Background

APL-130277 is a sublingual thin film formulation of apomorphine, a dopamine receptor agonist with anti-parkinsonian actions similar to levodopa. In May 2020, the FDA approved Kynmobi for on-demand treatment of Parkinson’s OFF episodes (company press release). This NDA was a resubmission of an earlier application in January 2019 that the agency had rejected.

Kynmobi’s active compound is apomorphine, which results from the chemical decomposition of morphine. It does not contain morphine or bind to opioid receptors. Apomorphine is used for the acute treatment of Parkinson’s symptom flare-ups called motor fluctuations. These OFF episodes plague people with advanced Parkinson’s disease who are otherwise stable on dopamine treatment.

Apomorphine is usually injected subcutaneously or infused. This mode of administration requires passage through the liver and its metabolism before apomorphine reaches the brain (Borkar et al., 2018). APL-130277 represents a new formulation that delivers apomorphine noninvasively, and more quickly, through the lining of the mouth, from a disintegrating strip placed under the tongue.

Apomorphine's side effects include nausea and vomiting, and it is normally given along with an anti-nausea drug. Other side effects are low blood pressure leading to drowsiness and fainting. In the 2000s, low-dose, sublingual tablet formulations of apomorphine were briefly marketed for erectile dysfunction, but were discontinued when safer and more effective PDE5 inhibitors took over for that indication. 

In vitro, apomorphine was found to inhibit Aβ fibril formation (Lashuel et al., 2002). In the 3xTg-AD mouse model, it was reported to improve memory and reduced levels of Aβ and hyperphosphorylated tau (Himeno et al., 2010; Himeno et al., 2011).

Findings

Starting in August 2014, a Phase 2, open-label study evaluated 10 to 30 mg doses of APL-130277 in 19 Parkinson’s patients after their previous dose of levodopa had worn off and they were in an OFF state. Within 30 minutes, 15 showed significant improvement in motor function as measured by the Movement Disorder Society Unified Parkinson’s disease rating scale (MDS-UPDRS) part III (Hauser et al., 2016). The most common side effects were dizziness, sleepiness, and nausea.

In June 2015, a Phase 3, placebo-controlled study began enrolling PD patients who suffered predictable morning OFF episodes plus two or more hours of OFF time daily, while on a stable dose of L-DOPA. After an open-label titration from 10 to 35 mg in 141 patients, 109 responders were randomized to drug or placebo for a 12-week double-blind phase. Apomorphine is intended to be used up to five times a day; most participants used it two or three times. Treatment resulted in an improvement in the primary outcome, i.e., change in MDS-UPDRS from pre-dose to 30 minutes after dosing measured in the clinic at the 12-week visit. The secondary outcome was also positive, with a higher percentage of patients showing a fuller response to drug than placebo, both in the clinic and at home. One-third of patients discontinued apomorphine treatment compared with 16 percent dropout on placebo, mainly because of mild to moderate mouth and throat irritation. Other side effects included transient nausea, sleepiness, and dizziness. Orthostatic hypotension, syncope, dyskinesia, hallucinations, prolonged QT interval, and impulse control disorders were rare, but one patient on apomorphine who had known cardiac risk factors died from cardiac arrest (Olanow et al., 2020).

Sunovion is recruiting up to 226 participants for a 24-week, open-label extension to the Phase 2 and 3 studies that will continue through March 2023.

The company has completed two additional Phase 2 studies. One evaluated drug effects on heart rhythms in people with Parkinson’s; the other compared Kynmobi to two brands of injectable apomorphine on pharmacokinetic outcomes. No results have been disclosed.

In December 2018, the company began a Phase 3 trial comparing Kynmobi’s effectiveness to that of subcutaneously injected apomorphine in 106 people with Parkinson’s. The study will run through October 2020.

For details on APL-130277 trials, see clinicaltrials.gov