On August 9, Axsome Therapeutics announced that its pipeline product AXS-05 (bupropion + dextromethorphan) achieved primary and key secondary endpoints in the MERIT Phase II trial for treatment-resistant depression (TRD). A large number of major depressive disorder (MDD) patients do not respond to the available treatments and are referred to as treatment-resistant. There is a need to develop therapies that target treatment-resistant patients, as well as products that improve remission rates and prevent relapses.

AXS-05 is a combination of bupropion and dextromethorphan and is an N-methyl-D-aspartate (NMDA) receptor antagonist with multimodal activity. The MERIT (Mechanistic Evaluation of Response in TRD) study was a randomized, double-blind, placebo-controlled, relapse-prevention, multi-center, Phase II trial, which evaluated 44 TRD patients in the US. In the trial results, AXS-05 met the primary endpoint by substantially and statistically significantly delaying the time to relapse of depressive symptoms as compared to placebo (p=0.002), with no relapses observed with AXS-05 over at least six months of double-blind treatment. AXS-05 also met the key secondary endpoint of relapse prevention, based on the rates of relapse during the double-blind treatment period (0.0% of AXS-05 patients, 36.4% of patients switched from AXS-05 to placebo, p=0.004). Moreover, AXS-05 was well tolerated during the trial.

Other than Janssen’s Spravato, which is approved for a limited patient population, none of the marketed products for depression can demonstrate rapid antidepressant effects, and most of the products take weeks to show effectiveness. The need for fast-acting therapies is more pressing in patients with the severe form of the disease, who, in many cases, have to be hospitalized. Furthermore, products used for the treatment of depression are associated with significant side effects, including weight gain and sexual dysfunction, and risk factors such as the boxed warning for the risk of suicidality amongst adolescents, which directly affects compliance and subsequently affects treatment efficiency.

Only a few pipeline agents in Phase II of development for MDD and TRD, namely Sage Therapeutics/Biogen’s zuranolone, Axsome Therapeutics’ AXS-05, and Relmada Therapeutics’ REL-1017, are aiming to offer rapid antidepressant effects. Zuranolone, AXS-05, and REL-1017 have novel mechanisms of action (MOAs) and show promise for providing rapid antidepressant effects. GlobalData anticipates that the most promising pipeline product will be Axsome Therapeutics’ AXS-05, which, with its novel MOA and potentially rapid onset of action, will have the potential to become a blockbuster drug. Currently a new drug application (NDA) for AXS-05 for the treatment of MDD is under priority review by the FDA, with a Prescription Drug User Fee Act (PDUFA) target action date of August 22, 2021. GlobalData forecasts that AXS-05 could generate global sales of approximately $1.3B by 2027.

Key opinion leaders (KOLs) interviewed by GlobalData highlighted that opportunities exist for products that will meet the significant unmet needs in this market. Products that have improved efficacy and safety profiles, and that can show rapid antidepressant effects when compared with available treatments, will be viewed favorably. Products with such characteristics will have significant competitive advantages, which would enable them to potentially move to the forefront of the treatment line and gain significant market share. However, it will be a challenge for new, expensive products to compete with the cheap, generic selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) that are very well established on the market.