2026 ECNP Congress

PS02-2123

Demographic and clinical characteristics of participants receiving COMP360 psilocybin treatment for treatment-resistant depression across two pivotal phase 3 trials

Nilay Hewitt — R.W. Taylor, L. Marwood, M.B. Young, G.M. Goodwin · Compass Pathfinder Ltd., Clinical Sciences, London, United Kingdom

2026 ECNP Congress

Introduction

COMP005 and COMP006 are ongoing Phase 3, double‑blind, randomised, controlled trials evaluating COMP360 (Compass Pathways’ proprietary, synthetic psilocybin formulation) in treatment‑resistant depression (TRD). These studies represent the largest double-blind, randomised-controlled trials of psilocybin conducted to date, and the first Phase 3 trials of a classic psychedelic to report data. Here, we describe the demographic and clinical characteristics of enrolled participants.

Methods

COMP005 participants were randomised 2:1 to receive 25mg COMP360 or placebo. COMP006 participants were randomised 2:1:1 to 25mg, 10mg or 1mg COMP360. Medical records, validated methods of assessment, and centralised medical monitor review were used to ensure eligibility.

Participants aged ≥18 years with TRD, defined as a failure to respond to two to four different protocol-defined pharmacological treatments taken at an adequate therapeutic dose for at least 8 weeks) during the current depressive episode. A Montgomery-Åsberg Depression Rating Scale (MADRS, performed by independent raters) total score ≥20 at Screening and Baseline was required to ensure at least moderate depression severity. Prior psychedelic use was capped. Participants taking antidepressant or antipsychotic medications at Screening completed medication washout at least two weeks before Baseline.

Results

In COMP005, 258 participants (54.3% female; mean age [standard deviation] 45.7 [13.7]) and in COMP006 581 participants (51.1% female; mean [SD] age 45.2 [13.4]), were randomised and received study drug. Approximately one-third of participants had failed 3 or more pharmacological treatments in the current episode (COMP005 30.6%; COMP006 31.8%). Approximately two-thirds (COMP005 57.8%; COMP006 62.1%) had a Baseline MADRS score of ≥31 indicating severe depressive symptoms. The mean duration of the current depressive episode amongst participants was 36.0 [31.1] and 41.8 [42.5] months, with a mean number of lifetime depressive episodes of 7.5 [9.9] and 6.2 [8.7] denoting the chronic and recurrent nature of TRD and the severity of the population enrolled. Over two-thirds of participants required washout of medications during the screening period (COMP005 67.4%; COMP006 76.8%). Prior use of any classic psychedelics, including psilocybin was low in both trials (COMP005 5.4%; COMP006 and 6.4%).

Conclusions

These data demonstrate that the COMP360 Phase 3 trial populations are broadly in line with other clinical trials of TRD with respect to demographic and clinical characteristics [1-3]. The trials capture a notably severe cohort, reflected in the high number of lifetime depressive episodes, chronicity of the current episode, and high proportion of participants with severe depression symptom severity. The requirement for at least 8 weeks of antidepressant treatment - exceeding the thresholds typically used in TRD trials - and the confirmation of these failures via medical records further strengthen the rigor and credibility of the severity classification. Notably, many participants had failed other pharmacological and non-pharmacological interventions that were not protocol defined treatment failures, indicating that the number of failures underestimates the actual degree of treatment resistance. Lifetime use of psychedelics was low indicating the representativeness of the trial population. Once completed, these pivotal trials will provide valuable data on durability of effects, and the safety and efficacy of repeat dosing over 52 weeks.

References

  1. Janik, A., Qiu, X., Lane, R., Popova, V., Drevets, W. C., Canuso, C. M., … & Fu, D. J. (2025). Esketamine monotherapy in adults with treatment-resistant depression: a randomized clinical trial. JAMA psychiatry, 82(9).
  2. Fava, M., Freeman, M. P., Flynn, M., Judge, H., Hoeppner, B. B., Cusin, C., … & Papakostas, G. I. (2020). Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Molecular psychiatry, 25(7), 1592-1603.
  3. Mrazek, D. A., Hornberger, J. C., Altar, C. A., & Degtiar, I. (2014). A review of the clinical, economic, and societal burden of treatment-resistant depression: 1996–2013. Psychiatric services, 65(8), 977-987.