Stephanie Sirota: In the coming year we could see the first FDA-approved Psilocybin therapy reach the market. For patients with treatment-resistant depression, individuals who have cycled through multiple therapies without relief, the need is urgent and often life-threatening.
And bringing a therapy like this through late-stage trials, regulatory scrutiny, and public market volatility is no small task.
Welcome to The RTW Podcast, where we aim to keep our audience healthy, wealthy, and wise. Today we welcome Dr. Steve Levine, Chief Patient Officer at Compass Pathways, the company that's currently developing COMP360 for treatment-resistant depression. Steve, thanks for joining us.
Dr. Steve Levine: Thank you for having me.
Stephanie Sirota: You're a psychiatrist. I'd love to know why you chose that field of medicine.
Dr. Steve Levine: I went to medical school thinking that I wanted to be a neurosurgeon, and it turned out that I was more interested in exploring people's stories than poking around in their grey matter, and psychiatry is the field of human stories.
Stephanie Sirota: In your earlier days, you worked in psychosomatic medicine and psycho-oncology. Can you define what that is?
Dr. Steve Levine: That was fellowship sub-specialty training that I did at Memorial Sloan Kettering Hospital. It describes the field where psychiatrists serve as the consultants to medical teams.
And it's a very interesting model of collaborative or team-based care.
It happens to be particularly relevant for COMP360 Psilocybin treatment, as it potentially moves in the not-too-distant future from clinical trial settings into real-world care delivery.
Steve Levine & Compass Pathways
Stephanie Sirota: You founded Actify Neurotherapies in 2010 before becoming Chief Patient Officer of Compass Pathways. What drew you away from clinical care toward solutions to scale interventional psychiatry?
Dr. Steve Levine: Early in my career practicing general psychiatry, too frequently, I'd be sitting across from someone who had been failed by multiple treatments and was unsure what options they had. What would be their next step?
And in many cases, I felt somewhat helpless and even ashamed with the options I had to present because I knew they weren't necessarily so different or better than what they'd already tried. So, I very much had a mindset of, "We need to do better."
And Actify was really born of that. We operated in 10 states. Starting in 2010, it was the first ketamine clinics.
But over time it evolved into an interventional psychiatry platform delivered in a supervised office setting, typically multi-hour treatments. And it was an opportunity to think more broadly about how do we bring more innovative treatments to patients with an eye towards equitable access.
Stephanie Sirota: Were the medicines paired with cognitive therapy as well?
Dr. Steve Levine: It's more of a model of monitoring and support, which involves preparing people for a unique experience ahead of time, building some trust and rapport, supporting them during treatment, and then following up and giving them the opportunity to talk about their experience, as well as to monitor for safety.
In my Actify days, when we were delivering treatments like ketamine off label or SPRAVATO, which is Esketamine, once it was FDA-approved we had many patients who were highly refractory to other treatments who were not accepting of psychotherapy.
I can't tell you how many conversations I had when I would recommend therapy to somebody and they would put their hands up and say, "No. I've had decades of therapy. It never helped me," which was understandable.
I needed to meet them where they were, so I didn't use language of therapy. It's instructive, thinking about the people we aim to serve, listening to them and what they feel they need, what will be helpful to them, and meeting them where they are along a path.
Stephanie Sirota: It's not just one size fits all. Was there a patient experience that impacted you deeply that you can share with full anonymity?
Dr. Steve Levine: People get through this very difficult life. And everyone does it differently.
One particular case was a branch point in my career. In 2010, I was doing a second opinion consultation with someone, and she had been through the mill.
She had tried everything under the sun for her depression. Nothing helped her, or she had side effects that she couldn't tolerate. And particularly in second opinion consultation situations, I've always focused not just on what's been your experience of taking psychiatric medications, but also what's happened if you've taken a recreational drug or over-the-counter medicines.
In her case, it turned out that when she would have a cough or a cold and she took cough medicine she felt better for some period of time. And as we dug into that, it turned out that the ingredient that was common across those different medications was Dextromethorphan, the cough suppressant.
And that made me really curious. What is it about Dextromethorphan that would explain her observation? And is there anything else out there that has a similar mechanism and any evidence to support its use in depression?
And that's what caused me to re-look at some of the early papers of using ketamine for psychiatric indications, in particular treatment-resistant depression.
That's really what prompted me to start the first ketamine clinic. Here is a group of people where there's an urgent need, a high risk of suicide.
For people who had no other options, why wouldn't we consider using this?
Stephanie Sirota: I'm curious; what's the path of a patient?
The Treatment Resistant Depression Journey
Dr. Steve Levine: In many cases people with treatment-resistant depression are just locked in the permafrost of primary care and never get referred out, in many cases because there's no one to refer to.
