Sublingual Drug for Parkinson’s ‘Off’ Episodes in Phase 3 Study

Cynapsus Therapeutics, Inc., a Toronto-based specialty pharmaceutical company, and The Michael J. Fox Foundation for Parkinson’s Research (MJFF) announced they are collaborating to incorporate wearable device technology and “big data” approaches into Cynapsus’ pivotal Phase 3 clinical study of APL-130277, a fast-dissolving, sublingual formulation of the drug apomorphine to treat “off” episodes in Parkinson’s disease (PD) patients.

Off episodes are a complication of Parkinson’s that leave patients rigid and unable to move and/or communicate.

As PD progresses, the efficacy of dopamine replacement medication (the gold standard treatment for the disease) shortens, and patients experience motor fluctuations known as off episodes. Cynapsus’ product candidate, APL-130277, in development since 2010, is a sublingual (under-the-tongue) thin-film formulation of apomorphine designed to be easy to administer, and to rapidly, safely, and reliably convert a patient from “off” to “on” status in all types of off episodes, including those experienced in the morning.

Cynapsus says its unique packaging would allow most patients, when they begin to experience an off episode or even while in an off state, to simply peel open the packaging, remove and self-administer the thin film by placing it under their tongue. The film dissolves over the course of a few minutes, allowing the apomorphine to quickly enter the bloodstream.

The company’s target market for APL-130277 is PD patients who suffer at least one off episode per day. A 2014 paper by A. Rizos, et al., published in the journal Parkinsonism & Related Disorders (DOI: https://dx.doi.org/10.1016/j.parkreldis.2014.09.013) found that approximately 60 percent of PD patients suffer morning off episodes, and Cynapsus believes that nearly all of these patients also suffer other types of off episodes, although necessarily daily. However, the company estimates that two-thirds of the approximately 600,000 patients who experience off episodes suffer at least one every day.

The Michael J. Fox Foundation says that apomorphine, despite its strong efficacy as a rescue medication for intermittent off episodes in PD, and its rapid action, is an underutilized drug largely because its delivery method — Apokyn (apomorphine hydrochloride) injections — can be painful, and patients are inclined to resist its use until later disease stages. Additionally, the foundation argues that physicians find the dose initiation cumbersome. Eliminating some of these barriers are key objectives for Cynapsus’ APL-130277, designed to achieve pharmacokinetics that mimic an Apokyn injection.

Another objective of a pilot effort involving Cynapsus, the MJFF, and microchip maker Intel is to advance understanding of how clinical studies can harness data science approaches, in order to objectively measure disease progression and speed progress toward breakthroughs in drug development. The project builds on MJFF’s ongoing data science partnership with Intel Corporation, launched in August 2014, to develop platforms for storing large volumes of patient-generated data and algorithms to glean insights from this data.

“This strategic alliance with The Michael J. Fox Foundation and the use of technology-enabled research solutions builds on our standing collaborative relationship as well as our individual commitments to change the lives of people with Parkinson’s disease,” says Anthony Giovinazzo, president and CEO of Cynapsus, in a release. “Employing wearable technology to collect data in clinical trials has enormous potential to improve our understanding of how drugs and other treatments impact patients living with the debilitating symptoms of this disease.”

MJFF chief executive officer Todd Sherer, PhD says: “Clinical studies are the most expensive and time-consuming stages of drug development. Data science approaches hold the potential to accelerate the pace of progress by allowing drug developers to objectively gather and analyze unprecedented volumes of data and more quickly reveal insights about a potential new treatment. We’re optimistic about the potential of this technology to help speed breakthroughs patients need.”

Eric Dishman, general manager of Health & Life Sciences at Intel, observes: “Amassing valuable objective data and turning it into insightful information can lead to advances in how new therapeutics are developed. This implementation of a consumer wearable and an analytics platform, developed by The Michael J. Fox Foundation and Intel for use in Parkinson’s disease research, is a great example of interdisciplinary collaboration harnessing the power of data to advance disease research while bringing value to patients.”

While the MJFF funded earlier phases of APL-130277 clinical development, neither the Foundation nor Intel is funding the current Phase 3 studies. Phase 3 results on the safety and efficacy of APL-130277 are expected in mid- and late 2016.

The Cynapsus release explains that a subset of participants in the Phase 3 safety study will take part in a data analytics sub-study. Through a wearable device and the Fox Insight smartphone application (developed jointly by MJFF and Intel), volunteers will contribute data on movement and medication effect. Data will be securely collected, and anonymously evaluated using advanced analytics, then stored in a cloud platform that will enable researchers to potentially gain insights into Parkinson’s disease, off episodes, and APL-130277’s efficacy. The technology platform and algorithms developed by Intel for the foundation are intended as a proof of concept, demonstrating that data science technologies can contribute to the objective measurement of Parkinson’s disease in interventional clinical studies.

“The data analytics capabilities enabled by Intel and The Michael J. Fox Foundation will allow us to better evaluate how APL-130277 is helping patients. As our Phase 3 clinical trials progress and we move toward gaining FDA approval of APL-130277, we plan to work closely with Intel and The Michael J. Fox Foundation to use this technology to improve the lives of patients with Parkinson’s disease,” says Cynapsus’ chief medical officer, Albert Agro, PhD.

Patients interested in participating in Parkinson’s clinical trials, such as Cynapsus’ ongoing APL-130277 study or other technology-enabled studies, are invited to register on the Fox Trial Finder at https://www.foxtrialfinder.org, an online tool that matches individuals to the trials best suited to them, based on factors such as time since diagnosis and medication/surgical status. The MJFF says more than 50,000 individuals have registered with Fox Trial Finder since 2011.

Cynapsus’ Pivotal Phase 3 Clinical Trial Program (CTH-300 and CTH-301)

Cynapsus announced enrollment of the first patient in the CTH-300 clinical trial on June 29, 2015. The CTH-300 trial is a double-blind, placebo-controlled, parallel-design efficacy study in an estimated 126 PD patients, enrolled at 35 centers, who have at least one off episode every 24 hours, with total off time of at least two hours per day. The study’s objective is to evaluate the efficacy and safety of APL-130277 versus a placebo. Participants are being observed for 12 weeks, with dosing both at home and in the clinic. The primary endpoint to be measured at week 12 is the mean change in the MDS-UPDRS Part III score at 30 minutes after dosing. The key secondary endpoint will be the percentage of patients who convert from the off to the on state at or before 30 minutes of dosing with APL-130277 at week 12.

Cynapsus announced enrollment of the first patient in the CTH-301 clinical trial on Sept. 2, 2015. The CTH-301 trial is a six-month, open-label, single-arm safety study in PD patients who have at least one off episode every 24 hours, with total off time of at least two hours per day. The study’s primary endpoint is the safety and tolerability of APL-130277. Secondary endpoints are the examination of efficacy variables, including the change in MDS-UPDRS Part III scores over the six months of treatment. Sites are recruiting patients over several months, with each patient being evaluated for six months. An estimated 226 patients will be enrolled, including up to 126 patients enrolled in the CTH-300 study.

Cynapsus cites National Parkinson’s Foundation metrics estimating that PD — a chronic and progressive neurodegenerative disorder that diminishes motor activity — afflicts more than 1 million people in the U.S., and an estimated 4 million to 6 million people globally.

Sources:
Cynapsus Therapeutics Inc.
The Michael J. Fox Foundation