Preclinical and clinical assessment of inhaled levodopa for OFF episodes in Parkinson’s disease

Abstract

Inhaled drugs offer advantages, such as rapid onset of action, but require formulations and delivery systems that reproducibly and conveniently administer the drug. CVT-301 is a powder formulation of levodopa delivered by a breath-actuated inhaler that has been developed for treating OFF episodes (motor fluctuations between doses of standard oral levodopa) in patients with Parkinson's disease (PD). We present preclinical, phase 1, and phase 2 results for CVT-301. In dogs insufflated with a levodopa powder, plasma levodopa peaked in all animals 2.5 min after administration; in contrast, in dogs dosed orally with levodopa plus carbidopa, plasma levodopa was not detected until 30 min after administration. In 18 healthy persons, comparisons between inhaled CVT-301 and oral carbidopa/levodopa showed analogous differences in pharmacokinetics. Among 24 PD patients inhaling CVT-301 as a single 50-mg dose during an OFF episode, 77% showed an increase in plasma levodopa (>400 ng/ml) within 10 min versus 27% for oral dosing with carbidopa/levodopa at a 25-mg/100-mg dose. Improvements in timed finger tapping and overall motor function (Part III of the Unified Parkinson's Disease Rating Scale) were seen 5 and 15 min after administration, the earliest assessment time points. For average and best change, the improvements were statistically significant compared to placebo. The most common adverse event was cough; all cough events were mild to moderate, occurred at the time of inhalation, resolved rapidly, and became less frequent after initial dosing. These results support further development of CVT-301 for better management of PD.

Orally inhaled levodopa (CVT-301) for early morning OFF periods in Parkinson's disease

“…The observed orthostatic hypotension was asymptomatic, was not more frequent after CVT-301 TEAEs, treatment-emergent adverse events. Cough was the most frequently reported TEAE following CVT-301 inhalation, which agrees with observations from previously published studies of CVT-301 [13,14,22]. All reported cough AEs were mild in severity and transient and did not lead to study discontinuation.…”

“…In a crossover study in patients with PD, plasma LD concentrations increased more rapidly after CVT-301 inhalation and with less variability in concentration than after oral CD/LD dosing, and in a pivotal phase 3 study it met the primary endpoint, improving the change in UPDRS-III score at 30 min post-dose compared with placebo at week 12, when administered during an OFF period [15]. The adverse events (AEs) and safety profile of CVT-301 were consistent with earlier studies [13,14]. However, treatment of early morning OFF symptoms was specifically excluded in these studies.…”

“…CVT-301 bypasses the gastrointestinal tract and enters the circulatory system rapidly and predictably [13,14]. In a crossover study in patients with PD, plasma LD concentrations increased more rapidly after CVT-301 inhalation and with less variability in concentration than after oral CD/LD dosing, and in a pivotal phase 3 study it met the primary endpoint, improving the change in UPDRS-III score at 30 min post-dose compared with placebo at week 12, when administered during an OFF period [15].…”

Aurrerapen terapeutikoak Parkinson gaixotasunean

“…CT-301-k ordubeteko iraupena duen hobekuntza moderatua eskaintzen du, eta efektu maximoa ordu erdira lortzen da. Ondorioen artean, eztula da arruntena (pazienteen % 15a), oro har jasangarria den arren [49], [50].…”

L‐DOPA for Parkinson's disease—a bittersweet pill

“…A trigel formulation with the addition of entacapone is currently in development, which may add increased clinical benefit (Senek, Nielsen, & Nyholm, ). New formulations in clinical trials currently include inhaled (CVT‐301) (Lipp, Batycky, Moore, Leinonen, & Freed, ) for management of “OFF‐phase” and liquid for subcutaneous administration (ND0612) as a patch‐pump. ND0612 is being developed for moderate and severe disease and could produce much improved control of plasma L‐DOPA levels and therefore dyskinesia (Freitas, Ruiz‐Lopez, & Fox, ; Ramot et al., ).…”