Corcept Therapeutics Takes Yet Another Shot at Psychotic Depression

Implications: Corcept Therapeutics is at it again with yet another clinical trial for its lead candidate mifeprisotone (Corlux), a GR-II (glucocorticoid) receptor antagonist, hoping to show efficacy on the psychotic features of psychotic major depression (PMD).   Corlux clearly offers a potentially novel paradigm unlike anything presently on the market for treating psychiatric disorders – it targets the hypothalamic-pituitary-adrenal (HPA) axis.   The key question to date, however, has been whether Corlux even works at all.  There are no FDA-approved treatments for psychotic depression though combination antidepressant/antipsychotic treatment or ECT is often the standard, with antipsychotic agents specifically used to treat the psychotic features.  

Analysis: Corcept’s latest round of financing and its partnership with MedAvante to handle clinical ratings is another breath of life for a drug that has looked on the brink of death a few times in its life.  In 2006, a published clinical trial for Corlux in psychotic depression received hard criticism on multiple fronts, from study design to flawed statistical analysis, and finally the drug’s efficacy itself on both psychotic and depressive symptoms.   The Corcept team has mustered whatever it could from prior data and is pulling all stops to show some efficacy – higher dosing, centralized video assessments, and a sizable study group.  This 4th clinical trial is designed with Corlux vs placebo for the first week, followed by antidepressant treatment.       

One problem is that prior data suggests Corlux carries only modest utility against either psychotic or depressive symptoms, a rather large obstacle for an illness this challenging to treat and appearing neurobiologically closer to schizophrenia than depression.  The lack of a second active comparator arm in this study will raise questions just how Corlux measures up against the kind of drugs so commonly used to treat the psychotic features of PMD nowadays – the atypical antipsychotics – which have versatility across both positive (ie, hallucinations) and negative (ie, flat affect, disorganization) symptoms of psychosis, and may help associated cognitive problems like verbal working memory. The other problem is that Corcept will require two positive studies for FDA approval. The first three trials don’t look all that helpful and another large trial for a drug with a history of recruitment issues will pose time and financial burdens for Corcept especially if they plan to still learn through this trial.  

Even if Corlux ultimately hits the market, there is the question of how it will fit into a clinical landscape where growing data suggests some atypical antipsychotics confer both antidepressant and antipsychotic effects, potentially with added value in combination with antidepressants.   Seroquel (Astra Zeneca) and Abilify (Bristol Myers Squib) have shown antidepressant and antipsychotic properties, along with FDA-indications spanning mood and psychosis, and Seroquel XR will be aiming broadly to target psychotic, mood, and anxiety disorders.   Unfortunately there is a surprising lack of data in treating psychotic major depression and Corcept has been its own guide at substantial cost.  It will be hard to have another chance.  Hopefully this drug will bring attention to a seriously unmet clinical need in psychiatry and even offer something clinically valuable though it may have better odds for treating weight gain associated with antipsychotic agents (like Zyprexa) and Cushing’s Syndrome, other viable indications.