Compass Pathways' COMP360 Psilocybin Shows Positive Phase 3 Results for Treatment-Resistant Depression

Analysis reveals significant industry trends and economic implications

Release Date

2025-06-23

Category

Clinical Trial Event

Reference

Source

Breakthrough Clinical Results

Compass Pathways announced positive top-line results from its Phase 3 COMP005 trial evaluating COMP360, a synthetic psilocybin formulation, for treatment-resistant depression (TRD). A single 25mg dose of COMP360 demonstrated a statistically significant and clinically meaningful reduction in depression severity compared to placebo (p<0.001, mean difference -3.6). The Independent Data Safety Monitoring Board (DSMB) reported no unexpected safety concerns. This is the first Phase 3 efficacy data reported for an investigational synthetic psilocybin and the first for a classic psychedelic. A second Phase 3 trial, COMP006, is ongoing, with 26-week data expected in the second half of 2026. Compass Pathways plans to discuss these data with the FDA.

Key Highlights

  • Positive top-line results from Phase 3 COMP005 trial for COMP360 in TRD.
  • Statistically significant and clinically meaningful reduction in depression severity with a single dose of COMP360 (25mg).
  • No unexpected safety findings reported by the DSMB.
  • First Phase 3 efficacy data for an investigational synthetic psilocybin and a classic psychedelic.

Study Design Parameters

Study Design Parameters and Endpoints in Treatment-Resistant Depression Trials

Study Designs

Various methodological approaches have been employed in treatment-resistant depression (TRD) trials:

  • Meta-analyses and systematic reviews were commonly used
  • Bayesian hierarchical model meta-analysis compared VNS Therapy plus treatment as usual (VNS+TAU) versus TAU alone
  • Network meta-analysis identified both direct and indirect evidence from relevant trials

  • Randomized controlled trials compared different treatment modalities:

  • Medication vs. psychotherapy

  • Medication vs. combined treatment

  • Psychotherapy vs. combined treatment

  • Open-label case series design explored DBS applied to the Bed Nucleus Of Stria Terminalis
  • Three-arm open-label study compared rTMS, venlafaxine, or combination as maintenance treatment
  • Pragmatic, multicenter, randomized-controlled trial compared TAU with MBCT+TAU
  • 1:1:1 randomization in a multi-site, 8-week, open-label study comparing augmentation with aripiprazole or repetitive transcranial magnetic stimulation versus switching to venlafaxine XR
  • Participants divided into active rTMS group and sham group

Patient Populations

  • Chronic treatment-resistant depression (TRD) patients
  • Sample sizes ranged from 5 patients (DBS study) to 1035 patients (VNS+TAU) and 425 patients (TAU)

  • Inclusion criteria often specified:

  • Previous failed treatments (pharmacotherapy ≥4 weeks, psychological treatment ≥10 sessions)

  • Specific depression subtypes (unipolar, bipolar, secondary)

  • Adults with TRD (defined as depression not responding to antidepressant therapy after 4 weeks of use)

  • Patients with persistent depressive disorder (PDD), including chronic major depression, dysthymia, double depression, or recurrent depression without complete remission between episodes

  • Patients with acute depressive episodes

Treatment Interventions

  • Pharmacological interventions: Various antidepressants including MAOIs, venlafaxine, duloxetine, fluoxetine

  • Neuromodulation techniques:

  • Vagus Nerve Stimulation (VNS) plus treatment as usual

  • Deep Brain Stimulation (DBS) to the Bed Nucleus Of Stria Terminalis

  • Repetitive Transcranial Magnetic Stimulation (rTMS)

  • Psychological interventions:

  • Mindfulness-based cognitive therapy (MBCT)

  • Cognitive-behavioral analysis system of psychotherapy (CBASP)

Primary Endpoints

  • Depression symptom reduction measured by:

  • Montgomery-Åsberg Depression Rating Scale (MADRS)

  • Hamilton Depression Rating Scale (HDRS)

  • Clinical Global Impressions scale's Improvement subscale (CGI-I)

