hase III Results of AVP-923 (formerly called Zenvia) Published, Showing It Can Reduce Episodes of Uncontrollable Laughing or Crying in MS and Other Di

Oct 08, 2010

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. (Annals of Neurology, published online September 13, 2010)

According to an Avanir press release dated August 5, the U.S. Food and Drug Administration set a date to complete its review of this drug by October 30, 2010. The company also has submitted trade names to the FDA for consideration after receiving notice that the agency did not accept the name “Zenvia” for marketing use.

Background: 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.

Study Details: 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.

Follow-up: 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)

Comment: “The availability of a therapy that could safely and effectively treat uncontrollable laughing and crying would be a real breakthrough for those with MS and other neurological conditions who experience this troubling symptom,” said Dr. Nicholas LaRocca, a clinical psychologist who directs the National MS Society’s research programs in patient management and health care delivery and policy.

Read more about MS and emotional changes.

A Clinical Bulletin for physicians, providing details about pseudobulbar affect and its treatment in MS is available on the National MS Society’s Professional Resource Center.