The Michael J. Fox Foundation for Parkinson`s Research Grants 2012

 

The Michael J. Fox Foundation for Parkinson's Research is using its 2012 distribution to fund the following:

A Novel, Validated, Dry Powder-Based Delivery of Intrapulmonary Levodopa as a Treatment for Motor Fluctuations in Parkinson's Disease Patients

 

PROJECT TITLE:  A Novel, Validated, Dry Powder-Based Delivery of Intrapulmonary Levodopa as a Treatment for Motor Fluctuations in Parkinson's Disease Patients

Investigators/Authors: Martin Freed, MD, Richard Batycky, PhD, Civitas Therapeutics, Inc.

Objective: Oral levodopa pharmacokinetics (PK) is subject to excessive within- and between-subject variability, reflecting challenges inherent to gastrointestinal (GI) delivery. Aerosol delivery of levodopa (LD) bypasses the GI tract and should significantly reduce the time to onset and improve PK consistency thereby optimizing therapeutic benefit when used with standard oral therapies. CVT-301 is a proprietary dry powder LD formulation that is optimized to deliver a precise dose to the lung for rapid, predictable and consistent LD absorption. Our objective is to demonstrate more rapid and consistent LD exposure and improved motor function following adjunct CVT-301 administration, compared to oral.

Methods/Design:  This project is designed to demonstrate the PK attributes of intrapulmonary levodopa delivery compared to standard oral administration and to investigate the pharmacodynamic (Pdyn) benefit of adding intrapulmonary levodopa to a standard oral regimen for Parkinson’s Disease patients. CVT-301 will be investigated first in healthy adult volunteers. In a single ascending dose, cross over design, the safety (including pulmonary safety) and PK of levodopa will be assessed comparing CVT-301 to oral levodopa. Following selection of dose(s), CVT-301 will be studied in Parkinson’s disease patients as an adjunct to their standard oral therapy. In a placebo-controlled, cross-over design, the safety, levodopa PK profile and PDyn effects (i.e., motor responses) will be assessed, comparing CVT-301 to oral levodopa and placebo.

Relevance to Diagnosis/Treatment of Parkinson’s disease:  Inconsistent levodopa exposure is a major factor contributing to the development of both motor fluctuations and dyskinesias. As an adjunct to standard oral therapies, CVT-301 may facilitate consistent levodopa exposure and improve therapeutic benefit of the most important anti-parkinsonian drug. Such a product that provides rapid, predictable and consistent levodopa exposure would be a major breakthrough in the Symptoms & Side Effects treatment of Parkinson’s disease.

Anticipated Outcome: Two key outcomes are anticipated from this project which will accelerate future clinical investigation of CVT-301. First, it is expected that the pharmacokinetic attributes of CVT-301 in humans will be consistent with those observed in pre-clinical models. Second, it is expected that adjunct administration of CVT-301 will enable more rapid and consistent levodopa exposure, leading to improved therapeutic benefit to Parkinson’s disease patients.

September 2013 Project Update:

The clinical trial testing CVT-301 as a treatment for motor fluctuations in Parkinson’s disease patients showed positive results in both Phase 1 and Phase 2 studies. Consistent with pre-clinical studies, CVT-301 administration resulted in rapidly increasing, dose-proportional plasma L-dopa concentrations with therapeutically relevant levels achieved in several minutes. These data also demonstrated that the resulting L-dopa levels were much less variable than occurs during standard oral administration.  

A Phase 2 dose finding study was also completed. The expectant PK profile with its rapid and more precise increase of plasma LD concentration was confirmed in PD patients and significant and rapid improvement in motor function was also demonstrated with no increase in the incidence or severity of dyskinesia relative to oral LD administration.  

A Phase 2b study investigating the “as needed” use of CVT-301 adjunct to a scheduled daily regimen of levodopa is currently planned for the treatment of episodic OFFs in Parkinson’s patients.

September 2014 Project Update:

The Phase 2b study investigating the “as needed” use of CVT-301 adjunct to a scheduled daily regimen was designed to investigate the safety and efficacy of CVT-301 when self-administered “as needed” by patients for the treatment of OFF episodes. Patients were permitted to use CVT-301 up to 3 times a day to treat their emerging OFF episodes over a 1-month period of observation. Two doses of CVT-301 were studied; these doses delivered approximately 35 mg and 50 mg levodopa to the lung, respectively.
    
86 PD patients who experienced frequent OFF periods were administered CVT-301 or placebo. Clinically and statistically significant improvements in motor response, as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) Part 3 motor score, were observed with onset of benefit apparent at about 10 minutes post-dose. In addition CVT-301 resulted in significant improvements in subjective motor response. These ‘in-office’ measurements translated to clinically important and statistically significant improvements in OFF time, recorded by patients without an increase in time ON with dyskinesia, relative to placebo.

CVT-301 was generally safe and well tolerated in both doses.  There were no adverse changes in any respiratory (spirometry) endpoints.
Results:

Civitas is now planning a larger Phase 3 clinical trial, which is expected to begin in Q1 2015.

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