  • Depressive symptoms measured on continuous observer-rated scales

  • Response rates (typically defined by percentage reduction in depression scales)
  • Remission rates (e.g., HDRS<8, MADRS-defined)
  • Relapse rates (e.g., HDRS<15)

Secondary Endpoints

  • Tolerability (discontinuations due to adverse events)
  • Sustained response/remission over extended periods (24, 48, 96 weeks)
  • Quality of life measures
  • Rumination levels
  • Mindfulness skills
  • Self-compassion
  • Interpersonal impact messages as perceived by psychotherapists
  • Symptoms of Depression Questionnaire scores
  • Cognitive function measured by IntegNeuro cognitive test battery
  • Dropout rates as a proxy measure of overall treatment acceptability

Follow-up Periods

  • Ranged from 12 weeks to 96 weeks (VNS study)
  • Long-term follow-up studies tracked patients for 8 to 84 months (mean=39 months)
  • Maintenance treatment schedules varied (e.g., rTMS: twice weekly for 1 month, weekly for 2 months, biweekly for 9 months)

Statistical Analysis Approaches

  • Random-effects meta-analyses using risk ratios (RR) for dichotomous outcomes
  • Mean differences (MD) for continuous outcomes with 95% confidence intervals
  • Effect size calculations using Hedges's g
  • Meta-regressions to explore potential moderators of response
  • One-step IPD-NMA (Individual Participant Data Network Meta-Analysis) to compare treatments
  • Models fitted in OpenBUGS using vague priors for location parameters
  • Half-normal prior on the SD for heterogeneity
  • Cochrane Risk of Bias Tool used to estimate risks

Moderators and Predictors

  • Social support was identified as a significant predictor of outcome
  • Educational status associated with quicker remission
  • Milder level of treatment resistance predicted better outcomes
  • Bipolar TRD diagnosis associated with early relapse

Incidence and Prevalence

Global Epidemiology of Treatment-Resistant Depression

Prevalence and Incidence

Treatment-resistant depression (TRD) affects approximately one-third of depressed patients who develop related sequelae including poor functionality and worse prognosis. Major depressive disorder (MDD) has a lifetime prevalence in the United States estimated at 17%, while one community sample study reported a cumulative incidence for depression of 27.0%.

Chronic depressive disorders are common, accounting for approximately one-third of all cases of depression and pose a major public health problem. When examining depression trajectories, research has identified two main patterns: those whose depression resolves and does not recur (44.7%) and those who experience repeated episodes (55.3%).

Regarding treatment resistance specifically, about 30% of patients do not achieve remission after 4 different antidepressant treatment trials. TRD is generally defined as failure to achieve remissions despite adequate treatment.

Risk Factors and Predictors

Several factors have been identified as predictors or risk factors for developing treatment-resistant depression:

Mental/Psychological Factors

  • Greater symptom severity (9 studies)
  • Suicidality (8 studies)
  • Recurrent depression (6 studies)
  • Higher levels of neuroticism (2 studies)

Physical/Medical Factors

  • Cardiovascular disease (4 studies)
  • Pain (3 studies)
  • Thyroid dysfunction (3 studies)

Demographic Factors

  • Younger age (7 studies)
  • Female gender (6 studies)

Economic Impact

TRD is associated with significantly higher per-patient medical costs due to higher healthcare utilization (HCU). The classification of TRD was associated with a 29.3% higher costs (P < 0.001) in medical expenditures compared with patients not meeting the study definition of TRD.

Treatment Approaches

Historically, chronic depression has been thought to be treatment-resistant, and evidence suggests it is currently underdiagnosed, misdiagnosed, and suboptimally treated. However, some studies have shown that chronic depressive disorders respond well to standard pharmacologic interventions in both acute and maintenance treatment phases.

Recent evidence suggests that treatment combining psychotherapy and medications may be superior to either treatment alone for chronic depression. Notably, standard psychotherapies alone may not be efficacious for chronic depression, especially dysthymia.

Biomarkers and Future Research

Despite decades of research, the specific genetic variations that contribute to antidepressant response and treatment-resistant depression (TRD) remain largely unknown. Genetic biomarkers to identify patients with higher risk of treatment-resistant depression or to guide treatment in these patients are not available yet.

