Rapid Levodopa Augmentation Following Inhaled CVT-301 Results in Rapid Improvement in Motor Response When Administered to PD Patients in the OFF State (S7.007)

OBJECTIVE: To evaluate levodopa pharmacokinetics (PK) and pharmacodynamics following CVT-301 inhalation in PD patients with motor fluctuations. BACKGROUND: Variability in oral levodopa absorption and pharmacokinetics (PK) contributes to the development of OFF states, the major problem of levodopa-treated PD patients. In nonclinical models, following intrapulmonary delivery, levodopa was more rapidly absorbed and PK was less variable, resulting in rapid motor function improvement. CVT-301, a dry powder inhaled levodopa formulation is being developed for the treatment of intermittent OFF episodes. DESIGN/METHODS: This was a double-blind (DB), placebo-controlled, crossover study of CVT-301 in 24 PD motor fluctuators experiencing >2hr/day OFF time. Subjects received single doses of study drug ~4-5hrs following usual morning oral PD medications, following their first OFF. Open-label oral Sinemet™ (25/100mg) was administered on the first treatment day; DB inhaled CVT-301 (25mg and 50mg levodopa fine particle dose [FPD]) or placebo were administered randomly on days 2, 3 and 4. Levodopa concentrations [levodopa], motor response (timed tapping, UPDRS III) and safety were evaluated over 3hrs postdose. RESULTS: Baseline-adjusted levodopa Cmax and AUC increased dose proportionally. Incremental [levodopa] following inhaled CVT-301 (50 mg FPD) approached therapeutically-relevant increments by 5min (mean baseline adjusted Cmax 698 ng/mL). Levodopa variability was considerably lower following CVT-301 than with oral Sinemet. Timed tapping and UPDRS responses were dose-ordered. Relative to placebo, only CVT-301 50 mg FPD resulted in statistically significant improvements in average and maximal changes in timed tapping and UPDRS; onset of motor response improvement was observed at 5min post-dose. There was no increase in frequency or severity of dyskinesia. CVT-301 was generally safe and well tolerated. There were no adverse events resulting in discontinuation or serious AEs. There were no adverse changes in spirometry measures at either inhaled CVT-301 dose. CONCLUSIONS: Inhaled CVT-301 rapidly augments [levodopa] and results in rapid motor function improvement in PD patients experiencing an OFF episode. Study Supported by: Grant from the Michael J. Fox Foundation for Parkinson9s Research Disclosure: Dr. Freed has received personal compensation for activities with Civitas Therapeutics as an employee. Dr. Grosset has received personal compensation for activities with Civitas Inc., Vectura Group, and General Electric Healthcare. Dr. Grosset has received research support from Merz Pharma. Dr. Worth has received personal compensation for activities with UCB Pharma, Genus, Teva Neuroscience, Lundbeck Research USA Inc., and Civitas as a speaker. Dr. Gurevich has nothing to disclose. Dr. Defeo-Fraulini has received personal compensation for activities with Civitas Therapeutics as an employee. Dr. Moore has received personal compensation for activities with Civitas Therapeutics as a consultant. Dr. Batycky has received personal compensation for activities with Civitas Therapeutics as an employee.