番茄社区

VANCOUVER -- Inhaled levodopa (CVT-301) passed a phase III test, significantly improving motor function during Parkinson's "off" periods compared with placebo, researchers reported here.

At 12 weeks, change in Unified Parkinson's Disease Rating Scale (UPDRS) Part III scores 30 minutes post-dose was significantly greater among those given 84 mg of CVT-301 compared with placebo (-9.83 versus -5.91, P=0.009), Peter LeWitt, MD, of Henry Ford Hospital in Detroit, and colleagues reported during a late-breaking poster session at the here.

The drug also produced better results than placebo at helping patients achieve an "on" state by 60 minutes -- although a pre-specified 12-point hierarchical analysis became non-significant at the third item of change in UPDRS Part III scores at 20 minutes, leaving the subsequent steps technically ineligible for statistical significance.

Nonetheless, investigators were encouraged by the results, and a new drug application will be filed with the FDA by the end of the month, according to co-author Charles Oh, MD, a vice president of clinical development at drugmaker Acorda Therapeutics.

"We have a different delivery of levodopa ... and there's some indication that it's much faster than oral levodopa, and from a safety standpoint it's not worse than oral levodopa," Oh told 番茄社区 during the poster session.

CVT-301 moves from the lungs into the bloodstream, bypassing liver metabolism for faster action. Its purpose is for on-demand use in "off" periods among patients on oral levodopa.

In the phase III SPAN-PD study, 339 patients received at least one dose of the drug or placebo, and 290 completed the study. Patients were randomized to placebo or to one of two doses of the drug (60 mg or 84 mg) for a period of 12 weeks. They were told to use the inhaled levodopa to treat their "off" periods on an as-needed basis, up to 5 times per day.

In addition to hitting the primary endpoint, a higher proportion of patients in the CVT-301 dose groups achieved an "on" state within 60 minutes of treatment and continued to remain "on" at 60 minutes by the end of 12 weeks (57.7% and 55.6% versus 36.1%, P<0.05).

But that was where the significance technically had to stop for the 12-point hierarchical analysis, given that the third step didn't muster significance (P=0.062) -- but the fourth item of patient-reported outcomes was significant, as was the fifth item of change in UPDRS Part III scores at 10 minutes.

Oh emphasized that a higher proportion of patients in the drug groups reported improvement in the Patient Global Impression of Change (71.4% and 61.6% versus 46.4%, P<0.05).

"It always helps to have supportive evidence from different types of endpoints, so by itself this may not be elevated to the point of whether it's approved or not, but the combination of endpoints pointing to the same outcome helps show the FDA that the treatment is effective and safe," he said.

In terms of safety, the most common adverse event was cough, and it occurred at a much higher rate in the drug groups compared with placebo (15% for both versus 2%). There was also more upper respiratory infection (6.1% versus 2.7%), nausea (5.3% versus 2.7%), and sputum discoloration (5.3% versus 0%) with the higher dose of the drug compared with placebo.

A total of nine patients in the drug groups and three in the placebo group withdrew due to adverse events. In the drug-treated groups, cough led to withdrawal in three drug treated patients, Oh said.

"This is something you're breathing in, and particulate matter is going into the lungs," he told 番茄社区. "That would be expected to trigger some cough reflex in people not used to breathing particulate matter. But for the most part, once patients get used to the sensation, it's not problematic."

Oh noted that a year-long safety study comparing patients on the drug with an observational Parkinson's cohort showed no difference between groups in terms of lung function. There was no indication of malignancy in that study, either: "It's a smaller molecule so it shouldn't linger in the lungs, and most of it is absorbed quickly."

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