There aren't enough psychiatrists. The ones who actually accept insurance, which is only about half of them, often have long waiting lists or aren't even accepting new patients, so they stay in primary care. They cycle through the same types of medicines over and over again.
They reach that treatment-resistant depression status but nothing different happens.
What should happen, what would be more efficient: primary care to refer directly into interventional psychiatry.
Stephanie Sirota: When we talk about treatment-resistant depression, we're talking about patients who have cycled through multiple therapies without relief.
From your perspective, how medically serious is treatment-resistant depression, or TRD? And how urgent is this need?
Dr. Steve Levine: It is incredibly urgent, but we haven't necessarily been treating it as such. And as a result, we really have only one pharmaceutical product that is available and being prescribed to patients today, and that is SPRAVATO.
Treatment-resistant depression is such a difficult condition to treat. We have 50+ approved antidepressants right now. Many of them have tried to show efficacy in treatment-resistant depression and failed. And many other treatments that were specifically developed for TRD have failed.
This is four million people. People with major depressive disorder, particularly if they haven't benefited from treatment and they have the accumulation of months, years, even decades of untreated depression, start to accumulate other psychiatric conditions as well as medical, and they're at high risk for suicide. which is why I'm really proud that at Compass we are leading the way towards potentially a new option for them.
Stephanie Sirota: Does this also include patients with P.T.S.D.? Or is that a different subset of patients?
Dr. Steve Levine: It's a different diagnosis, but there is a lot of overlap: people who both have depression and P.T.S.D. We, in addition to our TRD program, do have a P.T.S.D. development program. We ran a phase 2 study that we published last year, primarily a safety and feasibility study.
And on that front it was very encouraging. We did also have an efficacy end point and saw a really excited efficacy signal. So, we are now initiating a late-stage P.T.S.D. study. It's a phase 2b/3, designed to be registrational. This is going to be in about 300 participants, and this is also a huge area of unmet need. There are 13 million living with P.T.S.D.
Stephanie Sirota: Wow.
Dr. Steve Levine: There are only two approved pharmaceutical products. There hasn't been an approval this century. It's just two old generic SSRIs that are modestly effective.
Stephanie Sirota: Well, that's encouraging that you're doing all of this work. Compass recently presented data from the COMP005 and COMP006 studies evaluating a single or two doses of 25 milligrams of COMP360 in TRD. Was there anything in the data that changed how you think about implementing this therapy at scale? What feedback have you heard from clinicians?
Dr. Steve Levine: We have a medical science liaison team that is out in the field getting feedback from clinicians, bringing those insights back in-house. We have our network of strategic collaborations, so we get to hear feedback from them about our data all the time.
And what we've been hearing loudest is how impressed people are with the durability of effect. Up to this point, we've primarily had SPRAVATO, which for some people can be rapidly effective, but it needs to be administered very frequently. Somewhere between 25 and 50 three-hour appointments per year that they need to be driven to.
So, it’s a huge burden on patients and their caregivers. Contrasted with the profile that's emerging of COMP360, where it may be one or two initial administrations and then intermittent re-treatment that's probably going to be, on average, two to four times per year in total. So, that is a scale of durability that is so far beyond anything available to us today and really exciting to clinicians.
Who are the TRD Patients?
Stephanie Sirota: Can you talk a little bit about the patient population?
Dr. Steve Levine: If you look at the baseline characteristics the most common patient would be someone in their forties, female. Depression is somewhat more common in women than men. Typically, they've had this episode of depression for at least a year, if not two or three years.
On average, folks had six to seven prior episodes of depression. At baseline they have a moderate to severe level of depression. So, really people who have been through the ringer.
Stephanie Sirota: We often hear from Congress—FDA and other senior government officials—about how they're aware of this mental health crisis in America and they want to get more treatments to patients faster. Is it being heard and readily addressed?
Dr. Steve Levine: Everyone's talking about psychedelics, including members of senior leadership. Despite turnover in some FDA leadership or in government more broadly, fortunately the psychiatry division at FDA has remained largely intact.
We've been able to have robust dialogue with the FDA because of our breakthrough therapy designation. And that has been very collaborative and very productive.
They've been collaborative in thinking through the design of our trials. They've been supportive.
Stephanie Sirota: That's great to hear. Have you felt any pushback because of the additional baggage that comes with psychedelics?
Holding Psychedelics to the Same Standard
Dr. Steve Levine: Ultimately, the same standards are going to apply to the study and evaluation and potential approval of psychedelics as for any other psychiatric drug or in any condition.
So, we don't want there to be any kind of special handling of this. We don't want corners cut. We want our product to be evaluated in the same way that any other treatment-resistant depression product would be. And that's been the case so far.
Stephanie Sirota: We've heard that people's interactions with FDA have actually run pretty smoothly.
That's great for patient outcomes. While COMP360 is the first psychedelic that could make it to patients with severe mental illness, esketamine or SPRAVATO was also available. So, how does COMP360 fit into the paradigm that SPRAVATO has pioneered?
