Emestedastat Shows Late-Emerging Antidepressant Signal in Difficult-to-Treat MDD Despite Missing Cognitive Endpoint
核心洞察
A Phase 2a proof-of-concept trial found emestedastat (搜索) (Xanamem), a brain-penetrant 11β-HSD1 (搜索) inhibitor, produced no measurable benefit on cognitive impairment versus placebo in patients with major depressive disorder (搜索).
Depression scores (MADRS) showed a modest trend favoring emestedastat (搜索) at week 6 that widened to a potentially clinically meaningful difference of −2.72 points (p = 0.048) four weeks after treatment ended.
Emestedastat (搜索) was generally well tolerated with no treatment-related serious adverse events, though 9.8% of treated patients experienced mild-to-moderate asymptomatic liver enzyme elevations.
A first-of-its-kind Phase 2a trial has found that emestedastat (搜索) (Xanamem), a brain-penetrant inhibitor of the enzyme 11β-HSD1 (搜索), failed to improve cognitive impairment in patients with major depressive disorder (搜索) (MDD) but showed a late-emerging signal of benefit on depressive symptoms. The randomised, double-blind, placebo-controlled proof-of-concept trial, conducted at 16 centres in Australia and the UK and registered as NCT05657691, enrolled 167 participants between 8 December 2022 and 22 April 2024.
The trial is the first randomised, placebo-controlled study to assess a drug's ability to improve cognitive impairment in patients with MDD and a current depressive episode where measurable cognitive impairment was an inclusion criterion. It is also the first trial in this population to evaluate a brain-penetrant 11β-HSD1 (搜索) inhibitor designed to reduce brain cortisol levels.
Mechanism and Rationale
Emestedastat (搜索) is a highly selective small molecule inhibitor of 11β-HSD1 (搜索), the enzyme that catalyses the reduction of inert cortisone within cells to the active glucocorticoid hormone cortisol. Its hypothesised mechanism of action is the selective reduction of intracellular cortisol levels in brain cells without impacting adrenal cortisol production, leaving systemic cortisol levels unaffected.
This approach is grounded in the observation that alterations of the hypothalamic-pituitary-adrenal (HPA) axis and hypercortisolism are biochemical features consistently associated with MDD, with increased cortisol levels observed in approximately 40–60% of people with severe depression. Elevated cortisol levels have also been linked to treatment failure, depression severity, melancholic symptomology and cognitive impairment. However, compounds targeting systemic cortisol production in the adrenal gland are unsuitable for long-term therapy due to significant adverse peripheral hormonal safety effects, providing the rationale for a brain-selective agent.
Trial Design and Population
Eligible participants were aged 18–75 years with a DSM-5 diagnosis of MDD and a current depressive episode, persistent depressive symptoms (Hamilton Depression Rating Scale ≥17), and cognitive symptoms confirmed by both subjective self-report and objective impairment (a 0.5 standard deviation deficit on a symbol-coding task). Participants were randomised 1:1 to receive 10 mg emestedastat (搜索) or matching placebo orally each morning for a 6-week blinded treatment period, followed by a 4-week blinded follow-up.
The population was characterised as at least "moderately severe" and "difficult to treat," with a baseline mean MADRS score of 25, a mean of 10 previous depressive episodes, and more than 80% of participants taking background antidepressant therapy. The mean age was 49.1 years, with 62% female participants.
Cognitive Endpoint Missed
The primary endpoint, change in the attention composite (Att. Comp.) score from baseline to week 6, showed no difference between groups, with a least squares mean difference of −0.13 (95% CI −0.32 to 0.06; p = 0.17) in favour of placebo. Both groups improved during treatment, with least squares mean changes of 0.32 for emestedastat (搜索) and 0.46 for placebo at week 6.
The authors noted that the placebo response on cognitive measures was unexpectedly large—approximately three times larger than that observed in a previous dose-ranging trial of emestedastat (搜索) in cognitively normal older adults, and more than double that seen in an 8-week vortioxetine trial using the same cognitive tests. The researchers attributed this to therapeutic expectations, given the focus on cognition as the primary endpoint during participant consent, and noted that cognitive performance and depressive symptoms changed independently, supporting the hypothesis that these two symptom domains in MDD are distinct.
Depression Signal Emerges After Treatment
On the Montgomery–Åsberg Depression Rating Scale (MADRS), the least squares mean change at week 6 was −8.30 points for emestedastat (搜索) versus −6.89 for placebo (difference −1.40; 95% CI −3.88 to 1.07; p = 0.26; Cohen's d 0.22). Group separation favouring emestedastat increased at week 10, four weeks after treatment ended, when the least squares mean difference reached −2.72 (95% CI −5.41 to −0.03; p = 0.048; Cohen's d 0.43).
In a post hoc subgroup analysis, emestedastat (搜索) showed a potentially clinically meaningful improvement in depressive symptoms among participants on concurrent selective serotonin reuptake inhibitor (SSRI) therapy (n = 76), with a least squares mean difference of −4.17 (95% CI −7.88 to −0.44; p = 0.03; Cohen's d 0.61) at week 10.
The authors suggested the temporal pattern—benefit appearing late in treatment and increasing during follow-up—is consistent with the biology of cortisol and its slower onset of activity, contrasting with monoaminergic antidepressants whose effects typically occur within 3–4 weeks. They noted that the observed effect sizes are comparable to those of approved MDD therapies, including vortioxetine (Cohen's d 0.22) and agomelatine (Cohen's d 0.18–0.26), and to brexpiprazole as adjunctive treatment.
Safety Profile
Emestedastat (搜索) was generally well tolerated over the 6-week treatment period, with no treatment-related serious adverse events. Eight (9.8%) emestedastat-treated participants versus one (1.0%) placebo-treated participant experienced mild-to-moderate, asymptomatic elevations in liver function tests not associated with hyperbilirubinaemia. Of these, seven had elevations ≤2 times the upper limit of normal and one had elevations 3.3 times the upper limit of normal, which returned to normal within five days of discontinuation.
Notably, adverse effects commonly associated with monoamine antidepressants—such as sexual dysfunction, insomnia, drowsiness and increased anxiety—were not observed as emestedastat (搜索) adverse effects in this trial.
Implications and Limitations
The authors concluded that emestedastat (搜索) had no measurable benefit on cognitive impairment but showed trends toward potential benefit on depression symptoms, particularly four weeks after the end of treatment. They emphasised that the pronounced placebo effect on cognitive impairment is instructive for those seeking to investigate cognitive impairment in an MDD population, and proposed strategies such as masking the primary endpoint selection or employing placebo run-in designs to control for this in future trials.
Limitations acknowledged by the authors include the potentially short trial duration given the cortisol control mechanism of action, and limited generalisability given that the population was primarily Caucasian, heavily pre-treated with many prior depressive episodes, and selected for measurable cognitive impairment. The findings, they noted, will require replication and expansion in larger and longer trials, with emestedastat (搜索) meriting further study either as an add-on therapy or a stand-alone treatment.