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.