Our program now. Why did you pick adjunctive treatment in MDD? Why not go standalone, or why not go after treatment-resistant depression?
We think that adjunctive MDD reflects real-world patients. As we've spoken to payers, spoken to providers, by the time patients have tried first and second-line treatments, and they're at third line, which is where we expect to be positioned, they've already tried a lot of treatments. Often the number of SSRIs or SNRIs, a number of different adjunctive treatments. It isn't two trials. It's often four or five or six trials. Their options when they get to third line are quite limited: ECT, TMS, esketamine, ketamine at this point. We wouldn't see the rationale for limiting this treatment to treatment-resistant patients, which of course are further down the treatment cycle. The prospect of asking a patient to come off of their background medication, maybe that takes four or six weeks or so and can be challenging to trial a single treatment, just didn't make a lot of sense to us.
With our adjunctive treatment, we're targeting larger third-line MDD populations, about 3.5 million patients in the U.S., and it means the patients can trial CYB003 immediately and not have to go through that prolonged titration period.
If you look at a real-world scenario, what do you think the sweet spot in durability of effect could be for a product like yours? Is it three months, six months, 12? How are you thinking about that? How do you think that's eventually going to play out in the marketplace? How correlated do you think commercial success could be to time spent in the clinic during the dose?
Yeah, it's a balance of all of those things. The perspective of durability is probably different from a few different perspectives. From a patient's perspective, I doubt the patients will want to have these kinds of experiences more frequently than every two, three months or so. From an FDA point of view, to look at these treatments as acute rather than intermittent, we think they're looking for at least six months durability. Our internal perspective has always been, you know, what does it take for us to keep patients free from depression for a year? I think the payers are looking for that kind of understanding as well. What's it going to cost them for a year of treatment? So far in our Phase II study, we saw a little over 70% of patients in remission at one year after just two doses with no retreatment after that.
Our goal has been a year. In the Phase III program, we'll be following patients up for a year after dosing and we'll give patients a chance to redose if they relapse. For patients that don't respond in our short-term studies, they'll also get a chance to get another cycle of treatment. In some cases, we'll see the benefits of retreating patients that don't respond. I think a lot of data coming from this program.
What's the best way to think about price to make our life easier for modeling purposes?
Yeah, it's a little premature. You know, there aren't a lot of third-line choices. Of course, when you're looking at pricing intermittent treatments or infrequent treatments, it gets a little bit more challenging. Spravato right now, esketamine, is really the benchmark. Payers are spending $30,000- $50,000 a year. That gives you some kind of range. I think they would be certainly very attractive of a protocol that is two doses a year rather than 26 treatments a year, which is what we're comparing.
On the safety side, given these products could be fairly durable in terms of effect, what do you think the, I guess, statute of limitations on a safety event related to the product could be? Does it have to be as long as the efficacy, durability, or, I mean, like, you know, we've seen some data sets where, let's say I take the product today, I'm good for six months from an efficacy perspective, but if something happens to me from a safety perspective, will that be considered related to the drug if it happens in that same six-month time period?
We are only seeing adverse events during the dosing sessions. We've seen no serious adverse events at all, no incidents of suicidal ideation, which can be common in depression studies. In fact, we saw suicidal ideation scores reverse in all subjects. During dosing, patients can experience nausea, some headache, some elevated blood pressure, but it's all transient. It all returns to normal by the end of the dosing session. Pretty tolerable. Just two doses a year means that this experience only happens twice in a one-year period would be our expectation. In our larger pivotal program here, we'll be tracking adverse events at all periods of the study, not just the dosing.
Right. Would you eventually report to your Phase III trials? What do you expect to report as part of top line?
Bearing in mind that we'll still have other studies ongoing, we'll probably keep it to reduction in MADRS scores, relapse and remission rates, response rates.
Got it. How closely is a, or what's the frequency with which a DSMB or a data safety monitoring board looks at the Phase III trials that you have ongoing? What's the frequency that a DSMB would monitor your trials?
