Definium Therapeutics, Inc. Common Shares Study result

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Hello, everyone, and thank you for joining us this morning. I'm Rob Barrow, Chief Executive Officer of Definium Therapeutics, and I'm joined today by our Chief Medical Officer, Dr. Dan Karlin, and our Chief Financial Officer, Brandi Roberts. We could not be more excited to be here with you this morning to share the unprecedented top-line results from VOYAGE, our first pivotal study of DT120 ODT in generalized anxiety disorder, or GAD. Before we get started, please note that on today's call, we'll be making certain forward-looking statements. We encourage you to review our SEC filings for a discussion of the risks and uncertainties associated with these statements, including the risks described in our most recent annual and quarterly reports. When we presented our EMERGE results in June, I noted how rare it is to have an opportunity to share truly transformational data.

That is even more true today when we have the privilege of sharing such findings for a second time in a row. As with our MDD results, we believe the findings being presented today have the potential to redefine what patients can expect from the treatment of GAD and position DT120 as a potentially best-in-class product across two of the biggest and most impactful indications in psychiatry. I'd also like to take a moment to thank our study participants, investigators, partners, and our incredible team at Definium for making all this possible. We are deeply appreciative and humbled by your commitment, your trust, and your belief in our vision. Your efforts have brought us to this remarkable moment, and most importantly have brought us one step closer to making our dream a reality.

We have an ambitious vision at Definium and a belief that profound change in psychiatry is truly possible. We set a high standard for DT120 to demonstrate that a single supervised dose can deliver rapid, robust, and durable efficacy and offer new hope to the tens of millions of people living with depression, anxiety, and other mental health disorders. We've always believed there's a particular need for innovation in anxiety, and we've remained steadfast in prioritizing GAD as a lead indication for DT120. GAD places an enormous burden on patients, families, and society, impairing daily function, productivity, and quality of life. That burden has grown dramatically. Prevalence has increased from roughly 3% in the early 2000s to approximately 10% today. At the same time, we've entered an era of far greater awareness and openness around anxiety and its impact on people's lives.

But our ability to treat it simply hasn't kept pace. There hasn't been a new drug approved for GAD since 2007, and that's not for lack of trying. Over that period, roughly a dozen drug candidates spanning numerous mechanisms have advanced into late-stage development. Nearly all have failed, with most unable to demonstrate any meaningful improvement over placebo. That long period without success has also left the field without a modern benchmark for what truly compelling efficacy in GAD looks like. We believe the unprecedented VOYAGE results we're sharing today change that. They represent the promise of real progress for patients with GAD and further reinforce the potential of DT120 to help usher in a new era of psychiatric care. VOYAGE marks our second pivotal readout for DT120 this year and our first pivotal readout in GAD.

As with our EMERGE readout, VOYAGE met the primary and all key secondary endpoints with a high degree of statistical significance. Seeing consistent positive outcomes across two large phase III studies and two adjacent comorbid and highly prevalent psychiatric disorders further strengthens our confidence in the potential of DT120 and the broader opportunity ahead of us. To briefly summarize some of the key points, the primary endpoint demonstrated a 5.4-point placebo-adjusted improvement on the HAM-A at week 12, corresponding with an effect size of 0.81 and a P value of less than 0.0001. To our knowledge, this is both the largest nominal change and largest standardized effect size ever observed in a pivotal study in GAD. This efficacy was also rapid, with a 7.7-point placebo-adjusted improvement on the HAM-A at week 1 and a 0.8-point placebo-adjusted improvement on the CGIS at day 2.

DT120 was well-tolerated with no new safety signals identified, including no suicidality signal. We continue to observe an efficient and predictable dynamic of treatment sessions with an average time to clearing the structured end of session checklist of 6.4 hours and over 90% of participants clearing by hour 8. The strength of the DT120 program as a whole is anchored in consistency. DT120 has demonstrated a large and consistent effect size with a Cohen's d of over 0.8 in each study. Using the standardized effect size is especially useful in looking across studies, as changes in study design, population, baseline characteristics, and other study dynamics can impact nominal scores and make comparisons of nominal scores difficult.

