Tempest Therapeutics, Inc. Common Stock H.C. Wainwright 28th Annual Global Investment Conference

Matt, please go ahead. Thank you very much, Matt.

Good afternoon. My name is Matt Angel. I am CEO of Tempest Therapeutics. We are a company that is working to create a world without cancer and without autoimmune disease. It is a big vision, and it may sound and seem daunting, in part because we often think of cancer as being hundreds of different diseases or thousands of different diseases. What if I were to tell you that multiple myeloma, B-cell lymphoma, B-cell leukemia, but also the rare disease POEMS syndrome, and also autoimmune diseases like multiple sclerosis, myasthenia gravis, and lupus, that all of those are actually one disease, the same disease caused by B-cell and B-cell lineage dysfunction. That is what we believe, and that is what we are working to change. We are an in vivo CAR-T company. What is in vivo CAR-T? Everyone is familiar with CAR-T.

It is a kind of therapeutic approach that can create an immune reset that can deplete or destroy disease-causing cells, usually of the B-cell lineage, to allow healthy hematopoietic progenitors to repopulate the immune system. The problem with traditional CAR-T, which is autologous, is it is very difficult to manufacture those kinds of products. It is very difficult on the patient having to go through lymphodepletion or conditioning regimens. I think it is often underappreciated that as many as half of patients who would be recommended a CAR-T therapy cannot get it. They are ineligible because they cannot withstand the lymphodepletion, or their cells are not sufficient to go through the manufacturing process. We aim to change all of that by doing the cell engineering in the patient's body. The products that we are working to develop look much more like mRNA vaccines.

One of them is an mRNA molecule that is encapsulated in a lipid nanoparticle. The other is a lentiviral vector that is also very similar. The end result of both is the same. It is pushing the reset button on the patient's immune system so that they can be disease-free. This is our pipeline. I am very excited to announce a new collaboration, a new partnership today, with Sichuan Senlong Biotech Co.,Ltd, a company in China. We announced about a month ago a prelude to this partnership in which we described our work with them to take our mRNA-LNP in vivo CAR-T asset into the clinic later this year in China in an investigator-initiated trial, a phase I trial. We have now expanded that relationship to in-license the global ex-China rights upon exercise of our option, to their clinical stage lentiviral in vivo CAR-T asset.

I want to really emphasize that because that means that we are right now one of a very small handful of companies that has a clinical stage in vivo CAR-T asset. I am going to show a little preview of the clinical data in a couple of slides that I think are really exciting and give us a lot of confidence that the future of CAR-T really is in vivo. As you can see from this slide, the lentiviral asset, which we are calling TPST-4903, is a dual targeting BCMA GPRC5D in vivo CAR-T. The other asset, the mRNA asset, which is TPST-4003, is the mRNA-LNP asset that is also dual targeting CD19 and BCMA. I will talk a little bit more about each of these assets in a second. You can see the sort of top-line clinical results there at the moment.

Six patients so far enrolled in a dose escalation study. These are not healthy volunteers. These are actual relapsed refractory multiple myeloma patients for TPST-4903. The initial safety profile looks great so far and supports further dose escalation. Even at the current maximum dose tested, and again, we are going to continue to increase the dose, as we will see in a second, we are seeing CAR-T cell expansion inside the patient, and it actually looks very similar to what we see with autologous CAR-T, which gets us really excited about this asset. First, the mRNA-LNP asset. I mentioned this is a CD19 BCMA dual targeting CAR. That CAR, the identical sequence, has clinical support, so it is being evaluated in two ongoing phase I clinical trials right now, one of them in relapse refractory multiple myeloma, the other one in the rare disease POEMS syndrome that I mentioned.

Earlier this year, I presented the latest clinical update, which included a 100% complete response rate among CAR-T naive patients. That is really as good as it gets, but also safety profile was outstanding. No grade 3 or greater CRS or ICANS, which are two of the most important safety signals for these kinds of products. Really importantly, all of the patients that were evaluable 12 months after infusion were MRD negative. So they were negative for minimal residual disease, suggesting that this could be a very durable and effective CAR sequence. Again, this is the identical CAR that we are now working to develop in an in vivo format in the mRNA-LNP product, TPST-4003. We also have enough data now from a previous clinical trial for this autologous asset to measure the progression-free survival, and it is shown here 23.1 months in EMD patients.

