Synthetic Psilocybin Meets Primary Endpoint in Phase 3 Treatment-Resistant Depression Trial
Key Clinical Summary
- In the phase 3 COMP006 trial, COMP360 psilocybin 25 mg achieved a statistically significant reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) scores vs 1 mg at week 6 (mean difference −3.8; p < 0.001) in patients with treatment-resistant depression (TRD).
- Rapid onset was observed from the day after dosing and maintained through week 6; 39% achieved ≥25% MADRS reduction in COMP006.
- Across COMP005 and COMP006, safety was generally well tolerated, with most adverse events mild to moderate and resolving within 24 hours.
A synthetic form of psilocybin (COMP360) has met the primary endpoint in a second phase 3 trial evaluating its efficacy and safety in patients with treatment-resistant depression (TRD), announced manufacturer Compass Pathways. According to topline data, 25 mg of COMP360 compared with 1 mg showed a statistically significant and clinically meaningful reduction in symptom severity at 6 weeks.
Study Findings
COMP006, a randomized, double-blind phase 3 study conducted across North America and Europe, enrolled 581 participants with TRD. Patients received 2 fixed doses, administered 3 weeks apart, of COMP360 25 mg, 10 mg, or 1 mg. The primary endpoint was the difference in change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) scores between the 25 mg and 1 mg groups at week 6.
At week 6, the 25 mg dose demonstrated a highly statistically significant and clinically meaningful mean treatment difference of −3.8 points compared with 1 mg (95% CI, −5.8 to −1.8; p < 0.001). In the 25 mg arm, 39% of participants achieved a clinically meaningful ≥25% reduction in MADRS scores.
COMP005, an earlier trial conducted in the United States, evaluated a single 25 mg dose versus placebo in 258 participants. At week 6, the mean treatment difference was −3.6 points (95% CI, −5.7 to −1.5; p < 0.001). The study also found that 25% of participants in the 25 mg arm achieved a ≥25% reduction in MADRS at week 6, with durability maintained through week 26 after 1 or 2 doses.
Across both trials, rapid onset was observed from the day after administration and maintained through week 6 in the 25 mg arms. Safety data showed most treatment-emergent adverse events (TEAEs) occurred on dosing days (66%–73%), with 83%–88% resolving within 24 hours. Common TEAEs included headache, nausea, anxiety, and visual hallucination.
Serious adverse events were reported in 5% (COMP005) and 2% (COMP006) of participants in the 25 mg arms. Rates of serious suicidal ideation were <1%, with 1 event of suicidal behavior occurring in the 1 mg arm of COMP006.
Clinical Implications
An estimated 4 million US adults with major depressive disorder (MDD) live with TRD. Compared to MDD alone, TRD is associated with increased risk of suicide, increased comorbidities, and poorer quality of life outcomes. Despite a high need for treatment options, demonstrating clinically meaningful improvement in this population has historically been challenging.
If confirmed by regulatory review, COMP360 may represent a novel therapeutic approach within a limited TRD treatment landscape.
Expert Commentary
“TRD patients have extremely limited treatment options, and the unmet need remains profound,” said Guy Goodwin, MD, Chief Medical Officer, Compass Pathways, in a press release. “The promising clinical profile of COMP360 reinforces our belief in its potential to set a new standard of care for this population.”
The company has requested a meeting with the US Food and Drug Administration (FDA) to discuss a rolling submission and review, and expects to submit a New Drug Application (NDA) by the end of 2026. The company also plans to report 26-week data from the COMP006 trial by the third quarter of the year.
