Cynapsus is currently focused on clinical development and maximizing the commercialization potential of APL-130277, primarily through a semi-virtual outsourcing business model integrating a leading team of formulation developers, active pharmaceutical ingredient (“API”) suppliers, regulatory and intellectual property experts, neuroscientists and central nervous system researchers. To date, pilot proof-of-concept Phase 1 human volunteer clinical trials have been conducted by a Contract Research Organizations (“CROs”) in Asia. It is expected that CROs in Asia, the U.S. and/or Europe will be selected to manage future clinical trials.
APL-130277 is being developed under 505(b)(2) of the Federal Food, Drug and Cosmetic Act (“FFDCA”) of the United States. In an April 2011, the Corporation met with the U.S. Food and Drug Administration (“FDA”) in a pre-IND meeting to propose a regulatory strategy toward achieving approval of APL-130277. The results and meeting minutes reflect the FDA’s guidance on a two-step process: first, demonstrate bioequivalence to the approved subcutaneous injectable form of apomorphine (Apokyn®); and, second, demonstrate safety and tolerability of APL-130277’s sublingual thin film strip dosage form in an appropriate patient population.
Cynapsus’ drug candidate, APL-130277, is an easy-to-administer, fast-acting reformulation of apomorphine, being developed to rescue patients from “off” episodes. APL-130277 is a bilayer film that incorporates a neutralizing agent. The neutralizing agent is maintained in a separate layer from the API to avoid any reaction between the two before administration, as the neutral form of the drug is unstable to air oxidation. In a thin film format the neutralizing agent reacts immediately upon dissolving in saliva with the API and maintains a “normal”, near physiological pH, during absorption, thus obviating any issues with irritation. To date, short term administration of APl-130277 in animal and human studies has not shown any macroscopic or microscopic signs of irritation.
In July 2010, Cynapsus announced the results of a survey of neurologists and movement disorder specialists relating to Parkinson’s practices and treatments, specifically targeted at analyzing the use of apomorphine products. An independent, experienced, medical survey company in the U.S. questioned 50 neurologists in the United States and Europe, who collectively treat approximately 12,000 Parkinson’s patients for motor fluctuations. The results of the survey validated the APL-130277 product concept and showed that neurologists would value an approved drug using the Corporation’s sublingual delivery system and would use the APL-130277 product to treat several categories of Parkinson’s patients.
In November 2010, Cynapsus announced that it received favourable results from a second survey conducted, on behalf of the Corporation, by the same leading independent healthcare market research group. The survey results forecast favourable acceptance of APL-130277 by HMO’s and insurers as well as an attractive range of pricing for the product from a reimbursement perspective. This survey of 11 large U.S. payors gauged the opinion and acceptance of APL-130277. The results indicate that APL-130277 may be readily accepted by payors and reimbursed at price levels at or near the level at which apomorphine injection is currently reimbursed.
In December 2010, Cynapsus announced the completion of results of pre-clinical animal model studies of APL-130277. The results demonstrated that the APL-130277 sublingual thin film strip system was able to deliver apomorphine into the bloodstream of rabbits in a similar manner as injection, in the proper quantity and over the required period of time.
In April 2011, Cynapsus met with the FDA in a pre-IND meeting. Cynapsus reviewed the drug product concept, data obtained to date and proposed a 505(b)(2) type regulatory pathway for approval of APL-130227. As described in minutes from that meeting, the FDA agreed that a demonstration of bioequivalence of APL-130277 to Apokyn® subcutaneous injection would provide sufficient proof of PK equivalence of the new drug product. Bioequivalence is a Phase 1 pharmacokinetic clinical study where serum levels of a single dose of a test product are compared to a single dose of approved (reference) drug in an appropriately designed crossover study using healthy human volunteers. Statistical analysis of the maximum serum level (Cmax) and the total exposure, as measured by the area under the curve (AUC) should be between 80% and 125% with a confidence interval of 95%. In addition, the FDA will require an additional study in naïve Parkinson’s patients over a minimum of 12 weeks to demonstrate safety and tolerability of the drug that is administered via this new route of administration.
