2026 ECNP Congress

PS04-4219

Efficacy and safety of COMP360 psilocybin for treatment-resistant depression in two phase 3 double-blind randomised controlled studies

Rachael Taylor — G.M. Goodwin, L. Marwood, N. Hewitt, J. Chai-Rees, E. Teoh, H. Simmons, W. Haddock, S. Williams, R. Bastle, M. Gold · Compass Pathways, Clinical Sciences, London, United Kingdom

2026 ECNP Congress

Introduction

COMP360 is a novel, proprietary, synthetic formulation of psilocybin being investigated for treatment-resistant depression (TRD) and post-traumatic stress disorder. COMP005 and COMP006 are multi-center, randomised, double-blind, controlled phase 3 studies investigating the efficacy, safety, and tolerability of COMP360 in adults with TRD. We investigated the efficacy and safety of COMP360 in the first six weeks (primary endpoint) following either one (COMP005) or two (COMP006) administrations.

Methods

Adult participants were enrolled after meeting study eligibility, including presence of TRD defined as having experienced 2–4 inadequate responses to prior treatments during their current depressive episode. Participants in COMP005 were randomised in a 2:1 ratio to receive a single administration of either COMP360 25mg or placebo. Participants in COMP006 were randomised in a 2:1:1 ratio to receive two doses (3 weeks apart) of COMP360 25mg, 10mg, or 1mg. The primary endpoint for both studies was change in MADRS total score from baseline to Week 6.

Results

For COMP005, 258 participants were dosed with either COMP360 25mg (n=171) or placebo (n=87). The primary endpoint was achieved: the least square mean (LSM) change from baseline MADRS total score at week 6 was significantly greater in participants receiving a single administration of COMP360 25mg than those receiving placebo (p<0.001) with an LSM difference (LSMD) of -3.6 [95% confidence interval (CI): -5.7, -1.5]. All time points measured reached statistical significance from the day after dosing (Day 2) onwards.

For COMP006, 581 participants were dosed to either COMP360 25mg (n=296), 10mg (n=142), or 1mg (n=143). The primary endpoint was achieved: the LSM change from baseline MADRS total score at week 6 was significantly greater in participants receiving two doses of COMP360 25mg than those receiving 1mg (p<0.001) with an LSMD of -3.8 (CI: -5.8, -1.8). The COMP360 10mg group showed a smaller difference than 25mg compared to the 1mg group (LSMD of -2.5, CI: -4.9, -0.2; p=0.016). All time points measured reached statistical significance from the day after dosing (Day 2) onwards for both COMP360 25mg and 10mg groups compared to 1mg. The adverse event (AE) profile for COMP005 and COMP006 is consistent with the known profile of COMP360 psilocybin, where most treatment-emergent AEs (TEAEs) occurred on the day of administration (65.6% and 68.3%, respectively) and resolved within 1 day (88% and 84.3%, respectively). The most common TEAEs included headache, nausea, visual hallucinations, and anxiety. In the 25mg arm, there were 5 treatment-emergent serious AEs (SAEs) from 4 participants (2.3% overall) in COMP005, and 6 treatment-emergent SAEs from 6 participants (2% overall) in COMP006.

Conclusions

COMP360 25mg rapidly and meaningfully reduces depressive symptoms in adults with TRD across both single- and two-dose paradigms, with a possible added benefit seen after a second dose. COMP360 is demonstrating a generally well-tolerated and safe profile, with most of the TEAEs occurring on the day of drug administration and the majority resolving within one day.

References

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