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 is highly effective in reducing abnormal movements in animal models of Parkinson's disease (PD), and based on these data, Neurolixis is planning clinical trials in Parkinson's disease patients who exhibit L-DOPA-induced dyskinesia (LID), a complication associated with long-term treatment with L-DOPA.
Treatment of L-DOPA-induced dyskinesia with NLX-112
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.
NLX-112 has been tested in an animal model of dyskinesia in 'parkinsonian' rats (study funded by the Michael J. Fox Foundation for Parkinson's Research). In this animal model, repeated L-DOPA administration produces dyskinesia, and this is completely abolished by administering NLX-112. This striking result distinguishes NLX-112 from previous serotonergic agonists because previous serotonergic compounds only achieved a partial alleviation of dyskinesia, whereas NLX-112 completely alleviated it. In addition, previous serotonergic compounds interfere with the beneficial effects of L-DOPA whereas NLX-112 does not interfere with the activity of L-DOPA. Finally, NLX-112 also exhibits potent and efficacious antidepressant-like activity in animal models, suggesting that it may also alleviate some of the non-motor symptoms of PD.
Taken together, these data suggest that NLX-112 represents a promising strategy for treating Parkinson's disease patients who exhibit L-DOPA-induced dyskinesia. Funding is being sought to test NLX-112 in a clinical study in patients.
Publication describing the pharmacology of NLX-112: Iderberg et al. Experimental Neurology, 2015.