That's a good question that I don't have an immediate answer for you, but I can get back to you on that. We have a DSMB setup report. It's fairly new because the study only started a few months ago. I'll get back to you on that.
Okay. In terms of the contract research organizations that you might be using for your phase III trials, how experienced are they with this kind of paradigm of treatment? No pun intended. I know your program is called Paradigm. How closely are they linked to this type of treatment, the special needs that might come along with this?
Yeah, I think they're very experienced. One of the reasons we chose them was because of that experience. We've also been focusing on sites and investigators with experience as well. These treatments take a certain amount of infrastructure, accountable room with observation, session monitors in the room with the patients, preparation beforehand and follow-up after, as you'd expect with really anything, obviously paying close attention to these psychiatric patients. Our first study is focused in the U.S., primarily with sites that have had psychedelic trial experience. As we move into the second study, there are fewer and fewer of those, of course. As we move into Europe, there's less experience there as well, surprisingly. We are having to train sites and train investigators and train session monitors. I think that's normal for really any novel paradigm of treatment.
Got it. This could be potentially life-changing for some people, right, in terms of a treatment. With that as a background, if you have people in your phase III trial who respond very well, what prevents them from going in for another kind of psychedelic experience that is outside of the clinical trial purview? How are you accounting to control for that?
I would imagine if patients have responded very well, they wouldn't be seeking more treatment. I'd say that patients that have not responded in our studies get a chance to get retreated. They're incentivized to come back to the center and get retreated. Anyone that obviously has a psychedelic experience during the one-year follow-up would be excluded from that data. We're not seeing that. We're not really seeing that patients are hunting these compounds down. They are excited about the potential to change the course of their disease. We've been treating depressive symptoms only for the last 40 years or so since the advent of Prozac, really putting Band-Aids on depression. Many patients are still walking around with some level of depression, this emotional blunting. For the first time, we think we're seeing a change in the course of disease. If you can remove a patient's depressive symptoms for a year at a time from just a couple of doses, then something is happening in their biology that leads to that durable effect.
Right. In your Phase III programs, do you have a target % of treatment-naive patients who've never had a psychedelic experience before?
Yeah, that was an explicit conversation with the agency. They're eager that we pursue a largely psychedelic-naive population, again, to deal with expectancy bias. There's already enough expectancy bias in studies when patients know they're getting a drug, they expect to get better. It's pretty hard to hide a psychedelic experience. The agency would like to see our population reflect no more than experience in the general population, which is about 15% or so.
Okay. I thought it was really interesting that you actually had a placebo response of about a day or so in your Phase II trial. What might explain that?
I'm not surprised to see a placebo response. We see placebo responses in depression studies all the time. Patients expect to get better when they take something in a clinical trial. When you're dealing with a psychiatric disorder, you're particularly going to see placebo responses. What's nice about the placebo curve, though, is that we saw a rapid response. For a number of days, we saw a reduction in MADRS scores of about eight points, so meaningful. By the primary endpoint at day 21, that had reverted back to baseline and was at about three points. It kind of gives you exactly what you want to see that we don't normally see in depression studies, which is a placebo response that fades away and doesn't impact separation for the active at the primary endpoint.
When you report your first Phase III trial, what would you consider a good result and what would you consider clinically relevant for this type of approach?
Clinically relevant is likely two, three points of reduction in the MADRS scale. I think expectations are higher for these treatments because of the nature of them. They take some investment from the patient, of course. That said, we would fully expect to see some reduction in effect size going from phase II to phase III. Bearing in mind in phase II, we're seeing 75% remission rates and 14 points separation from placebo on the MADRS scale. Even if we lost half of the effect size and delivered seven points of benefit on average, that would be likely twice as effective as anything that's approved today. Still very clinically meaningful.
Hypothetical question, assuming you're not the CEO of Cybin, but a salesperson who's eventually selling these products. If you had a psychedelic versus a non-psychedelic with the same efficacy, but the psychedelic had a lot more durability, would you still consider that a win from a commercial standpoint?
