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.
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