EFFICACY AND SAFETY OF COMP360 PSILOCYBIN FOR TREATMENT-RESISTANT DEPRESSION (TRD) IN TWO PHASE 3 DOUBLE-BLIND RANDOMIZED CONTROLLED STUDIES

COMP360 is a novel, proprietary, synthetic formulation of psilocybin being investigated for treatment-resistant depression (TRD) and post-traumatic stress disorder. COMP 005 and COMP 006 are multi-center, randomized, double-blind, controlled phase 3 studies investigating the efficacy, safety, and tolerability of COMP360 monotherapy in adults with TRD. We investigated the efficacy and safety of COMP360 in the first six weeks (primary endpoint) following either one (COMP 005) or two (COMP 006) administrations.

Methods

Adult participants were enrolled after meeting study eligibility, including presence of TRD as defined as having experienced 2–4 inadequate responses to prior treatments during their current depressive episode. Participants in COMP 005 were randomized in a 2:1 ratio to receive a single administration of either COMP360 25 mg or placebo. Participants in COMP 006 were randomized in a 2:1:1 ratio to receive two doses (3 weeks apart) of COMP360 25 mg, 10 mg, or 1 mg. The primary endpoint for both studies was change in MADRS total score from baseline to Week 6.

Results

For COMP 005, 258 participants were dosed with either COMP360 25 mg (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 25 mg than in 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 COMP 006, 581 participants were dosed to either COMP360 25 mg (n=296), 10 mg (n=142), or 1 mg (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 25 mg than those receiving 1 mg (p < 0.001) with an LSMD of -3.8 (CI: 5.8, -1.8). The COMP360 10 mg group showed a smaller difference than 25 mg when compared to the 1 mg 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 the COMP360 25 mg and 10 mg groups compared to the 1 mg. The adverse event (AE) profile for COMP 005 and COMP 006 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, hallucination (visual), and anxiety. In the 25 mg arm, there were 5 treatment-emergent serious AEs (SAEs) from 4 participants (2.3% overall) in COMP 005, and 6 treatment-emergent SAEs from 6 participants (2% overall) in COMP 006. The Data and Safety Monitoring Board noted that there is no evidence, to date, of a clinically meaningful imbalance between treatment arms in suicidality in either study.

Discussion

COMP360 25 mg 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 in COMP 006. Across COMP 005 and COMP 006 to date, 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. Notably, the absence of a meaningful suicidality imbalance among groups, to date, are clinically reassuring in this high-risk population.