Civitas Therapeutics, Inc., a privately-held pharmaceutical company developing transformative therapeutics using the ARCUS respiratory delivery platform, has reported positive topline results from a phase II clinical trial of CVT-301, an inhaled formulation of levodopa (L-dopa).  CVT-301 is being developed as an adjunct therapy to provide rapid and reliable relief from intermittent debilitating motor fluctuations (OFF episodes) that impact a large proportion of Parkinson’s disease patients.

The study used a randomized, placebo-controlled design to evaluate L-dopa pharmacokinetics and pharmacodynamic effects following administration of CVT-301 to Parkinson’s disease patients experiencing motor fluctuations. Administering CVT-301 to patients in the OFF state produced a rapid and durable improvement in motor function.

The pharmacokinetic data recapitulated the phase I study results showing CVT-301 provided immediate L-dopa absorption and consistent increases in plasma concentrations in marked contrast to the delayed and variable L-dopa levels seen with Sinemet (oral Ldopa/carbidopa). All doses of CVT-301 were safe and well tolerated with no increase in the frequency or severity of dyskinesias relative to oral. Civitas plans to present the comprehensive data from the study at a future scientific meeting.

“The unpredictable wearing off of oral L-dopa and the dyskinetic side effects are among the most significant challenges with the current management of Parkinson's disease," said Dr Todd Sherer, CEO of The Michael J Fox Foundation for Parkinson's Research. "There remains a critical unmet need for therapies that increase the reliability of L-dopa while not exacerbating the side effects."

“The significant inherent variability of oral L-dopa absorption is known to be a major contributor to the development of debilitating OFF episodes,” said Dr Martin Freed, chief medical officer and co-founder of Civitas. “CVT-301 has the potential to provide a transformative benefit to patients by enabling more predictable and effective symptomatic relief without worsening side effects such as dyskinesia, thereby allowing them to regain control of their lives.”

“The results of this study represent proof-of-concept of CVT-301 as a therapy to provide rapid and precise control of patients’ L-dopa levels enabling better management of their intermittent motor fluctuations.  This has the potential to be a very meaningful advancement in the symptomatic treatment of Parkinson’s disease,” said Dr Karl Kieburtz, president of Clintrex LLC, the Robert J Joynt Professor of Neurology, University of Rochester, and a member of the Civitas Scientific Advisory Board.

This phase IIa study of CVT-301 was funded in part by a grant from The Michael J Fox Foundation for Parkinson’s Research.

The phase II study (CVT-301-002) was a multi-centre, randomized, double blind, placebo-controlled, single dose, cross-over design with three arms (placebo, 25mg and 50mg) and included an “open label” oral Sinemet arm.  The twenty four (24) patients treated in this study underwent serial evaluations of Ldopa plasma levels, motor response, and safety at each visit. The patients were administered the study drug in the OFF state with the serial evaluations starting prior to dosing and continuing for up to 180 minutes post-dose.

Motor function was measured using a tapping test, the Unified Parkinson’s Disease Rating Scale Part III (UPDRS III), and subjective evaluation of “meaningful” ON and OFF. Safety parameters monitored included pulmonary function, clinical laboratory data, EGCs, and vital signs (blood pressure, heart rate, and orthostatic blood pressure). This study was designed to measure the time, magnitude, and durability of CVT-301’s effect on motor function, to evaluate the safety and tolerability of CVT-301 in Parkinson’s disease patients, to confirm the results from a CVT-301 phase I healthy volunteer study (CVT-301-001), and to establish the dose for future clinical trials with CVT-301.

Civitas’ lead program, CVT-301, is an inhaled formulation of L-dopa for the rapid and reliable relief from debilitating motor fluctuations associated with Parkinson’s disease. For symptomatic relief, oral L-dopa is administered to maintain dopamine levels in the brain above the therapeutic threshold; yet the efficacy of oral L-dopa is significantly compromised by delayed and unpredictable absorption and excessive variability in the circulating plasma drug concentrations inherent to the oral delivery route. CVT-301 is an ARCUS therapeutic that incorporates L-dopa and is optimized to deliver a precise dose to the deep lung for rapid and predictable L-dopa absorption. The ARCUS platform is able to uniquely deliver the necessary L-dopa dose with the required precision.  CVT-301 is being developed as an adjunct to standard oral L-dopa therapy to enable patients to manage motor fluctuations caused in part by the inter-dose variability of oral L-dopa. In preclinical models, CVT-301 has demonstrated immediate and consistent increases in L-dopa peak plasma concentration providing rapid, durable symptomatic relief, even when compared to larger doses of oral L-dopa. A phase I study in healthy volunteers showed that CVT-301 rapidly achieved target L-dopa plasma levels with a pharmacokinetic profile supportive of its therapeutic potential.

Parkinson’s disease is a neurodegenerative disorder caused by the diminished production of dopamine, resulting in progressive impairment of motor function including tremors, rigidity, and difficulty in moving.