Future research should focus specifically on treatment-resistant depression and special populations that have been understudied.

Economic Burden

Economic Burden of Treatment-Resistant Depression in the United States

Prevalence and Overall Economic Impact

Treatment-resistant depression (TRD) affects approximately 12%-20% of all depressed patients in the United States. According to a recent study, the 12-month prevalence of medication-treated major depressive disorder (MDD) in the United States was estimated at 8.9 million adults, with 2.8 million (30.9%) having TRD.

The economic implications are substantial: - TRD may present an annual added societal cost of $29-$48 billion - This pushes the total societal costs of major depression to as much as $106-$118 billion - The total annual burden of medication-treated MDD among the US population was $92.7 billion, with $43.8 billion (47.2%) attributable to TRD

Direct Healthcare Costs

Patients with TRD incur significantly higher healthcare costs compared to those with treatment-responsive depression: - Annual healthcare costs were $5,481 higher for patients with TRD versus treatment-responsive depression - TRD-likely employees had significantly higher average direct 2-year costs ($22,784) compared with MDD controls ($11,733), p < 0.0001 - Patients in the hospitalized treatment-resistant group had over 6 times the mean total medical costs of non-treatment-resistant depressed patients ($42,344 vs. $6512) (p <.001) - Their total depression-related costs were 19 times greater than those of patients in the comparison group ($28,001 vs. $1455) (p <.001)

A study using the Optum Clinformatics™ claims database found that TRD patients had: - More emergency department visits (odds ratio = 1.39) - More inpatient hospitalizations (odds ratio = 1.73) - Longer hospital stays (mean difference = 2.86 days) - More total healthcare costs (mean difference = US$3,846)

These patterns remained consistent in year 2 of the follow-up period.

Indirect Costs and Productivity

The economic burden extends beyond direct healthcare costs: - Annual lost productivity costs were $4,048 higher for patients with TRD versus treatment-responsive depression - Average indirect costs were higher among TRD-likely employees ($12,765) compared with MDD controls ($6885), p < 0.0001

Of the total TRD burden: - 56.6% ($25.8 billion) was attributable to health care costs - 47.7% ($8.7 billion) to unemployment costs - 32.2% ($9.3 billion) to productivity costs of medication-treated MDD

Clinical Characteristics

TRD patients typically present with: - 3.8±2.1 prior depressive episodes - Illness duration of 4.4±3.3 years - 4.7±2.7 unsuccessful drug trials involving 2.1±.3 drug classes - Response rates of 36%±1% - 17%±6% had prior suicide attempts (1.1±.2 attempts per patient) - Quality-of-life scores for patients with TRD were .41±.8 and .26±.8 points lower, respectively, than for patients who experienced remission or response

International Comparison (South Korea)

For context, in South Korea: - The cost of medical care for TRD (6,610,487 KRW, 5881 USD) was approximately 5 times higher than the cost of non-TRD (1,273,045 KRW, 1133 USD) - Medical expenses incurred by non-psychiatrists were roughly 1.7 times higher than those incurred by psychiatrists

These findings underscore the need for early identification and effective long-term maintenance treatment for treatment-resistant depression, as TRD is associated with disproportionate health care costs and unemployment, suggesting potentially large economic and societal gains with effective management.

Drug used in other indications

COMP360 Clinical Indications and Intervention Models

Based on the available information, COMP360 is a proprietary, synthetic formulation of psilocybin that is currently being developed specifically for treatment-resistant depression (TRD).

The only clinical trial information available indicates that COMP360 has been studied in a phase 2 study conducted by COMPASS Pathways for TRD. In this study, the psilocybin-COMP360 treatment demonstrated rapid response and remission as early as three weeks following treatment for approximately one third of participants.

There is no information available about COMP360 being investigated for any clinical indications beyond treatment-resistant depression. Similarly, there is no data regarding intervention models, administration methodologies, treatment paradigms, or outcome measures for any conditions other than TRD.

The current evidence only supports COMP360's development and testing for treatment-resistant depression, with no mention of trials for other psychiatric or neurological conditions.