NLX-112 Eases L-dopa Dyskinesia in Marmosets With Parkinson’s, Study Says
An investigational therapy known as NLX-112 (befiradol) may hold promise to treat levodopa-induced dyskinesia, a complication of long-term levodopa therapy that affects people with Parkinson’s disease, a study found.
The study, “The selective 5-HT1A receptor agonist, NLX-112, exerts anti-dyskinetic and anti-parkinsonian-like effects in MPTP-treated marmosets,” was published in Neuropharmacology.
Motor symptoms of Parkinson’s disease include tremor; slow movement (bradykinesia); stiffness (rigidity); uncontrolled, involuntary movements that can affect the arms, legs, head, or the whole body (dyskinesia); and poor balance.
As the disease progresses, patients typically need to gradually increase treatment doses for maximum benefit. Even after that, symptoms sometimes reappear or worsen due to the dopaminergic therapy’s gradual loss of efficiency.
Dyskinesia is one of the complications of long-term levodopa therapy that affects many patients with advanced Parkinson’s disease. Currently, the main medication available to manage dyskinesia is amantadine. However, it can have side effects and may not be effective for every patient.
Studies indicate that Parkinson’s progression and symptoms may be associated with impaired signals from another important brain chemical, serotonin. Serotonin is involved in smooth muscle contraction, and serves as the “feel-good” chemical in the brain, influencing one’s sense of well-being and happiness.
Serotonin-producing neurons have an enzyme that is crucial to producing dopamine. This enzyme can be stored in vesicles and released as a “false neurotransmitter.” This results in excessive and inappropriate dopamine release, which generates dyskinesia.
NLX-112 (also known as befiradol or F13640) is an experimental medicine being developed by Neurolixis that activates a type of serotonin receptor called 5-HT1A. This investigational therapy has been shown to inhibit the “false neurotransmitter” release, thereby minimizing or even abolishing dyskinesia in rodent models of Parkinson’s disease.
In a study funded by Parkinson’s Virtual Biotech, the drug development arm of Parkinson’s UK, researchers tested NLX-112 in a marmoset model of levodopa-induced dyskinesia.
Animals were treated with 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that induces the death of dopamine-producing neurons and mimics Parkinson’s symptoms. Dyskinesia was then induced by chronic levodopa/benserazide combination therapy administered up to twice daily for up to a month.
NLX-112 treatment was administered alone or in combination with levodopa twice a week. Scientists also tested levodopa therapy combined with (+)8-OH-DPAT, another compound that activates the serotonin receptor 5-HT1A.
When administered together with levodopa at three different doses (0.025, 0.1 and 0.4 mg/kg ), NLX-112 reduced dyskinesia in a time and dose-dependent manner. The most prominent effects were at a dosage of 0,4 mg/kg.
In addition, NLX-112 was found to marginally interfere with the anti-parkinsonian effects of levodopa, unlike (+)8-OH-DPAT, which lessened levodopa-induced dyskinesia but also eliminated levodopa’s therapeutic efficacy.
When given alone (not combined with dopaminergic therapy), NLX-112 elicited anti-parkinsonian-like activity, easing disease-related motor disability in marmosets modeling Parkinson’s.
“Interestingly, the higher dose of NLX-112 (0.4 mg/kg) appeared less active than the lower doses, only reducing disability at a single, early time-point, suggesting an inverted dose-response relationship,” the researchers wrote.
Both NLX-112 and (+)8-OH-DPAT produced dose-dependent unusual behavior in marmosets, including sedation, scratching, wet-dog shakes, and sustained muscle contractions in the tail. These manifestations are all consistent with serotonin syndrome, a disorder that can occur when taking serotonin-boosting medications, and manifests itself with both behavioral and other general symptoms such as sweating and diarrhea.
Despite its effects, NLX-112 was not kept in animals’ blood circulation for long, which may limit its pharmacological effects in this particular species.
“This promising research on NLX-112 offers hope that we can find a treatment that can tackle dyskinesia, which can make everyday tasks, such as eating, writing, and walking, extremely difficult,” Arthur Roach, PhD, director of research at Parkinson’s UK, said in a press release.
“People with Parkinson’s tell us it is one of the most critical issues that impacts quality of life, so we’re delighted that this project is progressing so positively,” Roach said. “With 145,000 people living with Parkinson’s in the UK, we are desperately in need of a breakthrough treatment, and we’re committed to delivering one by 2024.”
“It is vital we continue to work with biotech companies like Neurolixis to drive forward new treatments that may slow, stop, or reverse Parkinson’s, and also those, like NLX-112, that could bring relief from symptoms or side effects,” said Roach.
“We are excited that NLX-112 has shown such positive results in reducing dyskinesia in marmosets,” said Adrian Newman-Tancredi, PhD, co-founder and CEO of Neurolixis. “If the striking preclinical data are reproduced in clinical trials, NLX-112 could significantly alleviate the troubling dyskinesia that prevent many Parkinson’s patients from performing routine daily tasks, thereby improving their quality of life.”
“We are currently making plans and seeking funding to take NLX-112 into clinical trials, and hope to be able to initiate these before the end of 2020,” Newman-Tancredi said.
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