Background

AVP-923 is a fixed-dose combination of two approved drugs. One is dextromethorphan, the active ingredient in several brands of cough syrup. Dextromethorphan is a weak antagonist of NMDA receptors, and an agonist of sigma 1 receptors, molecular chaperones located in membranes of the endoplasmic reticulum. The other is quinidine, a drug prescribed to treat irregular heartbeat. Quinidine increases the bioavailability of dextromethorphan by slowing its oxidative metabolism by the liver enzyme cytochrome P450-2D6 and by inhibiting the blood-brain-barrier protein pump P-glycoprotein. Avanir Pharmaceuticals is developing this combination under the name Nuedexta for the treatment of pseudobulbar affect. PBA accompanies primary neurological conditions, such as stroke, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and, less commonly, Alzheimer’s disease. The mechanism of action of AVP-923 on PBA is thought to involve reduction of glutamate excitotoxicity. Nuedexta capsules contain either 20 mg or 30 mg of dextromethorphan hydrobromide with 10 mg of quinidine sulfate. 

AVP-923’s safety profile is not benign. It is contraindicated for people with heart problems such as prolonged QT interval, atrioventricular block, and people with a history of thrombocytopenia, hepatitis, bone-marrow depression, or lupus-like syndrome. People who are overly sensitive to dextromethorphan-containing common cough medicines should not take AVP-923. Drug interactions with other CNS drugs, such as monoamine oxidase inhibitors (MAOs) and selective serotonin reuptake inhibitors (SSRIs), are known (Cruz, 2013; Schoedel et al., 2014). Quinidine's effect on P450-2D6 can also affect the pharmacokinetics of some concomitant medications; however, both dextromethorphan and quinidine are used at lower doses in this combination than when prescribed separately for cough or arrhythmia.

Findings

In October 2014, Avanir presented data from a multicenter Phase 2 study at the American Neurological Association annual meeting in Baltimore. Two hundred and twenty people with probable Alzheimer's and clinical agitation were enrolled into a sequential, parallel comparison trial design developed for indications that are prone to placebo effects. In these two-stage trials, a first randomization to drug or placebo is followed by analysis of the placebo group for responders and non-responders, and a subsequent re-randomization of both responders and non-responders to drug or placebo. This minimizes placebo effects during the trial (Ivanova et al., 2011). Two five-week treatment stages exposed 152 participants to 20 mg dextromethorphan hydrobromide and 10 mg quinidine sulfate, titrated up to 30 and 10 mg, respectively. On the primary outcome, the agitation/aggression domain of the neuropsychiatric inventory (NPI), the AVP-923 group improved 3.3 points compared with 1.7 points for placebo. Secondary outcomes also indicated a drug benefit. Clinicians and caregivers considered the benefit meaningful, according to the presentation. Side effects were in keeping with the combination's known safety profile. Adverse events were more frequent in the treatment group, and most were mild to moderate; serious adverse events were twice as frequent in drug versus placebo group. No deaths occurred in this trial (Sep 2015 news).

At the same conference, results were reported from the dementia cohort of a 750-person, open-label observation study of AVP-923 for the treatment of PBA accompanying dementia, stroke, or traumatic brain injury. This study used no placebo controls but gathered safety, tolerability, and efficacy data on indications poorly represented in the original New Drug Application for AVP-923. It reported a treatment benefit, with side effects within AVP-923's known safety profile (Oct 2014 conference news). A separate open-label safety study giving AVP-923 for a year reported that the combination was generally well-tolerated in a range of neurologic conditions, with serious adverse events consistent with the primary neurological conditions (Pattee et al., 2014).

In 2010, based on positive Phase 3 results, Nuedexta was approved by the U.S. FDA to improve pseudobulbar affect in people with ALS and multiple sclerosis (MS) (Pioro et al., 2010). After ALS patients in that study reported improved speech and swallowing, a subsequent trial confirmed gains in self-reported speech, swallowing, and salivation with drug treatment (Smith et al., 2017).

After its approval, Avanir aggressively promoted Nuedexta to treat disruptive behavior in nursing home residents, although it had not been tested in elderly people. Between 2010 and 2018, the drug was prescribed five times more often to people with PD and/or dementia than to people with ALS or MS (Fralick et al., 2019). Following an investigation by the U.S. Department of Justice, in 2019 Avanir paid $116 million in civil and criminal penalties to settle fraud charges related to illegal marketing of Nuedexta (CNN report).

Avanir is currently developing AVP-786, a second-generation version of Nuedexta, for agitation associated with Alzheimer’s disease.

Nuedexta is also being clinically evaluated for treatment of Huntington's disease. For all trials of AVP-923, see clinicaltrials.gov.