Objective: Evaluate the therapeutic potential of Lu AF28996 in the MPTP-macaque model of PD.

Background: Chronic levodopa treatment is associated with the development of motor complications, adding complexity to disease management in advanced Parkinson’s disease (PD). Dopamine agonists (DAs) are generally associated with fewer motor complications than levodopa, but may lack sufficient efficacy in advanced PD. The insufficient efficacy of DAs is likely related to their predominant activity at D2/D3 (D2‑like) dopamine receptors, with insufficient D1-like receptor engagement, critical for motor control. In contrast, apomorphine, which, similar to levodopa following conversion to dopamine, engages both D1/D5 (D1-like) and D2-like receptors, which may explain its superior motor efficacy in comparison with other DAs; however, it is not orally bioavailable.

Method: Lu AF28996, an oral prodrug converted in vivo into a potent D1-like/D2-like receptor agonist, was evaluated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) macaques. Lu AF28996 was administered orally at low, intermediate, and high-dose levels in sterile water vehicle, and motor performance and dyskinesia were assessed over an 8-hour post-dose period. Levodopa-treated MPTP-macaques were active-comparator controls.

Results: Following acute administration, the intermediate and high doses of Lu AF28996 significantly improved PD disability compared with vehicle-treated MPTP-macaques. Improvements were observed in multiple motor domains, including range of movement, bradykinesia, posture, and ON-time. In contrast to the rapid onset of effect observed with levodopa, the antiparkinsonian efficacy of Lu AF28996 began approximately 4 hours after administration. Dyskinesia increased in a dose-dependent manner, with the highest dose producing cumulative dyskinesia scores comparable to levodopa. At the intermediate dose, dyskinesia was less severe than that induced by the optimal dose of levodopa. Importantly, Good ON-time (defined as periods without bradykinesia and with absent or mild dyskinesia) was significantly longer following treatment with the intermediate dose of Lu AF28996 than with the optimal dose of levodopa.

Conclusion: These data demonstrate the potential for Lu AF28996 to provide robust antiparkinsonian efficacy that is comparable to levodopa, with reduced dyskinesia at therapeutically effective doses.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/oral-d1-like-d2-like-receptor-agonist-lu-af28996-provides-robust-antiparkinsonian-efficacy-with-reduced-dyskinesia-in-the-mptp-macaque-model/