Self-administered levodopa inhalation powder (Inbrija, Acorda) can significantly improve motor function during “off” periods in patients with Parkinson’s disease (PD), results from a phase 3 trial suggest. The findings are published in the February issue of Lancet Neurology.
As reported at the time by Medscape Medical News, topline results from the randomized SPAN-PD trial were released in 2017. The study weighed heavily in the December 2018 US Food and Drug Administration (FDA) approval of the drug, which is also known as CVT-301. This is the first publication of detailed findings from the study.
Among more than 300 patients with PD who were already taking both carbidopa and levodopa, those randomly assigned to receive the study drug at 84 mg during a return of symptoms (off periods) showed significantly greater improvement in motor scores on the Unified Parkinson’s Disease Rating Scale Part III (UPDRS III) at week 12 than the group taking placebo. Such improvement was the study‘s primary endpoint.
In addition, 58% of the 84-mg group returned to and stayed at an “on” state (symptom control) through 60 minutes compared with 36% of participants who received placebo.
“A well-tolerated, effective treatment for off periods between doses of scheduled medications can help fulfill one of the most important unmet needs for people with Parkinson’s,” principal investigator Peter LeWitt, MD, director of the PD and Movement Disorders Program at Henry Ford Hospital, West Bloomfield, Michigan, said in a press release.
He added that this new option does just that, delivering the “gold standard” of PD treatment in a novel, inhaled formulation.
“With all the problems that [oral] levodopa has getting absorbed into the bloodstream, this is an alternative that proved to be safe and acceptable to the average patient,” LeWitt told Medscape Medical News.
The company noted that it expects to make the inhaled drug available by prescription through specialty pharmacies before the end of 2019’s first quarter.
Although oral levodopa plus a dopa-decarboxylase inhibitor (LD-DCI) is considered to be standard of care for PD, patients often experience delayed onset or shorter duration of benefit from the treatment — especially after 2 years of continued use.
“Levodopa is a short-acting drug, and it’s one whose uptake from the GI tract has a number of competing factors, such as diet, the efficiency of the stomach getting the drug out, and the uptake not only in the gut but also the blood-brain barrier,” LeWitt said.
“In short, it’s a bit of a minor miracle that the drug actually gets to the brain with any regularity at all. And it does so with a fairly rapid clearance half-life. So if you’re lucky enough to remember to take your pill on time, it’s a drug that has about a 2.5- to 3-hour transit time,” he added.
Although the subcutaneously administered drug apomorphine (Apokyn, US WorldMeds) reverses off periods in PD, frequent AEs and the fact that it must be injected have led to its underuse, note the investigators.
CVT-301, on the other hand, is an orally inhaled, powdered form of levodopa that “bypasses the gastrointestinal tract,” they write.
Device Designed for PD Patients
The phase 3 SPAN-PD trial was created to assess safety and efficacy of the drug for improving motor function during off periods. In the study, 351 patients with PD (mean duration, 8.3 years) were enrolled at 65 sites in the United States, Canada, Poland, and Spain from December 2014 to August 2016.
All were aged 30 to 85 years and reported having daily off periods lasting at least 2 hours (mean average, 5.5 hours). They also showed a 25% or greater improvement in UPDRS motor score from “off” to “on” states after using an LD-DCI.
Among the 339 participants who underwent randomization, 113 received the study drug at 60 mg (71% men; mean age, 63.9 years), 114 received it at 84 mg (73% men; mean age, 63.5 years), and 112 received matching placebo (77% men; mean age, 62.6 years). In all three groups, 96, 97, and 97 participants, respectively, completed the study.
Each group received two capsules along with an inhaler and were told to self-administer during off episodes, as needed, for up to five doses per day, in or out of clinic, as adjunct therapy to their daily LD-DCI regimen. Interestingly, although the participants reported an average of 3.5 off periods per day at baseline, those in the 84-mg dosing group used an average of just two doses of treatment per day throughout the study.
During the 12-week treatment period, visits were conducted at baseline and at weeks 4, 8, and 12. Patients were trained in how to use the inhalers during screening visits; to be included in the study, they had to prove they could use the inhaler.
“For Parkinson’s patients who are impaired in dexterity or who may have other issues, even cognitive concerns, this product was designed for use in their hands,” LeWitt said. “The amount of breathing control to inhale the product is actually quite minimal. There’s no huge inhalation gasp needed to get delivery of the drug.”