I guess it depends on the nature of the non-psychedelic treatment, the adverse events, and whatever comes along with it, and the experience of dosing with it. It's hard to make the comparison. I would expect that if you reduce the doses of these compounds to non-psychedelic levels, sub-psychedelic levels, you're still likely going to see some level of neuroplasticity, but not to the scale that we're seeing with these higher acute treatments. It's that window that appears to allow patients to rewire their patterns of thinking and break out of those negative spirals of thinking. Once they've done that, they can't unthink that, so once they've stopped thinking negatively about the underlying cause or event that's driving their depression, it's very difficult to then revert back to that negative pattern of thinking, which is why we think that there's just such good durability from these treatments.
The questions I get around these compounds, around trial data, are generally never around will the compound work or not. It's like how good will the compound be in the trial? Given that type of investor thought process, what's the risk here? This is a neuropsychiatric trial and they are prone to risks that we all know about. How are you thinking about managing that risk?
Look, I can greatly agree. I think we've known for a number of years now that all of the molecules being studied in this space are active. They work. Our job has been to design a drug, a compound, a dose level, a dose protocol that delivers efficacy and durability. I think we've done that with our, very happy with what we've done with our CYB003 program. We know exactly what dose, we know how many doses, and we know the protocol. In our phase III program, we're simply repeating what we did in phase II. I see other programs out there that are clearly showing efficacy, but we don't really know what the protocol is or the final dosing is. They're going to make changes in their phase III programs compared to what was performed in phase II, which is always risky.
I don't think the task has been to demonstrate efficacy. It's been to develop something that could be a prescribable treatment.
Have you had any engagement with payers or is it too early for that? If you have, what's their tone been? What's been the main pressure point as to why they may not want to pay for these things?
Very positive. Yes, we've had some interaction with payers. They clearly see CYB003 as a third-line option. Given the potential dosing protocol of two doses a year, they would see it naturally positioned ahead of esketamine, which is 26 doses a year just for convenience. Think about that's about 50-plus reimbursement events in the course of a year compared to two to four. It takes the burden off of the clinics and the centers as well as the payers. MDD isn't really on payers' radar screens in terms of a third line, in terms of cost. First and second-line treatments are largely generic or inexpensive, and patients getting third-line treatment are fairly small numbers. Esketamine at the moment, I think the sales run rate is about $1.7 billion. It will clearly be a $3 or $4 billion drug in a few years.
We're only talking about 50,000, 60,000 patients, and at these kind of price levels, 100,000 patients would be a very successful compound. These aren't $250,000 a year oncology patients. They're not economically really on the radar screen.
Right. I do want to get to CYB004. You've said that you're going to finish the trial soon. When can we expect to see the top-line data on that?
Yeah, it's been a little bit slow, this study, primarily because it's a small study. We've been competing for space, resources, and staff with many other large studies. There are seven or eight large psychedelic studies going on right now, all trying to use the same centers. It's been a little bit slow, but we focus on quality of patients. We're pretty much fully enrolled at this point. I think we'll do the last dosing this month. It's a 12-week blinded period. We'll have data 12 weeks after that, towards the end of the year.
Okay. Within GAD, we've got kind of a flag post now that MindMed has data with LSD, MM120 compound. How are you thinking about how your compound should perform in a phase II relative to what we've seen from a competitor?
First of all, great to see something in this class being effective in GAD. That gives us some good proof of concept. We also, of course, have data from an earlier DMT program where we studied MDD patients and also took anxiety scores. We're pretty confident this will work in GAD. It's also, DMT is a pretty intense experience. LSD and psilocybin are somewhat similar in experience, and they have peaks and troughs of intensity over a number of hours. Patients can sometimes resist the effects to some degree, which is why with psilocybin, a second dose helps because patients know what to expect. DMT is fully immersive as compared to LSD. The treatment duration is about 90 minutes as well.
