An experimental drug that combines fixed doses of extended-release (ER) formulations of existing medications can significantly reduce symptoms in patients with untreated early-stage Parkinson’s disease (PD), new research suggests.
Results from a phase 3 trial of P2B001, a combination of pramipexole and rasagiline at currently unavailable low doses, showed the drug was more effective than its individual components and as effective as higher-dose pramipexole ER — with far less daytime sleepiness.
The combination drug is taken once a day and does not require titration, which investigators say make it a good option for first-line treatment of PD.
“I don’t think people, including me, expected intuitively that if you used small doses and combined it with a little rasagiline it would be equal to full doses of pramipexole, but it appears that it is,” lead investigator Warren Olanow, MD, professor and chair emeritus of neurology and professor emeritus of neuroscience at Icahn School of Medicine at Mount Sinai, New York City, told Medscape Medical News.
The findings were presented at the American Academy of Neurology (AAN) 2022 Annual Meeting.
“Synergistic Effects”
Levodopa is considered to be the most effective treatment for PD, but long-term use is associated with increased risk for motor complications, such as dyskinesia. Dopamine agonists such as pramipexole have been linked in previous research to excessive daytime sleepiness and impulse control disorders.
In addition, as reported by Medscape Medical News, monoamine oxidase-B inhibitors such as rasagiline are not as effective at controlling PD as other treatment options.
“There is no consistent agreement on how to initiate treatment because no one treatment is ideal,” Olanow said.
P2B001, developed by Pharma Two B, is a combination of 0.6 mg of pramipexole and 0.75 mg of rasagiline. The drugs work by dual mechanisms, which investigators suspected might have “synergistic effects.”
Following promising results from an earlier trial, researches launched a phase 3, 12-week, international, randomized, double-blind trial to study the efficacy, safety, and tolerability of P2B001 compared with its individual components and with a calibration arm of pramipexole ER in 519 patients with early PD.
Participants received P2B001, 0.6 mg of pramipexole ER, 0.75 mg of rasagiline ER, or pramipexole ER titrated to an optimal dose for each patient (1.5 to 4.5 mg).
New First-Line Treatment?
Results showed that the adjusted mean change from baseline in total Unified Parkinson’s Disease Rating Scale (UPDRS) score was -2.66 points for P2B001 vs pramipexole (P = .0018) and -3.30 points for P2B001 vs rasagiline (P = .0001).
There was no significant difference in UPDRS scores between P2B001 and pramipexole ER, but patients who received P2B001 reported significantly less daytime sleepiness.
The adjusted mean change from baseline in Epworth Sleepiness Scale score for P2B001 vs pramipexole ER was -2.66 points (P < .0001).
In addition, fewer dopaminergic adverse events were reported with the combination drug vs pramipexole ER (44.7% vs 66.2%), including somnolence (14.7% vs. 31.1%) and orthostatic hypotension (2.7% vs 12.2%).
As a first-line treatment, P2B001 could offer an effective option instead of levodopa, Olanow said.
“It could be really good for patients because it would delay the introduction of levodopa and allow levodopa to be used in lower doses when the time comes and hopefully reduce the risk of complications,” he added.
Questions, Cost Concerns
Commenting on the study for Medscape Medical News, Alfonso Fasano, MD, PhD, professor of neurology and chair in neuromodulation, University of Toronto, Canada, agreed that better therapeutic options are needed for Parkinson’s.
Combining available treatments into one pill “might help patients’ adherence, although this can compromise our ability to dose each compound individually,” said Fasano, who was not involved with the research.
He added there are also questions about dosage modification as a patient’s disease progresses and whether a higher dose might pose safety problems. There is also the issue of cost.
“Conducting large clinical trials like this one is expensive, and I wonder about the cost of the drug when approved,” Fasano noted. “Do we really need to invest in combination pills containing two already well-known compounds?”
Olanow, who is not directly involved with the developer of P2B001 Pharma Two B, said he has no information on what the drug might cost or how it might be marketed if approved for use.
“The advantage of the combination is the component doses are not replicable, they are both in an extended-release formulation, it doesn’t require titration, and it has been tested and proven to work,” he said.
The study was funded by Pharma Two B. Olanow is employed by Clintrex Research Corporation and owns stock in Clintrex Research Corporation. Fasano reported no relevant financial relationships.
American Academy of Neurology (AAN) 2022 Annual Meeting: Abstract 1082. Presented April 5, 2022.
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