Apomorphine sublingual film (Kynmobi, Sunovion Pharmaceuticals) was efficacious and generally safe and well tolerated for the on-demand treatment of OFF episodes in Parkinson's disease, long-term follow-up of a phase 3 study has shown.
Besides the usual adverse effects with apomorphine, the sublingual film was associated with more oral adverse effects than seen with the injectable drug. However, it may have some advantages over subcutaneous apomorphine injections in terms of administration during OFF episodes.
The study was presented at the Movement Disorder Society 23rd International Congress of Parkinson's Disease and Movement Disorders (Virtual) 2020.
For example, the new formulation is more convenient than carrying an injection. It comes in a small, tear-open packet that contains a medication strip the patient places under their tongue.
"When a patient is in the OFF state, depending on how OFF they are, they could have a little difficulty opening the strip [packet], but anyone can open the strip for them," lead author Rajesh Pahwa, MD, professor of neurology and chief of the Parkinson and Movement Disorder Division at the University of Kansas Medical Center in Kansas City, Kansas, told Medscape Medical News. "On the other hand with the subcutaneous, they have to give the injection themselves and a stranger or someone is not going to help them with that."
The aims of this open-label, 48-week follow-up were to add new patients to assess safety and tolerability over the long term and to see if continued benefit from a previous 12-week double-blind study was still present at 1 year for patients in the earlier study.
This multicenter study (NCT02542696) included "rollover" patients (n = 78 for safety; n = 70 for efficacy) from the previous phase 2/3 double-blind trial, as well as new patients with no prior exposure to apomorphine sublingual film (n = 347 for safety; n = 275 for efficacy).
New patients experienced one or more OFF episodes/day with a daily OFF time of ≥ 2 hours/day while on stable doses of levodopa-carbidopa. All had clinically meaningful responses to levodopa-carbidopa and were judged by the investigator to be Stage 1-3 by modified Hoehn and Yahr scale rating during ON periods.
Rollover patients completed the prior study and had no major changes in their anti-Parkinson's medications since then. Mouth cankers or sores were exclusion criteria for either group. New subjects could not have received subcutaneous apomorphine within 7 days of a screening visit.
The demographics and baseline characteristics of the new and rollover groups were similar (approximately 64 years, 65%-71% male; 96% white, 8.3 to 9.6 years since diagnosis, 3.9 to 4.1 OFF episodes/day, and total mean daily levodopa dose of 1120 to 1478 mg).
Assessing only the group of new patients, the investigators reported that 80% had a Hoehn and Yahr score of 2 or 2.5 when in the ON state and a Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III pre-dose score of 41.8.
At the beginning of this study, patients in an OFF period received titrated doses of 10 to 35 mg of sublingual apomorphine in 5 mg increments during sequential office visits until they achieved a tolerable full ON within 45 minutes of a dose. They then entered a 48-week safety and efficacy phase, during which they self-administered the drug at home up to 5 times daily for OFF episodes with a minimum of 2 hours between doses. The investigators could adjust the doses for safety or lack of efficacy.
Two thirds of new patients and three quarters of rollovers received doses in the 10-20 mg range. The highest dose in the study of 35 mg was used by only 8%-9% of patients, but the highest approved and marketed dose is 30 mg.
Onset of efficacy was achieved by 15 minutes post-dose for both new and rollover patients, and maximal efficacy occurred by 30 minutes. Results were very similar at 24, 36, and 48 weeks. The investigators did not perform statistical analyses.
| Table 1. Change From Pre-dose Mean MDS-UPDRS Part III Scores at Week 24 |
||
| Time Post-dose (min) |
New Patients |
Rollover Patients |
| 15 |
–13.7 |
–12.2 |
| 30 |
–19.6 |
–21.6 |
| 60 |
–18.0 |
–22.4 |
Across study weeks 1, 12, 24, 36, and 48, 77%-92% of new patients and 65%-77% of rollover patients self-reported full ON within 30 minutes. "The long-term benefits are maintained over a year as far as the speed of onset and the duration," Pahwa said.
Treatment-emergent adverse events (TEAEs) occurred in about half of the new and the rollover patient groups in the titration phase and in 71%-81% of patients during the long-term safety phase. Nearly all were mild to moderate in severity.
