Cynapsus Therapeutics, a specialty pharmaceutical company focused on Parkinson’s disease, announced positive top-line results from its CTH-105 Phase II clinical trial of APL-130277 for the management of OFF motor symptoms of Parkinson’s disease.
APL-130277 is the Company's fast-acting, sublingual, thin filmstrip formulation of apomorphine. OFF episodes are a complication of Parkinson's disease that leave patients rigid and unable to move and communicate.
An estimated one quarter to one half of all people with Parkinson's disease whose symptoms are otherwise managed with ongoing drug therapy, experience OFF episodes at least once daily and up to six times daily, with each episode lasting between 30 and 120 minutes.
"The purpose of the CTH-105 study was to better understand the APL-130277 dose range that produced efficacy as measured by the change in the Unified Parkinson's Disease Rating Scale (UPDRS) part III, a scale used by neurologists to measure the severity of Parkinson's disease OFF and motor symptoms, compared with baseline. We are encouraged that APL-130277 provided clinical benefit at all five doses used in this study," said Dr. Albert Agro, Chief Medical Officer of Cynapsus.
"These preliminary data show that APL-130277 was able to convert patients from a severe OFF state in the morning to ON. In addition, treatment was associated with a 45% improvement in motor function based on the change in UPDRS part III from baseline. The mean dose needed to terminate the OFF episode was 18.4mg. In addition, those patients achieving a response at higher doses appeared to adapt to the treatment, as seen by the lack of nausea at higher doses."
In the CTH-105 multicenter open-label study, APL-130277 was assessed in 16 patients with Parkinson's disease who experience the debilitating effects of OFF episodes, with a total duration of OFF of at least two hours daily.
To date, 16 patients have completed the dosing regimen, which was the planned sample size for the study. Due to over enrollment, an additional three patients are still in dosing. OFF episodes were achieved by having patients take their last dose of levodopa the night before they came into the clinic.
Patients were not allowed to take their first dose of levodopa in the morning, resulting in a severe OFF state that is one of the most difficult to convert and maintain in an ON state.
Patients were then given escalating doses of APL-130277 (at a minimum of three hours between doses) until ON was achieved, as documented by study staff, the patient, and a clinician assessment of UPDRS part III. The UPDRS III part score was measured at 15, 30, 45, 60 and 90 minutes.
All five doses of APL-130277 used in the study (10, 15, 20, 25 and 30mg) resulted in patients moving from OFF to ON. The mean baseline UPDRS part III in an OFF state was 41.4, and the maximum mean change from baseline UPDRS part III was 18.4.
The mean dose required to convert patients to ON was 18.4mg. The onset of a clinically meaningful improvement was seen in as early as 10 minutes and lasted up to 90 minutes, the last time point measured in this study.
The mean time to ON as reported by study staff was 22 minutes. Cynapsus believes that these data strongly support the conclusion that APL-130277 is associated with the robust and rapid management of OFF episodes.
The graph below (click the multimedia link) shows the mean change from baseline in UPDRS part III for the 14 subjects who converted to ON. Two patients dosed at the highest available dose (30mg) did not achieve a full ON as assessed by the investigator, suggesting that higher doses may be required for some patients.
Treatment with APL-130277 was safe and well tolerated. Nausea was reported by three subjects at doses of 10, 15 and 20mg. One of these patients also experienced a mild episode of emesis. There were no reports of nausea at higher doses. There were no reports of local irritation or hypotension in any subject treated. A total of 60 doses of APL-130277 were administered to the 16 patients who completed dosing in the CTH-105 study.
Based on the findings of this study, Cynapsus is planning to conduct pivotal studies of longer duration and with larger patient numbers to confirm these results. These pivotal studies are expected to form the registration package necessary for a 505(b)(2) New Drug Application with the U.S. Food and Drug Administration expected to be submitted in 2016.
"The results of this Phase 2 trial are important as the data show that APL-130277 provided Parkinson's patients with a rapid improvement in motor function during OFF episodes," said Anthony Giovinazzo, President and CEO of Cynapsus.
"APL-130277 is being developed to address a significant unmet need facing people with Parkinson's disease today. The CTH-105 trial results lead us to maintain that APL-130277 may be able to serve the majority of Parkinson's patients seeking to restore movement rapidly, on demand, with an easy to retrieve and to administer form of apomorphine, the only approved and most efficacious drug for this purpose."
"OFF episodes are debilitating events for people with Parkinson's disease. A recent survey by The Michael J. Fox Foundation of 3,000 Parkinson's patients revealed that nearly half said their OFF time was moderate or severe, causing them to avoid or stop activities," said Dr. Todd Sherer, CEO of The Michael J. Fox Foundation for Parkinson's Research, which provided $500,000 in funding for this study.
"A rapid and reliable therapy that can address OFF episodes would be a major advancement in treatment. These results suggest that APL-130277 could provide patients with improved quality of life, and as supporters of this program from its early days, we look forward to continued success in Phase 3 trials."
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