Therapeutics

AVP-923

Overview

Name: AVP-923
Synonyms: Nuedexta, Zenvia
Chemical Name: dextromethorphan hydrobromide/quinidine sulfate
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Parkinson's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 4), Amyotrophic Lateral Sclerosis (Phase 3), Parkinson's Disease (Phase 3)
Status in Select Countries: Approved in the United States and European Union for treatment of pseudobulbar affect.
Company: Avanir Pharmaceuticals

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 (see Cruz, 2013Schoedel 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 of agitation in Alzheimer's disease at the annual meeting of the American Neurological Association 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 (see 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 mg and 10 mg, respectively. On the primary outcome measure, the agitation/aggression domain of the neuropsychiatric inventory (NPI), the AVP-923 group improved 3.3 points compared with 1.7 points with 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, most were mild to moderate, and serious adverse events were twice as frequent in drug versus placebo group. No deaths occurred in this trial (see September 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 uses no placebo controls but gathers 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 (see October 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 and that serious adverse events appeared consistent with the primary neurological conditions (Pattee et al., 2014).

In 2010, a Phase 3 trial was reported to improve pseudobulbar affect in people with ALS and multiple sclerosis (MS) (see Pioro et al., 2010). Nuedexta is also being clinically evaluated for treatment of neuropathic pain, uncontrolled movements induced by levodopa therapy of Parkinson’s, as well as autism, migraine, and depression. For all trials of AVP-923, see clinicaltrials.gov.

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References

News Citations

  1. Paper Alert: Promising Phase 2 Results for Agitation Drug Published
  2. A New Drug to Calm Agitation, Uncontrollable Laughing and Crying, in Alzheimer’s?

Paper Citations

  1. . Optimality, sample size, and power calculations for the sequential parallel comparison design. Stat Med. 2011 Oct 15;30(23):2793-803. Epub 2011 Jul 29 PubMed.
  2. . An open-label multicenter study to assess the safety of dextromethorphan/quinidine in patients with pseudobulbar affect associated with a range of underlying neurological conditions. Curr Med Res Opin. 2014 Nov;30(11):2255-65. Epub 2014 Jul 28 PubMed.
  3. . Dextromethorphan plus ultra low-dose quinidine reduces pseudobulbar affect. Ann Neurol. 2010 Nov;68(5):693-702. PubMed.
  4. . Nuedexta for the treatment of pseudobulbar affect: a condition of involuntary crying or laughing. P T. 2013 Jun;38(6):325-8. PubMed.
  5. . Evaluating the safety and efficacy of dextromethorphan/quinidine in the treatment of pseudobulbar affect. Neuropsychiatr Dis Treat. 2014;10:1161-74. Epub 2014 Jun 26 PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. . Crying and suicidal, but not depressed. Pseudobulbar affect in multiple sclerosis successfully treated with valproic acid: Case report and literature review. Palliat Support Care. 2014 Jun 11;:1-5. PubMed.
  2. . Pseudobulbar affect: prevalence and management. Ther Clin Risk Manag. 2013;9:483-9. Epub 2013 Nov 29 PubMed.
  3. . A study of potential pharmacokinetic and pharmacodynamic interactions between dextromethorphan/quinidine and memantine in healthy volunteers. Clin Drug Investig. 2012 Aug 1;32(8):e1-15. PubMed.
  4. . Randomized open-label drug-drug interaction trial of dextromethorphan/quinidine and paroxetine in healthy volunteers. Clin Drug Investig. 2012 Mar 1;32(3):157-69. PubMed.
  5. . Current concepts in the pharmacotherapy of pseudobulbar affect. Drugs. 2011 Jun 18;71(9):1193-207. PubMed.
  6. . Memantine may affect pseudobulbar affect in patients with Alzheimer's disease. Acta Neuropsychiatr. 2013 Dec;25(6):361-6. PubMed.
  7. . ANTI-TUSSIVE EFFECTS OF MEMANTINE IN GUINEA PIGS. Chest. 2011 Oct 20; PubMed.
  8. . Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial. Neurology. 2004 Oct 26;63(8):1364-70. PubMed.