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Dyskinesias in Parkinson’s Disease: Promising New Treatment Approach

  • Celon Pharma has announced positive Phase II clinical trial results for CPL’36, a phosphodiesterase 10A (PDE10A) inhibitor in development for the treatment of dyskinesias associated with Parkinson’s disease.
  • The trial demonstrated statistically significant efficacy in reducing involuntary movements, offering new hope for patients struggling with the side effects of long-term dopaminergic therapy.

Dyskinesias in Parkinson’s Disease

Parkinson’s disease is a progressive neurodegenerative disorder characterized by the loss of dopamine-producing neurons in the brain. While levodopa, the primary treatment, helps manage motor symptoms, long-term use often leads to levodopa-induced dyskinesias (LID) – involuntary, erratic movements that significantly impact patients’ quality of life. They can involve the face, arms, legs or torso. They are often smooth, but can also cause sudden jerks or slow and prolonged muscle contractions. Current treatment options for dyskinesias are limited, creating a critical need for innovative therapies.

Studies estimate that 30-50% of individuals who have been on levodopa for 5-10 years develop levodopa-induced dyskinesias (LID), with the prevalence increasing to over 80% after 15 years of treatment. The incidence is particularly high in patients diagnosed at a younger age, with those under 50 facing a 50% risk within five years of starting levodopa therapy.1 Given that more than 10 million people worldwide are living with Parkinson’s disease, a substantial number of patients experience dyskinesias, leading to impaired motor function, reduced independence, and diminished quality of life. Despite the widespread impact, treatment options remain limited, highlighting the urgent need for novel therapeutic approaches such as PDE10A inhibitors like CPL’36.

Mechanism of Action

CPL’36 is a selective phosphodiesterase 10A (PDE10A) inhibitor targeting pathways involved in motor control. PDE10A is highly expressed in the striatum, a key region for movement regulation. This enzyme hydrolyzes cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), reducing intracellular signaling. Inhibiting PDE10A increases cAMP and cGMP levels, enhancing dopaminergic and glutamatergic signaling in the striatum.2, 3 This modulation restores balance between direct and indirect pathways of movement control. The direct pathway facilitates movement, while the indirect pathway suppresses excessive movement. In Parkinson’s disease, indirect pathway overactivity contributes to motor dysfunction and dyskinesias. CPL’36 reduces this overactivity, helping normalize motor function. It also prevents excessive dopamine fluctuations, which drive levodopa-induced dyskinesias (LID).

Unlike dopamine-based therapies, CPL’36 works downstream of dopamine receptors. This mechanism offers potential benefits without worsening dopamine-related side effects. By restoring striatal network function, CPL’36 improves motor control and reduces involuntary movements. Its selective action in the brain minimizes peripheral side effects. The compound has demonstrated efficacy in preclinical models and early clinical studies.

Clinical Trial Results

Celon Pharma conducted a Phase II clinical trial to evaluate CPL’36 in Parkinson’s disease 105 patients with dyskinesias. The trial was randomized, double-blind, and placebo-controlled, ensuring reliable and unbiased results. Participants received either CPL’36 or a placebo over a defined treatment period. The study assessed efficacy, safety, and tolerability using standardized clinical scales. CPL’36 showed a statistically significant reduction in dyskinesias compared to placebo. Patients experienced improved motor function without worsening Parkinson’s disease symptoms. The drug demonstrated a favorable safety profile with no severe adverse effects reported.4 Results support further development in larger clinical trials. CPL’36 met its primary endpoint, demonstrating a statistically significant reduction in dyskinesias compared to placebo. The results support the drug potential to improve motor outcomes while maintaining a favorable safety profile.

This is the first clinical trial to show that PDE10A inhibition with CPL’36 in patients with dyskinesias in Parkinson’s disease produces positive, statistically significant and clinically meaningful effects on primary and secondary endpoints.

Next Steps in Development

Following these promising findings, Celon Pharma is preparing for further clinical development, including regulatory discussions and potential advancement to Phase III trials. The company’s success with CPL’36 highlights its commitment to developing innovative treatments for neurological disorders and addressing unmet medical needs in Parkinson’s disease. Company potentially looking around to establish new partnerships.

These results reinforce the potential of PDE10A inhibition as a new therapeutic strategy for managing dyskinesias and improving the quality of life for individuals with Parkinson’s disease.5 Further studies will be essential to confirm its long-term efficacy and safety, paving the way for a possible new treatment option for this challenging condition.

Prepared by:

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Jakub Knurek

Sources and further reading

  1. Manson A, Stirpe P, Schrag A. Levodopa-induced-dyskinesias clinical features, incidence, risk factors, management and impact on quality of life. J Parkinsons Dis. 2012; 2(3): 189-198.
  2. Guimarães RP, Ribeiro DL, Dos Santos KB, Talarico CHZ, Godoy LD, Padovan-Neto FE. Phosphodiesterase 10A Inhibition Modulates the Corticostriatal Activity and L-DOPA-Induced Dyskinesia. Pharmaceuticals (Basel). 2022; 15(8): 947.
  3. Erro R, Mencacci NE, Bhatia KP. The Emerging Role of Phosphodiesterases in Movement Disorders. Mov Disord. 2021; 36(10): 2225-2243.
  4. Celon Pharma, Raport bieżący 4/2025 – Pozytywne wyniki II fazy klinicznej CPL’36, inhibitora PDE10A w leczeniu dyskinez w chorobie Parkinsona.
  5. Matloka M, Janowska S, Pankiewicz P, Kokhanovska S, Kos T, Hołuj M, Rutkowska-Wlodarczyk I, Abramski K, Janicka M, Jakubowski P, Świątkiewicz M, Welniak-Kaminska M, Hucz-Kalitowska J, Dera P, Bojarski L, Grieb P, Popik P, Wieczorek M, Pieczykolan J. A PDE10A inhibitor CPL500036 is a novel agent modulating striatal function devoid of most neuroleptic side-effects. Front Pharmacol. 2022; 13: 999685.
  6. Politis M, Wu K, Loane C, Brooks DJ, Kiferle L, Turkheimer FE, Bain P, Molloy S, Piccini P. Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson’s disease patients. J Clin Invest. 2014; 124(3): 1340-1349.

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