This is extramedullary disease, very severely affected patients with tumors outside of the bone marrow. That is far and away better than what is on the market right now. ABECMA, you can see there, 7.9 months, CARVYKTI, 13.8 months. So we think that this CAR really can offer some really outstanding value to patients. POEMS syndrome study, very similar, 100% complete response in all evaluable patients. I will not go through the science too much. You can see the structure of the dual targeting CAR there, but I show it because sometimes I get asked the question, how does this compare to bispecifics or T cell engagers? You can do things with a CAR that you cannot do with those kinds of molecules, and you will see it if you have really good eyesight and can read the fine print. The co-stimulatory domains of these two parallel structured CARs are different.

There's a 4-1BB and the BCMA CAR, but a modified CD28 and the CD19 CAR. I won't go through why that's important, but it's suffice it to say, you can only do that with a CAR structure when you're really engineering the protein, the receptor itself in the cell. I have to show these two patients' results and responses because they're so incredible and outstanding. In the center, a 58-year-old male, penta-refractory, 11 prior lines of therapy. Again, relapsed multiple myeloma, and you can see presented at the time of infusion with a very large skull plasmacytoma, a very large mass in the skull. 2 and 3 months after infusion, it's gone. It melted away. This was a single infusion with this dual targeting CAR-T product. MRD negative at month 6, strict complete response, and going. On the right, similar story, 55-year-old female.

You can see in the PET scan, 53 days before infusion, masses, tumors throughout the body. 3 months after infusion, they're gone. They melted away. This is the power of CAR-T as we see it, and we're really excited to bring this to more patients through the in vivo formats. Here is the data. This is a single patient worth of data from in vivo CAR-T, lentiviral, and you're seeing here on the right-hand side, the CAR-T cells. Number of CAR-T cells as a percentage of T cells, percentage of CD3 positive T cells. There's a peak about 2 weeks after a single infusion, and the peak is about 30, 31% of the T cells are CAR-T cells. On the left is the result from the autologous CAR-T. It's the same, basically identical.

If anything, the in vivo CAR outperformed in terms of the amount of expansion and amount of CAR-T that we're getting. This is the data that gets us really excited about the potential for this product to ultimately possibly displace cell-based CAR-Ts. We probably all saw the news yesterday from Cellectis, one of the big allogeneic CAR-T companies that announced that they're abandoning cell therapies across the board, and CAR-T, it seems, in general. Again, when in vivo CAR-T can do this, what we're looking at, it's very hard to justify cell therapy applications with it. So much opportunity in the market to address patients who have no good options right now. On the oncology side, on the left, I briefly mentioned some of these indications. They're all very serious cancers.

Patients very often, almost always relapse or are refractory from all of them, including from autologous CAR-T products, including from single target BCMA CAR-T products. This is another reason why using a dual targeting CAR gives us the opportunity to treat patients who have relapsed from a prior CAR-T. This is important for a couple of reasons. Obviously, it gives a patient another good option to try, but also from a development and regulatory standpoint, this means that we may be able to start testing for those specific indications in patients who have relapsed from a CAR-T. In those patients, there is no approved CAR-T product, so we don't anticipate having to run a randomized clinical trial with a CAR-T control arm, which would be more expensive. On the right-hand side, the autoimmune applications, very large markets.

Many of these patients are on lifelong maintenance therapies, high-dose steroids with a lot of side effects. Giving them a product that looks like an mRNA vaccine that can get them off of their maintenance therapy, even if they have to come back in a year for another dose, would be life-changing for these patients. That is what we are really hoping to achieve with TPST-4003. I should mention also that with that program, we are still planning to begin our clinical development with the first patient in China by the end of this year. Very fast track for both of these programs, the mRNA program in autoimmunity. We have patients lined up with multiple sclerosis, myasthenia gravis, and lupus. Then our new program, TPST-4903, the lentiviral, is currently in that phase I, enrolling patients with relapsed or refractory multiple myeloma.