Axsome Therapeutics Inc. is hoping the fixed-dose marriage of dextromethorphan (DM) with established depression player bupropion in oral AXS-05 will do the trick against treatment-resistant depression (TRD) in the newly launched phase III trial called STRIDE-1 (Symptom Treatment in Resistant Depression 1).

DM acts on a number of central nervous system (CNS) receptors but gets metabolized fast. Bupropion also hits CNS receptors, and AXS-05 is using it as a drug-delivery method to slow down DM metabolism, thereby keeping drug levels higher in the blood. "We expect the combination of DM and bupropion to provide a synergistic effect," Brean Capital analyst Jonathan Aschoff wrote in a research report when he started coverage of the New York-based company last December. Axsome officials could not be reached.

Already in TRD, lone player Symbyax (olanzapine and fluoxetine) is marketed by Eli Lilly and Co., of Indianapolis. Tokyo-based Otsuka Pharmaceutical Co. Ltd. is developing a DM/quinidine combo for the condition, and other firms with research in the space include Alkermes plc, Allergan plc, and Janssen Research & Development LLC. Axsome also is developing the compound in agitation associated with Alzheimer's disease (AD).

There, although nothing's approved, would-be competitors include Otsuka with its DM/quinidine duo, and Transition Therapeutics Inc., all potential competitors in both fields having been acknowledged by Axsome in an SEC filing last October, when it made known the plans for an IPO that went on to close in November. Axsome plans to ask for FDA approval in TRD, which afflicts about 3 million people in the U.S., using the 505(b)(2) pathway. (See BioWorld Today, Oct. 15, 2015.)

In STRIDE-1, patients with major depressive disorder (MDD) who have failed one or two therapies will be treated in an open-label fashion with bupropion during a six-week lead-in period, and those who don't respond to bupropion during that interval will be randomly assigned in a one-to-one ratio to continue with bupropion or get AXS-05 in a six-week double-blind experiment. The primary endpoint is the change in the Montgomery-Åsberg Depression Rating Scale, according to Axsome's press release, which did not disclose the number of patients likely to enroll in the study.

The firm's pain treatment, AXS-02, oral zoledronic acid, inhibits bone-remodeling cells from breaking down bone. Axsome is developing AXS-02 for three indications: complex regional pain syndrome (CRPS), knee osteoarthritis (KOA) with bone marrow lesions, and chronic lower back pain with Modic changes (pathological alterations in the spine, named after the doctor who analyzed them in 1988). AXS-02 has reached phase III for complex regional pain syndrome, with data expected by the end of next year. It's also in the late stages of research for knee osteoarthritis and chronic lower back pain. A 190-patient experiment called CREATE-1 is evaluating the drug's potential in CRPS. The EMA "has definitively agreed to review potential filings of AXS-02 based on just one phase III trial, and we are hopeful that Axsome will file for breakthrough designation for FDA approval based on CREATE-1 alone," Brean's Aschoff wrote. Shares of Axsome (NASDAQ:AXSM) took an upward bump earlier this week when the firm disclosed it had gained a new patent for AXS-02 for CRPS, protecting the intellectual property into 2033. The stock closed Thursday at $8.97, down $1.78, or 16.6 percent.

Previously known as reflex sympathetic dystrophy, CRPS, with which about 80,000 people in the U.S. are diagnosed every year, is characterized by severe and continuous pain in a limb, accompanied by autonomic, sensory, motor and other changes. Nothing is approved for the condition in the U.S. or Europe. In KOA, Axsome is drilling down to those patients with bone marrow lesions (BMLs). No treatment is cleared in the U.S. or Europe in that subset of OA, and the osteoclast-inhibiting mechanism of action with AXS-02 may preferentially target BMLs. As many as 7 million people in the U.S. belong to this patient segment.

The markets that Axsome aims to enter are plenty large. Chronic pain treatment in the U.S. totals about $13 billion annually, with more than 100 million prescriptions written each year. As for MDD, the NIH said about 6.7 percent of U.S. adults suffer from the condition, and two-thirds of the diagnosed and treated patients do not respond adequately to first-line therapy.

Most first-line failures also fail second-line treatment, which is how TRD is defined. In AD, about 5 million people in the U.S. are affected, with the number growing steadily, and about 40 percent show agitation symptoms.