Summary
The results of a Phase III trial of an oral drug designed to treat uncontrollable laughing and/or crying (known as pseudobulbar affect), a troubling symptom experienced by some people with MS, ALS, and other neurological disorders, have now been published. AVP-923 (Avanir Pharmaceuticals) significantly reduced the rate of laughing and crying episodes and appeared to be safe and well tolerated. Erik P. Pioro MD, PhD, Benjamin Rix Brooks MD, Jeffrey Cummings MD, Randolph Schiffer MD, Ronald A. Thisted PhD, Daniel Wynn MD, Adrian Hepner MD, Randall Kaye MD. Annals of Neurology September 13 epub ahead of print
Details
A small percentage (around 10%) of persons with MS experience
episodes of uncontrollable laughing and/or crying that are
unpredictable and seem to have little or no relationship to
actual events or the individual’s actual feelings. This condition
is thought to result from lesions – damaged areas – in emotional
pathways in the brain. It is important for family members and
caregivers to know this, and realize that people who experience
these episodes may not always be able to control their expression
of emotions. Some medications have shown benefit in small
clinical trials, but there is no medication approved specifically
to treat this symptom.
Avanir Pharmaceuticals has been conducting trials of AVP-923 in
its current and related formulations for several years as a
treatment for pseudobulbar affect in a number of disorders,
including MS, ALS, Alzheimer’s disease and stroke. AVP-923 is a
patented, orally-administered combination of dextromethorphan and
an enzyme inhibitor known as quinidine; quinidine is a drug that
inhibits the metabolism of dextromethorphan which results in a
sustained elevation of dextromethorphan in the brain. In 2006,
Avanir received a letter from the FDA indicating that the drug
was “approvable” and requesting that additional studies be
conducted, leading to the current study.
This trial, called the STAR trial, involved 326 individuals (197
with ALS and 129 with MS) across the U.S. and Latin America who
were experiencing pseudobulbar affect. Participants either
received one of two doses of AVP-923 or inactive placebo twice a
day for twelve weeks.
The primary endpoint established for this trial was the rate of
self-reported laughing or crying episodes over the course of the
trial. Both doses significantly reduced episode rates by about
47-49 percent compared to placebo. Secondary outcomes, including
patient diaries and episode-free days, also suggested significant
benefit among groups taking AVP-923, and those on the higher
dosage also showed improved measures of social functioning and
mental health.
The medication was relatively well tolerated. The adverse events
more frequently reported by those on therapy (especially the
higher dose) versus those on placebo were dizziness, nausea and
diarrhea. There were seven deaths in the study, all occurring in
participants who had ALS, and all of which were classified by an
independent committee as being likely due to progression of
respiratory problems related to the disease.
In an extension of this study, 253 people took the higher dose of
AVP-923 for 12 more weeks, during which safety and tolerability
were assessed. The drug continued to be well tolerated. (Abstract
#P06.128, American Academy of Neurology Annual Meeting, 2010)
With information from the national Ms Society
(USA)