Objective: To assess the safety, tolerability and preliminary efficacy of NLX-112 (a.k.a. befiradol) in patients with moderate to severe LID in PD: a randomized, double-blind, placebo (PBO)-controlled Phase 2A trial.

Background: NLX-112, a highly selective, high-efficacy serotonin 5-HT1A receptor biased agonist, strongly reduces dyskinesia in rodent, marmoset and macaque models of LID [1-4]. NLX-112 has previously shown favorable safety and tolerability in trials for other indications. The present trial was supported by Parkinson’s UK and The Michael J. Fox Foundation (MJFF- 019508).

Method: PD patients with troublesome LID received NLX-112 or PBO (2:1 ratio) as an adjunct to their regular stable antiparkinsonian medication. Study drug dosing was individually up-titrated over 28 days to a maximum of 2 mg/day (1 mg b.i.d.); dosing was then kept stable for 14 days and down-titrated over the next 14 days. Patients received levodopa challenge (150% of regular dose) at day 1 (baseline) and at test days 28 and 42. The primary outcome was safety and tolerability; secondary outcome measure of troublesome LID used UDysRS. Other motor and non-motor symptoms of PD were also assessed.

Results: 22 patients (15 on NLX-112, 7 on PBO) completed the treatment according to protocol. Safety and tolerability were good, with no serious adverse events in the NLX-112 group. Adverse events were mild or moderate, and mostly occurred during the 4-week dose up-titration. Safety did not differ between NLX-112 and PBO groups. Significant reductions in LID were observed in the NLX-112 group: at day 28, UDysRS total score (parts 1-4) decreased by 4.1 points (p=0.0281) and part 3+4 score (dyskinesia disability) by 1.7 points (n.s.) compared to baseline; PBO group changes were n.s. (-2.0 and -1.0, respectively). At day 42, a greater reduction of UDysRS scores was observed in the NLX-112 group: total score decreased by 6.3 points (p=0.0016) and part 3+4 score by 3.1 (p=0.0038) compared to baseline; PBO group changes were n.s. (-2.4 and -0.1, respectively). Full analysis of UDysRS and other assessment scales will be presented.

Conclusion: NLX-112 was safe, well tolerated and significantly reduced LID in an apparently treatment-duration dependent manner, suggesting that NLX-112 could be a promising first-in-class serotonergic drug candidate for improved treatment of PD-LID.

References: 1. Newman-Tancredi, A., et al., J Pharm Pharmacol, 2017. 69(9): p. 1178-1190.
2. Iderberg, H., et al., Exp Neurol, 2015. 271: p. 335-350.
3. Fisher, R., et al., Neuropharmacology, 2020. 167: p. 107997.
4. Depoortere, R., et al., Parkinsonism Relat Disord, 2020. 78: p. 151-157.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/nlx-112-has-favorable-safety-and-tolerability-and-displays-efficacy-against-levodopa-induced-dyskinesia-lid-in-parkinsons-disease-pd/