The fact that this extraordinary effect size has now been shown across three studies and two indications gives us a high degree of confidence in the robustness of the efficacy and continues to build the case for a potential multi-indication practice-changing profile. And finally, to put all this in context with the broader treatment landscape, DT120 has now shown in two studies in GAD an effect size of 0.81, and that is more than double the standard of care. To reiterate that, in a disorder with high prevalence, high burden, high unmet need, and no innovation in decades, a single dose of DT120 has shown a rapid and durable effect with a magnitude that is more than twice as large as the drugs approved today. With that, I'll turn the call over to Dan, who will walk through the study results in greater detail.

Hey, thanks, Rob. Today is a special day. As a psychiatrist who has treated many patients with GAD, I have seen firsthand how difficult it is to help these folks find relief from the complex interplay among the emotional, cognitive, and somatic experiences of the illness. In our studies, these are measured using standardized assessments like the HAM-A, but in people's lives, they produce a nearly constant onslaught of distressing internal experiences. Medications available today may tamp down one aspect of someone's experience of anxiety, but often leave the others untouched. What we've seen in phase II and now in VOYAGE is that DT120 provides a different kind of relief in those who benefit from it, a relief that isn't bound to one domain of the illness. I'm excited to share further specifics of the VOYAGE results with you.

As Rob highlighted, the study demonstrated rapid, robust, and durable improvements in anxiety, along with a favorable tolerability profile and efficient treatment session dynamics. Let me begin with the study design. VOYAGE is comprised of two parts. Part A, which is a 12-week randomized, double-blind, placebo-controlled period, and Part B, which is a 40-week extension period with opportunities for open-label treatment. Participants were tapered off background antidepressant and anxiolytic medications prior to enrollment, and no psychotherapeutic intervention was provided as a part of the study. In Part A, participants received a single dose of DT120, 100 micrograms or placebo, and were followed for 12 weeks. The primary endpoint in the study was changed from baseline in HAM-A total score at week 12, assessed by independent central raters who were blinded to treatment assignment and visit number.

In Part B, participants continued to be followed for an additional 40 weeks and completed regular, blinded, centrally rated efficacy assessments for a total of 52 weeks of blinded efficacy assessments. Each time a participant meets the study's pre-specified criteria for retreatment, they become eligible for an open-label dose of DT120 for a total of up to four open-label doses. The retreatment threshold in Part B is a HAM-A total score of 16 or greater, which corresponds to the cutoff for moderate illness and is characterized by a meaningful increase in disease burden, functional impairment, and disability. From the outset, we picked this cutoff as the target for treatment because we thought it was both achievable and meaningful to patients. A total of 214 participants were randomized in the study, with 107 participants in each arm. Approximately 90% of randomized participants completed Part A.

The demographics of participants enrolled in VOYAGE were generally balanced between treatment groups and representative of GAD patients commonly encountered in clinical practice. Participants entered the study with a high degree of disease severity, as reflected by baseline HAM-A and CGIS scores of 27.9 and 4.6 across the groups. These values place participants firmly within the severe range of anxiety. We also observed past psychedelic exposure consistent with the background range of use in the population we would expect based on epidemiological estimates, with 21% reporting any prior psychedelic use and 9% reporting prior LSD use. Another way to understand the enrolled population is to look at the distribution of disease characteristics at baseline. Three-quarters of participants were characterized as severe on the HAM-A, with a score of 24 or higher, and the remaining one-quarter categorized as moderate with a HAM-A of 20, the minimum for study enrollment to 23.

Despite a limited number of treatment options, we observed a population with characteristic prior treatment experience. 36% of participants reported receiving two or more prior GAD pharmacotherapies. One particularly notable aspect of the experience of GAD for these participants is the time since diagnosis and time since symptom onset. On average, participants in the study reported experiencing GAD symptoms for approximately 24 years at the time of enrollment, and on average, received their GAD diagnosis about 12 years prior to enrollment. This speaks to both the long delays in diagnosing GAD and the reality that GAD is a chronic, lifelong condition that leaves the folks who suffer from it to do so without diagnosis or explanation for many years, and in cases like our enrolled population, to continue to not find relief even long after diagnosis.