Disc Medicine, Inc. Common Stock Study result

Good morning and welcome, everyone. This is John Quisel speaking, CEO at Disc Medicine, and I'll be joined today by Will Savage, our Chief Medical Officer, and Pamela Stephenson, our Chief Commercial Officer. We're here to review the top-line results for the APOLLO phase III trial of bitopertin in erythropoietic protoporphyria, or EPP. Before we get started, a few preliminaries. I'd like to remind everyone that we will be making forward-looking statements, and these should be taken in context with respect to materials that we have filed with the SEC and have posted on our website. Additionally, bitopertin, selcodebart, and DISC-3405 are investigational agents and are not approved for use as therapies in any jurisdiction worldwide. Okay. As indicated in the press release earlier this morning, the top-line APOLLO data are very positive, achieving all primary and secondary endpoints with remarkably robust P values.

We will provide additional data in this call in a few minutes. First, I just want to step back and take a look at the big picture. These results mark a significant scientific advancement in EPP, demonstrating for the first time in the clinic that by targeting the production of the toxic metabolite protoporphyrin IX, or PpIX, that causes this debilitating disease, it is possible to achieve unprecedented improvements in important metrics of disease status. I expect these results will permanently change the focus of drug development in this field. Moreover, this combination of data and the numerous publicly documented patient stories suggest that bitopertin has the potential to fundamentally change the care and life experience of EPP patients. So very exciting results altogether. I want to express gratitude to everyone who helped make this possible.

The patients deserve the greatest thanks for entrusting us with their health and participating in our trials. Much gratitude goes to the advocacy groups and the doctors who've worked closely with us and to the academic scientists who described the molecular basis of this disease over decades of research. I also should say that we're grateful to those who stepped up with the capital to support these R&D efforts. We couldn't do this without any of you. I want to thank the team here at Disc that designed and executed a beautiful series of trials, taking the experiences that we learned in phase II and using those experiences to design a winning phase III trial. There was a lot of anxiety headed into this readout, and fair enough, these endpoints are extremely challenging ones. Our team showed up and delivered both operationally and statistically.

This was our first multinational phase III trial as a company, and I believe it won't be our last. We can now progress with great confidence as we begin to design and plan to execute on phase III trials for our pipeline programs in other severe blood disorders. We have a great team of drug developers here at Disc, and the future is exciting. Okay. Now turning to the top-line data, APOLLO met both co-primary endpoints and all secondary endpoints. We showed again that bitopertin targets the underlying pathophysiology of EPP, reducing whole blood PPIX, which is the biochemical driver of light intolerance and other complications of the disease. For the first time, we also showed unequivocally that bitopertin increased the amount of time patients on the trial were able to spend in light without pain while significantly decreasing the number of phototoxic reactions they experienced.

We also saw significant improvements in the time to prodrome and in patient-reported quality-of-life measures. Bitopertin has now been studied in over 4,000 clinical trial participants across its development history, and we saw a generally favorable safety and tolerability profile in APOLLO that was consistent with prior EPP studies. It is also worth noting that APOLLO was completed on a remarkably fast timeline, and nearly every patient elected to continue receiving treatment in the open-label extension portion. Collectively, these data provide compelling evidence of the clinical benefit of bitopertin for EPP patients. We look forward to resubmitting an NDA to the FDA by the end of this year, and that would set up a timeline where we would anticipate an FDA decision by mid-2027.

Now, we recognize that some of the attendees on today's call may be less familiar with EPP and XLP, so I'll turn it over to Will to provide a brief overview of the disease before he reviews the APOLLO trial design and top-line results in greater detail.

Thanks, John. I want to take a moment to talk about EPP and why new treatments for this patient population are needed so much. This is a serious, rare, debilitating, lifelong disease that is driven by a genetic mutation which causes the toxic accumulation of the heme metabolic precursor, PPIX. X-linked protoporphyria is a genetic variant of EPP that similarly results in the accumulation of PPIX. The main clinical manifestation is extreme photosensitivity with severe disabling pain attacks called phototoxic reactions when patients are exposed to light. PPIX is a photoreactive molecule, and patients essentially get a chemical burn from the inside out when overexposed to sunlight.

