All right. Thanks, everybody, for joining. Thanks especially to Max for joining. Happy to be here with Dan Karlin, Chief Medical Officer of Definium Therapeutics. I am sure folks know the story well, but super topical time for Definium, so maybe I will just have Dan briefly set the stage on what is coming up from you guys from an update perspective, and then we will dig into it. Thanks again. Good to see you.
Yeah. It is great to be here. Thanks for coming, everybody. Dan Karlin, Chief Medical Officer of Definium Therapeutics. I am a psychiatrist by training. Still practice a tiny little bit of psychotherapy, and I am also trained in addictions and clinical informatics. I have been with the company for just about six years, working alongside Rob Barrow, who is our CEO, to build now to 194 people as of Monday, and we are adding like 10 a week, which is a bit alarming in certain ways, but really exciting to be at this point. We are developing DT120, which is our lab code for our LSD formulation, which is a pharmaceutically optimized version of LSD in a Zydis oral dissolving tablet formulation.
We have now read out three phase III studies with DT120, two in GAD and one in MDD, and we did that just about 10 weeks over the summer, which was made for not the most relaxing summer in most of our lives, but extraordinarily reassuring about the strength of the drug. On the back of those three positive phase III readouts, we will be submitting an NDA to FDA in the first half of next year, and we intend to find a path to submit for both GAD and MDD. So that is where we are at. We also, just recently, as of yesterday, announced that our second molecule in clinical development, which is DT402, which is our R, the right enantiomer of MDMA, which we are developing as a daily drug for autism spectrum disorder.
We announced that our EOSE study, early signals of efficacy, had read out as positive, and that will enable us to continue the development of that drug.
That is one of my two favorite enantiomers of MDMA.
Well, you know.
God, with you up here, I have to hit you with the nerdiest joke possible.
It is really actually kind of an interesting thing, right? Stereospecificity in neurobiology is wild, and the two enantiomers of MDMA behave really differently.
Yeah.
We picked this one for a reason, but the level of differentiation between the enantiomers is something that we could nerd out about for a while.
Okay. All right. We'll definitely save some time to do that. Obviously, the update around the NDA filing is around the corner. You guys have talked about this base case of filing the two together, and I think there is some regulatory precedent and context for sort of a second indication having one study, but these are coming together. Most of the time, people with MDD have two pivotals. What's sort of the current thought process or confidence level that this is a realistic base case still?
Yeah. I mean, we've been engaged with FDA through this entire process, and the evidence for that, like our fingerprints are all over the psychedelics guidance. We made choices, we brought FDA along on those choices, they gave us some direction that they wanted to see, and all of that ended up being more or less enshrined in what is now the sort of standard for conducting these studies. From the outset, we made sure to bring them along on this journey. How these filings look exactly is still under discussion, right? The main goal with the filings is we come out of the far side with both labels, and FDA's got a lot on their plate.
They are more understaffed than they've been in quite a long time because of things that happened at the beginning of the current administration, but they are really enthusiastic, a weird kind of framework, but they're enthusiastic to regulate these drugs and to do it in a way that has exactly the same objective we do, which is get drug to patients in a way that's maximally safe and efficacious. They see that shared responsibility as very much an opportunity for them, and I think that's a change from, say, five years ago when it felt much more like they saw their objective as protecting people from these drugs.
Yeah, to slow this pace down and make sure nothing bad happens.
Yeah, can we make sure nothing bad happens?
Yeah.
There's still, there's certainly, none of us want to see bad things, but the framework in psychiatry is so often sort of focus on the potential risk then maybe there's some benefit. It's like, can you imagine if you're having a conversation with an oncology company and someone's like, "Well, someone might be hurt by that drug." It's like, well, these are diseases that truly hurt people, right? That kill people. The recognition of that, both at a regulatory level and a societal level, you see this in the current political process with the conversation around veterans and their mental illness. A Veteran a day dying of mental illness, right? This is not something that has really penetrated the sort of cultural consciousness in this way before.
Currently, you can feel that in the interaction with FDA, that they are really focused on the potential to be the regulators in the seats when a massive change in a field hits.
Yep. Okay. You guys will update us soon, and I guess you've decided to wait for the meeting minutes from whenever this meeting has or hasn't taken place. Is that the thought?
Yeah. We've treated the relationship with the respect I think it deserves, which is to say that we don't go out in public and guide to anything until we are sure that we are entirely aligned on exactly where they stand. I think that is one of the reasons we're in the place we are with them is because we don't put that kind of pressure on them, especially in the current political climate where that could be a real challenge, right? There's a lot of attention on the category, and so we wouldn't say anything about an engagement with them until we were absolutely certain that we were aligned.
