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FDA Issues CRL to Sunovion for Apomorphine Sublingual Film (APL-130277)

The regulatory agency determined that it was unable to approve the treatment in its present form, requesting additional information and analyses but no additional clinical studies.

Antony Loebel, MD

The FDA has issued a Complete Response Letter to Sunovion for its New Drug Application (NDA) for its apomorphine sublingual film (also known as APL-130277) to treat off episodes experienced by patients with Parkinson disease.1

The regulatory agency determined that it was unable to approve the treatment in its present form, requesting additional information and analyses but no additional clinical studies. The NDA was based on findings from the phase 3 CTH-300 trial, in which the apomorphine sublingual film demonstrated significant improvements in motor function compared with placebo.

“Off episodes are a common and challenging part of Parkinson’s disease with few existing treatment options,” said Antony Loebel, MD, the executive vice president and chief medical officer at Sunovion, Head of Global Clinical Development for Sumitomo Dainippon Pharma Group, in a statement. “Sunovion remains committed to working with the FDA to address its requests so that we can bring apomorphine sublingual film to patients as expeditiously as possible.”

In the CTH-300 trial, the mean change in Unified Parkinson's Disease Rating Scale (UPDRS) part III at 30 minutes’ post-treatment at week 12 was -11.1 with APL-130277 compared with -3.5 with placebo, representing a -7.6 difference between the 2 groups (P = .0002). Apomorphine sublingual film was administered at 10 mg to 35 mg in a titration phase to identify a dose required to achieve full on time. Then, in the randomized maintenance phase, patients received the titrated dose of treatment or placebo, up to 5 times per day for 12 weeks. Overall, 109 patients with 3.9 median off days at baseline were randomized.2

A similar decline in UPDRS-III was observed at day 1 and weeks 4 and 8. Improvements in UPDRS-III with apomorphine sublingual film over placebo were seen at 15 minutes and continued up to 90 minutes. At week 12, more patients treated with the Sunovion product reported being full on at 30 minutes compared with placebo (P = .04).

Additionally, according to home diary entries, 78.7% were on at 30 minutes with apomorphine sublingual film compared with just 31.1% for placebo.

Treatment discontinuation in the CTH-300 trial was higher in the apomorphine sublingual film arm (27.8%) than the placebo arm (9.1%). Adverse events (AEs) were the most common cause of discontinuation. The most frequent AEs during the maintenance phase for apomorphine sublingual film were nausea (27.8%), somnolence (13%), and dizziness (9.3%). Across the study, there were 6 serious AEs and 1 death reported in the placebo arm.

The treatment is a novel formulation of apomorphine and a dopamine agonist. Apomorphine is currently FDA approved for the acute, intermittent treatment of hypomobility and off episodes associated with advanced Parkinson disease, and it is currently available in the U.S. as a subcutaneous injection. The Sunovion product is intended to rapidly convert those with Parkinson from the off to the on state and has been studied for the treatment of motor off episodes up to 5 times per day and no sooner than 2 hours from the previous dose. Sunovion acquired the therapeutic candidate in October 2016 when it acquired Cynapsus Therapeutics Inc.

The Michael J. Fox Foundation funded, in part, 2 phase 1 trials of apomorphine sublingual film— a comparative biostudy in healthy volunteers and a dosing study in patients with Parkinson disease.

Kathrin LaFaver, DM, the Raymond Lee Lebby Chari in Parkinson Disease Research, the Director of the Movement Disorders Clinic, and an assistant professor of neurology at the University of Louisville, told NeurologyLive that this Sunovion product is an attempt to try to fill a need for patients that experience off symptoms, “to have a medication available that is very fast, rapidly acting and can help with these off periods, and trying to find a way to do the delivery of these things rapidly and conveniently.”

However, LaFaver did note that in her mind, “it would be even better if we try to manage patients so that this need doesn’t even arise, or not at least that much, and so there are other product developments that are already on the market that have carbidopa-levodopa with a more extended half-life.”


1. Sunovion Receives Complete Response Letter from FDA for Apomorphine Sublingual Film (APL-130277) [press release]. Marlborough, MA: Sunovion Pharmaceuticals; Published January 30, 2019. businesswire.com/news/home/20190130005919/en/Sunovion-Receives-Complete-Response-Letter-FDA-Apomorphine. Accessed January 31, 2019.

2. Navia B, Factor S, Pahwa R, et al. Efficacy and Safety of Sublingual Apomorphine film (APL-130277) for the Treatment of OFF Episodes in Patients with Parkinson's Disease: Results from a Double-Blind, Placebo-Controlled Trial. Presented at: 2nd Pan American Parkinson's Disease and Movement Disorders Congress; Miami, FL, June 24-28, 2018. LBA03