Definium Therapeutics, Inc. Common Shares Study result

Please proceed. Hello, everyone, and thank you for joining us this morning.

I'm joined today by our Chief Medical Officer, Dr. Dan Karlin, our Chief Financial Officer, Brandi Roberts, and our Chief Commercial Officer, Matt Wiley. We could not be more excited to be here with you this morning to share the top-line results from PANORAMA, our third pivotal study of DT120 ODT 100 micrograms and our second phase III study 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 discussion of the risks and uncertainties associated with these statements, including the risks described in our most recent annual and quarterly reports.

Today's results mark an important milestone for Definium in our DT120 program, as we have now replicated the unprecedented results reported last month from VOYAGE, our first pivotal study of DT120 in GAD. Having delivered three positive phase III studies across GAD and MDD over the past 12 weeks, our confidence in the transformational potential of DT120 has never been higher. We believe DT120 represents a highly differentiated profile with the potential to redefine standards of care and become a best-in-class therapy across two of the largest and most impactful indications in psychiatry. I'd like to thank our study participants, investigators, partners, and the incredible Definium team for making all of this possible. We are deeply appreciative and humbled by the commitment, trust, and belief in our shared vision. Only together could we have arrived at this remarkable moment.

At Definium, we have an ambitious vision and believe 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 anxiety, depression, and other mental health disorders. The burden that GAD places on patients, families, and society is enormous, impairing daily function, productivity, and quality of life, and that burden continues to grow. The prevalence has more than tripled since the early 2000s, and GAD is now estimated to be experienced by 10% of the U.S. adult population. Promisingly, we've entered a new era of far greater awareness and openness around anxiety and its impact on people's lives. Despite this need and awareness, there hasn't been a new drug approved for GAD since 2007.

That is not because of a lack of effort. Over that period, roughly a dozen drug candidates spanning numerous mechanisms have advanced into late-stage development. Nearly all have failed, none have been approved, and most have been unable to demonstrate 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 PANORAMA results we are sharing today continue to change that picture. 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. PANORAMA marks our third pivotal readout for DT120 this year and our second pivotal readout in GAD. As with our EMERGE and VOYAGE readouts, PANORAMA met its primary and all key secondary endpoints with a high degree of statistical significance.

Consistent positive outcomes across three complementary studies further strengthens our confidence in DT120's potential and the broader opportunity ahead. In PANORAMA, DT120 ODT 100 micrograms showed a 5.1-point placebo-adjusted improvement over placebo at the week 12 primary endpoint with a P value of less than 0.0001. This efficacy was rapid, with a 5.3-point placebo-adjusted improvement on the HAM-A at week one and a 0.8-point placebo-adjusted improvement on the CGIS at day two, both with P values also less than 0.0001. DT120 was well-tolerated with no new safety signals identified, including no suicidality signal. We continued to observe efficient and predictable treatment session dynamics with an average time to clearance on the structured end of session checklist of 6.2 hours and 94% of participants clearing by hour eight.

PANORAMA included a DT120 ODT 50 microgram arm, which served as a functional control but was not powered for or assessed in pre-specified statistical comparisons. The 50 microgram dose produced a 3.6-point improvement over placebo at weeks four and 12, approximately 50% and 29% less than the 100 microgram dose. The results from both VOYAGE and PANORAMA are closely aligned with the dose response model generated from our phase II-B study. It is also worth noting that as in phase II, at both the 50 and 100 microgram doses of DT120, over 90% of participants correctly guessed their assignment to drug, supporting the conclusion that the dose response observed is a real treatment effect and is not attributable to functional unblinding. To further emphasize this point, across studies, the 100 microgram dose has consistently exceeded our efficacy target of a placebo-adjusted improvement of at least four points on the HAM-A.

The 50 microgram dose has not. At the same time, the adverse event profile was similar across the 50 and 100 microgram doses, and the median time to end of session clearance was six hours for both. In our view, these results decisively settle the question of dose selection and clearly support the advancement of DT120 ODT 100 micrograms. To put these results in perspective, we have now consistently shown that DT120 100 micrograms delivers a large effect that stands out against the current standard of care in GAD at both week 12 and at earlier time points. In summary, in a disorder with high prevalence, high burden, high unmet need, and no innovation in decades, a single dose of DT120 has consistently shown a rapid and durable effect with a magnitude that is considerably larger than the drugs approved today.

We could not be more excited about what this could mean for patients and the potential to redefine what they can expect from psychiatric care. With that, I will turn the call over to Dan Karlin to walk through the results in greater detail.

Thanks, Rob. Today is another important milestone for DT120 and for patients living with GAD. As a psychiatrist, I have seen firsthand the profound impact that chronic anxiety can have on every aspect of a person's life. While existing treatments can help some patients, many continue to struggle with persistent symptoms or wait weeks or months to experience meaningful relief. The positive VOYAGE results we reported in August marked a major step forward, and today, PANORAMA provides further confirmation of DT120's potential in GAD. Consistent findings across two phase III trials are especially meaningful because they reinforce the reproducibility of the efficacy signal and the strength of the overall clinical profile. Let me begin with the study design. PANORAMA is comprised of two parts. Part A, a 12-week randomized double-blind period, and Part B, a 40-week extension period with opportunities for open-label treatment.

As in our prior studies, participants were tapered off background antidepressant and anxiolytic medications prior to enrollment. Notably, as with our entire development program, we did not provide any psychotherapeutic intervention as a part of the study. In Part A, 245 participants were randomized in a 2 to 1 to 2 ratio to receive a single dose of DT120 ODT 100 micrograms, DT120 ODT 50 micrograms as a control, or placebo. The primary endpoint was the change from baseline in HAM-A total score at week 12, assessed by independent central raters, blinded to treatment assignment and visit number. In Part B, participants continued to be followed for an additional 40 weeks and complete regular efficacy assessments.

Participants who meet the pre-specified treatment threshold of HAM-A score of 16 or greater become eligible to receive an open-label dose of DT120 for up to four open-label treatments over the course of the study. The treatment threshold of a HAM-A score of 16 corresponds to the cutoff for moderate illness and reflects an increase in symptom burden such that participants are experiencing functional impairments. As in VOYAGE, we selected this threshold prospectively as a clinically meaningful marker for when additional treatment may be warranted. We randomized 245 participants, 96 to DT120 ODT 100 micrograms, 52 to the DT120 ODT 50 microgram control, and 97 to placebo. All randomized participants were included in the intention to treat population. Approximately 90% of participants completed Part A. Participants entered the study with high disease severity as reflected by baseline HAM-A and CGIS scores of 28 and 4.7 across treatment groups.

These values placed participants firmly within the severe range of anxiety. Demographics and baseline disease characteristics were generally balanced across treatment groups. We observed prior psychedelic use consistent with what might be expected in a broad GAD population, with 14% of participants reporting any previous psychedelic use and only 7% reporting prior LSD use. Importantly, these characteristics were balanced across treatment arms, supporting the comparability of the study groups at baseline. Despite a limited number of available treatment options, this population had substantial prior treatment experience and a high disease burden. Half of participants reported receiving 2 or more prior treatments for GAD, and three-quarters of participants had severe anxiety at baseline. On average, participants had been diagnosed with GAD for approximately 9 years and reported experiencing anxiety symptoms from nearly 18 years prior to enrollment.