CEO Shawn Singh of Vistagen Therapeutics Inc. called the favorable vote for ketamine derivative esketamine by a joint meeting of FDA advisory panels "the writing of a bright new chapter in the history of neuropsychiatry," telling BioWorld that the "next transformative step" will involve developing more convenient, at-home options. Esketamine is given under medical supervision.
The FDA's Psychopharmacologic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee provided missed blessings to N-methyl-D-aspartate (NMDA) receptor antagonist esketamine (branded Spravato) 28-mg single-use nasal spray for treatment-resistant depression (TRD) from Johnson & Johnson unit Janssen Pharmaceuticals Inc., thereby raising hopes for the likes of South San Francisco-based Vistagen, also busy in the NMDA receptor space. Regarding the key question of three on which panelists balloted, "Given the effectiveness and safety of esketamine and the FDA's proposed risk evaluation and mitigation strategy (REMS), do the benefits outweigh the risks of esketamine for the treatment of treatment-resistant depression?" the vote was 14 yes, 2 no, and 1 abstain. (See BioWorld, Feb. 13, 2019.)
Vistagen is moving along with AV-101 and PH-10. The former is an NMDA receptor GlyB antagonist that inhibits NMDA receptor function rather than blocking it, a strategy that, along with activation of AMPA receptor pathways, could bypass the adverse side effects that occur with ketamine while still achieving fast-acting ketamine-like antidepressant effects. In preclinical findings, the compound – distinct from fluoxetine (a selective serotonin reuptake inhibitor) and similar to ketamine – turned up rapid, dose-dependent and persistent antidepressant-like effects following a single treatment and was not associated with the rewarding and psychotomimetic effects of ketamine, while also not inducing locomotor sensitization or stereotypical behaviors. In a pair of NIH-funded randomized, double-blind, placebo-controlled phase I safety studies in healthy people, AV-101 was safe, well-tolerated, and not associated with any drug-related severe adverse events. No signs of side effects such as sedation, hallucinations or schizophrenia-like experience turned up, though these are often linked with ketamine and other ion channel-blocking NMDA receptor antagonists. PH-10, another candidate for major depressive disorder (MDD), is described as a first-in-class investigational neuroactive steroid administered as a nasal spray to bind locally on nasal chemosensory receptors and trigger neural responses in the hypothalamus, amygdala, prefrontal cortex and hippocampus believed to be related to depression. In an exploratory phase IIa study in MDD, PH-10 showed rapid-onset antidepressant effects.
Maxim analyst Jason McCarthy said AV-101 "is moving toward proof of concept data in MDD at a time when big pharma players like J&J are on the cusp of opening up a new and large market opportunity in depression," writing in a report yesterday that, "combined, we believe that success in the NMDA space for others should also have a positive impact for Vistagen."
Those others include Allergan plc, of Dublin, with rapastinel, approaching a phase III data readout in the first half of this year. "The panel and FDA generally agreed that [J&J's] Study 3003 showed long-term maintenance of benefit using esketamine, which supports potential long-term duration of rapastinel as it is also targeting the NMDA pathway," SVB Leerink analyst Marc Goodman wrote in a Tuesday report. In his view, the J&J adcom result could also bode well for Cambridge, Mass.-based Sage Therapeutics Inc., which in January reported topline results from the phase III study called Robin. The trial evaluated the effect of SAGE-217 30 mg on depressive symptoms in women with postpartum depression. After two weeks of outpatient treatment, patients treated with the drug had a statistically significant improvement of 17.8 points in the Hamilton Rating Scale for Depression (HAMD-17) score, compared to 13.6 for placebo (primary endpoint, p=0.0029), with statistically significant reductions in HAMD-17 compared to placebo maintained through the end of the four-week follow-up. Remission was achieved in 45 percent of patients treated with SAGE-217 for two weeks as measured by the HAMD-17 compared with 23 percent of patients receiving placebo (p=0.0122). Results from secondary endpoints were statistically significant and consistent with the primary endpoint, Sage said. "The FDA appears to want new, novel mechanism of action [MOA] agents to be available for treatment of depression, as it was repeatedly highlighted that the standard of care [SOC] is insufficient, especially in TRD patients, and we know that SAGE-217 and rapastinel also offer novel MOAs vs. SOC." SAGE-217 is described as a next-generation positive allosteric modulator that has been optimized for selectivity to synaptic and extra-synaptic GABAA receptors, with a pharmacokinetic profile intended for daily oral dosing.
