Daniel M. Keller, PhD

June 19, 2015

SAN DIEGO — A novel, inhaled form of levodopa provides relief of "off" episodes for patients with Parkinson's disease (PD) and does not increase the amount of "on" time with dyskinesia, a recent study shows.

Levodopa is the most effective oral medication for relief of PD symptoms, but up to half of patients treated with levodopa experience motor fluctuations with prominent "off" episodes.

The drug, CVT-301 (Acorda Therapeutics) addresses the problem of "delayed 'on' or unreliable onset of levodopa effects," lead author Peter LeWitt, MD, MMedSc, director of the Parkinson's Disease and Movement Disorders Program at Henry Ford Hospital in West Bloomfield, Michigan, and professor of neurology at Wayne State University School of Medicine in Detroit, Michigan, told Medscape Medical News.

"The route of administration by inhalation is rapid, less than 10 minutes in some of the reported data, and also the reliability is quite good," he said. Oral medications can take up to 45 minutes before having an effect.

The phase 2 trial reported here at the 19th International Congress of Parkinson's Disease and Movement Disorders (MDS).

For this study, patients with 2 or more hours a day of "off" time were randomly assigned to self-administer CVT-301 or placebo as needed to treat emergence of these states up to three times a day over a 4-week period as an adjunct to their oral levodopa/dopamine-decarboxylase inhibitor regimen. They used 35 mg of inhaled levodopa each time for the first 2 weeks and then 50 mg for the next 2 weeks.

During a pretreatment screening phase of the trial, the drug and placebo groups were well matched for age, sex, duration of disease, "off" time and episodes per day, PD drug use, and Unified Parkinson's Disease Rating Scale (UPDRS) Part III scores during "on" and "off" times. PD diary categories did not significantly differ between the groups at screening.

The average patient age among the 86 patients was about 62 years, and the patients averaged 9 to 10 years since diagnosis. Their mean "off" time was 5.9 hours a day over an average of 3.5 to 3.7 episodes a day. Levodopa intake averaged 770 mg/day divided over 6 doses.

The average study drug or placebo use frequency was 2.1 times a day. Patients did not report any problems using the drug inhaler system, which took about 30 seconds to prepare and use each time.

Rapid Relief of "Off" Episodes

Patients' motor function improved in a dose-ordered fashion in response to CVT-301, as assessed by the UPDRS Part III. Assessments made at 10-minute intervals from 0 to 60 minutes showed improvements at all time points of 10 to 60 minutes compared with placebo for both doses (for 35 mg at week 1 and for 50 mg at week 4). The primary efficacy analysis was made at week 4.

The 35-mg dose reduced daily "off" time by 1.1 hours, and the 50-mg dose significantly reduced "off" time by 1.6 hours/day.

Table. Least-Squares Mean Change on UPDRS Part III

CVT-301 Dose CVT-301 (n = 43) Placebo (n = 43) Least-Squares Mean Difference P Value
35 mg –9.9 –5.3 –4.6 .007
50 mg –10.0 –3.1 –7.0 <.001

 

The medication was safe and well tolerated during the 1-month study. About half the patients in the CVT-301 group and one third of patients in the placebo group reported treatment-emergent adverse effects, but none occurred in more than 7% of patients in the drug or placebo groups.

There were no differences in "on" time with dyskinesia at either dose at any time point compared with placebo. One patient in the placebo group experienced a severe adverse event of dyskinesia. All pulmonary functions were within normal ranges (with spirometry fluctuations characteristic of patients with PD), and no cardiovascular adverse effects were seen.

Dr LeWitt noted that the comparator for CVT-301 would be apomorphine (Apokyn, US WorldMeds) injections "so people who are using Apokyn injection as a rescue would be the target audience presumably for this product to replace, and the difference is that apomorphine by itself works very well."

In the case of levodopa, "if you don't have carbidopa on board from previous oral administration, this dose of levodopa might not work because most of levodopa is metabolized peripherally and doesn't get into the brain," Dr LeWitt said.

It is possible that direct inhalation may allow levodopa by itself to work, "and I think the preliminary data that have been presented suggest that it does work, but how well it works relative to apomorphine, how rapidly it works, which one will have fewer side effects — it's possible that one is better than the other," he said, and proposed that a crossover study with the two therapies would be informative.

Although an inhaled drug may be easier for the patient than an injection, the key to acceptance will probably be high and reliable efficacy without adverse effects, such as hallucinations or dyskinesias. Apomorphine has been available in the United States for almost 10 years, "so it sets a standard for which this better do better if they're going to be successful in marketing, in my opinion," Dr LeWitt said.

A statement from Acorda notes that the company is enrolling patients in a phase 3 pivotal study, a randomized, multicenter, placebo-controlled, double-blind study of inhaled CVT-301 vs placebo in patients with PD with motor fluctuations as an outpatient and in the clinic.

The primary outcome is change in UPDRS Part III motor score from predose state, over an average of four time points (10, 20, 30, and 60 minutes postdose) at weeks 8 and 12. The study will be recruiting approximately 345 patients from sites in the United States and Canada.

Maurizio Facheris, MD, senior associate director for research programs at the Michael J. Fox Foundation for Parkinson's Research, pointed out to Medscape Medical News that the rapidity of action of CVT-301 is a major benefit. "It takes up to 5 minutes to...potentially reach concentrations of the drug that are efficacious to bring the 'on' state," he said.

 
Having something that can truly rescue and bring the concentration of the drug back to normal in as short as 5 minutes, it would be an incredible both clinical and psychological advantage. Dr Maurizio Facheris
 

This rapid action can provide a patient with a psychological advantage. "The majority of people in my opinion that have motor fluctuations try to avoid going out for dinner or going to the theater because what if they get frozen?" he said. "Having something that can truly rescue and bring the concentration of the drug back to normal in as short as 5 minutes, it would be an incredible both clinical and psychological" advantage.

He reiterated Dr LeWitt's caution that the drug is only levodopa, so it is for people already taking levodopa/carbidopa. "Otherwise, it will be inefficacious because without carbidopa the drug will be destroyed in the periphery without reaching the brain."

Dr Facheris said besides injectable apomorphine, competition may be coming from a company developing a sublingual form of apomorphine, also with an expected quick onset of action.

The study was funded by Civitas, which is now owned by Acorda Therapeutics. Dr LeWitt has received compensation for advisory services, consulting, research support, or speaker honoraria from AbbVie, Acadia, Adamas, Addex, Allergan, Biotie, Civitas, Concit, Depomed, Great Lakes, Impax, Insightec, Intec, Ipsen, Knopp, Kyowa, Lundbeck, Merck, NeuroDerm, Noven, Osmotica, Pfizer, Pharma 2B, ProStrakan, Phytopharm, Teva, Tremor Research Group, UCB, US WorldMeds, and XenoPort. Dr Facheris is an employee of the Michael J. Fox Foundation for Parkinson's Research. The foundation supported preclinical development of CVT-301.

19th International Congress of Parkinson's Disease and Movement Disorders (MDS). Abstract 260. Presented June 15, 2015.

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