A large number of participants withdrew from this long-term safety phase because of adverse events — 90 (33%) of new enrollees and 16 (23%) of rollover patients. Only 4% dropped out for lack of efficacy, all in the new enrollee group. Because the sublingual formulation is delivered under the tongue, patients in that group had more oral side effects, Pahwa said. Otherwise, "the side effects were very similar to the subcutaneous delivery."
TEAEs specific to sublingual apomorphine included oral mucosal erythema, lip or tongue swelling, and mouth ulceration (6%-7% of patients each). Occurring less often were glossodynia, oral candidiasis, stomatitis, and tongue ulceration (2% each).
These were in addition to adverse events typically occurring with subcutaneous apomorphine, which are nausea, falls, dizziness, somnolence, dyskinesia, syncope, and yawning.
There are no head-to-head comparisons of sublingual vs subcutaneous delivery of apomorphine. But based on experience, Pahwa said, "With the subcut[aneous], you have a slightly faster onset of action compared to the sublingual. However, sublingual has a slightly longer duration of benefit."
He predicted that patients may prefer using an injection for a faster benefit or a sublingual for a slightly longer benefit.
Commenting to Medscape Medical News, Ray Dorsey, MD, professor of neurology at the University of Rochester, New York, said that for people with more advanced Parkinson's disease "there's usually a caregiver who's injecting someone with an OFF period, as opposed to sublingual, which seems like a much easier way of administering a drug, especially for people with motor fluctuations."
He noted that adverse events that led to premature discontinuation from the study "are concerning about the overall tolerability of the drug, which also will be determined in clinical practice, and will likely influence its overall utility."
However, more therapeutic options are welcome as "the number of people with advanced Parkinson's disease is going to grow and grow substantially," he said. "So having therapies that help people with more advanced Parkinson's disease...many of whom don't reach the clinic...are going to be increasingly important."
The study was supported by Sunovion. Pahwa serves as a consultant for Abbott, AbbVie, ACADIA, Acorda, Adamas, Amneal, CalaHealth, DisperSol technologies, Global Kinetics, Impel, Neuropharma, Kyowa, Lundbeck, Mitsubishi, Neurocrine, Orbis Bioscience, PhotoPharmics, Prilenia, Sunovion, Teva Neuroscience, and US World Meds. He receives research support from Abbott, AbbVie, Addex, Biogen, Biohaven, Boston Scientific, EIP, Global Kinetics, Impax, Intec, Lilly, Neuroderm, Neuraly, Parkinson's Foundation, Pharma 2B, Prelinia, Roche, Sage, SIS, Sun Pharma, Sunovion, Theranexus, Theravance, US WorldMeds, and Voyager. Dorsey has received honoraria for speaking at American Academy of Neurology courses, the American Neurological Association, and the University of Michigan; received compensation for consulting services from 23andMe, Abbott, AbbVie, American Well, Biogen, BrainNeuroBio, Clintrex, Curasen Therapeutics, DeciBio, Denali Therapeutics, GlaxoSmithKline, Grand Rounds, Karger, Lundbeck, MC10, MedAvante, Medical-Legal Services, Mednick Associates, the National Institute of Neurological Disorders and Stroke, Olson Research Group, Optio, Origent Data Sciences Inc, Otsuka, Prilenia, Putnam Associates, Roche, Sanofi, Shire, Spark, Sunovion Pharma, Teva, Theravance, UCB, and Voyager Therapeutics; research support from AbbVie, Acadia Pharmaceuticals, AMC Health, Biosensics, Burroughs Wellcome Fund, Davis Phinney Foundation, Duke University, Food and Drug Administration, GlaxoSmithKline, Greater Rochester Health Foundation, Huntington Study Group, Michael J. Fox Foundation, National Institutes of Health/National Institute of Neurological Disorders and Stroke, National Science Foundation, Nuredis Pharmaceuticals, Patient-Centered Outcomes Research Institute, Pfizer, Prana Biotechnology, Raptor Pharmaceuticals, Roche, Safra Foundation, Teva Pharmaceuticals, and University of California Irvine; editorial services for Karger Publishers; and has ownership interests with Grand Rounds (second opinion service).
Movement Disorder Society 23rd International Congress of Parkinson's Disease and Movement Disorders (Virtual) 2020: Presented September 12, 2020.
Follow Medscape on Facebook, Twitter, Instagram, and YouTube.
Medscape Medical News © 2020
Cite this: Daniel M. Keller. Sublingual Apomorphine Alleviates Parkinson's OFF Episodes - Medscape - Oct 30, 2020.
Comments