Oral levodopa pharmacokinetics are subject to excessive within- and between-subject variability, reflecting challenges inherent to gastrointestinal delivery. Aerosol delivery of levodopa bypasses the gastrointestinal tract and should significantly reduce the time to onset and improve pharmokinetic consistency, thereby optimizing therapeutic benefit when used with standard oral therapies. CVT-301 is a proprietary dry powder levodopa formulation that is optimized to deliver a precise dose to the lungs for rapid, predictable and consistent levodopa absorption. The objective is to demonstrate more rapid and consistent levodopa exposure and improved motor function following adjunct CVT-301 administration, compared to oral.
This project is designed to demonstrate the pharmokinetic attributes of intrapulmonary levodopa delivery compared to standard oral administration and to investigate the benefit of adding intrapulmonary levodopa to a standard oral regimen for Parkinson’s disease (PD) patients. The safety of CVT-301 will be investigated first in control volunteers. Following selection of dose(s), CVT-301 will be studied in PD patients as an adjunct to their standard oral therapy. In a placebo-controlled, cross-over design, the safety, levodopa profile and effects (i.e., motor responses) will be assessed, comparing CVT-301 to oral levodopa and placebo.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Inconsistent levodopa exposure is a major factor contributing to the development of both motor fluctuations and dyskinesias. As an adjunct to standard oral therapies, CVT-301 may facilitate consistent levodopa exposure and improve therapeutic benefit of the most used anti-parkinsonian drug. Such a product that provides rapid, predictable and consistent levodopa exposure would be a major breakthrough in the treatment of Parkinson’s disease.
Two key outcomes are anticipated from this project that will accelerate future clinical investigation of CVT-301. First, it is expected that the pharmacokinetic attributes of CVT-301 in humans will be consistent with those observed in pre-clinical models. Second, it is expected that adjunct administration of CVT-301 will enable more rapid and consistent levodopa exposure, leading to improved therapeutic benefit to PD patients.
A Phase I healthy volunteer study was completed in 26 subjects. Consistent with pre-clinical studies, CVT-301 administration resulted in rapidly increasing, dose-proportional plasma levodopa concentrations with therapeutically relevant levels achieved in five minutes. These data also demonstrated that the resulting levodopa levels were much less variable than occurs during oral administration.
A Phase II dose finding study was completed in 24 Parkinson's patients in the "off" state. The expectant pharmacokinetic profile (rapid and more precise increase of plasma levodopa concentration) was confirmed in patients. Significant and rapid improvement in motor function was also demonstrated with no increase in dyskinesia relative to oral levodopa administration. Response was durable, lasting for approximately 100 minutes.
CVT-301 was generally safe and well tolerated in all doses tested across both studies. There were no adverse changes in any respiratory (spirometry) endpoints. A Phase II-B study investigating the “as needed” use of CVT-301 adjunct to a scheduled daily regimen is currently underway for the treatment of "off" episodes.
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