Celon’s small molecule eases levodopa-induced dyskinesia
Phase 2 trial data 'unequivocally positive,' CEO says
A daily dose of CPL’36, an oral small molecule in the pipeline of Celon Pharma, may ease symptoms for patients who experience levodopa-induced dyskinesia, or uncontrolled movements as a side effect of the mainstay Parkinson’s disease treatment, within one week.
That’s according to data from a Phase 2 clinical study (NCT05297201) that’s testing how well CPL’36 works compared with a placebo to ease levodopa-induced dyskinesia in 105 adults with Parkinson’s. It’s also testing how safe CPL’36 is and its pharmacokinetics, or how it moves into, through, and out of the body.
“I am very pleased that the clinical effect of CPL’36 has now been confirmed … for the treatment of [levodopa-induced dyskinesia] in Parkinson’s disease,” Maciej Wieczorek, PhD, Celon’s CEO, said in a company press release. “The results are unequivocally positive, clinically meaningful, and statistically significant.”
Parkinson’s occurs due to the loss of dopaminergic neurons, the nerve cells that produce dopamine, a signaling molecule needed for motor control by a brain region called the striatum. Loss of dopamine causes motor symptoms, such as tremors, stiffness, slow movements, and problems with balance.
Levodopa, a molecule that cells can use to make dopamine, remains a mainstay Parkinson’s treatment. However, as the disease progresses, patients may need higher doses of levodopa more frequently. They also may develop dyskinesia as a side effect of levodopa.
Breaking down an enzyme
CPL’36, also known as CPL500036, is an inhibitor of PDE10A, an enzyme that normally breaks down signaling molecules called cAMP and cGMP. This enzyme is mainly found in brain cells called medium spiny neurons in the striatum. By inhibiting PDE10A and preventing cAMP and cGMP from being broken down, CPL’36 may help normalize nerve signaling in the striatum, potentially improving motor function in Parkinson’s.
In a rat model of Parkinson’s, CPL’36 eased some motor symptoms when given alone or in combination with levodopa. It also eased levodopa-induced dyskinesia, but didn’t cut the benefits from levodopa, suggesting it may be used as an add-on treatment for the disease.
“CPL’36 has a unique pharmacodynamic profile, characterized by rapid enzyme dissociation, which distinguishes it from other PDE10A inhibitors,” said Joanna Sierzputowska-Prarat, Celon’s main clinical neuropsychiatry lead. “We believe this attribute is key to the positive clinical outcomes we have generated thus far.”
In the Phase 2 clinical study, patients were randomly divided into three groups: one in which they received a 20 mg dose of CPL’36; another in which they were given a 40 mg dose of the therapy; and the third in which they were given a placebo. Treatment lasted for up to four weeks, and the study’s main goal was to see if CPL’36 was able to reduce dyskinesia, as measured by the Unified Dyskinesia Rating Scale (UDysRS).
After four weeks, patients taking 20 mg of CPL’36 improved by 12.3 points on the UDysRS compared with the placebo, and those taking the 40 mg dose improved by 13.6 points. Improvements in other motor symptoms started as early as one week after patients began treatment with CPL’36.
The most common side effect was drowsiness, which was mild to moderate. Severe side effects were more frequently reported in the placebo group (8.8%), than in the 40 mg (5.7%) and 20 mg (0%) groups.
CPL’36 was relatively well tolerated, but some patients stopped taking it due to side effects: 11.1% in the 20 mg group and 8.6% in the 40 mg group. One patient in the 40 mg group experienced atrial fibrillation (a rapid and irregular heartbeat).
“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 [levodopa-induced dyskinesia] patients who are underserved by current treatments,” Wieczorek said.
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