Objective/Rationale:
It has been suggested that a nicotinic acetylcholine receptor (nAChR) agonists may restore the deficits caused by the loss of nicotinic acetylcholine subunits found in Parkinson’s disease patients. We will test whether our nicotinic agonist possess therapeutic benefit in a pre-clinical model of L-DOPA induced dyskinesia. If our nicotinic agonist demonstrates efficacy in these studies we will use the data from the study to support further testing in Parkinson’s disease patients.
Project Description:
AstraZeneca’s novel nicotinic agonist has been tested for safety, tolerability in humans but we currently lack direct evidence that it will improve dyskinesia in pre-clinical or clinical studies. The purpose of this study will be two-fold: 1) first, to evaluate, in a well validated pre-clinical model of levodopa induced dyskinesia, the ability of our nicotinic agonist to suppress dyskinesia, and to define a dose(s) that provides maximal benefit and 2) secondly, to assess whether this compound modifies the anti-parkinsonian actions of L-DOPA. The goal will be to deliver the accompanying biology and biomarker package to support clinical development.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The value of current therapies for Parkinson’s disease is limited by significant complications of long-term treatment, particularly dyskinesia. The occurrence of dyskinesia limits the ability to optimize the treatment regime, affects functional disability and impacts the quality of life. A novel therapy, with the ability to alleviate parkinsonian symptoms to the same extent as currently available dopamine replacing agents, while producing fewer side effects, would be of great value in the treatment of Parkinson’s disease. One approach to this goal is to develop a non-dopaminergic treatment that can be used as an adjunct to L-DOPA and suppress the expression of dyskinesia once it has been established, while maintaining the anti-parkinsonian benefit of L-DOPA.
Anticipated Outcome:
AstraZeneca’s nicotinic agonist is currently a phase II ready clinical candidate that has the potential to treat levodopa-induced dyskinesia in Parkinson’s disease patients (PD-LID). The study plan outlined in this proposal would confirm this. This molecule has already completed the extensive preclinical safety and toxicology package that is required to test the candidate in pivotal phase II clinical trials. Should the study proposed show success, AstraZeneca plans to conduct studies in clinical models.
Final Outcome
The nicotinic agonist, AZD1446, has unique pharmacological properties when compared to nicotine and other known nicotinic agonists. AZD1446 has been shown to be safe and tolerable in pre-clinical studies, and has been studied in 424 healthy young and elderly volunteers as well as Alzheimer’s and ADHD patients.
We have demonstrated that the immediate release formulation of AZD1446 (IR) is efficacious in a pre-clinical model of levodopa-induced dyskinesia. However increasing target exposure by utilizing AZD1446 in a sustained or modified-release (MR) formulation does not reduce levodopa-induced dyskinesia in pre-clinical models. Our data suggests that sustained activation of AZD1446-activated nicotinic acetylcholine receptors by AZD1446 MR does not improve and may worsen L-dopa induced dyskinesia. AZD1446 would be of limited therapeutic benefit for Parkinson’s disease patients suffering from troublesome dyskinesia.