The Michael J. Fox Foundation for Parkinson's Research

The Michael J. Fox Foundation for Parkinson's Research is using its 2017 distribution to fund the following:

α4β2 Nicotinic Agonist for Treatment of L-Dopa Refractory Gait and Balance Disorders in Parkinson Disease

PROJECT TITLE: α4β2 Nicotinic Agonist for Treatment of L-Dopa Refractory Gait and Balance Disorders in Parkinson Disease

Investigator/Author: Roger L. Albin, MD; William T. Dauer, MD, University of Michigan

Objective: To test the hypothesis that Varenicline will improve gait speed and improve balance in Parkinson disease patients.

Background: Gait and balance problems, particularly falls, are a common and disabling symptoms in Parkinson disease, and do not improve markedly with existing treatments.  A combination of experimental animal and human studies indicates that loss of the brain chemical messenger acetylcholine is a cause of gait and balance problems in Parkinson disease.  A widely used FDA approved drug, varenicline (Trade name: Chantix), mimics some of the important actions of acetylcholine.  Using a combination of modern imaging methods and laboratory measures of gait and balance, we will determine whether varenicline improves the control of gait and balance in Parkinson disease patients.

Methods/Design: This study has 2 phases.  In the first phase, we will use an neuroimaging method called positron emission tomography and gradually escalating doses of varenicline to find the most appropriate dose for Parkinson disease patients.  In the second phase, we will administer the selected dose of varenicline to Parkinson disease patients in a double-blind crossover trial. Laboratory measures of gait and balance will be obtained on and off varenicline.  This will allow us to determine if varenicline, or similar drugs, should be pursued as treatments for Parkinson disease.  

Relevance to Diagnosis/Treatment of Parkinson’s Disease: If successful, we will identify a drug that may be useful in reducing falls in Parkinson disease patients.

Next Steps for Development: If successful, the next step would be to pursue a larger study addressing the safety of varenicline in a larger number and broader variety of Parkinson disease patients.  Subsequently, we would pursue a large clinical trial aimed at determining whether varenicline reduced falls in Parkinson disease.

September 2018 Project Update:

We made excellent progress over the last year.  We completed the initial phase of the experiment using positron emission tomography to select a trial dose of varenicline.  We were able to select a dose that is one half the usual clinical dose used for smoking cessation, probably reducing the likelihood of side effects.  In addition, we performed a parallel study in matched controls to determine that there are not major changes in the expression of this receptor in Parkinson disease.  We are over half way through the second phase of the study evaluating the effects of varenicline on gait and balance measures.  Data collection is going well and we anticipate study completion and data analysis in the spring.  To date, varenicline is very well tolerated in Parkinson disease patients.

September 2019 Project Update:

We completed the study and now are performing final analyses.  Our goal was to perform a target engagement study to assess whether a larger trial of varenicline was justified as a treatment of gait and balance problems in PD.  To briefly recapitulate, this study had three phases. 1) An initial dose selection phase using [18F]flubatine PET to assess a4B2 nicotinic receptor occupancy in PwP subjects.  2) A parallel study in healthy controls to assess if there were gross changes in a4B2 nicotinic receptor behavior in PwP.  3) A double-blind, cross-over trial of varenicline with laboratory measures of gait and balance as endpoints.  All phases are complete. In phase 1, we studied ascending doses from 0.25 mg per day to 1.0 mg 2x/day and found high receptor occupancy at all doses. We chose 0.5 mg 2x/day as the subsequent study dose because it is below the maximum, clinically used dose.  Our second phase study of normal subjects showed identical results, consistent with normal regulation-expression of a4B2 nicotinic receptors in PwP.  For the third phase, our statistical plan projected enrolling 36 PwP subjects and 33 completing.  We enrolled 34, had one dropout, and 33 completed.  Tolerability was excellent.  There were more adverse events in the varenicline treatment phase, but these were unrelated, expected, known side effects of varenicline.  There were 2 serious adverse events (SAEs), both unrelated to varenicline.  There were 2 dose reductions.  Initial statistical analyses of the primary outcome measures are negative.  We did not find an improvement in gait speed or our chosen balance measure.  UPDRSIII scores were slightly worse in the treatment periods.  Additional analysis examining cognitive function, attentional function, and other gait/balance measures are underway.  With this subject population, we have the potential to perform analyses incorporating PET measures of dopamine and cholinergic system integrity, which may be enlightening.  An abstract of this work will be presented at the Michael J. Fox Foundation Therapy meeting and we anticipate submitting a manuscript by the end of the year.