Definium Therapeutics, Inc. Common Shares TD Cowen 6th Annual Novel Mechanisms in Neuropsychiatry Summit

Yeah, absolutely. It's great to be here. Thanks so much for having us. We're incredibly excited to be in the position we're in now. Through this summer, over the course of just 10 weeks, we had three phase III readouts, two in GAD with VOYAGE and Panorama, and one in MDD with EMERGE, which read out first, of course. All three of these studies had very similar designs, which is that they had a primary observation period, which was a 12-week double-blind randomized period, and then they all had a Part B, which is ongoing for all these studies, which is an additional 40 weeks of observation with opportunities for open label treatment. So in total, these are year-long studies.

What we were able to do, though, was read out those primary periods and provide a little bit of data on the Part B as well for the folks who had gotten through six months in the Part Bs. What we saw across these studies is that we were treating people who were quite ill. We had people starting well into the severe range of the relevant scales. In GAD, we measured the Hamilton Anxiety Rating Scale. In MDD, we used the MADRS, the Montgomery-Åsberg Depression Rating Scale. We had folks starting on the HAM-A at around 28 in this study, which is again, well into the severe category. On the MADRS, we had folks starting at just about 35. So again, quite sick with MDD and GAD.

Notably, in each of those indications, the opposite scale, so in the anxiety patients, the MADRS, and in the depression patients, the HAM-A, we kept that pretty suppressed. We wanted to really demonstrate that we were able to treat specifically the disorder in question so that there would be no question that, oh, in the anxiety patients, did you just make their depression better, and the depression patients- Right.

Did you just make their anxiety better? By doing that, we actually raised the bar quite a bit for ourselves, because when you have people with comorbid symptoms, it can be a bit easier to move these scales because the scales, of course, have a lot of construct overlap. But we segregated out these patients into these discrete populations, I think very effectively. What we ended up being able to do was with a single treatment of DT120, with no adjuvant additional therapy, no psychotherapy, no other anxiolytics or antidepressants, we were able to move the primary endpoint in each of these populations between 5 and 8 points. We had in VOYAGE, a 5.4-point change versus placebo. In PANORAMA, a 5.1-point change versus placebo. In MDD, on the MADRS, we had an 8.1-point change versus placebo.

All of these measured, in the case of GAD, 12 weeks after the single treatment, and in the case of MDD, 6 weeks after the single treatment, which is pretty standard for MDD studies. All of those were highly statistically significant with a p-value of less than 0.0001. Again, we are talking about single treatment day, no additional treatment in the interval, and efficacy being demonstrated 6 to 12 weeks after that single treatment.

Yeah. The phase II, we saw nearly 50% remission rates, which again, we weren't expecting to see.

It's incredibly unprecedented. While of course, we'd always like to see a higher remission rate, we'd like to see everyone who gets the drug be in remission with a single treatment, that would be great, that's not a realistic outcome for these disease states and is not something that we could even really hope for.

What we see with the response and remission rates in phase III, though, is remarkably strong and more than can reasonably be expected from existing standards of care, particularly when you look at the gap between the placebo response and remission rates and the treatment arm response and remission rates.

When you're looking at odds ratios of nearly 4 across that gap between response and remission in VOYAGE, and 3 to 4, 2.5 to 4 in Panorama, we're still quite pleased with this, and we think that this represents really clinically meaningful differentiation from the existing standards of care. When we look across these different studies, why is there some degree of wobble? That is just the nature of studies. There's the reason you do more than one study in phase III programs, and that's to make sure that you're accommodating the sort of artifacts of the individual study and the sites that you're using. The one big difference, though, of course, between VOYAGE and Panorama is that Panorama included a 50 microgram control arm.

Now, we enrolled that at half the rate that we enrolled the full dose in the placebo arms, and it wasn't an arm of analytic interest. But what we were able to use that arm to do was to say that if someone felt the effects of the drug, and of course, there are transient effects of the drug that people feel, they wouldn't know that they were in the arm of analytic interest or not. So it existed purely to confound the understanding of people as to which arm of the study they were in.