The photosensitivity to accumulated PPIX means patients can typically spend about 30 minutes, and sometimes as few as a couple minutes, in the sun before experiencing symptoms, including excruciating pain, swelling, and burning, all of which can last continuously for days. The fear associated with the sun and the psychosocial impact of a lifestyle of sunlight avoidance mean many patients experience anxiety and depression. The consequences of PPIX accumulation are systemic. For example, about a third of patients develop hepatobiliary complications, which can advance to liver failure and be life-threatening. There is no cure or disease-modifying treatment for EPP, so patients typically manage the disease by avoiding light, wearing head-to-toe protective clothing, or sometimes using tanning agents.

Our aspiration here is to provide an oral treatment option that targets the cause of the disease and allows patients to be relieved of the debilitating impact of EPP, to be relieved from the multifaceted burden of light intolerance, to be free from the need to plan every day around sun exposure, to be free from the pain of phototoxic reactions, and to just be able to live their lives. We designed APOLLO, our global phase III study, to specifically capture these aspects of the disease. APOLLO is a randomized, double-blind, placebo-controlled trial of 60 milligrams of bitopertin versus placebo for six months. APOLLO enrolled adults and adolescents aged 12 and over with EPP or XLP. Randomization was stratified by baseline light tolerance and geographic region. The study had two co-primary endpoints.

Average total monthly time in sunlight without pain between 10:00 A.M. and 6:00 P.M. during month six, and percent change from baseline in whole blood metal-free PPIX at six months. Today, we will share the top-line results of APOLLO. Here's a look at the baseline characteristics for the 183 APOLLO participants. You can see that the treatment arms were generally well-balanced across key demographic and disease characteristics. The study exceeded its original enrollment target of 150 participants, ultimately randomizing 183 participants in just 10 months, reflecting strong patient and physician enthusiasm. Notably, we have meaningful adolescent representation, with 34 of the participants being aged 12 to 17, and there is substantial unmet need in this younger group. 7% of participants had XLP. Geographically, we had good global representation with a roughly even split between patients coming from the U.S. and ex-U.S.

We also had even distribution of the season in which patients completed the APOLLO study, with half of the patients completing their last month in the spring/summer, and the other half completing their last month in the fall/winter months. Overall, these demographic and baseline characteristics are typical of the EPP patient population and are similar to those in our phase II studies. Before I review the top-line data, I need to remark how compelling these results are. All primary and secondary endpoints were not only met but met with clinically meaningful magnitude and strong statistical significance. Looking at our co-primary endpoints, bitopertin met both of them, demonstrating statistically significant reduction in PPIX, an increase in total time and light without pain in month six of the trial.

Bitopertin-treated participants had a 45.8% reduction in whole blood metal-free PPIX at month 6 compared to baseline, and a 41.4% greater reduction in PPIX relative to placebo, with a P value of less than 0.0001. Consistent with the AURORA and BEACON clinical trials, these results continue to support bitopertin's potential to modify EPP and XLP through reducing production of the disease-causing metabolite in the body. With this PPIX reduction, we observed a statistically significant 12.2-hour improvement in average total time in light without pain during month 6 of treatment relative to placebo, with a P value of 0.001. You can see that the Y-axis starts at 20, which is intended to roughly indicate an extrapolated baseline monthly light tolerance from the 2-week baseline assessment. The average baseline time in light over the 14-day screening period was 11.4 hours for the bitopertin group and 10.7 hours for the placebo group.

It's important to note that this endpoint is not a measure of maximum light tolerance. It is a measure of how much time patients were able to choose to spend in light on the study. The secondary endpoints give more insight on the light tolerance improvements with bitopertin. Looking at the first secondary endpoint, bitopertin dramatically decreased the incidence rate of the severe painful phototoxic reactions experienced by patients by 71% relative to placebo, with a P value less than 0.0001. To help put this reduction into perspective, we've also provided on the right the total number of phototoxic reactions observed in each treatment arm over the 6-month treatment period. 231 for patients on placebo and 71 for patients on bitopertin. Notably, this marked reduction in phototoxic reactions occurred while patients were spending more time in the sun.