Therapy Type: Combination, Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2/3)
Company: Axsome Therapeutics, Inc.
AXS-05 is a fixed-dose combination of two approved drugs being developed for the treatment of agitation in people with Alzheimer’s disease. One component, dextromethorphan, is the active ingredient in several brands of cough syrup. Dextromethorphan is a weak antagonist of NMDA receptors, an agonist of sigma 1 receptors—molecular chaperones located in membranes of the endoplasmic reticulum—and inhibits serotonin and norepinephrine transporters, nicotinic acetylcholine receptors, and microglial activation. The other component is bupropion, a drug prescribed to treat depression and to help people stop smoking. Bupropion slows the metabolism of dextromethorphan and increases its plasma concentration. This approach is similar to that taken for AVP-923, which combined dextromethorphan with quinidine. Bupropion also acts as a norepinephrine and dopamine reuptake inhibitor and a nicotinic acetylcholine receptor antagonist.
Trial registries or the peer-reviewed literature contain no information on Phase 1 trials.
In July 2017, Axsome began ADVANCE, a Phase 2/3 multisite study to compare the efficacy and safety of a five-week course of AXS-05, bupropion, or placebo in 366 people with a diagnosis of probable AD and agitation. AXS-05 was titrated to a final dose of 45 mg dextromethorphan and 105 mg bupropion twice daily. The primary outcome was change from baseline in the Cohen-Mansfield Agitation Inventory. In April 2020, the company released topline results, claiming a statistically significant 15.4 reduction in CMAI with treatment, compared to a decrease of 11.5 points with placebo or 10.0 points with bupropion only. Seventy percent of patients had a clinical response, defined as 30 percent or greater improvement on the CMAI. The drug reportedly improved scores on a clinical global assessment of change for agitation. Most common side effects were sleepiness, dizziness and diarrhea; no serious adverse events were observed related to the drug. AXS-05 caused no cognitive decline as measured by the MMSE, or sedation (see press release, slides).
On June 26, 2020, the U.S. Food and Drug Administration granted AXS-05 breakthrough therapy designation for agitation in Alzheimer’s disease; the drug combination already holds breakthrough therapy as well as fast-track status for depression. After meeting with the FDA in August 2020, the company announced it would start two trials in late 2020 to support a new drug application for agitation in AD. One will be a Phase 3 efficacy trial; the other, an open-label long-term safety study (press release).
AXS-05 has completed trials in major depressive disorder, treatment-resistant depression, and smoking cessation. The company plans to request marketing approval for major depression in 2020 (press release).
For details on AXS-05 trials, see clinicaltrials.gov.
Last Updated: 13 Nov 2020
- Wilkinson ST, Sanacora G. A new generation of antidepressants: an update on the pharmaceutical pipeline for novel and rapid-acting therapeutics in mood disorders based on glutamate/GABA neurotransmitter systems. Drug Discov Today. 2019 Feb;24(2):606-615. Epub 2018 Nov 14 PubMed.