Kynmobi Does Not Significantly Alter Heartbeat, Study Finds
Treatment with Kynmobi (apomorphine hydrochloride), an approved under-the-tongue therapy for “off” episodes in Parkinson’s disease, does not substantially alter heartbeat dynamics at approved doses, according to new clinical trial data.
The study, “A Randomized Thorough QT Study of Apomorphine Sublingual Film in Patients With Parkinson’s Disease,” was published in Clinical Pharmacology in Drug Development. The work was funded by Sunovion Pharmaceuticals, which markets Kynmobi.
Parkinson’s disease is characterized by the dysfunction of brain cells that make an important signaling molecule called dopamine. The gold standard Parkinson’s treatment, levodopa and its derivatives, which give the brain more material with which to manufacture dopamine. The therapy may ease disease symptoms, but many patients experience “off” episodes where symptoms are not adequately controlled by levodopa.
Kynmobi, previously known as APL-130277, is a sublingual (under-the-tongue) film containing apomorphine, a molecule that mimics dopamine’s activity in the brain. It was approved by the U.S. Food and Drug Administration for the acute, intermittent treatment of “off” episodes in people with Parkinson’s, was based on data from other clinical trials that have demonstrated the therapy can ease motor fluctuations during “off” episodes.
Other formulations of apomorphine that are given via injection under the skin have been reported to alter heart rate. This Phase 2 clinical trial (NCT03187301) is aimed at evaluating how Kynmobi affects the heart in Parkinson’s patients.
The study included 40 people with idiopathic (non-familial) Parkinson’s disease at 13 clinical sites in Italy and the U.S. Among the participants, about two-thirds were male, more than 90% were white, and the average disease duration was more than eight years.
In the first part of the study, participants were given increasing doses of Kynmobi during planned “off” episodes (e.g., before taking a planned dose), until the participants and investigators identified the minimum dosage needed to achieve a “full on” (i.e., an effect similar to what would be expected with levodopa) within 90 minutes of dosing.
Then, if tolerated, participants were given a slightly higher dose than the minimum needed, up to a maximum possible dosage of 60 mg. For most patients, the dose needed to achieve “full on” was relatively low (10 mg), and the maximum dose used in the study was 50 mg.
Patients then entered the study’s crossover phase. Participants were given a single dose of either Kynmobi or placebo, and then a few days later, those given Kynmobi were given placebo, and vice versa. Electrocardiograms (ECG) to measure heart function were performed at both study visits.
As a positive control, participants also completed a study visit where they were treated with moxifloxacin, an antibiotic known to cause heart rate changes as a side effect.
As expected, treatment with moxifloxacin led to a marked change in Fridericia-corrected QTc interval (QTcF), which is a measure of the length of the average heart beat. After taking moxifloxacin, the average QTcF increased by 10.4 milliseconds at two hours post-dosing, and this increase remained until four hours post-dosing, before decreasing back to the original value by eight hours after dosing.
By comparison, treatment with Kynmobi led to a slight elevation in average QTcF, by 3.3 milliseconds after one hour. The QTcF then promptly decreased, reaching normal values by four hours after dosing. Placebo did not alter QTcF, as expected.
Assessment of other cardiac and ECG parameters broadly showed that Kynmobi “did not result in any deleterious effects on other cardiac conduction measures or ECG morphology as evidenced by comparable effects on cardiac parameters between apomorphine sublingual film and placebo,” the researchers said.
Expected side effects
The safety profile of Kynmobi in this study was broadly similar to what has been reported for the therapy previously. Common side effects included nausea and drowsiness.
“Overall, these data suggest that apomorphine sublingual film is not associated with QT prolongation [slower heart rate] for the approved dose range (10‒30 mg),” the scientists concluded.
The team noted that, as most patients in this study were on lower dosages of Kynmobi, it is unclear whether higher doses might increase the risk of heartbeat abnormalities, highlighting a need for further study.