Yep. Okay. You guys are pretty firmed up that if the FDA wants another MDD study, you will forge ahead full speed with GAD alone to start as an NDA. Is that right?
Oh, absolutely. I mean, there's no question that what we have right now for GAD is more than adequate for a submission in any situation. There's been a lot of talk about one study versus two study approvals. We have the second MDD, our fourth phase III, second MDD running now. That's enrolling really well. So, if there's some reassurance from additional MDD data or the ability to say, "Yes, this is a positive study," we're able to do that on the timeframes we've discussed.
Yep. Do you want to just talk about the design of that MDD study? Is there any nuance there or any difference in the types of patients you've selected for that study versus the prior overwhelmingly positive readout you had?
Yeah. In each of these indications, GAD and MDD, we've run extraordinarily similar studies, nearly identical studies. The only difference is that in each indication, we've run one head-to-head study, two arms, placebo versus 100 micrograms of DT120. In the second of each indication, we have added a 50 microgram control arm, and that arm enrolls at 50% of the numerical target for number of participants and exists only to confound participants, right? So there's this question of, might there be a role of participants knowing they got drug and therefore feeling better or believing that they got placebo and therefore not feeling better and underrepresenting the placebo effect? We think that's been pretty overblown in the category, in part because of the modern history of the drug development process with these drugs.
Nonetheless, including a lower dose control arm, one that is quite perceptible to participants, confuses participants in the other groups as to what their allocation is. So we did this more in service of sort of the idea of complementary study design so that we can say across indications and across control conditions, we repeatedly see about the same effect. And all of that serves to say that the effect we measure in these studies is representative of real drug effect, not some artifact of study design.
Yep. Okay. Very good. Those updates are coming soon. Anything else that is on your mind with DT120 over the next year? Obviously, you have the NDA, which is like an enormous undertaking. What are kind of the steps there to, I guess, getting that in?
A lot of writing and reviewing and making sure that we're making the arguments that we want to make. The data are in the bag at this point. One interesting thing about the current FDA is that they are clearly using modern analytic tools to directly look at the data. They have biostats. They get our data transfers in just structured data files, so they can do any analysis that they want. The big thing that we are still working, the kind of joke around the office after the summer was, "Okay, well, now it'll lighten up," which, of course, not at all the case because we are now running the Part Bs of these studies, which are the additional nine months of opportunity for open-label treatment. So we continue to observe folks, and we can give them up to four additional doses of drug.
We're running that as we speak, and while those are not necessary components for the sort of primary safety and efficacy claims, they produce an enormous amount of less constrained data. In essence, we have the opportunity with these studies to do a really well-controlled, tight 12-week observational period in the double-blind phase, and then in the extension phase, we do essentially a naturalistic treatment study. What we are seeing now is what it looks like when we give patients who were sick and maybe aren't anymore and physicians the opportunity to use the drug to treat folks if they're moderately ill or worse.
With those data coming in and the ongoing conduct of the studies along with ASCEND, and we're starting PTSD next year as well, plenty to do, plenty more data rolling in, but none of it really modifies what we've got in the bag already, which is really well-controlled evidence of efficacy and safety.
Yeah. The next sort of big regulatory decisions in this space will be with COMP360 and also maybe Usona's product. Just as it relates to DT120, how should investors be thinking about the REMS that comes out from COMP360 and also how the product is labeled as it relates to redosing? Do you feel like those are good benchmarks for what to expect with DT120?
Yeah. I mean, we have the same visibility into Compass and Usona that you all do, which is some into Compass, very little into Usona. We do not know what the output of their phase III was. We understand they did a single phase III. Beyond that, do not know. What I can say is that we formulated our development program very intentionally, and we had an end in mind from the outset. We started after Compass. We have caught up quite a bit in the interim. We started after Usona. The extent to which their studies were conducted with that same level of attention to the ultimate processes, there is sort of an analogous story here with SPRAVATO, which is that J&J developed SPRAVATO without a whole lot of attention to the end.
They imagined that this would be a drug that was used in ERs and inpatient units, and they did not pay a lot of attention to what happened around the administration of the drug in its development. They ended up with a REMS that was not particularly favorable to them. They had pushed for a 90-minute observation period. They ended up with a two-hour observation period. They had no argument to make based on data for a shorter one because they had not really measured it. We have measured everything, and we designed each of these studies with the intention of going and making very specific arguments with FDA, with an ad com, if it comes to that, for specific label and REMS elements. Whatever happens on the path to there with other companies, we know what we have, and we know the arguments that we intended to make.
