Login to Your Account

'Thar' she blows: CRPS bid harpooned by IDMC; Axsome phase III OA effort still afloat


By Randy Osborne
Staff Writer

Advice from the independent data monitoring committee (IDMC) that Axsome Therapeutics Inc. quit the phase III trial called CREATE-1 with AXS-02 (disodium zoledronate tetrahydrate) put a dent in the company's shares and reshuffled the landscape for complex regional pain syndrome (CRPS) candidates. But the IDMC also told New York-based Axsome that the phase III push with the same compound, fast-tracked in osteoarthritis (OA) of the knee with bone marrow lesions (BMLs), COAST-1, should proceed.

"I see it, and hopefully the market will come to see it this way, as very strong positive news," Cedric O'Gorman, senior vice president of clinical development and medical affairs, told BioWorld. "For a company our size or indeed a company of any size, to have two interim analyses read out and one of them get the support of the IDMC to continue the study is a remarkable achievement." Two-for-two would have been ideal, he said, but the quashed CRPS study turned up a significant reduction of serum C-terminal telopeptide crosslinked, or CTx, a marker of bone resorption – a finding that likely will prove useful as the OA push continues, helped by a special protocol assessment from the FDA. The rest of the pipeline, with its varied mechanisms of action, leaves "a lot of tantalizing directions one could go in," he added. Axsome's stock (NASDAQ:AXSM) fell $2, or 36 percent, to close Tuesday at $3.55.

The slip in CRPS may have pleased Aachen, Germany-based Grunenthal GmbH, which has neridronic acid, the first investigational medicine to receive breakthrough therapy designation for the treatment of CRPS, at the phase III stage. Intravenous (I.V.) neridronic acid was discovered and developed by Abiogen Pharma SpA, of Pisa, Italy, and Grunenthal gained the development and commercialization rights for North America and South America in 2013. The latter firm has proven its broad appetite for would-be CRPS therapies, bringing aboard T-121, an oral version of the bisphosphonate zoledronic acid, in its 2016 buyout of Thar Pharmaceuticals Inc., of Pittsburgh, for undisclosed terms. Thar had filed for a $50 million IPO in the summer of the same year. (See BioWorld Today, Aug. 23, 2016.)

In Thar's S-1 related to the IPO, the company describes T-121 more precisely as "a zoledronic acid DL-lysine monohydrate molecular complex, formulated as a delayed-release composition that has been shown to display similar biological effects as the currently approved I.V. formulation." Mark Jacobson, senior vice president of operations for Axsome, noted that the description makes T-121 "distinct from AXS-02. We developed the synthesis route for that salt." He added that his firm hasn't "seen much from Grunenthal in regard to how they're actually developing T-121." As for neridronic acid, Grunenthal "did conduct a study that was supposed to have concluded last year," but the company has offered no data readout or public statement, he said. According to clinicaltrials.gov, the study finished in November 2016.

A progressive disease of the autonomic nervous system, CRPS is characterized by intense pain, typically accompanied by swelling, skin changes, and extreme sensitivity. The disorder can be debilitating, usually affecting one or more limbs, though it can occur in any part of the body. In more than 70 percent of the victims, CRPS spreads to new areas. The main symptoms are chronic, burning pain, inflammation, spasms, insomnia and emotional disturbance.

CRPS became the subject of a phase II trial attempted by the National Institute of Nursing Research using neurotropin, a non-protein extract of cutaneous tissue from rabbits inoculated with vaccinia virus. The study was to enroll patients with CRPS-I (also called reflex sympathetic dystrophy) and patients with CRPS-II. CRPS-I is pain that develops after relatively minor injury to an arm or leg, but lasts much longer and is much more severe than would normally be expected, whereas CRPS-II is pain resulting from injury to a large nerve. Candidates for the trial were to have a history and physical examination, blood tests, and electrocardiogram. But the trial stopped in 2016 because of difficulty recruiting participants. "There's a reason that there is no approved treatment for this indication," O'Gorman said. At an earlier stage for CRPS and other disorders, Cleveland Clinic spin-off Neurotherapia Inc., a company launched in 2015, has NTRX-07, previously known as MDA-7, which has been shown to decrease activation of microglial cells in the brain.

Strong 'patent fence' around programs

Axsome has plenty going on. The portfolio includes four clinical-stage candidates, AXS-02, AXS-05, AXS-06, and AXS-07. AXS-05 is in a phase III trial in treatment-resistant depression (TRD) and a phase II/III trial in agitation in patients with Alzheimer's disease (AD), with both indications fast-tracked. "Everyone is rightly concerned about the cognitive impairment associated with AD," O'Gorman said, but the agitation symptom is important, too, and often leads to patients ending up in nursing homes. "Their caregivers just can't cope," he said. "It's a very troubling, difficult and sad condition." AXS-05 is under investigation for smoking cessation as well, in collaboration with Duke University. The compound pairs bupropion and dextromethorphan. Dextromethorphan is an NMDA receptor antagonist, sigma-1 receptor agonist, and inhibitor of the serotonin and norepinephrine transporters. Bupropion serves to increase the bioavailability of dextromethorphan, and functions as a norepinephrine and dopamine reuptake inhibitor, plus a nicotinic acetylcholine receptor antagonist.

AXS-02, along with the phase III trial in knee OA with BMLs, has another phase III study planned in chronic low back pain associated with Modic changes. AXS-06 is an oral, non-opioid, once-daily, fixed-dose combo that deploys Axsome's Molecular Solubility Enhanced Inclusion Complex, or MoSEIC, platform to pair meloxicam and esomeprazole. Meloxicam is a long-acting nonsteroidal anti-inflammatory drug (NSAID) with COX-2 preferential inhibition and pain-relieving efficacy. MoSEIC boosts the speed of absorption of meloxicam while maintaining durability of action. Esomeprazole is a proton pump inhibitor that lowers stomach acidity and which has been shown to reduce the occurrence of NSAID-induced gastrointestinal ulcers.

Phase III-ready AXS-07 is being developed for the acute treatment of migraine. It's an oral, fixed-dose combo of the same MoSEIC meloxicam and rizatriptan. "You're talking about 15 minutes as opposed to about four and a half hours," O'Gorman said, or nine times faster to peak plasma concentrations of meloxicam. Rizatriptan is known to do the job in migraine as a single agent; adding the distinct mechanism of action and rapid absorption of MoSEIC meloxicam should lead to a strong therapy in the abortive treatment of migraine, he said.

Founded in 2012, Axsome has enough cash to last into the fourth quarter of 2019. Topline data from the Stride-1 phase III trial in TRD will probably be available by then, and the phase II smoking-cessation experiment with AXS-05 will have started, with "potential to see results from that study," Jacobson said. Results from Advance-1, which is the phase III AD agitation study, and the migraine trial with AXS-07 "are not definitive with our current cash position but possible" to see within the time frame, he said.

About partnering, O'Gorman said the company "take[s] great pride in identifying patient populations and therapeutic areas, but we are always open to any opportunity that makes sense." Jacobson said the firm maintains a "robust patent fence around our programs." For AXS-02, Axsome owns more than 60 issued patents, including 50 in the U.S., covering methods of use and bioavailability in a variety of claim types, with 80 applications pending. For AXS-05, 21 patents are issued in the U.S. and one outside the country, and more than 40 are pending. The MoSEIC platform is "still in its infancy," but one patent has been issued and more than 10 are pending, he said.