Fixed-dose combo tackles PD symptoms while minimizing daytime sleepiness

P2B001, an investigational drug formulation that combines extended release (ER) doses of pramipexole and rasagiline, shows promise in managing Parkinson’s Disease (PD), conferring symptom control similar to that achieved with the marketed ER pramipexole while reducing the troublesome side effect of excessive daytime sleepiness (EDS).

“The combination of pramipexole [0.6 mg] and rasagiline [0.75 mg] aims to improve striatal dopaminergic transmission via distinct and potentially synergistic mechanisms, while the lower doses allow for a favourable safety profile,” according to Dr Cheryl Fitzer-Attas of Pharma Two B in Rehovot, Israel, who spoke to an audience at AAN 2023.  [Adv Ther 2022;39:1881-1894]

Fitzer-Attas and colleagues used data from a phase III study to compare the EDS profiles of P2B001 and ER pramipexole in patients with untreated PD and found that P2B001 was associated with 83-percent lower odds of developing EDS (adjusted odds ratio, 0.17, 95 percent confidence interval, 0.08–0.36; p<0.0001). [AAN 2023, abstract P2-11.001]

Results of the primary efficacy analyses that were released earlier also showed that P2B001 was superior to each of its individual components in terms of the change from baseline in Unified Parkinson's Disease Rating Scale (UPDRS) total scores (parts II+III). Furthermore, P2B001 had an efficacy (~8-point reduction) that was comparable to that of ER pramipexole (ER-PPX) individually titrated to optimal effect. [Mov Disord 2022;37(suppl 1):abstract 750]

“The development of dose-related EDS is considered a key limiting factor to the utility of pramipexole in early PD,” Fitzer-Attas pointed out. “The findings support the potential of P2B001 as a first-line, once-daily treatment for people with PD that may offer effective symptomatic control with a favourable safety profile and no need for titration.”

Keeping more patients awake

In the phase III study, 519 patients with untreated PD (time from diagnosis <3 years) were randomly assigned to receive 12-weeks double-blind treatment with one of the following: P2B001, pramipexole-ER-0.6 mg, rasagiline-ER-0.75mg, or marketed ER pramipexole (ER PPX; 6-week titration).

Daytime sleepiness-related adverse events (AEs) were predefined as somnolence and sudden onset of sleep. EDS was assessed using the Epworth Sleepiness Scale (ESS) and treatment-emergent adverse event (TEAE) reporting. Rates of new-onset clinically relevant EDS were assessed using shift analysis (from ESS ≤10 at baseline to >10 at week 12).

At baseline, the percentage of patients without significant EDS (ESS ≤10) was similar across the four treatment groups and ranged from 86.1 percent to 88.4 percent. At week 12, the rates of new-onset EDS were highest among patients treated with the marketed ER pramipexole (mean dose 3.2 mg; 35.7 percent) or pramipexole (15.6 percent) and were lowest among patients treated with P2B001 (8.5 percent) or rasagiline (6.6 percent).

Likewise, somnolence reported as TEAEs occurred with the greatest frequency with ER pramipexole (31.1 percent), followed by pramipexole (18.2 percent), P2B001 (14.7 percent), and rasagiline (4.8 percent).

“Temporally, 6–7 percent of patients treated with ER pramipexole, pramipexole, and P2B001 reported sleepiness-related TEAEs within the first days of treatment. While these rates remained relatively stable for pramipexole and P2B001, the proportion of patients experiencing sleepiness events steadily increased with ER pramipexole titration and maintenance therapy (plateau ~24 percent at week 6),” according to Fitzer-Attas.

“[C]urrent AAN guidelines have recently moved away from recommending dopamine agonist monotherapy, primarily due to the risks of dose-related side effects such as daytime sleepiness, impulse control disorders, cognitive impairment, and hallucinosis,” she said. [Neurology 2021;97:942-957]

In light of the results of the present analysis, Fitzer-Attas pointed out that P2B001 provides benefits comparable to marketed doses of ER pramipexole titrated to individual optimal doses while minimizing important daytime sleepiness-related side effects associated with this drug.