Can Durable Response to Psilocybin Reshape Treatment-Resistant Depression Care?

Real-world analyses presented by Compass Pathways found that the economic burden of treatment-resistant depression (TRD) was concentrated during treatment-resistant depressive episodes, with healthcare costs and resource utilization declining as patients moved toward more stable health states, shared Guy Goodwin, MD. Treatment-resistant episodes were substantially longer than other depressive episodes, patients with TRD had higher rates of acute exacerbations, and patients who did not meet traditional TRD definitions still experienced a comparable disease burden, suggesting that antidepressant dose and duration alone do not capture the full trajectory of illness.¹ Goodwin noted that these analyses did not establish that COMP360 would reduce healthcare costs, but they reinforced the value of durability of response. In the pivotal phase 3 COMP005 and COMP006 studies of COMP360, a psilocybin formulation, 25% of participants receiving 25 mg in COMP005 and 39% of those receiving 2 fixed 25-mg doses in COMP006 achieved a clinically meaningful reduction in depressive symptoms at week 6, with benefit maintained on average through at least week 26.² Additional dosing enhanced benefit for some patients, with 28% of those who had a clinically meaningful reduction but not remission at week 6 achieving remission after retreatment in COMP006, and no new safety findings were observed through 26 weeks.

Psychiatric Times: TRD is often discussed in terms of clinical symptoms. Why was it important for Compass to also quantify its economic and societal burden, and what gap in the existing evidence were you trying to fill?

Guy Goodwin, MD: TRD is a serious and often debilitating condition. Critically, it can affect patients’ ability to work, maintain relationships and participate fully in everyday life. For healthcare systems, it can mean significant and ongoing demands on resources.

While the clinical burden of TRD is generally well understood, there's an opportunity to better illustrate how that burden evolves throughout the course of illness. Much of the existing evidence focuses on the total costs associated with TRD, rather than distinguishing between different stages of illness and the associated healthcare needs.

Our research sought to provide a more nuanced picture of this by examining real-world healthcare utilization and costs across different health states. Understanding where the burden is greatest, and how it changes as patients stabilize, is important for informing future approaches to treatment and evaluating their potential broader value.

PT: One analysis examines real-world healthcare costs and resource utilization across health states in TRD. What did you find, and which results most surprised you?

Goodwin: Our analysis found that the economic burden of TRD is concentrated during treatment-resistant depressive episodes, with healthcare costs and resource utilization declining as patients move toward more stable health states.

What stands out is how closely the economic burden of TRD is tied to where a patient is in the course of their illness. It reinforces that TRD is not only a significant clinical challenge, but also one with substantial implications for healthcare systems the longer a patient is left in a depressive episode without relief.

These findings underscore the importance of helping patients achieve and sustain meaningful improvement. They also provide a valuable foundation for understanding how future treatment approaches that deliver rapid and sustained benefit could potentially influence healthcare utilization and costs over time.

PT: Another poster characterizes depression episodes to define real-world health states for MDD and TRD. Why do those definitions matter, and how might they change the way clinicians think about disease trajectory?

Goodwin: How we define depressive episodes matters because it shapes our understanding of how patients experience depression over time, including the duration and recurrence of episodes and the burden associated with them.

Our research introduces a more comprehensive way of characterizing depressive episodes using real-world data, accounting for both medication management and acute healthcare utilization. We found that treatment-resistant episodes were substantially longer than other depressive episodes, and patients with TRD experienced higher rates of acute exacerbations.

Importantly, we also found that patients who did not meet traditional definitions of TRD could still experience a significant disease burden similar in magnitude to TRD. This suggests that adequate antidepressant dose and duration may not tell the full story of a patient's illness.

For clinicians, these findings reinforce the importance of looking at the broader disease trajectory, including the duration of episodes, recurrence and acute healthcare needs, when evaluating patients and making treatment decisions.

PT: How do these HEOR findings relate to the clinical case for COMP360? In particular, how might a treatment with a limited number of dosing sessions affect the cost and resource-use patterns you observed?

Goodwin: These findings help us better understand the significant burden associated with TRD and why new treatment approaches are urgently needed. They also provide important context for our clinical development program.

With COMP360, we're investigating a fundamentally different treatment approach, one that has the potential to provide rapid and sustained benefit with infrequent dosing, rather than requiring daily or frequent administration. Such conventional treatment almost always also imposes a burden of significant adverse effects.

If a treatment can provide sustained improvement in depressive symptoms, there's the potential for that benefit to extend beyond clinical measures, potentially changing patients' healthcare needs and patterns of resource utilization over time.

Of course, these analyses don't establish that COMP360 will reduce healthcare costs, and additional research would be needed to evaluate its economic impact. But they do reinforce the value of durability in mental health care, not only within the current treatment paradigm, but also when considering the potential role of new treatment options.

PT: Compass is presenting encore analyses from the 2 phase 3 studies, including 26-week efficacy and safety data. What do the longer-term results tell us about durability of response, and what should clinicians take from them?

Goodwin: Across our pivotal phase 3 studies, we've demonstrated consistent evidence of rapid onset and sustained clinical benefit in a chronic TRD population. These were patients whose current depressive episodes had lasted more than 3 years on average, with more than 6 lifetime depressive episodes.

In COMP005, 25% of participants receiving 25 mg COMP360 achieved a clinically meaningful reduction in depressive symptoms at week 6, maintaining that benefit, on average, through at least week 26 following 1 or 2 doses. In COMP006, 39% of participants receiving 2 fixed doses of 25 mg COMP360 achieved a clinically meaningful reduction at week 6, maintaining benefit, on average, through at least week 26. We also saw that additional dosing could enhance clinical benefit for some patients, with 28% of participants who achieved a clinically meaningful reduction at week 6 but had not reached remission subsequently achieving remission following retreatment in COMP006.

Importantly, COMP360 continued to demonstrate a generally well-tolerated safety profile, with no new safety findings through 26 weeks.

For clinicians, the key takeaway is the potential to move beyond treatment approaches that require daily or frequent administration toward an option that could deliver meaningful, sustained benefit with just a limited number of dosing sessions. We believe that's particularly compelling in a population where patients have often spent years searching for relief.

Dr Goodwin is the chief medical officer at Compass Pathways.

References

1. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917.

2. Goodwin GM, Aaronson ST, Alvarez O, et al. Single-dose psilocybin for a treatment-resistant episode of major depression. N Engl J Med. 2022;387(18):1637-1648.