"Given the high unmet need in depression, the FDA appears willing to break from precedent and allow a randomized withdrawal trial to serve as one of the confirmatory positive trials for approval, in spite of the fact that only one of the three planned [esketamine] phase III randomized controlled trials was statistically significant," he added. "This could be good for both products as it may indicate greater flexibility of the FDA when assessing less common clinical trial designs and treatment approaches."
Cold Spring calms the receptors
Also in the mix is Axsome Therapeutics Inc., of New York, with AXS-05, an oral candidate in the pipeline for central nervous system disorders, deploying Axsome's technology that combines bupropion and dextromethorphan (DM). DM is an NMDA receptor antagonist, sigma-1 receptor agonist, and inhibitor of the serotonin and norepinephrine transporters, while bupropion serves to increase the bioavailability of DM and is a norepinephrine and dopamine reuptake inhibitor, and a nicotinic acetylcholine receptor antagonist. The drug has been granted fast track designation by the FDA for both agitation associated with Alzheimer's disease and TRD. In January, the company said AXS-05 met the prespecified primary endpoint and significantly improved symptoms of depression in the Ascend phase II trial in MDD. A randomized, double-blind, active-controlled, multicenter U.S. effort with Ascend was conducted in 80 adult patients with confirmed moderate to severe MDD were treated either with AXS-05 (45 mg dextromethorphan/105 mg bupropion), or the active comparator bupropion (105 mg), twice daily for six weeks. The compound showed a highly statistically significant reduction in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score, averaged over the six-week treatment period (overall treatment effect), as compared to bupropion (p<0.001). At the sixth week, AXS-05 demonstrated a 17.2 point reduction in the MADRS total score compared to a 12.1 point reduction for bupropion (p=0.013). The drug also rapidly reduced depressive symptoms, demonstrating a statistically significant improvement over bupropion on the Clinical Global Impression-Improvement scale at the first week (p=0.045).
Yielding less encouraging results in the NMDA zone was Evanston, Ill.-based Aptinyx Inc., which in January rolled out topline results from a phase II experiment with NYX-2925 in subjects with painful diabetic peripheral neuropathy. NYX-2925 did not show statistically significant separation from placebo on the primary endpoint, change in subjects' average daily pain scores on the Numerical Rating Scale during the final treatment week compared to baseline. Of the three dose levels evaluated, 50 mg showed the most meaningful improvements across multiple measures. The NMDA receptor modulator was well-tolerated in the study with no serious adverse events. J.P. Morgan analyst Jessica Fye said she "continue[s] to view Aptinyx's NMDA receptor modulator platform as interesting and offering potential long-term value creation with a strong management team at the helm," but finds "the near-term outlook as more challenging following these results. Looking ahead, the immediate focus for NYX-2925 will shift to fibromyalgia, where we have seen encouraging interim data in small number of patients, and we will watch for data from the exploratory fibromyalgia study in about 24 patients in the first half of this year, although we believe it will take more than positive results there for the stock to recover," she said in a report.
There's also Biohaven Pharmaceutical Holding Co. Ltd., of New Haven, Conn., with NMDA receptor antagonist BHV-5000, which Leerink's Goodman seems optimistic. It's an oral prodrug of the intravenous therapy lanicemine. BHV-5000 and lanicemine were licensed from London-based Astrazeneca plc in 2016. Biohaven said it plans to pursue development in Rett syndrome and complex regional pain syndrome, as well as neurological or neuropsychiatric indications with high unmet medical needs, including MDD. Lanicemine has been administered to about 770 subjects in single or multiple doses in 18 clinical trials conducted by Astrazeneca and has been generally well tolerated, Biohaven said.
Findings related to NMDA continue to emerge from the laboratory. In Nature Communications, research by scientists at Cold Spring Harbor Laboratory and Emory University explored ways to prevent NMDA receptors from firing too much, which could lead to more specific therapies involving the mechanism, especially in brain injuries such as stroke.