May 09, 2018 Therapy focus – J&J confirms hope for new mechanism in depression Amy Brown The first look at late-stage data on Johnson & Johnson’s hotly-tipped novel antidepressant esketamine came at a medical conference last weekend, and the results were not quite as strong as many were hoping to see. Encouraging signals could be certainly be found, however, and J&J seems undeterred from trying to seek regulatory approval. Others pursing NMDA modulation in depression are also likely to draw comfort in the results, which provide the first phase III validation of this mechanism, and a clear bar to beat (see table below). Hopes for esketamine and other products like it lie in their similarity to ketamine, which at low doses displays antidepressant effects that kick in very quickly. Traditional antidepressants which act via the serotonergic system – selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) – can take weeks to have an effect; a large proportion of patients fail to respond at all. Hence the need for both faster acting agents – for example in suicidal patients – and novel mechanisms to treat those who need different options. A new target NMDA receptor modulation is a novel mechanism in depression. Over the last decade researchers have become increasingly convinced that dysregulation of glutamate, a neurotransmitter which signals through NMDA, plays an important role in the condition. This system is already known to be a factor in cognitive function and neurodegeneration and Namenda, the NMDA antagonist mematine, has been available as a treatment for Alzheimer’s dementia for several years. In depression, it is thought that blocking NMDA receptors can improve brain plasticity and strengthen synaptic connections. Ketamine works via this mechanism but its psychotomimetic properties – it can cause dissociation and hallucinations, for example – limit its use in medical practice. Knowledge of ketamine’s potential spurred a quest to find similar compounds with different side-effect profiles, but the same rapid onset. J&J has come the furthest to date and is running a substantial clinical programme with esketamine. The drug is an enantiomer of ketamine – effectively a mirror image of the original molecule – and the big question is whether it is different enough to shake off the side effect profile. Esketamine phase III programme - active trials Acronym Status Enrollment NCT ID Primary Completion Date Sustain-1 Active, not recruiting 718 NCT02493868 Mar-18 Transform-1 Completed 346 NCT02417064 Feb-18 Transform-2 Completed 236 NCT02418585 Reported Transform-3 Completed 139 NCT02422186 Reported Sustain-2 Completed 821 NCT02497287 Oct-17 - Recruiting 1,150 NCT02782104 Aug-21 - Recruiting 224 NCT03039192 Sep-19 - Recruiting 224 NCT03097133 Sep-19 Source: clinicaltrials.gov Data released at the American Psychiatric Association annual meeting over the weekend suggest there are lingering doubts. Dissociation was one of the most common adverse events reported, though in less than 10% of patients. And efficacy is still a big concern. Of the two trials reported, only one, Transform-2, which tested esketamine in adult patients, met the primary endpoint. Also worryingly, this study missed significance in its first key secondary endpoint, which rendered all further secondary readings exploratory. A second trial, Transform-3, in elderly patients with treatment-resistant depression, narrowly missed significance on its primary endpoint. J&J maintained that the trials showed esketamine can produce a rapid effect, and with breakthrough therapy designation in treatment-resistant depression and major depressive disorder with imminent risk for suicide, the company appears to believe that esketamine can convince the regulators. With other trials underway and a filing possible in the second half of this year, the question is whether the FDA will want to see more evidence. Prominent projects targeting NMDA - a novel mechanism in depression Product Company Mechanism of Action Ongoing trials Phase III Esketamine Johnson & Johnson NMDA receptor antagonist See above NCT02932943; NCT02943564; Rapastinel Allergan NMDA receptor partial agonist NCT02932943 Phase II VistaGen NMDA receptor glycine B AV-101 NCT03078322 Therapeutics antagonist CERC-301 Cerecor NMDA receptor 2B antagonist NCT02459236 (completed) Source: EvaluatePharma, company statements As the closest competitor in this field, Allergan will be scrutinising J&J’s data closely. Allergan’s agent rapastinel is in two phase III trials, though data are unlikely to emerge until next year. The compound works slightly differently to esketamine in that its blocks the glycine-binding site on the NMDA receptor. Allergan believes this should result in a much more benign side-effect profile. Rapastinel is injected, while esketamine is delivered via a nasal spray. Vistagen’s AV-101 also targets the glycine-binding site. The California company started a large phase II study last month called Elevate, which should read out early next year. Others have approached NMDA modulation via another receptor subunit called NR2B. CERC-101, a compound originally discovered by Merck but which was taken on by Cerecor, appears to be the only asset left in development, though the company recently switched its focus to orphan neurological conditions. Two phase II trials failed to establish a therapeutic window, although the agent was found to be safe. Others targeting NR2B have also failed – Pfizer scrapped traxoprodil on heart safety concerns a few years ago – and it seems that for now this approach has run out of steam. Thus the main contenders chasing J&J are Allergan and Vistagen. Both are due to unveil their data next year, and both will be looking to generate stronger efficacy and fewer side effects. At least esketamine is well ahead of the pack and has generated one positive pivotal trial – against an active comparator – which in this field should not be brushed off lightly. To contact the writer of this story email Amy Brown in London at [email protected] or follow @ByAmyBrown on Twitter. More from Evaluate Vantage Evaluate HQ 44-(0)20-7377-0800 Evaluate Americas +1-617-573-9450 Evaluate APAC +81-(0)80-1164-4754 © Copyright 2021 Evaluate Ltd..