The dopamine precursor levodopa is the gold-standard treatment for Parkinson’s disease. However, as PD progresses, serotonin neurons increasingly convert levodopa to dopamine as a “false neurotransmitter.” This activity underlies the development of troubling levodopa-induced dyskinesia that affects many PD patients. One strategy is to silence the activity of serotonergic neurons by targeting inhibitory receptors such as 5-HT1A. Data gathered in a previous project funded by MJFF showed that a novel, exceptionally selective drug (NLX-112) blunted levodopa-induced dopamine release and completely abolished the dyskinesia-like symptoms observed in models of PD. These results suggest that NLX-112 is a promising therapeutic for treatment of levodopa-induced dyskinesia.
Our hypothesis is that NLX-112 possesses suitable pharmacokinetic and pharmacodynamic properties that will enable identification of an appropriate dosing regimen for clinical trials.
This study is designed to generate a sophisticated computer model of the pharmacokinetics (what the body does to the drug) and pharmacodynamics (what the drug does to the body) of NLX-112 and use that computer model to predict the efficacious doses for clinical studies in PD patients. We will experimentally determine a number of pharmacokinetic parameters including blood/brain barrier penetration, transporter activity, concentrations in cerebrospinal fluid and 5-HT1A receptor occupancy. This information will be used to develop a detailed computer-simulated pharmacokinetic-pharmacodynamic model to predict optimal clinical dosing schedules.
Impact on Diagnosis/Treatment of Parkinson’s disease:
There is currently no approved treatment for levodopa-induced dyskinesia. If the present study is successful, it could lead to the development of a novel therapeutic that could improve patients’ wellbeing and facilitate treatment of their parkinsonian symptoms.
Next Steps for Development:
Neurolixis intends to run a Phase II clinical study in Parkinson’s disease patients with troubling dyskinesia with the doses of NLX-112 predicted from these studies.
This grant was selected by The Michael J. Fox Foundation staff to be highlighted via the Foundation’s Partnering Program.
NLX-112 is a novel serotonergic agonist that targets 5-HT1A receptors with exceptional selectivity and potency. In previous studies supported by MJFF, NLX-112 abolished L-DOPA-induced dyskinesia (LID) in a pre-clinical model of Parkinson’s disease, suggesting considerable potential therapeutic benefit for PD patients.
The present work showed that NLX-112 possesses a pharmacokinetic profile (drug properties) that is compatible with clinical development. In particular, NLX-112 exhibited rapid brain penetration, extended brain half-life, absence of interaction with brain-barrier transporters and no interference with the pharmacokinetics of L-DOPA. A detailed computer modeling study predicted that the brain levels of NLX-112 elicited by active doses in a pre-clinical model can be achieved clinically at a dose of NLX-112 that has previously been safely tested clinically in healthy volunteers. In addition, NLX-112 was radiolabeled with [18F] to generate a novel agonist PET radiotracer, i.e. [18F]NLX-112, targeting 5-HT1A receptors. In pre-clinical model microPET experiments it was shown that modest receptor occupancy of 5-HT1A receptors was sufficient to elicit pronounced anti-LID activity. It is anticipated that this detailed pharmacokinetic study, together with the availability of a novel brain-imaging tool will facilitate clinical studies in PD patients with LID.