Cynapsus Therapeutics Inc., a specialty pharmaceutical company, has announced positive top line data from its recently completed healthy volunteer pilot crossover trial comparing APL-130277, a sublingual thin film strip formulation of apomorphine, to a commercially available injectable formulation of apomorphine. The study results further support the advancement of APL-130277 for management of "OFF" episodes in Parkinson's disease through the section 505(b)(2) regulations of the United States Food and Drug Administration Act, which provides an accelerated path to approval for new formulations of approved medicines.
Mr. Anthony Giovinazzo, President and CEO of Cynapsus commented, "Results from this CTH103 clinical study are an important de-risking event for our product and set the stage for completing in the next two years the clinical requirements for qualifying APL-130277 for a 505(b)(2) New Drug Application. Importantly, the data indicate that APL-130277 may have advantages over an injectable product (i.e. apomorphine hydrochloride subcutaneous injection, Apokyn® or Apo-Go®) by reducing the frequency and intensity of side effects including nausea and vomiting versus those commonly reported for a subcutaneous injectable formulation. The results also suggest that APL-130277 exhibits comparable time to maximal concentrations in the blood and therapeutic plasma levels that are similar or longer than those seen following subcutaneous injection."
Mr. Giovinazzo added, "Assuming concurrence with the regulatory authorities, we expect that results of this study will enable us to proceed directly to the completion of two small efficacy studies and a safety study, in patients with Parkinson's disease. Our plan is to design a clinical registration program for APL-130277 that demonstrates efficacy as measured by both time to "ON" and duration of "ON" in patients with Parkinson's disease, with possible advantageous adverse event claims. If substantiated in the registration clinical trials, the findings from the CTH103 healthy volunteer study indicate that the sublingual formulation of APL-130277 could have measurable advantages for patients and their caregivers over a subcutaneous injection of apomorphine."
Dr. Albert Agro, Chief Medical Officer at Cynapsus, also commented: "We are indebted to The Michael J. Fox Foundation for Parkinson's Research for supporting this important milestone for APL-130277. Their support was fundamental to the success of this study. We are very pleased with the results, which confirm that our sublingual thin film strip formulation is effective at delivering apomorphine with the potential to reach efficacious plasma levels, but with what appears to be a reduced side effect profile compared to the subcutaneous injectable formulation. We look forward to initiating the efficacy program in patients suffering from Parkinson's disease with debilitating motor complications."
CTH103 Clinical Trial Design and Results
The CTH103 study was a three-dose active comparator, placebo-controlled, randomized cross-over trial to examine the pharmacokinetic profile of sublingual administered APL-130277 compared to the subcutaneous injection of apomorphine in healthy volunteers. The study was completed outside the United States with the active comparator Apo-go®, the approved subcutaneous injection in Europe and Asia.
The 10mg and 15mg APL-130277 sublingual thin film strips were crossed over to 2mg and 3mg subcutaneous injections, with N=15 and N=14 for the two cohorts, respectively. The Tmax (time to maximum concentration) was 31 minutes and 40 minutes for the two doses of APL-130277. The rapid uptake of apomorphine is similar to that described in the Apokyn® label (i.e. between 10 and 60 minutes). In addition, the sublingual thin film strip delivery system achieved an average minimum threshold exposure of approximately 3 ng/ml in plasma for both dose levels administered, which is expected to be sufficient to restore motor control (the "ON") in patients requiring the lowest titratable doses of a subcutaneous injection. The sublingual thin film strips also demonstrated proportionality between the doses. The results from CTH103 support the pursuit of an efficacy program under the 505(b)(2) regulatory path.
The intent in the CTH103 study for the third cohort was to compare the 25mg sublingual thin film strip (APL-130277) to the 4mg subcutaneous injection, but this third cohort could not be dosed due to the dose-limiting adverse events experienced with the 3mg subcutaneous injection. The 15mg APL-130277 side effects were mild-to-moderate and not dose limiting. The Company is in the process of preparing a single arm, healthy volunteer pharmacokinetic study to look at the 25mg APL-130277 sublingual strip (without a crossover to the injection), which is expected to be completed in Q1 2014.
- Sublingual delivery of apomorphine with APL-130277 was better tolerated than the subcutaneous injection in the studied doses;
- The PK profile of APL-130277 was proportional between doses and exposures above the minimum expected efficacious level were similar to or longer than seen following subcutaneous injection;
- APL-130277 achieved apomorphine mean Tmax of 31 and 40 minutes for the 10mg and 15mg formulations, respectively. The subcutaneous injection achieved apomorphine Tmax of27 and 24 minutes for the 2mg and 3mg formulations, respectively;
- The mean time to reaching a plasma concentration of apomorphine associated with therapeutic benefit of "Time to ON" was 10-13 minutes for the two doses of APL-130277 versus 4-5 minutes for the subcutaneous injection. The times achieved are reflective of patients' expectations for a rapid return to "ON"; and
- APL-130277 was safe and well-tolerated in CTH103 as in previous clinical studies (i.e. CTH101 and CTH102). There were fewer adverse events and the adverse events were less intense for subjects exposed to the 10mg and 15mg strips versus the subcutaneous 2mg and 3mg injections. The adverse events for the 3mg injection dose were dose-limiting and escalation of the subcutaneous injection to a higher dose as a comparator could not be pursued.
Cynapsus believes that results of the CTH103 study justify requesting a meeting with the US FDA to confirm the Company's plan to demonstrate efficacy and safety benefits in a limited number of small clinical studies of APL-130277. Specifically, the Company seeks to conduct small efficacy studies in "OFF" episode management, similar to those completed as part of the Apokyn® NDA (total of 62 patients), including studies in apomorphine-naïve and in apomorphine-experienced Parkinson's patients, plus a safety study in apomorphine-naïve Parkinson's patients. Cynapsus currently expects the initial efficacy studies to be completed by the end of 2014 and a safety study to be completed by the end of 2015, with a 505(b)(2) NDA filing possible in the first half of 2016.
Apomorphine, a potent dopamine agonist, is the only drug approved specifically for the treatment of acute motor fluctuations/hypomobility (freezing or "OFF" episodes) in patients with advanced Parkinson's disease. Presently, apomorphine is administered by intermittent subcutaneous injection usually via a pre-filled injection pen, or, in some cases outside the US, by continuous infusion pump. Drawbacks associated with subcutaneous injection therapy for patients and caregivers include aversion to needles, the need for multiple injections, which can be painful and are often associated with irritation and inflammation at the injection site, and the requirement for a degree of manual dexterity that some Parkinson's patients find difficult.