In home diaries, patients recorded information about their on and off states and assigned scores on the Patient Global Impression of Change (PGI-C) scale for symptoms of PD.
“Generally Safe, Well Tolerated”
The mean difference in UPDRS motor score change at the week 12 office visit from predose to 30 minutes postdose was -9.83 (95% confidence interval [CI], -12.79 to -6.87) for the patients who received the 84-mg dose vs -5.91 (95% CI, -8.86 to -2.96) for those who received placebo (between group comparison, P = .009).
Among the patients who completed the study, 56 of 97 patients in the 84-mg group (58%) achieved and maintained an on response for 60 minutes at the same 12-week visit, compared with 35 of 97 members of the group that received placebo (36%; comparison, P = .003).
The change in UPDRS motor score from predose to 20 minutes after dosing was not significantly different between the groups (P = .06), so “subsequent secondary analyses were ineligible for being declared statistically significant,” the investigators write.
Still, 71% of the 84-mg group vs 46% of the group that received placebo showed symptom improvement on the PGI-C scale at week 12 (P < .001). Also, in-clinic observations showed that motor rating improvements in the 84-mg group started at 10 minutes after inhalation.
“Overall, CVT-301 at 60 mg and 84 mg doses was generally safe and well tolerated,” the researchers write.
There were 19 serious AEs reported in the full group of 339 participants. Serious AEs occurred 5% of the 60-mg group, 2% of the 80-mg group, and 3% of the group that received placebo. The only serious AEs deemed to be possibly related to the study drug were one case of hypotension in the 60-mg group and one case of atrial fibrillation in the 84-mg group.
In addition, 3%, 5%, and 3% of the groups, respectively, reported an AE serious enough for study withdrawal.
There were also five reports of dyskinesia in the 60-mg group and four reports in the 84-mg group. Although 42% of all participants had dyskinesia at baseline, “it should be noted that the study excluded patients with pre-existing severe dyskinesias,” the investigators write.
Most reports noted that the cough was mild or moderate and began within the first 30 days of treatment. Only one patient had a severe cough (in the 60-mg group).
“In our study, CVT-301 treatment achieved reliable improvements of off periods without an increase in dyskinesia and with an acceptable safety profile,” the investigators write.
“With this drug, which is the same one that people rely on and have been doing for 50 years, they have a way to carry it around as an insurance policy if they don’t use it or as an active tool if they do use it to get back on for a period of time while their oral medications can kick in. They can use it multiple times during a day and can station it around their home in multiple places,” LeWitt said.
“I see it as a tool to guide people back to responsiveness of levodopa in a way that…is effective and acceptable to patients,” he added.
In an accompanying editorial, Olivier Rascol, MD, PhD, Services de Neurologie et de Pharmacologie Clinique, Centre Hospitalier Universitaire de Toulouse, France, notes concern that “CVT-301 was not better than placebo, or the effect was smaller than anticipated” for several of the secondary efficacy outcomes, which he says calls into question the drug‘s usefulness in clinical practice.
Also, the reduction by 3.9 units on the UPDRS at 30 minutes was smaller than the 7-unit reduction shown in the phase 2 trial.
“This finding was surprising, knowing the robust effect of levodopa and considering the strong dopaminergic responsiveness of this cohort,” Rascol writes.
He notes that although the investigators suggest that the drug could have been inhaled when the patients weren’t in “fully off” states, it could be that the tested doses weren’t high enough. Other possibilities he cites for the poorer-than-expected results include the study‘s insufficient statistical power and the low daily usage of the active drug.
“In summary, the trial by LeWitt and colleagues is a welcome addition, because the principle of inhaling levodopa is appealing and findings provide evidence that CVT-301 improves symptoms” of PD, he writes.
“However, the effect sizes recorded in this trial are not as good as anticipated, in terms of speed and amplitude of the acute response and of the effect on daily time spent in an off state,” Rascol notes.
He adds that more research is needed, including studies comparing the drug with injectable apomorphine and assessing the efficacy of CVT-301 in doses higher than 84 mg, “if technically possible with this device.”
The FDA approved the drug at 84 mg. “As a drug comes into the real world, if it’s a very safe one and a local physician chooses to give higher doses, it looks like the drug is safe enough both from oral experience and in the context of the study that that would be a safe endeavor,” said LeWitt.
“I agree that that would be a nice thing to explore, since patients often have different optimal doses of levodopa and the other Parkinson’s medications,” he added.
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