Civitas Therapeutics, a privately-held pharmaceutical company developing and commercialising transformative therapeutics using its proprietary ARCUS technology, announced positive results from a phase 2b clinical trial of CVT-301, an inhaled formulation of levodopa (L-dopa). Study results from phase 2 studies will be presented at the 66th Annual American Academy of Neurology Meeting on April 29, 2014 at 2:30pm ET in Philadelphia, PA.

“We are extremely pleased that we met our primary endpoints in our phase 2b trial with statistical significance, demonstrating that CVT-301 was safe and well tolerated and provides patients with a rapid, clinically important improvement in motor function.  CVT-301 provided onset of action by 10 minutes with durable effects lasting for at least 60 minutes,” said Mark Iwicki, president and
chief executive officer, of Civitas. “CVT-301 is being developed to address a significant unmet need facing Parkinson’s disease patients today, and these results, particularly the efficacy and ease-of-use seen in the outpatient setting, give us confidence that CVT-301 can have a transformative impact on the daily lives of patients.”  

CVT-301 is being developed as an adjunctive, as-needed therapy to provide rapid and reliable relief from intermittent debilitating motor fluctuations, known as OFF episodes, suffered by Parkinson’s disease patients.  OFF episodes, which result from the unpredictable nature of oral baseline therapies, affect over half of all patients on an oral L-dopa treatment regimen and are considered to be one of the most important issues facing Parkinson’s disease patients today.

“OFF episodes are debilitating events for Parkinson’s disease patients. A rapid and reliable therapy that can address these episodes would be a major advancement in treatment," said Dr. Todd Sherer, chief executive officer, of The Michael J. Fox Foundation for Parkinson's Research, which provided supportive funding for the study. “These results suggest that CVT-301 could have a transformative impact on patients’ lives,” said Dr. Sherer.  “As supporters of this programme from its early days, we are pleased with its performance thus far and look forward to continued success in phase 3 trials.”

The phase 2b study was designed to assess the on-demand use of CVT-301 in Parkinson’s disease patients experiencing motor fluctuations over a one-month period.  The trial evaluated the efficacy, safety and tolerability of two doses of CVT-301.  Motor responses were evaluated during regularly scheduled clinical visits using the Unified Parkinson’s Disease Rating Scale Part 3 (UPDRS III).  In addition, efficacy was also evaluated during out-patient use with commonly used diary-based outcomes measures.

The primary endpoint was successfully met with CVT-301 achieving a clinically important and statistically significant reduction in average UPDRS III motor score versus placebo at time points ranging from 10 to 60 minutes post-administration (p < 0.001).  Furthermore, clinically important and statistically significant improvements in UPDRS III were seen at every time point including 10 minutes, the earliest time point tested, for both tested doses.

Over the course of the study, patients self-administered CVT-301 as-needed to treat approximately 4,500 OFF episodes, at an average of approximately two treatments per day.  With self-administration during at-home use, CVT-301 use was not associated with any increase in either non-troublesome or troublesome dyskinesia.  All doses of CVT-301 were safe and well-tolerated, and the CVT-301 inhaler was also shown to be easily utilised by Parkinson’s disease patients in the OFF state.

“Patients today live with the reality that their oral medications could fail them at any moment,” said Dr. Karl Kieburtz, the Robert J. Joynt Professor of Neurology, University of Rochester, president of Clintrex LLC and a member of the Civitas Scientific Advisory Board.  “By providing rapid onset and reliable relief using levodopa, the standard of care and backbone of patients’ therapy, in a simple patient-friendly device, CVT-301 has the potential to usher in a new paradigm in the treatment of Parkinson’s disease.”

The phase 2b trial (CVT-301-003) was a randomised, double-blind, placebo-controlled, multicentre study of inhaled CVT-301 or placebo for the treatment of up to 3 OFF episodes per day in Parkinson’s disease subjects experiencing intermittent OFF episodes.  The 86 patients treated in this study underwent an initial screen and run-in period of 2-4 weeks during which baseline motor assessments, measured using the Unified Parkinson’s Disease Rating Scale Part 3 (UPDRS III), as well as other baseline efficacy and safety/pulmonary function assessments, were conducted.  Following this phase, patients were randomised to receive CVT-301 or inhaled placebo in a double-blinded fashion.  During the first two weeks of treatment, patients self-administered an inhaled levodopa dose of approximately 35 mg or placebo.  During the final two treatment weeks, patients were dose-escalated to an inhaled levodopa dose of approximately 50 mg or placebo.

In-office assessments of UPDRS III were performed at week one, week two and week  The primary endpoint was defined as the mean change from pre-dose in average UPDRS III score (10-60 minutes post dose) after 4 weeks of treatment.  Patients were also instructed to complete a Parkinson’s disease diary for three days prior to the office visits, recording daily OFF time and ON time without and with dyskinesias, as well as a daily treatment log.  Safety parameters measured included pulmonary function, ECGs and vital signs (blood pressure, heart rate and orthostatic blood pressure).

CVT-301 is being developed as a self-administered, as needed, inhaled L-dopa therapy for OFF episodes, providing rapid delivery of L-dopa to the brain without altering a patient’s individually optimiSed oral L-dopa regimen.  Oral L-dopa, used for chronic symptom management, is administered to maintain dopamine levels in the brain above the therapeutic threshold; however, the reliability of oral L-dopa formulations is significantly compromised by delayed and unpredictable absorption and excessive variability in drug concentrations in the bloodstream inherent to the oral delivery route. L-dopa remains widely recognised as the most efficacious treatment for Parkinson’s disease symptoms in spite of this intrinsic unreliability, which results in OFF episodes.  CVT-301 is being developed as an adjunct as needed therapy to standard oral L-dopa therapy to address OFF episodes as they emerge and enable patients to reliably manage their symptoms.

CVT-301 leverages Civitas’ proprietary ARCUS technology to optimally deliver a precise dose to the lung for rapid and predictable L-dopa absorption. The ARCUSTM platform is uniquely able to deliver the necessary L-dopa dose with the required precision in a convenient, non-invasive manner. A Phase 1 study in healthy volunteers showed that CVT-301 rapidly achieved target L-dopa plasma levels with a pharmacokinetic (PK) profile supportive of its therapeutic potential.  The Phase 2a double-blind, placebo-controlled dose finding study (CVT-301-002) confirmed the PK profile in patients, produced rapid and durable improvement in motor function when administered to patients in the OFF state, and was generally safe and well-tolerated at all doses tested. Civitas has recently completed a successful

Phase 2b study to evaluate the efficacy and safety of CVT-301 in treating emergent OFF episodes during one month of continued use.  CVT-301 clinical studies conducted to date have been funded in part by grants from The Michael J. Fox Foundation for Parkinson’s Research.