Moderna, Inc. Common Stock Study update

24. Yes, hi. We'll be starting in about 5 or 10 minutes.

We're just waiting for the KOLs to arrive from the convention center. Just give another 5 or 10 Hello?

Good evening. thank you for joining us today. This is a very exciting day for cancer patients. It's an exciting day for cancer immunologists, and it's an exciting day for Moderna. Here's our forward-looking statement: Today I'm going to start by giving just some brief contextual statements on infismarin. I'll then invite up Dr. Dragina Long, who was the, lead investigator for IntraPath 001 and gave a fantastic presentation today to give a reprise of that presentation. I'll, conclude with a few concluding statements, and then we're very fortunate to have two world experts in melanoma: Professor Asierto, who was the senior author of IntraPath 001, and Professor Ribas, who is a melanoma expert and a world leader in cancer immunotherapy as well. Immune surveillance controls emerging cancer cells, and it does this by detecting neoantigen that form in cancer cells. These neoantigen drain, or are carried, to regional lymph nodes. They're processed in antigen-presenting cells, and then brought to the surface of the antigen-presenting cell and presented to T cells.

T cells that recognize these neoantigen are activated, they circulate throughout the body, looking for the cancer, and they eliminate the cancer. However, as we know, cancer can escape immune surveillance. When either the cancer lacks sufficient neoantigen the neoantigen aren't released, or aren't transported to the lymph node. The antigen-presenting cells don't process them or present them on the surface. The T cell is insufficiently activated, or the T cells become exhausted. Checkpoints act on T cells, anti-PD-1, PD-L1, reverse T cell exhaustion. An anti-CTLA4 lowers the threshold for T cell activation. However, they act only on T cells, and are limited by whatever available neoantigen are present, in that lymph node. In tismaran, as shown today by the phase 3 data, has an entirely different mechanism. It optimizes neoantigen presentation. And how does it do this? Well, first we take the tumor, out of the patient, and use an algorithm to select the most promising neoantigenes. We package those neoantigen into an mRNA lipid nanoparticle, and that's used to inject into the muscle of the patient. Now, we know from non-human primate studies and from rodent studies that when an mRNA LNP is injected into muscle, it it drains into the regional lymph node, is taken up by antigen-presenting cells, and dendritic cells.

The RNA is produced into protein, and that protein in the case of neo in the case of, our neoantigen in tismaran can be presented on the surface. So there are three important points to take away about why we think in tismaran it's so potent. First, high neoantigen expression in the cells where it's required. In the antigen-presenting cells, and in the dendritic cells. Number two, this isn't an optimal environment. It's far away from the immunosuppressive microenvironments of the tumor. And number three, because CD4 and CD8 T cells are activated, dendritic cells are activated, and cytokines are released, there's a perfect poly there's a perfect milieu to create poly-functional CD4 and CD8 T cells. And we have translational data to support some of these. Let me take you to ASCO 2026, just a few months ago, where we presented the phase 2 data. I first like to draw your attention to the initial phase 2 data that was presented a few years ago. Recall the hazard ratio at the primary analysis which had the same follow-up as IntraPath 001 today, the hazard ratio was 0.561. 0.561 at the primary analysis. With longer follow-up, as we showed a few months ago, the hazard ratio improved to 0.51.

Now, why did the hazard ratio improve? This can be seen looking at the the arts of the Kaplan-Meier curve. For the first six months, on the left-hand side, the hazard the the Kaplan-Meier's are overlapping. And as you heard today, from, Dr. Long, this is in part due to the weeks required to produce the in tismaran, and then weeks or a month for the immune system to be activated. At month 6, the curve separates, and we know they'll eventually remain separated. However, in the primary analysis, that first six months takes up about a quarter of the entire Kaplan-Meier curve. That hazard ratio 1 for the first six months takes up a quarter of that curve. In the longer five-year follow-up, that's six-month hazard ratio 1 is still there, but now we have follow-up up to 60 months. And therefore, that initial six months takes up about a fraction of the entire hazard ratio. And this is why we pre-specified to conduct a piecewise analysis. At six months, and you'll hear that from Dr. Long, during her presentation. But it's very important, I think, to recall that the primary hazard ratio was essentially identical to what you'll hear today. 0.5, 61. And this analysis and we do believe the phase 3 data, for this reason, will continue to improve.

In tismaran, as I mentioned, activates T cells, and we should expect to see novel T cell clones in the peripheral blood. This is a, figure, the y-axis is the sum of novel T cells that we detect in the blood, and the x-axis is four different time points: baseline, post the pembrolizumab lead-in, and just prior to in tismaran, at at cycle 5, so in the middle of the in tismaran regimen, and then at a follow-up. And this is the phase 2 in tismaran plus pembrol versus pembrol. For the first portion, notice the two arms are overlapping, because both patient both groups of patients are receiving pembrolizumab, exactly what you would expect to see. However, once in tismaran is administered, the combination curve continues to go up. More novel T cell clones are generated compared to the control arm. This leads to the question we asked: would higher levels of neo of, novel T cell clones be associated with clinical benefit? And in theory, this should be most evident in the combination arm. And that's exactly what we see.

