APL-130277 is a fast-acting and easy-to-use thin-strip film coated with the drug apomorphine, a small molecule dopamine receptor agonist. It is currently under investigation by Cynapsus Therapeutics (acquired by Sunovion) for use in people with Parkinson’s disease (PD) to control so-called “off” episodes.” Those episodes are the re-emergence of PD symptoms (motor fluctuations) that are either intermittent or due to the treatment wearing off. Drug candidate APL-130277 is intended to reverse all manifestations of “off” episodes, both predictable and unpredictable, including the morning episodes that are considered the most difficult to treat.

An injectable apomorphine called Apokyn already has been approved to treat acute intermittent “off” episodes in patients with advanced PD. However, its use is limited because of pain associated with administering injections under the skin and subsequent injection-site reactions due to apomorphine’s acidic nature. These limitations are overcome by APL-130277 that is administered by placing the oral strip under the tongue, and it works as rapidly as the injection. Such an approach has the potential to allow patients to manage their “off” episodes with a convenient, rapid, effective, and patient-friendly approach.

How APL-130277 works

APL-130277 is designed as a “turning-on” medication to acutely manage “off” episodes by rapidly delivering apomorphine from the oral cavity mucosa (inner lining of the mouth) without inducing local skin or mucosal irritation or reactions.

The thin film of APL-130277 consists of a bilayer designed in a way that maximizes apomorphine drug delivery while optimizing film disintegration and compatibility with the mouth tissue.

The first layer is the apomorphine layer, which is designed to ensure drug stability, rapid drug diffusion (dissolving within minutes), and maximal bioavailability (maximal availability in the circulation).

The second layer is a separate buffer layer, which is designed to enhance the permeability of the drug, as well as neutralize the acid that is generated following drug absorption.

APL-130277 in clinical trials

An open-label Phase 2 clinical trial (NCT02228590) that aimed to assess the safety, effectiveness and tolerability of APL-130277 in 19 PD patients was successfully completed. The study reported positive results with patients converting from “off” to “on” states without any complications that are typically associated with the under-the-skin administration of apomorphine.

Cynapsus started a Phase 3 clinical trial program in the U.S., consisting of two pivotal Phase 3 clinical trials — CTH-300 (NCT02469090) and CTH-301 (NCT02542696) — for APL-130277. Patients are being invited to participate in both trials, which are taking place at multiple sites across the U.S. and in Ontario, Canada.

The CTH-300 trial (NCT02469090) is a randomized, double-blind, placebo-controlled study to determine the effectiveness, safety and tolerability of APL-130277 in 126 PD patients, who are responsive to standard therapy (levodopa) and have at least one “off” episode every day, and a total “off” time of at least two hours per day. The trial design includes an open-label dose titration phase (DTP) and a double-blind maintenance treatment phase (MTP). DTP was conducted to determine the appropriate dose for each patient in the placebo-controlled MTP. The titration sequence for APL-130277 was 10 mg, 15 mg, 20 mg, 25 mg, 30 mg and 35 mg. Patients who responded with a full “ON” within 45 minutes could move to the MTP. Patients who did not achieve a full “ON” returned to the clinic for the next dose. The process was repeated until patients achieved a full “ON” within 45 minutes, or reached a dose of 35 mg.

The company presented preliminary efficacy data for 76 patients (46 men and 30 women) who have completed the DTP phase of the CTH-300 trial and responded to treatment, at the 21st International Congress of International Parkinson and Movement Disorder Society, In this preliminary analysis, APL-130277 provided rapid improvement in patients with PD in the “off” state. The onset of clinical benefit appeared within five to 12 minutes and was sustained over 90 minutes.

The preliminary safety data for 96 patients showed that APL-130277 was well-tolerated. The most common adverse events were associated with dopaminergic medications and/or apomorphine. In this analysis, the APL-130277 dose that turned patients from the “off” to the fully “on” state was not correlated with disease severity.

Following the completion of this study, participants will be able to join the CTH-301 trial, a 24-week, open-label study that will determine the long-term safety, tolerability, and effectiveness of APL-130277 in 226 advanced PD patients, who meet similar conditions as in the CTH-300 trial.

Other information

In August 2016, the U.S. Food and Drug Administration (FDA) granted APL-130277 fast track designation for the treatment of “off” episodes in patients with PD. Cynapsus plans to submit a new drug application (NDA) for APL-130277 in 2017.

Some of the patients enrolled in the Phase 3 studies will participate in a sub-study, using a wearable device and a Fox Insight smartphone application, developed jointly by the Michael J. Fox Foundation (MJFF) and Intel Corporation, to track data on movement and the effect of the medication. This pilot study aims to understand how clinical studies can benefit from data science technologies, which are a faster way to assess disease progression and have the potential to speed up the clinical development of new drugs.

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