NLX-112 : a Phase 2 drug for the treatment of L-DOPA-induced dyskinesia in Parkinson's disease

NLX-112 (also known as befiradol or F13640) is a novel compound that activates serotonin 5-HT1A receptors. NLX-112 has two main advantages over older compounds: 1. NLX-112 is extremely selective for the 5-HT1A receptor, with over 1000-fold selectivity compared to other types of receptor types, and 2. NLX-112 is a full agonist at 5-HT1A receptors, maximally activating the receptor.

NLX-112 strongly reduces L-DOPA-induced abnormal movements ('dyskinesias') in animal models of Parkinson's disease (PD). Based on these observations, Neurolixis conducted a Phase 2 clinical study in Parkinson's disease patients with L-DOPA-induced dyskinesias. This study, completed in March 2023, was a success: NLX-112 was well tolerated in patients and significantly reduced their dyskinesias (see press release). Neurolixis is now looking to advance the development of NLX-112 in larger clinical trials.

Treatment of L-DOPA-induced dyskinesia with NLX-112: mechanism of action

L-DOPA is the most effective drug for treating Parkinson's disease. However, its long-term use is often complicated by significantly disabling fluctuations and dyskinesias, reducing the beneficial effect of L-DOPA. Dyskinesia consists of involuntary, rapid, irregular, purposeless, and unsustained movement that seems to flow from one body part to another. The risk of developing LID depends on age of onset and severity of PD, with up to 80% of patients suffering from LID as the disease progresses.

The onset of LID is related to dysfunction in serotonergic systems. Indeed, recent research shows that L-DOPA can be taken up by serotonin neurons and converted to dopamine in an unregulated manner, thus eliciting the uncontrolled motor functions that typify dyskinesia. Inhibition of serotonergic neurons is therefore a promising strategy to diminish dyskinesia in PD and can be achieved by targeting serotonin 5-HT1A receptors, which inhibit serotonergic function.