Compass Pathways clears second phase III hurdle for psilocybin in treatment-resistant depression

In the COMP006 trial, two doses of COMP360 25 mg administered three weeks apart demonstrated a statistically significant reduction in depression severity compared to a 1 mg control, with a mean treatment difference of -3.8 points on the Montgomery-Åsberg Depression Rating Scale (MADRS), a clinician-rated measure of depression severity, at six weeks. The MADRS ranges from 0 to 60, and in antidepressant trials, differences of 2–3 points versus placebo are typically considered clinically meaningful.

The result closely mirrors the first trial, COMP005, which reported a -3.6-point advantage over placebo last June. Together with earlier phase IIb data, COMP360 has now demonstrated efficacy in three consecutive controlled trials. Both phase III studies are continuing to 52 weeks.

“The [FDA] agency has shown strong interest in an aggressive filing strategy, including the potential for a rolling submission and rolling review,” said Compass’s CEO Kabir Nath during a live webcast on February 17. “We expect to be ready to launch commercially [in the USA] at the end of this year.”

Significant unmet need

The commercial case rests on a market with major unmet need and only one approved treatment. More than four million adults in the US are affected by TRD each year, and only Johnson & Johnson’s Spravato (esketamine) – a nasal spray approved for TRD in 2019, and subsequently approved also for major depressive disorder – has received FDA clearance for the condition. Spravato’s annual revenue is nearing $2 billion.

Compass is positioning COMP360 as a fundamentally different proposition. “Importantly, patients need 10 Spravato treatments by week 6 to achieve a similar effect to what we are seeing with COMP360 at week 6, with one or two treatments,” Nath said. “There are no approved drugs for depression, including Spravato, that offer rapid-onset, clinically-meaningful effect and durable outcomes from just one or two treatments.”

The durability data reinforce this. In COMP005, 25% of patients achieved a clinically meaningful reduction in symptoms at six weeks, and that improvement persisted through week 26 after just one or two doses. In COMP006, the proportion of patients who achieved a clinically meaningful reduction in symptoms at six weeks was higher, at 39%. The 26-week data from COMP006 are expected in early Q3.

Safety, scalability, and the road to approval

Across both phase III trials, COMP360 was generally well-tolerated. Adverse events were mostly mild, occurred on dosing days, and the vast majority resolved within 24 hours. 

The broader psychedelic therapy field has been operating under heightened regulatory scrutiny since the FDA rejected Lykos Therapeutics’ MDMA-assisted therapy for PTSD in August 2024, citing concerns over trial design and safety reporting. Compass itself acknowledged that context when it adjusted the COMP006 timeline that same year, citing “a high degree of scrutiny regarding unblinding, which is very relevant to our studies,” meaning the possibility that patients or clinicians could infer treatment assignment because of the drug’s noticeable effects, thereby undermining the integrity of a blinded trial.

Practical questions also remain. Administering a psychedelic requires supervised sessions in controlled settings, raising challenges around scalability, reimbursement, and integration into routine psychiatric care. But Spravato’s commercial trajectory demonstrates clinic-based models can work and COMP360’s far lighter dosing burden may prove an advantage.

“Across the very limited TRD treatment landscape, this potential treatment truly stands out for its extremely rapid and sustained efficacy,” said Compass’ CMO Dr. Guy Goodwin in a press release. “We are incredibly grateful to the participants, investigators, and clinical trial staff for their invaluable contributions to our trials and for making this significant progress possible.”