When a woman in Cork, Ireland, cutting off her own right index finger to relieve her pain made headlines recently, the mainstream media brought to popular knowledge the condition with which she had been diagnosed: chronic regional pain syndrome (CRPS), a devilish affliction being pursued by the likes of New York-based Axsome Therapeutics Inc. and the Grunenthal GmbH, of Aachen, Germany.
CRPS is a chronic pain condition that most often affects one limb, usually after an injury (the Irish woman had jammed her finger in a car door). It's believed to be caused by damage to, or malfunction of, the peripheral and central nervous systems (CNS) and is characterized by prolonged or excessive pain and changes in skin color, temperature and/or swelling in the affected area. A British woman had her lower leg amputated because of CRPS, which turned up after she hurt her foot playing tennis.
Clinicians divide CRPS is into two types: CRPS-I and CRPS-II. People without a confirmed nerve injury are classified as having CRPS-I (previously known as reflex sympathetic dystrophy syndrome). CRPS-II (previously known as causalgia) involves an associated, confirmed nerve injury. The NIH notes that, because some research has identified evidence of nerve injury in CRPS-I, the disorder may not always be divided into two kinds. In any case, treatment is similar for both: rehab and physical therapy; psychotherapy; and medications that include nonsteroidal anti-inflammatory drugs and bisphosphonates such as high-dose alendronate or intravenous (I.V.) pamidronate.
Axsome has the bisphosphonate AXS-02 (disodium zoledronate tetrahydrate), described as a potentially first-in-class, oral, non-opioid therapeutic for chronic pain. The drug inhibits osteoclasts, which break down bone by secreting protons or acid. Since acid is known to excite pain receptors, the effects of AXS-02 on osteoclasts may reduce pain by suppressing localized overproduction of acid in bone, the company said. AXS-02 may also inhibit the production of pro-inflammatory cytokines which have been shown to contribute to pain. Zoledronic acid from Basel, Switzerland-based Novartis AG is approved as the bone drugs Reclast and Zometa.
The company first developed AXS-02 for the treatment of pain in knee osteoarthritis (OA) associated with bone marrow lesions and chronic low back pain associated with Modic changes. AXS-02 has been granted fast track status by the FDA in the OA indication, as well as orphan drug designation. A trial early last year yielded negative CRPS data, though H.C. Wainwright analyst Raghuram Selvaraju pointed out in a June 2018 report that the indication is "much more challenging than the [other] areas in which Axsome is currently developing AXS-02," such as OA. But the company also has the bisphosphonate neridronate (neridronic acid), a phase III-stage I.V. bisphosphonate, the use of which for pain conditions including CRPS is covered by 20 issued and one allowed Axsome patents, providing protection to 2033.
Cold comfort in ambroxol?
Enter Grunenthal, with its neridronic acid, in-licensed from another privately held firm, Abiogen Pharma SpA, of Pisa, Italy, via Novapharm Therapeutics LLC in 2013. Grunenthal in mid-2018 kicked off two pivotal phase III trials in a total of 360 patients in CRPS, having won breakthrough designation from the FDA in late 2016. Because Axsome pioneered the characterization of the role of bisphosphonates in CRPS, and "accordingly possesses what we believe to be blocking intellectual property [IP] on the use of such agents" in the indication, Wainwright's Selvaraju said in an October 2018 report. He expects Grunenthal to "come to its senses soon" and has "substantial incentives to work with Axsome, not against it," since Grunenthal owns only orphan drug status vs. Axsome's IP, "which could double the commercial lifespan of the putative Grunenthal product franchise." He added that "the market potential for neridronic acid is not inconsequential."
Axsome's management has estimated that there are about 100,000 cases in the U.S., with a reported annual incidence of 80,000 new cases. Pricing of about $30,000 per patient "may be considered reasonable, in our view," he said, and pegged the peak annual sales potential for neridronic acid, assuming even 10 percent market penetration in the U.S., could reach about $300 million. Grunenthal "clearly appreciates the strategic implications of Axsome's IP, because it has filed post-grant reviews on two of Axsome's patents containing claims related to neridronic acid and CRPS," he noted.
Also at work in CRPS is Cleveland Clinic spin-off Neurotherapia Inc., focused on new chemical entities for the treatment of neuroinflammatory disease. Activating microglia immune cells in the CNS promotes an inflammatory response that serves as a hallmark for a range of neurologic disorders such as neuropathic pain, multiple sclerosis, traumatic brain injury and Alzheimer's disease (AD), the company said. Lead product NTRX-07 is a highly selective cannabinoid type 2 (CB2) receptor agonist with demonstrated CNS activity; targeting CB2 receptors on microglia significantly reduces the expression of inflammatory agents resulting in neuronal survival and proliferation, according to Neurotherapia, and preclinical efficacy has been established in multiple neuropathic pain models, including chemotherapy-induced peripheral neuropathy, nerve ligation and CRPS induced by ischemic injury. NTRX-07 also has been shown to improve memory loss observed in AD rodent models. The company has completed IND-enabling studies and plans to start first-in-human studies during the first half of this year.
Findings regarding potential new therapies for CRPS continue to roll out. The journal Headache recently published a study suggesting that a substance found in cough syrup and cold medications, ambroxol, could relieve trigeminal neuralgia pain, and other research featured in Pain Management found that it did the same in CRPS.