Some good news for patients suffering from Parkinson’s Disease

Parkinson’s Disease (PD) is a devastating and progressive neurological disease for which we only have therapies that treat the symptoms rather than slow the progression of the disease.

The mainstay of treatment is L-Dopa which is converted to dopamine (DA), the neurotransmitter that is decreased in the neurones of the substantia nigra. Dopamine plays a vital role in regulating the movement of the body. A reduction in dopamine is responsible for many of the symptoms of Parkinson’s disease.

L-Dopa is the most effective drug for treating Parkinson’s Disease. However, its long-term use is often complicated by significantly disabling fluctuations therapeutic effect (often referred to as the “On Off” effect) 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 L-DOPA-induced dyskinesia (LID) depends on age of onset and severity of PD, with up to 80% of patients suffering from LID as the disease progresses (1, 2). This can lead to patients questioning “Is the treatment worse than the disease?”

Despite significant advances, the pathogenesis of LID remains incompletely understood. It is well accepted that LID is caused by the combination of nigral denervation and chronic pulsatile dopaminergic receptor stimulation, which establishes inappropriate signalling between the motor cortex and the striatum, contributing to the generation of dyskinesia.

In PD, as the disease progresses, most of dopaminergic neurons of the substantia nigra die, and the ability to control extracellular DA in the brain is impaired. In this situation, most of the conversion of L-Dopa to DA occurs in serotonergic neurons. However serotonergic neurons cannot modulate the release of DA (3), which results in the fluctuation of DA levels at the synaptic clefts.

Current treatment strategies include identifying the kind of dyskinesia and tailoring treatment accordingly. Peak-dose dyskinesia is treated mainly by reducing individual doses of levodopa and adding amantadine and dopamine agonists, whereas off-period dystonia often responds to baclofen and botulinum toxin injections (4).

Amantadine has several neurological/psychiatric side effects e.g., depression, confusional states, hallucinations, anxiety, euphoric mood, insomnia, dizziness, lethargy, ataxia, disturbance in attention and dysarthria (5). 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.

Neurolixis is developing NLX-112 as a highly selective 5-HT1A full agonist. In a two-arm, double-blind, randomized, placebo-controlled Phase 2a study, run by Professor Per Svenningsson in Sweden, the safety, tolerability, and preliminary efficacy of up to 2 mg/day of NLX 112 versus placebo in patients with moderate to severe L-DOPA induced dyskinesia was evaluated (6). Efficacy data were recorded using an electronic Home Dyskinesia Diary and a wearable dyskinesia assessment device was used to monitor the participants dyskinesias. A total of 22 participants took part (15 participants received NLX-112 and 7 received a placebo drug). NLX-112 met the primary outcome of safety and tolerability and, in addition, showed statistically significant efficacy in reducing LID symptoms in Parkinson’s disease patients.

Further studies, in much larger numbers of patients, will be required to confirm this agent is beneficial and to determine if higher doses and/or longer treatment could produce even better results.

Researchers continue to look at the underlying pathological changes in Parkinson’s disease. There is a strong association between the neurotoxicity caused by α-synuclein oligomers and PD pathogenesis which places the balance between α-synuclein production and clearance as a new therapeutic goal.  Mechanisms involved in achieving α-synuclein homeostasis include decreasing its production, boosting its clearance, or preventing cell transmission. A polyphenol called epigallocatechin gallate has been shown to reduce α-synuclein accumulation and its neurotoxicity in a Phase II clinical trial (7).

References

1. Thanvi B, Lo N, Robinson T. Levodopa-induced dyskinesia in Parkinson’s disease: clinical features, pathogenesis, prevention and treatment. Postgrad Med J. 2007;83(980):384-8.

2. Neurolixis. NLX-112 : a Phase 2 drug for the treatment of L-DOPA-induced dyskinesia in Parkinson’s disease 2023 [Available from: https://www.neurolixis.com/en/company/pipeline/nlx-112.html.

3. Yang K, Zhao X, Wang C, Zeng C, Luo Y, Sun T. Circuit Mechanisms of L-DOPA-Induced Dyskinesia (LID). Frontiers in Neuroscience. 2021;15.

4. Vijayakumar D, Jankovic J. Drug-Induced Dyskinesia, Part 1: Treatment of Levodopa-Induced Dyskinesia. Drugs. 2016;76(7):759-77.

5. Pharmaceuticals A. Amantadine hydrochloride SmPC 1998 [updated 11 May 2023.

6. UK Ps. Could this existing drug be a new treatment for dyskinesia? 2023 [Available from: https://www.parkinsons.org.uk/get-involved/could-existing-drug-be-new-treatment-dyskinesia.

7. Pardo-Moreno T, García-Morales V, Suleiman-Martos S, Rivas-Domínguez A, Mohamed-Mohamed H, Ramos-Rodríguez JJ, et al. Current Treatments and New, Tentative Therapies for Parkinson’s Disease. Pharmaceutics. 2023;15(3).