Dr. Steve Levine: We have a very clear idea of where SPRAVATO is being delivered and therefore who is ready operationally and otherwise to potentially deliver our product if approved.
SPRAVATO is a multi-hour in-office treatment. It also has a REMs, a risk evaluation and mitigation strategy program which is an FDA program to evaluate side effects associated with a product over a longer period of time.
It's a Schedule 3 controlled substance. So, the considerations of ordering and storage and handling are the same. The physical plant is the same. A SPRAVATO room is a COMP360 room. And the staffing, the workforce, is the same.
SPRAVATO is typically a team-based model of care delivery. There's a prescriber on site and then there's usually a multi-disciplinary staff that may include nurses, medical assistants, technicians, perhaps a therapist on site. Multiple rooms operate simultaneously. That is exactly what is needed and what is appropriate for COMP360.
Stephanie Sirota: You're a competitive entrant to them, so is SPRAVATO afraid of COMP360 and what you might do to the treatment paradigm?
Dr. Steve Levine: When you consider that there are four million people with treatment-resistant depression and only about 100,000 are getting SPRAVATO right now, we're not really thinking about people switching from SPRAVATO to COMP360.
Stephanie Sirota: It's taking untouched market share.
Dr. Steve Levine: Exactly. We need as many effective tools for this population as possible. It's likely that a rising tide raises all ships here because it increases awareness.
Stephanie Sirota: Compared to SPRAVATO, what are the unique considerations for scalability and commercialization specific to COMP360?
Dr. Steve Levine: Fortunately, in terms of the physical infrastructure needed, as well as the workforce, they are essentially one to one. There are about 7,300 sites delivering SPRAVATO today. The bulk of prescriptions are relatively concentrated within that number.
But a SPRAVATO room is a COMP360 room in terms of its size and its furnishing and configuration and so on. And the workforce is the same as well. For SPRAVATO, typically it is within an interventional psychiatry center that may be delivering not just SPRAVATO but also TMS, which is transcranial magnetic stimulation, perhaps other treatments as well.
But that is typically staffed with a single prescriber (that could be a psychiatrist, but it might be a nurse practitioner or a physician's assistant), and then a multi-disciplinary team. That might include nurses, medical assistants, technicians, perhaps a therapist.
There are typically multiple rooms operating simultaneously with different treatments happening in different rooms. In many cases, the monitoring is supplemented with CCTV cameras in the rooms and central viewing area. And as a team, they are caring for these patients simultaneously having treatment.
We do specially train health care providers to monitor and support patients having COMP360. And as we move into commercialization, we will also require some amount of training of health care providers because that is important to make sure that they are effectively and safely caring for these patients while they're having a multi-hour experience.
Stephanie Sirota: Now, because COMP360 is administered in a clinical setting, physicians and medical staff will need to be reimbursed for their time. A lot of medicine is about aligning incentives between best practice and best economics. How is Compass working to make sure clinics can deliver the transformative potential of COMP360 without hurting the bottom line and without having to choose between what's good for business and what's good for patients?
Dr. Steve Levine: No one is going to prescribe COMP360 if they lose money on it, unfortunately. So, we have done a lot of early work in this area. Even though we will most likely be the first FDA-approved psychedelic treatment, we'll be first in class.
We do have a somewhat analogous treatment in SPRAVATO to follow behind and to have learned some lessons from.
But we also got to see what happens when you don't have the necessary reimbursement infrastructure in place. Because when SPRAVATO first launched, there was not a CPT code. CPT codes are the codes that providers submit to payers for reimbursement of their services.
We took a note from that. We banded together with some of the specialty societies and WyCos and we applied to the AMA for new CPT codes that are specific to the monitoring and potential intervention necessary on the day of a psychedelic administration.
Those codes went live in January of 2024. They are reportable on an hour-by-hour basis.
Stephanie Sirota: Psilocybin is a Schedule 1 substance in the U.S. This adds obviously to the complexity of running a trial and also the commercialization. How do you deal with this as you prepare to launch COMP360?
Dr. Steve Levine: More complex for the trials because it is still Schedule 1. A little bit less complex as we move into potential commercialization, and that's because part of the definition of Schedule 1 is no approved medical use.
But if our product is approved, then it no longer meets that definition for Schedule 1, which means towards the end of FDA's review process the controlled substance's staff will perform an analysis called an eight-factor analysis and use that to make a recommendation to the DEA for how to reschedule this product.
Base case assumption being Schedule 3, this is now on par with SPRAVATO.
Stephanie Sirota: That's interesting that you mention that about the states, because my assumption was if this is an FDA-approved drug then I didn't know that the states get to have a say in this. How does that work?
