Article In Brief
New research suggests apomorphine sublingual film is an effective on-demand rescue treatment for off-episodes for most patients with Parkinson's disease who were able to tolerate the treatment. Independent experts expressed concerns about the long-term adverse effects of the therapy.
New research comparing the sublingual apomorphine (Apokyn) to placebo found that the drug reduced Parkinson's disease (PD) motor symptoms significantly within 30 minutes, according to a new paper published online December 6, 2019, in The Lancet Neurology.
The study sponsors, Sunovian and Cynapsus Therapeutics, which developed the sublingual formulation, applied to the US Food and Drug Administration (FDA) for approval in April 2018. Last February, the FDA declined to approve the application and requested additional information regarding safety and human factor issues.
Neurologists who specialize in PD told Neurology Today the new formulation of apomorphine would fill a much-needed therapeutic gap in treating off episodes for some patients. But they expressed concerns about the long-term adverse effects and the possible costs of the new therapy.
That said, the evidence for the drug's effectiveness appears promising, the researchers involved in the new study said. “Our study supports earlier findings that apomorphine sublingual film is an effective on-demand treatment for off-episodes for most patients with PD who could tolerate treatment. This gives them another treatment option for off-episodes,” said lead investigator C. Warren Olanow, MD, chief executive officer of Clintrex, which provided advisory services to the study sponsors, Sunovian and Cynapsus Therapeutics, during the study. Dr. Olanow is a professor emeritus in the departments of neurology and neuroscience at the Mount Sinai School of Medicine in New York.
The US Food and Drug Administration (FDA) approved a levodopa inhaler in 2018 and apomorphine injections in 2004, Dr. Olanow noted. But despite their effectiveness, the injections never really caught on with patients due to the need for self-injection, in-office titration, and the risk of skin nodules and ulcers developing at the injection site, he said.
The levodopa inhaler is another effective treatment but has a dose limitation and requires co-administration of carbidopa, said Dr. Olanow.
In contrast, the soluble sublingual film is simpler to administer and has two layers—one for the drug and another for the PH-controlling buffer. The drug is absorbed systemically through the oral mucosa, which bypasses the rapid metabolism of the drug associated with gastrointestinal (GI) administration.
Study Design, Findings
Researchers conducted a randomized, double-blind, placebo-controlled trial at 32 academic neurology centers in the US and one in Canada between June 2015 and December 2017. Patients were eligible if they were diagnosed with PD consistent with UK Brain Bank criteria, were receiving stable doses of anti-parkinsonian medications, had a good response to levodopa, and had at least two off-periods per day along with predictable early morning ones.
Of the 141 eligible patients enrolled in the open-label dose titration phase, 32 discontinued treatment including 12 due to adverse events. The remaining 109 were randomly assigned to sublingual apomorphine or matching placebo in a 12-week double-blind maintenance phase.
Most of the participants were white men with an average age of 62. At baseline, patients had an average of 3.9 episodes daily and the average dose of levodopa was 1033 mg daily.
The starting daily dose of sublingual apomorphine was titrated from a 10 mg dose in 5 mg increments to a maximum of 35 mg until a full-on response was achieved within 45 minutes without intolerable side-effects. A full-on response was defined as an on-response similar to that obtained with levodopa.
The study met the primary endpoint of the study, which was the change in the Movement Disorder Society Unified Parkinson's Disease Rating Scale-part 3 [motor] between pre-dose and 30 minutes after dose at the 12th-week maintenance visit. The sublingual apomorphine group had a statistically significant 7.6-point reduction in motor symptoms compared with the placebo group (p<0.001).
The study also met the key secondary endpoint, which was the percentage of patients who achieved a full-on response within 30 minutes post-dose at week 12 of the study. Thirty-five percent of the patients treated with apomorphine sublingual had a full-on response compared with 16 percent of the placebo group (p<0.05).
