Vistagen yesterday tried to reassure investors that the failure of its ketamine-like antidepressant project AV-101 in an investigator-sponsored trial might not bode ill for a bigger mid-stage trial. But the group’s stock plunged 47% yesterday as backers got the jitters ahead of the Elevate study readout, expected in the third quarter.
There are some differences between the two studies, which Vistagen was keen to point out. The 19-patient NIMH-sponsored trial that failed yesterday was testing AV-101 as a monotherapy, while Elevate is evaluating the project on top of standard antidepressants.
This latter adjunctive use is the same one for which Johnson & Johnson’s ketamine-like drug Spravato was recently approved, albeit on flimsy evidence of efficacy (Esketamine floats past adcom vote, February 13, 2019).
Vistagen will no doubt take heart from the two projects’ similar mechanisms of action. Both inhibit the NMDA receptor, though Spravato, which is given intranasally, is a complete channel blocker, while the oral AV-101 inhibits NMDA receptor function rather than blocking it.
Vistagen’s chief executive, Shawn Singh, has described AV-101 as more like a dimmer light switch versus Spravato’s cruder “on/off” button.
This could help AV-101 avoid the ketamine-like side effects that have been linked with Spravato, Vistagen hopes. However, the latest data raise fears that AV-101’s different mechanism could mean that it is less effective.
The recent failure of Allergan’s NMDA-modulating contender rapastinel will not have helped Vistagen’s cause, either – that was also supposed to be a safer alternative to Spravato (Rapastinel flop leaves Allergan in a hole, March 7, 2019).
Now Vistagen must await readout of Elevate. The phase II trial has enrolled 180 patients with an inadequate response to one to three FDA-approved oral antidepressants, whose current depressive episode has lasted two years or less.
The trial will compare AV-101 with placebo, both on top of an oral antidepressant; the primary endpoint is change in the 10-item Montgomery Åsberg Depression Rating Scale (MADRS-10) at two weeks.
Vistagen is also planning another trial, called Relay, evaluating whether AV-101 can prevent relapse in patients who have previously responded to intravenous ketamine or Spravato. However, this is not slated to start until next year, and might be a dead end if Elevate disappoints.
The company is heavily reliant on AV-101, which is also in phase I development for suicidal ideation and is set to go into phase II in neuropathic pain and levodopa-induced dyskinesia in Parkinson’s disease. Mr Singh previously told Vantage that the group also had high hopes for AV-101 as monotherapy in depression.
These aspirations have now been dashed by the NIMH trial failure. Vistagen's market cap now sits at just $23m, so investors clearly do not think much of AV-101's chances. If Elevate is also a flop, the company's future will look bleak.
|Project||Indication||Description||Status||2024e sales ($m)|
|PH94B||Social anxiety disorder||Neuroactive steroid nasal spray||Phase III imminent||-|
|AV-101||Major depressive disorder||AMPA agonist and NMDA antagonist||Phase II||68|
|PH10||Major depressive disorder||Neuroactive steroid nasal spray||Phase II||-|
|Source: company website, EvaluatePharma.|