is a first-in-class dual A2A/A1 receptor antagonist that was shown to display excellent metabolic and safety profile. This led us to further test the efficacy using MPTP-lesioned macaque model of PD. Plus, we used cognitively impaired macaques to test the efficacy in cognitive improvement.

Method: The Parkinsonism study was conducted in female macaques (n=8) which had been previously treated with L-DOPA such that motor complications, including LID, had been established. This study assessed the effects of acute administration of IDAA-338 as monotherapy or in combination with a low dose of L-DOPA for a period of 6 h. The cognitive fuction of the study was conducted in male macaques (n=4). Three doses of IDAA-338 were assessed (3, 10, and 30mg/kg) following 7 days of pre-dosing and daily dosing for 2 weeks.

Results: IDAA-338 provided a modest alleviation of parkinsonian disability as monotherapy with the absence of dyskinesia and enhanced the anti-parkinsonian benefit of low-dose L-DOPA in combination. IDAA-338 at doses 10 and 30mg/kg given in combination with a low dose of L-DOPA, produced a significant enhancement of ‘good’ on-time [figure1], while the enhancement triggered by 3mg/kg was comparable to that triggered by istradefylline at 100mg/kg. IDAA-338 monotherapy also significantly improved performance of SDR (simple visual discrimination reversal learning) [figure2].

Conclusion: In combination with low dose of L-DOPA, IDAA-338 demonstrated significantly better enhancement of ‘good’ on-time compared to istradefylline at much higher dose tested. Furthermore, IDAA-338 monotherapy displayed excellent improvement in SDR, suggesting its beneficial effect in the cognitive function of CLD MPTP-lesioned macaques. Altogether, these data revealed exciting potential for IDAA-338 as future treatment option for PD.

[figure 1] Effect of IDAA-338 on good on-time

[figure 2] Effect of IDAA-338 on SDR

« Back to 2024 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/efficacy-of-novel-a2a-a1-antagonist-in-motor-and-non-motor-symptoms-of-mptp-treated-macaques/