Of significance is that 31 percent of patients taking sublingual apomorphine experienced side-effects compared with 7 percent taking placebo. Primarily these were mild-to-moderate oropharyngeal events, including soreness and swelling of the mouth and tongue, which contributed to the dropout rate. Dr. Olanow noted that once patients stopped using the drug, the oropharyngeal events rapidly disappeared. In some instances, the side-effects resolved spontaneously while the patients were still using the drug.
Patients also reported other adverse treatment events, including transient nausea (28 percent), somnolence (13 percent), and dizziness (9 percent).
Dr. Olanow indicated that he was surprised at the frequency of the side-effects, which was higher than previously observed.
Dr. Olanow noted that the side-effects did not appear to be dose-related. In addition, the researchers found that the benefit of treatment with apomorphine improved when the dose was increased to a higher tolerable level than the one that just turned the patient to an on-state. “For example, if a patient responded at 15 mg, we found their symptoms improved further at 20 mg.”
The main limitation was that the researchers randomly assigned only patients who were responsive to levodopa and achieved a full-on response during titration at a tolerable dose, thereby enriching the trial for responders.
The long-term safety and efficacy of apomorphine sublingual film are currently being investigated.
“There's a clear need in the PD community for rescue medications that bypass the GI tract, in an effort to improve likelihood of absorption. This study shows that the drug appeared to rescue people from off-states most of the time, according to home diaries they kept,” said Kathryn A. Chung, MD, associate professor of neurology at Oregon Health Sciences University, who was not involved in the study.
However, she said she was concerned about the significant dropout rate from the titration period through the end of the maintenance period. Nearly one-quarter of the subjects discontinued the drug by the end of the titration phase, and more than one-third discontinued the drug in the blinded maintenance phase. Treatment-emergent adverse events were listed as the reason 28 percent of patients taking the drug dropped out, but oropharyngeal symptoms were also a contributor, said Dr. Chung.
She noted that 28 percent of patients taking the drug reported nausea in spite of receiving anti-nausea medication beforehand. “While some patients may develop a tolerance to side-effects and continue on the drug, others may feel that they are too bothersome and discontinue using it.”
Dr. Chung also pointed to the trial result that 35 percent of patients taking the drug reported achieving an on-state within 30 minutes at the 12th week visit, which was a secondary endpoint.
“The authors were surprised with this result and countered this by showing that home diaries indicated that 80 percent of the time, an on-state was achieved. The study also required a 12-hour drug-free overnight period, which may explain why the drug may not be as successful in the clinic visit versus at home,” said Dr. Chung.
The cost of the drug remains to be seen. “If the drug is approved and affordable, I would prescribe it with the caveat that there's a good chance of having a side-effect, which might be a limiting factor. If the patient tolerates this well, it may be easier to take than what's currently on the market, which means giving themselves a shot or loading an inhaler,” said Dr. Chung.
“This is a novel delivery system for a drug that previously was available. But requiring an injection likely hindered the medication's widespread uptake,” said Janis Miyasaki, MD, MEd, FRCPC, FAAN, director of the Parkinson and Movement Disorders Program at the University of Alberta in Edmonton Canada, in an email.
Patients need a rescue medication for off-periods because excessive off-time or unexpected off- time restricts their social activities and exercise at times, said Dr. Miyasaki.
She also expressed concern about the drug's long-term adverse event profile. “Patients without strict guidelines on using the drug may overuse it due to the rapid onset of action and short duration, which may enhance the potential for abuse.”
She, too, was concerned about the drug's affordability. “Given the study used up to five [sublingual] wafers a day, this may result in patients using up to 150 wafers per month,” which could make it costly, said Dr. Miyasaki.
Dr. Olanow is a CEO and a shareholder in Clintrex, which provides advisory services for the pharmaceutical industry, and has consulted for Cynapsus Therapeutics and Sunovion. Drs. Chung reported no disclosures. Dr. Miyasaki disclosed that she received royalties for an UpToDate chapter on functional movement disorders.