Compass Pathways Achieves Primary Endpoint in Second Phase 3 Trial of Psilocybin for Depression

Compass Pathways reported positive results from its second phase 3 trial evaluating COMP360 psilocybin for treatment-resistant depression, achieving the primary endpoint and preparing to discuss FDA filing for approval. Shares in Nasdaq-listed Compass were up around a third following the announcement.

The randomized, fixed repeat dose, double-blind phase 3 COMP006 study (ClinicalTrials.gov Identifier: NCT05711940) evaluated the efficacy, safety, and tolerability of COMP360 psilocybin in patients aged 18 years and older with treatment-resistant depression. Study participants (N=581) were randomly assigned 2:1:1 to receive 2 administrations of COMP360 psilocybin in doses of 25mg (n=296), 10mg (n=142) or 1mg (n=143), taken 3 weeks apart. The primary endpoint was the change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at 6 weeks.

COMP360 psilocybin 25mg statistically significantly reduced symptom severity, as measured by MADRS, compared with the 1mg dose at week 6 (mean difference, -3.8 points [95% CI, -5.8, -1.8]; P <.001). In the 25mg arm, 39% of patients achieved a clinically meaningful MADRS reduction of 25% or greater; improvements were seen as early as 1 day post-administration and were sustained through 6 weeks.

Two doses of COMP360, given in a controlled environment with psychological support from a trained therapist, were significantly more effective at reducing symptoms of depression compared to a control based on a 1mg dose of the drug. The company said the results show "a level of clinical effect that has historically been extremely difficult to achieve in TRD."

The most common treatment-emergent adverse events were headache, nausea, anxiety and hallucination. Most events occurred on the days of administration and were resolved within a day.

The findings are consistent with previously reported results from Part A of the COMP005 study (ClinicalTrials.gov Identifier: NCT05624268), which demonstrated that COMP360 psilocybin 25mg significantly improved depression symptom severity vs placebo. The COMP005 study showed a significant 3.6-point reduction in MADRS after a single dose of COMP360, with a quarter of patients reporting a reduction of 25% or more with durability extending to 26 weeks.

Updated Part B results demonstrated sustained efficacy for COMP360 psilocybin 25mg, maintaining symptom severity reductions through week 26 after just 1 or 2 doses. Greater than 40% of participants who achieved a clinically meaningful reduction in MADRS total score but remained not remitted by 6 weeks went into remission after a second dose.

The Chief Medical Officer stated that TRD patients have extremely limited treatment options, and the unmet need remains profound. The results redefine rapidity and durability for TRD patients with onset as early as the next day and, for those who respond, effects from just 1 or 2 doses lasted at least through 26 weeks, alongside a well tolerated safety profile.

The company said in 2024 that it had decided to wait until after the 26-week data endpoint for both trials before seeking FDA approval, saying it was hoping to avoid FDA concerns about "functional unblinding" – where patients will likely know if they received the active study drug rather than a control due the obvious psychedelic effect. The 26-week data for COMP006 is due in the third quarter.

With 26-week data for COMP005 in hand, the company said it hopes to discuss a rolling submission for COMP360 with the FDA, which could allow some of the dossier to be filed early and updated when the longer-term COMP006 follow-up results become available. A New Drug Application submission is expected to be completed in the fourth quarter of 2026.

The CEO called the new data "a remarkable achievement for the field of psychiatry, especially in the TRD population, where proving benefit has historically been extraordinarily challenging." He added that the results "strengthen our conviction in the highly differentiated profile for COMP360," and the company is now working towards a goal of filing the psychedelic for approval before the end of the year.

Approximately 100 million people in the world live with treatment-resistant depression, which means they have not responded to at least two antidepressant treatments for their major depressive disorder. There are around 5 million patients in the US who could potentially benefit from this form of treatment.

The study consists of 3 parts: a 9 week blinded period (Part A), an extension phase through week 26 (Part B), and an open-label treatment phase from week 26 to week 52 (Part C). COMP360 is a synthetic, proprietary formulation of psilocybin.