If we can deliver at least equivalent efficacy in a 90-minute experience versus a 12-hour one, then clearly that's beneficial for patients and a lot more convenient for clinics and providers.
It comes down to time in the clinic on that one.
I think it comes down to time in the clinic when you're comparing 90 minutes to 12 hours. If you're comparing 2 hours-4 hours , then I think other things start to come into play, like tolerability, the experience itself, durability starts to then become important. Ninety minutes to 12 hours, that's a big difference. I think even if there was less durability, which I'm not expecting, but even if there was, perhaps patients would be more willing to come back in repeatedly rather than for a single 12-hour experience. I think it is important there. I think 12 hours is just at the point where it's somewhat impractical, most of these sites and clinics that have eight-hour shifts.
I think there's a question there, sir. No problem.
It won't. Still not getting the importance of 12 hours to work. Big shift, huge shift in there, creating more anxiety for some. I mean, to find the perfect... How do you find that perfect measurement of doses together? You're right at that cutting edge. What's going to bring you over that? Is it the perfect dosing and the perfect timing? The second standard? I mean, just try to biodiversity? How does what is that? Is it that you got your cloud?
Yeah, we've done more work on DMT than any other company on any compound in the sector. We've done five studies with DMT. A lot of work on the PK/PD relationship. DMT is not all the way bioavailable, so trying to figure out how to get the right PK curve and the right rhythm of administration, not wanting to blunt that curve because you want a peak experience and not a slow experience. We think from all of the work we've done with IV infusions, bolus, intramuscular, subcutaneous, inhaled, that we've got the right profile. What we see is an intramuscular injection that we're studying, so a shot in the deltoid. It's very easy to give. A tech could give the shot. We see peak effects in two to three minutes, so pretty quickly, which for anxiety patients is ideal.
You don't want them sitting around for an hour waiting for something to kick in and having remorse. To get past that peak fairly quickly, the rest of the tail of the PK curve is where we think the psychological work happens, and that's about 90 minutes. It's a guess, frankly. We're trying to, I mean, we've been working with the duration on the compound to extend the experience. DMT typically is a five or ten-minute experience, very intense up and down. We thought that that short, intense experience was probably not the best, not optimal for clinical use. We didn't want it to be a four-hour experience either. We get patients up there quickly. They're in there for about 90 minutes, and our hope is then that's a balance of intensity and enough time that the effects will be durable. We'll see when the data come.
I'll squeeze one in before we're out of time. You've been in biopharma for some time now. You've been through mergers, acquisitions, all of that. We've seen some recent news come out that maybe a large biopharma is contemplating an acquisition of a company that involves a molecule like this. What have been your discussions with Strategics like? Is there some kind of de-risking event that needs to happen either from a molecule safety or a clinical stage perspective for Major Pharma to step in?
Yeah, I've definitely seen the interest evolve over the last five years or so. There's obviously interest from Strategics. There's been nothing new like this in psychiatry that's going to break through for 40, 50 years. It's an opportunity that they just can't miss out on. We're past the point now where there's any questions about efficacy, of course. We went through a phase where they were trying to figure out how to commercialize these compounds and some of the challenges around administration. The success of esketamine has gone a long way to dispel some of those concerns. I think if I was sitting in their shoes in a business development team at a large pharma company, I'd be looking at this small sector and I'd want to buy the best asset. Right now, not all of the data is out.
I think our CYB004 data readout will be the last one amongst the publicly traded companies. Once all of the data is on the table, you might start to see some movement. There's definitely interest. It's interesting over the last several months where we've had a few Phase II readouts and you're starting to see some differentiation between assets, not all the same in terms of efficacy and durability. I think it's just a matter of time. As is usual in these cases, you see one transaction and then you see three or four. Time will tell.
Great. Thanks for waiting for that time. Thanks again, Doug.
Great.
Thank you.
Thanks, everyone. Take care.
Thank you. Great.