In December 2011, Cynapsus announced the results of the Global 500 Neurologists Survey. Collectively, the professionals surveyed treat approximately 62,000 Parkinson’s patients per year with approximately 41.4% classified as mild-moderate in severity, 42.2% as moderate-severe, and 16.4% as severe. The results of this survey confirm and expand on the results of the smaller neurologist survey that was completed at the direction of the Corporation in July 2010.
The pharmacokinetics and safety/tolerability of APL-130277 were demonstrated in 15 healthy volunteers with 12 of 15 subjects receiving drug product and 3 subjects receiving placebo. Patients were dosed in a two period crossover with APL-130277 placing the drug in a different orientation under the tongue. The study determined that the sublingual orientation does impact the Tmax and PK of APL-130277. In the majority of subjects, maximum blood levels were reached within 20 minutes of administration. Pharmacokinetic parameters mirrored those seen with a subcutaneous injection of apomorphine after an expected dose adjustment. The study showed that APL-130277 was safe and showed good local tolerability (no irritation). Adverse events were mostly mild in intensity with one subject having moderate nausea and dizziness post dosing. In placebo treated subjects, 33% had at least one adverse event during the treatment period, with 17% of subjects having at least one adverse event in the APL-130277 treatment group. The adverse effects were typical of those commonly observed with apomorphine injection.
In August 2012, Cynapsus announced that it had been awarded a grant of USD$947,925 from the MJFF for Parkinson’s Research to support clinical studies to develop APL-130277, a sublingual thin film strip reformulation of apomorphine. The grant was awarded under the MJFF’s The Edmond J. Safra Core Programs for Parkinson’s Research, Clinical Intervention Award, aimed at supporting human clinical trials testing promising Parkinson’s therapies that may significantly and fundamentally improve treatment for people with Parkinson’s.
In August 2012, Cynapsus announced the results of a second human volunteer pilot proof-of-concept clinical trial (CTH-102) of APL-130277. The results of the first study (CTH-101) were reported on January 10, 2012. This second pilot study was closed out in August 2012 after it was determined that the goal of finding a therapeutic dose had been reached. The first dose evaluated in the study was deemed to be dose proportional to the dose evaluated in the CTH-101 clinical pilot study and achieved a pharmacokinetic profile (Cmax, AUC and Tmax) that was sufficiently similar to subcutaneous injectable apomorphine. Management decided that it was unnecessary to proceed with a second dose, and then began preparations for a Comparative Biostudy (CTH-103) to be funded by the MJFF.
The pharmacokinetics and safety/tolerability of APL-130277 were demonstrated in a second Phase 1 pilot study in 12 healthy volunteers with 10 of 12 subjects receiving active drug product and 2 receiving placebo. Patients were dosed in a two period crossover with APL-130277 placing the drug in a different orientation under the tongue. The study determined that the sublingual orientation does impact the Tmax and PK of APL-130277. The dose was deemed to be dose proportional to the dose evaluated in CTH101 and achieved a pharmacokinetic profile (Cmax, AUC and Tmax) that was sufficiently similar to subcutaneous injectable apomorphine that management decided to begin preparations for the Comparative Biostudy (CTH-103).
In September 2012, Cynapsus commenced activities for the CTH-103, a Comparative Biostudy of APL-130277. CTH-103 will be a placebo-controlled, randomized cross-over Phase 1 trial in healthy volunteers to examine the pharmacokinetic profile of three dose strengths of APL-130277 as compared to equivalent doses of apomorphine subcutaneous injection. The objective of this study is to directly compare the pharmacokinetic profile of APL-130277 to subcutaneous apomorphine in healthy subjects to more precisely design the subsequent bio-equivalent registration trial to support an FDA 505(b)(2) NDA in 2015.