Cabaletta Bio, Inc. Common Stock 12th Annual Cantor Fitzgerald Global Healthcare Conference

Yeah. So thanks for having us, Josh. It's been an exciting two weeks. Patients simply want to be off of their medicines and free of disease. The only modality that's been able to deliver on that promise since 2022, when the first data was published, is the Autologous CAR-T product space. rese-cel, as an Autologous CAR-T product, was designed specifically for patients with autoimmune disease. By that I mean we use a standard, well-characterized, nine-day manufacturing process. We use a 4-1BB-containing, fully human binder, and we use weight-adjusted dosing. These are actually aspects of our product that are just about unique in the Autologous space and very similar to what Professor Schett did at Erlangen, which is why all of us are so excited about the field.

Because we made these choices early on, with a high insight and regard for patient safety in autoimmune disease, we've now published a bunch of clinical data. What does that data show? It shows that we can provide reliably and durably the vast majority of patients who get a single dose of rese-cel when they discontinue their medications, all of their immunosuppressants, are never going to take another immunosuppressant for as long as we have been following them. They'll also reduce their steroids oftentimes to zero, and if not, almost always to less than physiologic doses. As a product offering, because of the efficacy, we now need to look at the safety. The choices we made in our design of the construct have paid off dividends for patients. Our safety is beginning to differentiate in highly meaningful ways.

In over 60 patients reported, we have 94% of all of our patients either have no CRS at all, or a minority of that number have a fever, grade 1 CRS that is transient. 97% of those 62 patients that we have published and reported have no ICANS at all. There is no case of IEC-HS, the outcome that caused Novartis to pause their clinical program. There is no case of IEC-HS in any patient at any time in the rese-cel program to date. That does not mean it will never happen with us or any CAR-T program, but we think the design choices we have made have truly minimized the risks, and you will hear a lot about this, minimized the risks of all safety events that we know of. What that has allowed us to do is create a pipeline in a product.

As we go forward, the remainder of this year, you can expect us to start our second indication on a pivotal pathway to approval. Scleroderma, 12-year mortality risk for a 30 or 40-year-old person who is diagnosed with scleroderma, in 12 years, there is a 50/50 shot they are alive. There is real urgency, and there are no treatments. That is in addition to, by the middle of next year, we expect to report out the pivotal program on myositis. Because of our safety data, and our weight-based dosing, which is, we think, unique in the field, we have been advancing aggressively our pediatric myositis program, which we will file, we anticipate, by the end of 2027, along with our adult myositis program. We are excited about that because, first of all, nobody else can even begin to go after it. The safety profile has to be there. You need weight-adjusted dosing. There is a moat around the entire pediatric universe for us.

The other reason we are excited is there is the possibility of a voucher with that pediatric filing if it is accepted. After that, we have innovations coming like PC-free, which is a terrific upside to expand the market opportunity, as well as an approach to eliminate the need for apheresis. To close in these comments, I would say our vision of what rese-cel will do is patients will come in with a safe opportunity to reset their disease, to be free of drug and to be free of their disease.

All they need to do is come in, donate blood, in a regular whole blood draw, allow us about a month to turn around their product, their cells for them, and on an outpatient basis in a clinic, be infused on one afternoon, and then go home off of their immunosuppressants. I would ask you to think about that promise versus any other modality, which is multiple infusions, multiple reconditioning, whatever it is. Ask yourself if you would rather have that or anything else that is in development. We are really thrilled with the opportunities that we have been given because of the choices that the group here has made early on in our development program.

Yeah. I can start, and then I'll pass it to Shamik. I think first, we really want to communicate with everybody what is different about our product and our manufacturing process. As Steven mentioned in his opening comments, our process is a 9-day process. That means that the cells are modified and then they're expanded ex vivo, and during that time, the cells change their characteristics. This 9-day process is the same as all of the approved CAR-Ts. All of the approved products like KYMRIAH and BREYANZI, they all use this type of process. All of the clinical data, safety data that's out there is characterized with this type of process. Also, as Steven mentioned, we use this process because this is what also the Erlangen group used. It allowed us to move quickly. It allowed us to leverage learnings from that group.

Also we were very aware of, and Shamik will talk more about this, we were very aware of differences between oncology patients and autoimmune patients, and that's one of the learnings we really want to communicate with you today. When you look at the process that Novartis and BMS have used in autoimmune disease, they're using shorter processes. Specifically, Novartis uses a 2-day process, and BMS uses a 5 to 6-day process. The cells have less time to grow and they have less time to change and differentiate. That correlates with very specific changes in biologic behavior that actually have been published by Novartis themselves. They published a paper outlining the preclinical validation of their product that they're using in autoimmune patients that had the deaths. Their 2-day process was directly compared using the same donor match material with their KYMRIAH process.

The cells have approximately 10 to 15-fold higher levels of interferon gamma, which is a pro-inflammatory cytokine, than the KYMRIAH cells. In cancer, you really want to have more pro-inflammatory cytokines because you want to create inflammation in the patient because that helps support the anti-tumor effect. But it's exactly the opposite in autoimmune disease because they're already revved up immune systems, and you don't need that extra pro-inflammatory kick in order to get to that efficacy. I think that's a good time to turn over to Shamik because he can talk about the influence of interferon gamma on monocytes.

Yeah. Let me just back up a little bit. The inflammatory adverse events, think CRS, ICANS, IEC-HS, they are all mediated by macrophage activation. For those who are unfamiliar, macrophages are a subset of white blood cells in the body. They are primarily involved in phagocytosis and presenting antigen to other immune cells, particularly T cells. With the interferon gamma that Gwen mentioned, that binds interferon gamma receptors on these macrophage cells, and those cells then secrete IL-6 and IL-8, and that is what mediates a lot of these inflammatory adverse events. In autoimmune patients, the macrophages are already very polarized, very pro-inflammatory to begin with, and so they are more likely to make even more IL-6 and IL-8 in response to interferon gamma.

When you have higher amounts of gamma, let us say with a short manufacturing process, you have even higher levels of 6 and 8, thereby increasing both the grade and the frequency of these inflammatory adverse events. It is really connected to the manufacturing process, these inflammatory adverse events.