NLX-112: a First-in-Class, Dual-Acting, Non-Dopaminergic, Drug Candidate for Treatment of Parkinson’s Disease
The main drug used to treat Parkinson’s disease (PD) is levodopa, a substance which enhances brain levels of dopamine, a neurotransmitter that is compromised by the disease. Although levodopa is highly effective in managing the motor symptoms of PD, after extended treatment it can elicit troublesome involuntary movements called dyskinesia (levodopa-induced dyskinesia, LID). Current treatment options for LID are not satisfactory: lowering levodopa dosing can worsen parkinsonism, Deep Brain Stimulation requires invasive surgery and amantadine (the only approved drug for LID) is only partially effective and has side-effects of its own. Thus, well-tolerated and effective treatments for LID remain a pressing medical need.
A new drug candidate, NLX-112, may be able to address this need. It was previously investigated as a possible treatment for pain indications, but is now aimed at LID, based on its promising activity in a series of studies using animal models of PD. Two charities, Parkinson’s UK and The Michael J Fox Foundation, co-funded a clinical trial in Sweden to test, for the first time, the effects of NLX-112 in people with Parkinson’s (PwP) with troublesome LID.
The trial was a placebo-controlled, double-blind study. 15 patients treated with NLX-112 and 7 treated with placebo completed the study. The primary outcome was to determine the safety and tolerability of NLX-112. The compound has previously been safely administered to over 600 people in other studies, but not to PwP, so it was important to check that it is well tolerated in this population. This was indeed the case: side-effects were mild or moderate and their number was similar between the NLX-112 and the placebo groups.
The secondary outcome of the clinical trial was therapeutic efficacy against LID. To measure this, study participants came into the clinic before starting treatment and twice during the study. At each clinic visit, they received a booster dose of levodopa and the severity of their dyskinesia was assessed by a clinical investigator using an established rating scale, the Unified Dyskinesia Rating Scale (UDysRS). As expected, LID was significantly reduced in the NLX-112 group and not in the placebo group. In addition, the anti-dyskinetic effect of NLX-112 increased over the course of the study, suggesting that additional benefit could be obtained with longer treatment durations.
The next important parameter of the clinical trial was to determine whether NLX-112 influenced parkinsonian symptoms, measured using another rating scale, the Unified Parkinson’s Disease Rating Scale (UPDRS). Some previous anti-LID drug candidates have been reported to interfere with the beneficial anti-parkinsonian effect of levodopa, but this was not the case for NLX-112. In fact, NLX-112 lowered UPDRS scores, indicating that it further reduced parkinsonism, even though the study participants had taken a booster dose of levodopa.
These are striking findings: NLX-112 had a dual benefit, not only decreasing LID, but also further reducing parkinsonism symptoms. Such a profile has not been observed for other anti-parkinsonian drugs and may arise from NLX-112’s original mechanism of action. Indeed, whereas levodopa and most other existing drugs target the dopamine neurotransmitter system in the brain, NLX-112 targets the serotonin (5-hydroxytryptamine, 5-HT) system. Over recent years, there has been increasing interest in the role of serotonin in PD, and particularly in a serotonin receptor called the 5‑HT1A receptor. NLX-112 is both exceptionally selective for 5-HT1A receptors and fully activates them, properties which likely underlie the clinical benefits seen in the present study. Moreover, the serotonergic properties of NLX‑112 raise the intriguing possibility that it may also improve non-motor symptoms of PD. This is because serotonin is involved in the control of depression, anxiety and pain, all of which are experienced by PwP and may be alleviated by a 5-HT1A activator such as NLX‑112.
Nevertheless, further clinical studies are necessary before NLX-112 can be made available as an approved drug. Specifically, trials need to be carried out with larger numbers of patients, longer treatment durations and higher doses of NLX-112. If successful, these trials will provide the data necessary for regulatory submission and approval for commercial use, bringing much-needed relief to many PwP living daily with LID and other motor and non-motor symptoms of PD.
Adrian Newman-Tancredi, PhD, DSc is the CEO at NeurolixisInc. His abstract submitted to the WPC 2023 was selected for a Hot Topics talk. He presented his research at WPC 2023 in Barcelona.
Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not necessarily reflect the opinions or positions of the World Parkinson Coalition®