SynAgile Corporation Announces Positive Phase 2a Results for Continuous, Noninvasive, Intraoral Levodopa-Carbidopa Administration to Treat Parkinson's Disease

WILSON, Wyo., Oct. 8, 2015 /PRNewswire/ -- SynAgile Corporation (www.SynAgile.com), a privately held pharmaceutical company that develops and commercializes drug delivery systems using its proprietary OraFuse™ intraoral technology platform, today announced positive results from a proof-of-concept, Phase 2a, open-label clinical trial of continuous intraoral administration of levodopa-carbidopa (LD/CD).

"We are extremely pleased that the primary and secondary endpoints in our Phase 2a trial were met, demonstrating that continuous intraoral delivery of LD/CD provides reduced variability in plasma levodopa concentrations and a significant reduction in motor complications. OFF time was reduced by 43% compared to standard oral LD/CD tablet therapy," said Ephraim Heller, CEO of SynAgile. "SynAgile is developing its DopaFuse™ product as a continuous, noninvasive LD/CD therapy to address the problem of levodopa-induced motor complications, a large, unmet need facing Parkinson's patients today. These results were achieved with a noninvasive therapy that requires no surgery, bulky pumps, or needles. Continuous intraoral LD/CD therapy will appeal to many patients whose motor complications are not adequately controlled with standard oral medications. Furthermore, DopaFuse™ will potentially avoid the side effects and human factor problems associated with deep brain stimulation and Duodopa™ therapy."

Motor complications include OFF time and dyskinesia associated with chronic levodopa treatment. Motor complications affect most patients with advanced Parkinson's disease and are considered to be one of the most important issues facing Parkinson's disease patients today.

"Motor complications, and specifically OFF time, can have a profoundly negative impact on the lives of Parkinson's disease patients. A safe, convenient, noninvasive, nonsurgical, oral levodopa therapy would be a major advance in treatment," said Prof. Warren Olanow, co-Principal Investigator of the study, Chairman Emeritus, Department of Neurology, Mount Sinai School of Medicine, CEO of Clintrex LLC, and a member of the SynAgile Scientific Advisory Board. "The reduction in OFF time was clinically significant, and there were no treatment-related adverse events. The results suggest that continuous intraoral LD/CD administration may provide a safe, noninvasive approach for controlling OFF time," said Prof. Olanow.

The study compared continuous intraoral administration of LD/CD versus standard intermittent LD/CD tablets taken 4–8 times daily in patients with advanced Parkinson's disease. Continuous administration was defined as administration of a dose of LD/CD suspension every 5–10 minutes. Each patient served as his/her own control (described below). For the primary endpoint, statistically significant improvements were observed for variability in plasma levodopa concentration (as determined by linearity) and for reduction in 1-hour and 2-hour fluctuation indexes (p < 0.001 for each). OFF time was reduced by 43% (p < 0.001), and the UPDRS Part III motor score improved (p = 0.010).

Trial Design

The Phase 2a trial was an open-label, single-center study of 18 Parkinson's disease patients who experienced ≥2 hours of OFF time per day. Profs. Warren Olanow and Fabrizzio Stocchi served as Co-Principal Investigators. Standard intermittent oral LC/CD tablets were compared with the same total doses of LD/CD suspension delivered into the mouth every 5–10 minutes. The study was conducted at Hospital San Raffaele in Rome, Italy. Patients were admitted to the clinic on Day 1 for baseline evaluations. On Day 2 (the "Control Day"), LD/CD was administered as commercially available LD/CD tablets at each patient's pre-baseline dosing regimen. Plasma levels of levodopa as well as ON and OFF time were measured repeatedly over the course of 8 hours. On Day 3 (the "PK Day"), a suspension of LD/CD was administered intraorally every 5–10 minutes over a period of 8 hours at a dose equal to the total dose of standard oral LD/CD that the patient consumed over the same 8-hour period on the Control Day, and plasma levels of levodopa were obtained. On Day 4 (the "Efficacy Day"), each patient received his or her first LD/CD morning dose as an oral tablet at the same dosage as the first morning dose on the Control Day. They then received the balance of the total 8-hour dose that they took on the Control Day by way of intraoral administration of a suspension of LD/CD every 5–10 minutes over a period of 8 hours. ON and OFF time were assessed as on Day 2. Patients were then discharged from the clinic on their standard medication and returned on Day 18 for a safety evaluation.

