Apomorphine Sublingual Film Shows Long-Term Efficacy in OFF Episode Treatment

Stewart Factor, DO

Interim results of a long-term study (NCT02542696) of apomorphine sublingual film (Kynmobi; Sunovion) presented at 2020 MDS Virtual Congress, September 12–16, 2020, suggest that the recently approved treatment is safe and effective as an on-demand therapy for addressing OFF episodes in patients with Parkinson disease.¹

Led by Stewart Factor, DO, director, Movement Disorders Program, and Vance Lanier Chair of Neurology, Emory University School of Medicine, the analysis included 345 patients who received at least 1 dose of apomorphine sublingual film (median exposure: 141 d [range, 1–723]).

By Week 48 of the study, 84% of patients (27 of 32) reported full ON status 30 minutes post-dose. Comparatively, those rates were 78% (267 of 342) at Week 1, 78% (171 of 218) at Week 12, 74% (117 of 159) at Week 24, and 89% (41 of 46) at Week 36.

"It has a significant effect on switching people from OFF to ON rather quickly, most patients within 15 minutes," Factor told NeurologyLive. "This responsiveness, in this poster, has been shown to be maintained over 48 weeks. The initial double-blind study showed 12-week data, so this really demonstrated that tolerance doesn't appear to occur at least out to 48 weeks."

Additionally, at Week 24, the changes from pre-dose state in mean Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III scores were reductions of 13.3 at 15 minutes post-dose, 20.1 at 30 minutes, and 19.2 points at 60 minutes. Similar results were also observed for these time points at Week 36—reductions of 11.2, 21.6, and 20.8, respectively—and Week 48—reductions of 13.3, 22.6, and 21.1, respectively.

READ MORE: ​Parkinson Disease Gene Therapy VY-AADC01 Proves Safe With Signs of Efficacy

Notably, in the agent’s comparison against placebo in clinical trial CTH-300 (NCT02469090), the primary end point of change from pre-dose to 30 minutes post-dose at Week 12 in MDS-UPDRS Part III score was significantly improved with apomorphine sublingual film (–11.1) compared to placebo (–3.5), for a least-squares mean difference of –7.6 (P = .0002).²

This analysis included 425 patients who received ≥1 dose during the dose-titration phase (new patients, n = 347; rollover patients from phase 2/3 studies, n = 78), though 60 patients (14%) discontinued prior to the long-term safety phase. Those discontinuations were due to AEs (n = 26; 6%), withdrawal of consent (n = 16; 4%), lack of efficacy (n = 12; 3%), protocol violation (n = 4; 1%), and other (n = 2; <1%).

As for safety, treatment-related adverse events (AEs) occurred in 85% of patients, with the majority (66%) being rated as mild. The most common, occurring in ≥10% of patients, included nausea (27%), yawning (12%), dizziness (11%), and somnolence (11%). There were oral treatment-related AEs, most notably mucosal erythema (8%) and lip swelling (5%), which were the only such to occur in 5% or more of patients. Syncope occurred in 2%.

In total, 31% of patients experienced an AE leading to discontinuation, most of which were nausea (6%), lip swelling (3%), and dizziness (2%). There were 4 deaths were reported, none deemed drug-related.

"I think most people would be concerned about oral lesions that could occur in this long-term study—only about 8% dropped out because of these events," Factor explained. "It's very possible that, in practice, if they were to hold the drug until the lesions clear, they may be able to restart it again. That's something we need to see with time and experience."

Most patients utilized doses ranging from 10–20 mg during both the dose-titration (10 mg: 18%, n = 63; 15 mg: 27%, n = 92; 20 mg: 22%, n = 77) and the long-term safety phases (10 mg: 18%, n = 63; 15 mg: 25%, n = 85; 20 mg: 23%, n = 78). Although, a dose of 25 mg was taken by 16% (n = 56) and 17% (n = 57) of those in the 2 phases, respectively. Doses of 30 mg and 35 mg were administered to 8% (n = 28) and 8% (n = 29), respectively, during titration and 10% (n = 35) and 8% (n = 27) in the long-term phase, respectively.

The treatment was approved by the FDA as the first therapy for OFF episodes associated with Parkinson disease that is administered sublingually in May 2020, based on the data from the CTH-300 trial. In January 2019, the FDA sent a complete response letter (CRL) to Sunovion in response to its original filing in mid-2018 for the sublingual film, requesting additional information and analyses but no additional clinical studies. After then resubmitting the application in November 2019, its acceptance set its Prescription Drug User Fee Act (PDUFA) action date.³

Apomorphine sublingual film is meant to be used in on-demand treatment of all types of motor OFF episodes, including morning and unpredictable OFF, delayed/partial ON, and end-of-dose wearing OFF episodes. Sunovion has noted in releases that these episodes are experienced by 40% to 60% of patients, and limited treatment options are available to treat the population. This treatment joins Acorda’s inhaled levodopa (Inbrija) and US WorldMeds' apomorphine hydrochloride injection (Apokyn) as one of the few acute treatment options for OFF episodes.

For more coverage of MDS 2020, click here.

REFERENCES
1. Factor S, Ondo W, Isaacson S, Bhargava P, Navia B. A Long-Term Safety, Tolerability, and Efficacy Study of Apomorphine Sublingual Film for On-Demand Treatment of “OFF” Episodes in Patients With Parkinson’s Disease: Interim Results. Presented at: MDS Virtual Congress; September 12–16, 2020. Abstract 888.
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.
3. Sunovion Announces U.S. FDA Approval of Kynmobi (apomorphine hydrochloride) Sublingual Film for the Treatment of Parkinson’s Disease OFF Episodes. News Release. Sunovion; May 21, 2020. Accessed September 16, 2020. https://www.businesswire.com/news/home/20200521005786/en/Sunovion-Announces-U.S.-FDA-Approval-KYNMOBI%E2%84%A2-apomorphine