Inhaled Levodopa Shows Promise for Treatment of Parkinson’s Disease
Therapy provides relief from 'off' episodes
Positive results have been reported from a phase IIb trial of CVT-301 (Civitas Therapeutics), an inhaled formulation of levodopa (L-dopa). The new findings were presented April 29 at the 66th Annual American Academy of Neurology meeting, held in Philadelphia, Pennsylvania.
CVT-301 is being developed as an adjunctive, as-needed therapy to provide relief from intermittent debilitating motor fluctuations — “off” episodes — experienced by patients with Parkinson’s disease (PD). The treatment provides rapid delivery of L-dopa to the brain without altering a patient’s individually optimized oral L-dopa regimen.
Oral L-dopa, used for chronic symptom management, is administered to maintain dopamine levels in the brain above the therapeutic threshold; however, the reliability of oral L-dopa formulations is significantly compromised by delayed and unpredictable absorption and by excessive variability in drug concentrations in the bloodstream inherent to the oral delivery route. L-dopa remains widely recognized as the most efficacious treatment for PD symptoms in spite of this intrinsic unreliability, which results in “off” episodes, which affect more than half of all patients treated with an oral L-dopa regimen.
The new phase IIb trial was a randomized, double-blind, placebo-controlled study of CVT-301 or placebo for the treatment of up to three “off” episodes per day in PD patients experiencing intermittent “off” episodes. The 86 patients treated in this study underwent an initial screening and run-in period of 2 to 4 weeks, during which baseline motor assessments, were conducted using the Unified Parkinson’s Disease Rating Scale Part III (UPDRS III), as well as other baseline efficacy, safety, and pulmonary-function measurements.
After the initial screening and run-in period, the patients were randomly assigned to receive CVT-301 or inhaled placebo in a double-blind fashion. During the first 2 weeks of treatment, patients self-administered an inhaled levodopa dose of approximately 35 mg or placebo. During the final two treatment weeks, patients were dose-escalated to an inhaled levodopa dose of approximately 50 mg or placebo. In-office assessments of UPDRS III were performed at week 1, week 2, and week 4.
The study’s primary efficacy endpoint was the mean change from pre-dose values in average UPDRS III scores (10 to 60 minutes post-dose) after 4 weeks of treatment. The patients were also instructed to complete a PD diary for 3 days prior to the office visits, recording daily “off” and “on” times with and without dyskinesia, as well as a daily treatment log. Safety parameters included pulmonary function, electrocardiograms, and vital signs (i.e., blood pressure, heart rate, and orthostatic blood pressure).
The trial’s primary endpoint was successfully met, with CVT-301 achieving a clinically important and statistically significant reduction in average UPDRS III motor scores compared with placebo at time points ranging from 10 to 60 minutes after administration (P < 0.001). Further, clinically important and statistically significant improvements in UPDRS III were seen at every time point, including 10 minutes (the earliest time point tested), for both doses.
Over the course of the study, patients self-administered CVT-301 as-needed to treat approximately 4,500 “off” episodes, with an average of approximately two treatments per day. During self-administration at home, CVT-301 was not associated with an increase in dyskinesia. All doses of CVT-301 were safe and well-tolerated, and the CVT-301 inhaler was shown to be easily used by PD patients in the “off” state.
Source: Civitas Therapeutics; April 28, 2014.