COMP360 Safety Data in Phase 3 TRD Trials, With Steve Levine, MD

New phase 3 data from COMP005 and COMP006 further clarify the safety and tolerability profile of COMP360, a synthetic psilocybin, in treatment-resistant depression (TRD). In an interview with HCPLive, Steve Levine, MD, chief patient officer at Compass Pathways, emphasized that most treatment-emergent adverse events (TEAEs) were transient and resolved within 24 hours of administration.

Unlike traditional oral antidepressants, which are associated with chronic daily exposure and cumulative adverse event burden, COMP360 is administered episodically in a supervised setting. Across both phase 3 trials, the majority of adverse events occurred on the dosing day and were generally mild to moderate in severity.

Adverse events were dose-dependent but typically resolved by the following day. The most commonly reported events included headache, nausea, fatigue, anxiety, and visual hallucinations.

“They were transient, and so it suggests a very tolerable profile for patients,” Levine told HCPLive.

Suicidality remains a critical concern in TRD populations, where baseline risk is inherently elevated. Levine highlighted that across Part A of both COMP005 and COMP006, as well as longer-term follow-up through 26 weeks in COMP005, there was no imbalance in suicidal ideation or behavior between treatment arms. The study had < 1% reports of suicidality.

Questions remain regarding optimal retreatment frequency and long-term maintenance. Data to date suggest that 1 or 2 administrations may provide benefit lasting up to 6 months in responders. Additional 26-week data from COMP006 Part B are expected to further clarify retreatment intervals and inform real-world implementation, including payer considerations. Levine characterized the anticipated model as episodic rather than maintenance-based therapy.

Although COMP360 requires multi-hour supervised administration, Levine pointed to > 7000 US sites currently certified to administer esketamine nasal spray as a potential infrastructure foundation. The team-based delivery model used for esketamine, including psychiatrists, licensed healthcare professionals, and support staff, may be readily adaptable.

If approved, Levine suggested COMP360 could introduce a fundamentally different treatment paradigm in TRD, defined by rapid onset, limited dosing sessions, and durable benefit.

“For patients living with treatment-resistant depression, there currently is only one marketed pharmacologic option, which is Spravato,” Levine said. “That is a treatment that, while relatively rapidly acting, represents a high burden on patients and their caregivers given the frequency of induction treatment, as well as the frequency of maintenance treatment, which we [need] to maintain the effect. COMP360, with the rapidity and durability that we have now demonstrated in phase three, with the efficacy detectable on the first day following administration…represents an entirely new paradigm of care.”

A relevant disclosure for Levine includes Janssen Pharmaceuticals, Inc.

References

1. Compass Pathways Successfully Achieves Primary Endpoint in Second Phase 3 Trial Evaluating COMP360 Psilocybin for Treatment-Resistant Depression. Compass Pathways. Published on February 17, 2026. Accessed on February 19, 2026. https://ir.compasspathways.com/News--Events-/news/news-details/2026/Compass-Pathways-Successfully-Achieves-Primary-Endpoint-in-Second-Phase-3-Trial-Evaluating-COMP360-Psilocybin-for-Treatment-Resistant-Depression/default.aspx

2. Derman C. COMP360 Psilocybin Meets Primary Endpoint in Second Phase 3 Trial for TRD. HCPLive. Published on February 19, 2026. Accessed on February 20, 2026. https://www.hcplive.com/view/comp360-psilocybin-meets-primary-endpoint-second-phase-3-trial-trd