We have front-run this, and I think FDA also sees this with the argument at both a agency level, but also at a political level, that these drugs are not the same, right? We can slap the psychedelic label on a lot of drugs, and people call ketamine a psychedelic, people call MDMA a psychedelic. LSD is absolutely defined as a classic psychedelic, so much so that the definition of classic psychedelic is usually 5-HT2A binding and LSD-like effects. We have got those. The outcome that Usona or Compass or anybody else has in the interim does not change our target and our intention, and we think that the agency recognizes that these drugs are, as much as they have certain features in common, are quite different and ought to be regulated based on their individual characteristics.
Yep. Okay. How do you expect the FDA to label and guide providers around the right way to think about redosing?
Yeah, the redosing paradigm is a really interesting one for these drugs, and in many ways, at least in psychiatry, unique. Every other drug, and in fact, every other intervention we have in psychiatry, has some sort of a repeat dosing schedule, right? That's just the nature of our drugs. They don't leave people changed. If you start someone on an SSRI, you got to give them a daily SSRI. If you stop it, maybe their episode of MDD will be over, maybe their life stressors will be different, but if everything else is the same, you stop an SSRI, they are as they were when you started it. Same thing for SPRAVATO. Even though the dosing is less frequent, it's twice weekly for a while, and then it's weekly for most people until they can't tolerate two hours a week of treatment.
With ours, it's different, right? We give people drug, there's no drug there the next day. By the next day, they're different and better in many cases, and they stay better for some period of time. We don't expect DT120 to be prophylactically dosed. We don't think that people who otherwise feel great should get this, and we have not and probably will never gather evidence to suggest that it can be used preventively. It's a pretty intense intervention. It's a full day of treatment. It requires human observers to make sure that folks are able to be safe and to generate efficacy.
What we expect at the end of all of this is that the label will reflect that the label will say, "Treat," and something like, "Use the minimum amount necessary to maintain people in a state of response." What we think will happen, and what we did in the clinical trials, was that when folks feel worse, they come back in and get treated again. What we've seen at least, and we showed this to the extent we were able when we did the top line readouts, is that when people have responded to drug, that predicts subsequent response, and when folks haven't responded to the first or second dose, subsequent doses generate pickup.
Makes sense. Okay, great. Do you want to talk a little bit about the autism program since you guys have some data? Maybe just kind of review for people, like, what was the actual biological hypothesis here at the outset?
MDMA is interesting. Like I said, not a classic psychedelic, does not generate the characteristic changes in perception and affect and cognition and behavior that classic psychedelics do. While MDMA has been used in session-based treatment, that is just the nature of the Lykos now Resilient treatment, it has got a long history as a psychotherapy adjuvant. You give someone MDMA at a pretty high dose, and psychotherapy works better. I was trained in psychotherapy by people who practiced in the 1980s and were doing exactly that, and they all kind of. Everyone who used it said, "It is great." You give people a pretty high dose of MDMA, you do psychotherapy, it is like skipping a dozen sessions. You just move really fast-forward.
That same characteristic that makes people more trusting, more interactive, more aware of their own emotions, more aware of the emotions of the person in the room with them, we have harnessed to treat the core symptoms of ASD. Specifically, social awareness, emotional awareness, communication. The idea here is analogous to psychostimulants in ADHD. People take drug. While the drug is on board, they feel in a different way. With ADHD, they are more able to attend to selective stimuli versus attending to everything in the room. With ASD, the thought was R-MDMA specifically, which is the serotonergic enantiomer. The R and S difference here is that S has a more amphetamine-like effect, so it is more of a stimulant. It is also associated with the toxicity of MDMA, whereas R is an enantiomer that generates social effects.
In animal studies, R-MDMA does not lead to more movement in rodent species, but it does cause them to choose to be in the side of the cage with another rat. So it generates this sort of social intention and social awareness in animal models. What we have now seen is that in people, over the course of a pretty intensive evaluation day, we brought people in and did assessments pretty much constantly over the course of a six-hour day. What we are able to see is that as the drug comes on and then has a plateau level of exposure, people are more able to attend to the emotions of others, they are more aware of their own feelings, and are more able to engage in social communication.
How do you think about the target population with this? Because I guess, one question some might have is, where is the population where the severity of the impairment is worth whatever the risk is of, I guess, I understand this is not the same as other psychedelics, but something that could have some side effects or safety risks down the road?
