Martin Freed

A randomized trial of inhaled levodopa (CVT-301) for motor fluctuations in Parkinson's disease.

Although levodopa is the most effective oral PD therapy, many patients experience motor fluctuations, including sudden loss of dose effect and delayed benefit. CVT‐301 is a levodopa inhalation powder with the potential for rapid onset of action. The objective of this study was to evaluate CVT‐301 self‐administered by PD patients to relieve OFF episodes.

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

A levodopa powder delivered by a breath-actuated inhaler produced a rapid increase in plasma drug concentrations and improved motor function during OFF episodes in patients with Parkinson’s disease. An inhaled treatment for Parkinson’s Disease Half a century after its introduction, levodopa remains the most effective orally administered drug for suppressing the symptoms of Parkinson’s disease. As the disease advances, however, the drug’s effectiveness becomes increasingly prone to failure between doses. Inhalation of the same drug might address this problem. CVT-301 is a levodopa powder administered by an inhaler for use on an as-needed basis. Inhalation gives levodopa immediate access to the lungs, from which it can promptly reach the brain. Lipp et al. now present preclinical and clinical evidence that CVT-301 is suitable for inhaled dosing and that it ameliorates OFF episodes when the benefits of the oral drug wear off. 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.

Prospective evaluation of pulmonary function in Parkinson's disease patients with motor fluctuations

Background. Spirometry patterns suggesting restrictive and obstructive pulmonary dysfunction have been reported in Parkinson’s disease (PD). However, the patterns’ precise relation to PD pathophysiology remains unclear. Purpose/Aim. To assess ON- versus OFF-state pulmonary function, the quality of its spirometric evaluation, and the quality of longitudinal spirometric findings in a large sample of PD patients with motor fluctuations. Methods. During a placebo-controlled trial of an inhaled levodopa formulation, CVT-301, in PD patients with ≥2 h/d of OFF time, spirometry was performed by American Thoracic Society (ATS) guidelines at screening and throughout the 4-week treatment period. Results. Among 86 patients, mean motor impairment during an OFF state at screening was moderately severe. However, mean spirometry results at screening were within normal ranges, and in a mixed model for repeated measures (MMRM), the results at screening were not dependent on motor state (ON vs. OFF). In the placebo group (n = 43), 76% of ON-state and 81% of OFF-state examinations throughout the study met ATS quality metrics, and in an MMRM analysis, mean findings at these patients’ arrivals for treatment-period visits showed no significant 4-week change. Across all 86 patients, flow-volume curves prior to any study-drug administration showed only a 3% incidence of “sawtooth” morphology. Conclusions. In PD patients with motor fluctuations, longitudinal spirometry of acceptable quality was generally obtained. Although mean findings were normal, about a quarter of spirograms did not meet ATS quality criteria. Spirogram morphology may be less indicative of various forms of respiratory dysfunction than has previously been reported in PD.