Dr. Steve Levine: Yeah, ain't nothin' easy. (LAUGHTER) There's a federal determination with federal DEA, but then each state does have their own DEA agency and their own rules about the rescheduling of products. And about half of states have trigger laws.
But in the others, there is some administrative or legislative action, whether it's managed through the attorney general's office of board of pharmacy or otherwise. That's why we've already been very active with our government affairs team in those states to make sure there's no undue delay once there's been an approved and federally rescheduled product.
Stephanie Sirota: So, if TRD is the first chapter and P.T.S.D. is often mentioned as a potential next step, why is that indication so compelling?
Why PTSD Is the Next Frontier
Dr. Steve Levine: Huge unmet need. It also is driven by the excitement we had following our phase 2 study, seeing that our treatment was so well tolerated by this group. It was a small, open-label study, 22 participants, but we also did qualitative interviews with the participants afterwards.
And beyond what we saw in the scales hearing from these participants' mouths the experience they went through, the impact that it had on them, it blew me away. This is a very good fit between the profile of COMP360, the model that we used to deliver it, and the experience and the disease state of those living with P.T.S.D..
Stephanie Sirota: Can you talk a little bit about the experience of those living with P.T.S.D. before treatment?
Dr. Steve Levine: Whether it's the impacts on sleep and how the quality of your sleep affects the way you feel the next day, the fact that people with P.T.S.D. often re-experience the trauma; they are continuously re-exposed to the thing that precipitated the P.T.S.D. diagnosis in the first place, which is terrifying.
The perceptual changes that happen in terms of seeing things that aren't there or having feelings of unreality, sometimes called depersonalization or derealization, the suicidality that accompanies the other comorbidities, like substance use disorders — all combined, make it very difficult to function both socially and occupationally.
What tends to represent effective treatment for P.T.S.D. is not forgetting the trauma, but rather changing one's relationship to the trauma so that when you do think about it you don't have the same reaction to it.
Stephanie Sirota: And that must have a tremendous ripple effect to the people around them, their family members, their friends and neighbors.
Dr. Steve Levine: Yes. You know, we tend to focus on the person living with the condition, but we can't forget about caregivers and loved ones as well. And whether it's treatment-resistant depression or P.T.S.D., they are conditions where people often either feel isolated or wind up isolating themselves, which is of course counterproductive because it's a time when you need more support, not less.
If you effectively help someone with P.T.S.D., you're not only helping them, you're helping everyone around them too.
Stephanie Sirota: Now, this may be post-treatment but some of the softer things like sleep and nutrition and exercise and social connection, what role do they play in the durability of someone's treatment?
Lifestyle's Role in Treatment Durability
Dr. Steve Levine: Beyond the context of COMP360, we certainly know some things about the relationship between stress and your diet and exercise and social connection and their impact.
When we talk about psychiatric conditions or anything of the mind, we metaphorically decapitate people. We think that there's this barrier between the mind and the body and nothing should pass across.
But the brain bone's connected to the neck bone's connected to the shin bone. And so, it logically follows that things affecting the rest of your system may have some impact on your emotional state or on psychiatric conditions. And so, I think as we look ahead to potentially having an approved COMP360 product, it may have some bearing on the durability of people's response, whether people have a relapse at some point and what the total treatment plan may look like.
Stephanie Sirota: COMP360, approval, commercialization is the goal. And then what's next?
Dr. Steve Levine: We don't intend to be a single-asset company forever. Beyond P.T.S.D., we've seen really exciting signals with some investigator-initiated studies in conditions like OCD, the depressed phase of bipolar disorder and more.
We will certainly be looking for additional development programs. Unfortunately, there are so many conditions with incredible unmet need within mental health that there are a lot of opportunities.
Stephanie Sirota: This conversation is a reminder that medicine isn't just about treating disease. It's about treating people. And that means that understanding more than just what is happening in the body but what's happening in the mind and the experience of the patient. Thank you so much for your special insights.
Dr. Steve Levine: Thank you so much.
Credits: Check out part one of this discussion in our previous episode, featuring Senior Research Analyst, Connor Williams, discussing psilocybin. The RTW Podcast was produced and directed by Devon Leaver, at the RTW headquarters in New York and edited by Dominique Guerra, with Production Coordinator, Ying Yu Lin, and production support by Annabelle Chan.
Executive editorial advisor was our Partner, Chief Business Officer, Stephanie Sirota, and our Research Consultant was Connor Williams, Senior Research Analyst at RTW Investments.
This interview was given by Steve Levine, Chief Patient Officer of Compass Pathways, and moderated by Stephanie Sirota, Partner and Chief Business Officer at RTW Investments. Statements reflect RTW's views and opinions as of the date hereof and not as of any future date.
All expressions of opinion are subject to change without notice and are not intended to be a forecast of future events or results. The views expressed by guests are their own, and their appearance on the program does not imply an endorsement of them or any entity they represent.
