Despite being a mainstay of Parkinson’s disease treatment, levodopa, a dopamine-replenishing medication, can cause nasty side-effects with long-term use. A recent human trial found that a new drug significantly reduces these effects, representing a breakthrough milestone in Parkinson’s treatment.
Levels of dopamine, a neurotransmitter that helps control movement, coordination, and muscle control, are reduced in Parkinson’s disease (PD). Levodopa, or L-DOPA, is commonly used to treat PD symptoms. The precursor to dopamine, it crosses the blood-brain barrier and is converted to dopamine inside the brain, helping restore movement.
Unfortunately, in around 80% of people with PD, its long-term use causes levodopa-induced dyskinesia (LID), a condition characterized by uncontrolled jerking, writhing, or fidgeting. A recent clinical trial testing the effectiveness of CPL’36, a drug initially developed as a schizophrenia treatment by pharmaceutical company Celon Pharma SA, has yielded positive results as a treatment for LID.
“I am very pleased that the clinical effect of CPL’36 has now been confirmed also for the treatment of LID dyskinesia in Parkinson’s disease,” said Celon’s CEO Maciej Wieczorek, PhD. “The results are unequivocally positive, clinically meaningful, and statistically significant, and have met all the criteria we prespecified.”
The enzyme phosphodiesterase 10A (PDE10A) is found mainly in the brain, particularly in areas involved in movement. It controls chemical messengers (cAMP and cGMP), which help regulate brain signaling. When these messengers stick around the brain longer, they improve communication between brain cells, particularly in movement-controlling pathways. CPL’36 blocks PDE10A from breaking down cAMP and cGMP, reducing dyskinesia by improving the brain’s ability to process movement-related signals.
“It’s important to note that CPL’36 has a unique pharmacodynamic profile, characterized by rapid enzyme dissociation, which distinguishes it from other PDE10A inhibitors,” said Joanna Sierzputowska-Prarat, the Main Clinical Neuropsychiatry Lead at Celon Pharma. “We believe this attribute is key to the positive clinical outcomes we have generated thus far.”
In the multinational, multicenter Phase 2 clinical trial, 105 adult patients with PD and LID were randomly assigned to receive one of three oral interventions once a day for four weeks: 20 mg of CPL’36, 40 mg of CPL’36, or a placebo. Treatment effectiveness was assessed by comparing participants’ baseline Unified Dyskinesia Rating Scale (UDysRS) scores with their score after the intervention. The UDysRS specifically measures the severity of LID, evaluating both objective and subjective criteria in a single scale. The total score ranges from zero to 104, with higher scores indicating greater severity or disability. In PD patients with dyskinesia, a total score reduction of eight points is considered a minimal clinically important change – the smallest change in a treatment outcome that a patient considers important.
At baseline, patients’ UDysRS was around 45, placing them in the moderately severe to severe category. At four weeks, patients taking 20 mg of CPL’36 had a 12.3-point reduction in UDysRS score, and those on 40 mg had a 13.58-point reduction. The reductions reported were the improvements seen in treatment groups compared to placebo (the least squares mean difference), meaning that patients on CPL’36 saw this degree of symptom improvement beyond what placebo patients experienced. The results were statistically significant and the effect size (Cohen’s d values) of both treatment doses indicated large effects, meaning the drug had a strong impact on reducing dyskinesia.
The novel drug was well-tolerated by patients. Indeed, a higher percentage of severe adverse events was seen in the placebo group (8.8%) than in the 40 mg dose (5.7%) and 20 mg dose (0.0%) groups. The most common adverse event reported in treatment groups was mild-to-moderate drowsiness. No deaths were reported.
Celon Pharma considers the results from its clinical trial represent a milestone in the treatment of Parkinson’s disease and, particularly, the side-effects of levodopa treatment that affect so many with the condition.
“We believe that CPL’36 has potential to significantly contribute to the expansion and advancement of the global market for Parkinson’s disease pharmacotherapy, and to provide sizeable clinical benefits to LID patients who are underserved by current treatments,” Wieczorek said.
The study results reported here were provided by Celon Pharma. As far as New Atlas knows, they have not at the time of publication been peer-reviewed or published in a scientific journal.
Sources: Celon Pharma, Globe Newswire