The primary endpoint was defined as the variability of the levodopa concentrations; we compared standard intermittent oral and continuous intraoral administration. Pharmacokinetic endpoints included deviation from linearity and the mean levodopa fluctuation index (Cmax−Cmin)/Caverage). Efficacy was measured by neurologist-based assessment of motor state and dyskinesia at 30-minute intervals over the 8 hours and by UPDRS Part III, assessed at 0, 2, 4, and 8 hours on the Control Day (Day 2) and the Efficacy Day (Day 4).

Safety parameters measured included physical examinations, neurological examinations, ECGs, vital signs, blood and urine laboratory assessments, and oral site assessments by both the neurologist and the patient.

Full results of the study will be presented at an upcoming scientific meeting.

About OraFuse™ and DopaFuse™

SynAgile is developing the OraFuse™ drug delivery platform for the continuous oral delivery of drugs with poor pharmacokinetics. OraFuse™ consists of a miniature, disposable, drug-delivery device carried on a small, tooth-attached retainer that continuously infuses medication into the mouth. SynAgile's first product is DopaFuse™, which uses the OraFuse™ device to infuse a proprietary formulation of LD/CD into the mouth for the treatment of Parkinson's disease. DopaFuse™ is being developed for daily use by Parkinson's disease patients. The LD/CD is swallowed with the patient's saliva and absorbed via the conventional gastrointestinal route. The DopaFuse™ drug formulation has no taste, and the infusion is imperceptible to the patient. The DopaFuse™ system is not visible to others, is comfortable to wear, and does not interfere with speech, swallowing, or drinking. DopaFuse™ is intended to enable patients with Parkinson's disease to achieve more-constant plasma levodopa levels and reduce their motor complications. DopaFuse™ will provide patients with a safe, convenient, noninvasive therapy to reduce motor complications. In contrast to other continuous levodopa delivery systems, DopaFuse™ requires no surgical procedures or needles.

Levodopa is widely recognized as the most efficacious treatment for Parkinson's disease symptoms. However, levodopa is quickly broken down in the body and its absorption is unpredictable. Even when taken 4–8 times per day, standard oral levodopa tablets often produce widely varying plasma levodopa concentrations over the course of the day. Low plasma levodopa concentrations typically result in OFF time, characterized by tremor, rigidity, slowness of movement, and postural instability. High plasma levodopa concentrations often result in dyskinesia, characterized by involuntary muscle movements. Patients with advanced Parkinson's disease can spend many hours each day in the OFF state or with dyskinesia.

About Parkinson's Disease

Over one million people in the US and over seven million people worldwide suffer from Parkinson's disease, a neurodegenerative disorder caused by the diminished production of dopamine, which results in progressive impairment of motor function, including tremors at rest, rigidity, and impaired movement. Even when treated with the current standard of care, the majority of patients with advanced Parkinson's disease continue to experience motor complications (OFF periods and dyskinesia). These motor complications reduce patients' ability to lead productive, independent lives and are recognized by patients, caregivers, and healthcare professionals as one of the most troubling and debilitating issues associated with the disease.

About SynAgile

SynAgile is a biopharmaceutical company focused on developing and commercializing transformative therapeutics using its proprietary OraFuse™ intraoral continuous dosing technology, with an initial focus on treating debilitating motor complications in patients with Parkinson's disease using its DopaFuse™ levodopa-carbidopa therapy.

OraFuse and DopaFuse are trademarks of SynAgile Corporation. Duodopa is a trademark of AbbVie Inc.

Contact
SynAgile Corporation
Ephraim Heller, CEO
(510) 788-4435
[email protected]

SOURCE SynAgile Corporation

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