We are awfully attentive to potential safety risks, and we are doing a really robust set of tox studies to make sure that there is not any unknown safety risk. All drugs have side effects, otherwise they would not have effects. Where we are able to start anyway and where we have been with this drug is people with preserved language skills. Autism spectrum disorder indicates that there is a spectrum of the severity of the illness, and that ranges from people who have somewhat isolated challenges or differences in their social attention and communication, all the way to people who never had or subsequently lost language. For the purpose of these early studies, we are working with people who still have preserved language.
It makes us much more able to evaluate their internal state because they can report their internal state, so we do not have to do it based solely on observable behavior. We will continue to develop in that population and try to push further along down the spectrum to folks who have more profound deficits. The idea here being that unlike, say, an SSRI where take it daily, four, six, eight, 12 weeks to get benefit, this, like psychostimulants, will be a drug where people can take it and just get the benefits on the day they take it, right? If someone is engaging in a behavior where they think that they will be more challenged, they can take the drug.
That opportunity for as-needed dosing all the way up to daily dosing is something we are going to continue to observe, and certainly we would hope that there are two big things that we can hope for. One is that people who on the more profoundly challenged side of the spectrum sustain some benefit, and we would like to go see if we can find that. The other is that a lot like psychostimulants, while we do not think that a single dose will lead to profound lasting changes the way that we have seen with DT120, the idea that people who have better ability to engage in their lives, to be socially engaged, to connect with other people, will see trajectory change in their lives. We see that with psychostimulants, right?
Kids who are treated early in development have a different developmental trajectory because they are better able to engage in school and work and all the things that lead to sort of the life that they want. We are hopeful that we might be able to generate some degree of trajectory changes in people.
Do you want to talk about what you saw in this cohort of five patients? I guess maybe just to play the devil's advocate, like five-patient open-label cohort, for any subjective scale, you might see some level of benefit whether or not the drug is doing something. So in your mind, how sort of definitive is this in terms of actual proof of concept?
Well, so we designed the study. I mean, it's a really good question, and certainly this isn't like something we would take to regulators and say, "Hey, give us a label on this." The point of this study was we had a theory, and we wanted to, as quickly as possible and efficiently as possible with your money, make sure that that theory played out. We could have enrolled up to 20 participants in this study. We were watching the data in an open-label fashion, right? The open-label study has the advantage that you know everybody got drug and you can see the data as they come in. We would have run to 20 if we weren't sure enough that what we were seeing was a real enough drug effect to continue development.
So five out of five consistent drug effect that has a real relationship to PK and exposure, right? That's the advantage of a high-density day is we can literally see the drug effects come on as the drug is absorbed and then fall off as the drug is eliminated. So what we got from five was a strong and consistent signal that gives us the confidence to take this to the next steps.
What's the right endpoint for this?
End points in ASD, someone asked me this yesterday. Was it you? No? Okay.
I don't know what day it is, man.
Yeah. Oh, man. We talk about regulatory precedent in drug development for measures of disease, and in drugs with labels, there's real regulatory precedent. The regulators gave someone a label based on the outcome on a measure. ASD doesn't have drugs for its core symptoms. It's one of the reasons that we're operating there is we think this drug is truly different and really can help people with the core symptoms of ASD. While there's regulatory precedent of drugs not getting approved on instruments, and we will use those same instruments because we want to be able to show change on well-established instruments, we will be engaging with the agency over the course of this development program to really think about how best to measure life experience, really life function in folks with ASD.
How do you think about what is the theoretical safety concern with this enantiomer? Do you worry about serotonin syndrome? Is there anything there that when you push this that you could run into issues?
I do not so much worry about serotonin syndrome. The concern with MDMA is usually valvulopathy, so cardiac toxicity. That is, it is a soft...
Is that like the overlapping mechanism with fen-phen?
That is the hypothesis.
Right.
There is this hypothesis around serotonin and valve thickening and ultimately valve fibrosis. The association between MDMA in general, the racemic MDMA, and that is a soft one. It is epidemiological, it is retrospective, not super clear whether that is real. But we, like I said, we are doing everything we need to do to get ourselves comfortable with any risk for toxicity. And we think that the R enantiomer for much of the toxicity that has been attributed to racemic MDMA does reduce that across the board.
Okay. We covered DT120. I think this was a good way to dive a little bit deeper into the ASD program. Anything else you want to add before we wrap up, Dan? I guess maybe on the autism program, when will we get kind of the next updates on study design, your thoughts on next steps?
We are really excited to bring some study design concepts out into public view, and we're working through that now. The release of these data was kind of hot off the presses here. We are, as with everything else we're doing, we're spooling up to be able to do this in the way we've done everything else.
All right. Great. Thank you. Best of luck.
Thanks.