So the same y-axis is the number of unique clones, x-axis is the same. On the left-hand side, is the combination arm, and on the right-hand side is the pembrolizumab arm. Now, we've separated the patients into two groups. Those who quote had benefit, i.e., never had a recurrence, and those who had, let's say, no benefit, those who had a recurrence, we did that for both arms. And you'll notice for the combination arm, patients who had no recurrence, which is the top, their novel T cell clones continue to increase. During treatment. Whereas the ones who had recurrence, plateaued. For the pembrolizumab arm, there's an initial increase, and then there's a plateau. So this is evidence that there's an association mechanistically between the number of novel T cell clones and clinical benefit. Now, these are novel T cell clones, and we don't know if they were if they are related to the in tismaran drug product. And it is a little more complex to match T cells to neoantigens, but we were able to do it in seven patients. This requires a lot more blood than is typically taken, during the routine blood assessment. So we had so we consented seven patients and we matched their T cells to the 34 neoantigens they received in their cassette.

And what we found is, on average, one out of every three neoantigens in the 34 cassette is immunogenic. That is, it induces a T cell that is novel in the blood that reacts specifically to that neoantigen peptide. And it ranges from about 1 to 18. And interestingly, it includes both CD4 and CD8 T cells. We then sought to further characterize the phenotype of these T cells. And we find this is an example. It's, CD8 T cell that recognizes neoantigen 14 from patient 3, and a CD4 T cell that recognizes neoantigen 27. And when we phenotype it, using flow cytometry, what we see is that both T cell clones are polyfunctional. They make different types of cytokines. And they're also have markers of a cytotoxic phenotype, meaning that they're ready to go out and kill the cancer cell. Because we were able to clone out those T cells that recognize those neoantigenes, we had the TCR sequences. And we could go back to whole blood, and we could follow the frequency or the prevalence of those T cells, during treatment. So it's the same time frame on the bottom, screening, lead-in with pembrolizumab, in the middle of the in tismaran regimen, and then at the end.

And what you'll see in these three examples, that all T cell clones, only appear, after in tismaran, not during pembrolizumab. And most of them remain element elevated for the entirety of the, treatment. As a side note for the, for those who are immunologists, one of the interesting features, which is known, is that there are usually multiple T cell clones that can recognize the same neoantigen peptide. So at this point, I'd like to invite up Dr. Long to give, the presentation of InterPath 001, and then I'll return to give a few closing, comments. And please come up this way so you don't fall. Okay. Thank you. And you press this one to advance.

Strangely. Okay. Thank you. Thank you.

It's a, a pleasure to present these data again. To a smaller, more cozy audience. so, and it is a true honor to be able to present results on something so transformational for cancer. So this is a phase 3 randomized clinical trial of in tismaran combined with pembrolizumab. We refer to in tismaran as an I a type of INT therapy versus pembrolizumab alone for the adjuvant treatment of stage 2B, up to stage 4 melanoma. Now, I don't have my glasses, but I can see this slide. I'm not that blind, but, so, and, and I do present this on behalf of my co-investigators. There were 157, global sites, and all of their teams. These are my disclosures. So, we know that there is a clinical benefit for the adjuvant treatment of melanoma patients, with anti-PD-1 monotherapy alone. That's clear. But shown here are the two curves for stage 3 resected melanoma and stage 2 resected melanoma. Stage 2B. The red curve is placebo. The blue curve is pembrolizumab alone. And yet, despite their significant clinical benefit and absolutely changing the field, we still have 44 and 33 percent of patients recurring or dying at five years.

So in the melanoma field, we see that there is a big s a lot more work to do in terms of getting to zero deaths, and to curing cancer. Now, it's not that we haven't been working at it. These are three landmark phase 3 clinical trials, combining anti-PD-1 with three different checkpoints: C2LA4, LAG-3, and anti-TIGIT, all negative. And so we have not had any improvement in the adjuvant setting over and above anti-PD-1. Sorry. Go back again. And what I presented today was really asking the oncology world, you know, how did we get here to reflect on how we got here in 2026? And there really is, you know, over 100 years of work in immunology, cancer biology, and the technological innovation that's happened, particularly in the last 60 years. And so if you're looking at where we are today with in tismaran, there are three really important scientific advances. First of all, the discovery that neoantigens exist back in the, the 1980s. These are unique mutations that are only found in an individual's tumor. They are not found in their normal cells, and they are not found in anyone else's cancer. And that begs the question, if they're so unique, could they be seen as foreign to that patient's immune system?

Then the second big scientific advance is really built on next-generation sequencing. And that's the ability to rapidly sequence the tumor and also use the computational algorithms to identify and rank which neoantigens we think, or we predict, will give us the most robust anti-tumor response. And then the third is a platform that really is built for speed. And that's the fact that mRNA, you can include many, multiple antigens in a single strand of mRNA. And there's demonstrated robust CD4 and CD8, tumor response or responses to these proteins. That's wrapped in a lipid nanoparticle. Injected into the patient, so altogether that is a very rapid individualized manufacturing process, giving us in tismaran. In tismaran, as you heard before, encodes up to 34 neoantigens. And this is based on the patient's individual, what we call tumor mutanome, and their HLA type. The workflow for in tismaran is standardized from collecting the tumor tissue and blood, right around to administration of to the patient, takes 6 to 8 weeks. In terms of the mechanism of action, this is now a busy slide without the animations, but so it's injected intramuscularly. The mRNA is then taken up by nearby cells, all sorts of cells.