Topic: Safety of AVP-923 in the Treatment of Multiple Sclerosis Patients with Involuntary Emotional Expression Disorder
By Kristin Jenkins

Investigational therapy AVP-923 in multiple sclerosis (MS) patients with Involuntary Emotional Expression Disorder (IEED) appears to be safe and well-tolerated over a 52-week period and beyond.

Importantly, this proprietary combination of dextromethorphan (DM; 30 mg) and quinidine (Q; 30 mg) inhibits the bursts of abnormal neuronal activity, which lead to IEED—a devastating condition characterized by inappropriate laughing and crying. “Very low doses of both produce clinically efficacious results and few side effects,” reported James P. Wymer MD of Upstate Neurology, Albany, NY. “AVP-923 quiets down the bursts of neuronal activity so that IEED is not as severe.”

Studies by Pope LE, et al, (J. Clin. Pharmacol. 2004; 44: 1132-1142) have shown that DM acts as an uncompetitive antagonist of NMDA and a sigma-1 receptor agonist to suppress the release of excitatory neurotransmitters such as glutamate. It is suspected that sigma-1 receptor sites in the cerebellum and brain stem may be involved in IEED.

Q inhibits metabolism of DM, resulting in increased and sustained plasma DM levels. It is important to note, said Dr. Wymer, that the Q levels used to block DM metabolism are 10-20 times lower than those used to treat cardiac arrhythmias.

Most of the common adverse events associated with the use of AVP-923 were reported in the first week of treatment and decreased in frequency over time, said Dr. Wymer, adding that the adverse event profile in MS patients appears similar to that of other disease populations that have been studied. “Other than some transient dizziness lasting for about one day, AVP-923 was very well tolerated,”
he said.

A condition characterized by the disinhibition of emotional expression secondary to neurological disease or injury, IEED can also be seen in patients with ALS, Alzheimer’s disease (AD), Parkinson’s disease (PD), stroke and traumatic brain injury (TBI). In addition to uncontrollable laughing and/or crying, classic symptoms of IEED include facial displays that don’t correspond with mood or situation. Inappropriate emotional outbursts can be extremely distressing and lead to clinically significant impairment at work as well as in social or other settings.

IEED is a relatively new term for a disorder that has been known by many different names, including pathological laughing and crying, emotional lability, emotional incontinence, and pseudobulbar affect. “The problem with the old terms is that they tend to be specific to crying and laughing,” explained Dr. Wymer in an interview. “The disorder appears to involve a lot more than that, so we are now using a term that is much broader, covers all the components and explains really what it is – involuntary emotional expression.”

In the analysis of investigational therapy AVP-923 in MS patients with IEED , common adverse event rates were analyzed and compared to IEED patients with differing diagnoses. The analysis looked at two groups of patients: 76 IEED patients from a phase III study in MS patients in which AVP-923 was shown to be effective (Panitch H, et al. Annals of Neurology May 2006; 59 (5); 780-7) and a large open-label safety study of 294 MS patients.

In the MS phase III multi-center, double-blind, placebo-controlled study, safety assessments included vital signs, clinical labs, ECGs and adverse events (AE). Following completion of the study, patients were allowed to roll over into an open label safety study.

Common AEs reported in the AVP-923 patients (n=76) included: dizziness (26.3%); headache (15.8%); nausea 22.4%); fatigue (14.5%);, fatigue aggravated (5.3%); arthralgia (7.9%); and weakness (10.5%). By comparison, in the placebo patients (n=74), 9.5% reported dizziness, 29.7% headache, 14.9% nausea, 8.1% fatigue, 12.2% fatigue aggravated and arthralgia, and 5.4% said they had weakness.

By comparison, patients in the multi-center, open-label study to assess the long-term safety of AVP-923 in patients with IEED, 264 patients were enrolled at the time of the analysis. (There are now more than 500 patients enrolled.) All patients entered into a 52-week treatment phase with the option of moving on to an extension phase.

Enrollment was not limited by underlying disease or condition and as a result, more than 30 underlying neurologic diseases or injuries are represented in the study, including MS, ALS, stroke, TBI, PD, AD, and other dementias. Some 45.9% of patients, however, had MS as their primary neurological condition and 36.1% had ALS as their primary neurological condition. In the MS patients, 19% reported dizziness, 5% somnolence, 21% nausea, 16% diarrhea, 24% fatigue, 16% weakness, 15% reported a fall, and 7% said they experienced muscle cramps.

Dr. Wymer also reported that in MS patients with IEED receiving AVP-923:

* there was no difference in the frequency of AEs based on age (greater than 65 years versus less than 65 years), sex or race;

* common AEs tended to be mild to moderate;

* there were no treatment-related SAEs;

* during study treatment, standard serum panel measurements were stable overall; and

* there were no clinical relevant changes in vital signs or on physical exam.

Evaluation of cardiac measures showed that electrocardiographic results were consistent with previous studies of AVP-923. There was no evidence of any clinically meaningful effect on cardiac repolarization or on ECG variable during long-term exposure.

AVP-923 is currently under FDA review for use in IEED and “hopefully” will be available in the next year, said Dr. Wymer. The trade name now being considered is “Neurodex.”