Faeth Therapeutics, Inc. Common Stock 25th Annual Needham Virtual Healthcare Conference

Sensei Biotherapeutics? Faeth. Phythera Therapeutics, yeah.

Thank you, Gil, and thank you, Needham, for the platform. Faeth is a company focused on cancer metabolism and crucial multi-node pathways in cancer. Before I start, I just want to mention that today's presentation will contain forward-looking statements subject to risks and uncertainties detailed in our 10-K and other SEC filings. Faeth recently went public in a reverse merger transaction with Sensei Biotherapeutics. This was structured as a stock-for-stock transaction, and concurrent with the deal, we raised $200 million in a private placement from institutional investors. The Faeth leadership team has been merged with the Sensei leadership team, and we're very excited that the capital that we've raised is primarily dedicated to advancing Faeth's lead program, PIKTOR, which is expected to have phase II topline data in endometrial cancer, and initiate a phase Ib in HR-positive, HER2-negative breast cancer, both expected by year-end 2026.

A little bit of an overview on Faeth. Faeth is a company focused on multi-node pathways, complex pathways in cancer, where multi-node inhibition is going to lead to not only hopefully better efficacy, but also less toxicity. We're beginning our work with the PI3K pathway, the most frequently mutated pathway in solid tumors, and we are engaging in vertical blockade with two oral small molecules. That vertical blockade inhibits PI3K alpha, TORC1, and TORC2. Compared to other pathway inhibitors, we believe that not only are we oral compared to intravenous, that we have similar rates of all grade hypoglycemia, we have lower rates of stomatitis with no prophylaxis, and that we have greater exposure above common efficacy thresholds like IC90, staying above those thresholds for longer than the competition, which should translate to greater efficacy.

In terms of recent and anticipated readouts, we had a phase II recently read out at ESMO, which met its primary endpoint. That was with one half of the PIKTOR intervention, sapanisertib with paclitaxel. That's a randomized phase II. We also have a phase II with the entire PIKTOR intervention in endometrial cancer. That will read out in the second half of 2026. As I mentioned, the money we raised will also fund, in addition to the phase II in endometrial cancer, a phase Ib trial in HR-positive, HER2-negative advanced breast cancer. That trial will initiate in the first half of this year. We have a pipeline beyond PIKTOR, but PIKTOR is the focus of the company. One thing I would note about the origins of Faeth has really been, from the beginning, focused on multi-node inhibition of crucial cancer pathways.

Our team and our scientific co-founders really reflect that with Lewis C. Cantley, in particular, being notable as the discoverer of the PI3K pathway. We're glad to have Lewis C. Cantley and our other esteemed scientific co-founders on our side as we attack this very important problem for patients worldwide. As I mentioned, the PI3K/AKT/mTOR pathway, also colloquially known as the PAM pathway, is the most frequently mutated genomic driver across all solid tumors. The way we are attacking this is with two oral small molecules that target what we believe to be the most crucial nodes in this pathway. Serabelisib, which inhibits PI3K-alpha, and sapanisertib, which inhibits mTORC1 and mTORC2. Together, we call this PIKTOR. One of the major benefits of targeting this pathway at multiple nodes is you're actually able to shut the entire pathway down.

We believe that single node inhibitors which target components of this pathway are partial pathway inhibitors. When you actually inhibit this highly correlated and interdependent pathway, you are able to decrease the dose of any individual agent, which sets a firm lower bound to your therapeutic window and allows for much greater tolerability. Another benefit that arises from actually setting that firm lower bound on the therapeutic window is that evolved resistance is far less likely. Evolutionarily-derived mutations, resistance mutations that occur as a result of pressure being placed on an individual point of this pathway, escape mutations, can be avoided by multi-node inhibition. The other benefit of multi-node inhibition is it's a much larger addressable market.

Of course, if you're focused on single point mutations in the pathway, then you're limited to that market. We, on the other hand, have shown the ability to target patients with mutations throughout the pathway and actually outside of the pathway as well, as our phase Ib shows. Finally, one of the benefits of Faeth's method of multi-node inhibition is that we are orally administered. While oral administration is, of course, a convenience advantage for patients and physicians alike, it also provides important PK advantages, which I'll detail throughout the course of this presentation. I want to walk through some science here that I think is crucial to understanding the benefits of multi-node inhibition.

While targeted therapies focus on shutting down the genomic drivers of cancer, the actual translational readouts at the bottom of these pathways are the key to shutting down the activity of these pathways in cancer cells. For the PI3K/AKT/mTOR pathway, the key translational readouts are phosphorylated S6 and phosphorylated 4E-BP1. As you can see from these western blots, single-node inhibitors do a good job of shutting down phospho-S6, but not such a good job shutting down phospho-4E-BP1. Our agents in combination, however, are able to shut down both S6 and 4E-BP1. As has been demonstrated in the literature, it's 4E-BP1 that correlates far more closely with drug potency. This is true not only of the approved therapeutics in the class, but also the investigational therapeutics, including mutant-specific inhibitors, as detailed on the western blots to the right.

We shut down phospho-AKT, phospho-S6, and phospho-4E-BP1 in a far more complete way than any single node inhibitor. As it relates to the multi-node inhibitors, we think we have some crucial and important advantages. The historical development of multi-node and pan PI3Kinase inhibitors has shown that alpha selectivity is important. Pan PI3Kinase inhibitors have traditionally been dogged with less tolerability and also potential immunological toxicities due to the fact that PI3Kinase gamma and PI3Kinase delta are largely expressed in immune cells. In solid tumors, it is PI3Kinase alpha that predominates, and any limited signaling that may occur through beta or other PI3Kinase isoforms is largely inhibited by the fact that we are also shutting down downstream mTORC1 and mTORC2. The initial clinical data for our combination was really demonstrated in this phase Ib study.

This was the first time that PIKTOR was put together with another mechanism of action, paclitaxel. In this case, although we also believe and are undertaking trials with other cytotoxic agents, including CDK4/6 and potentially hormone therapy, in this trial, however, paclitaxel was the partner of choice. Within these advanced solid tumors, you can see that the doses tested for sapanisertib and serabelisib were significantly lower than the monotherapy RP2D of these agents. These agents, when given in monotherapy, the RP2Ds were determined to be 900 mg and 9 mg. Our recommended phase II dose was 3 mg of sapanisertib, so threefold lower than the RP2D, and 200 mg of serabelisib, so over fourfold lower of its RP2D.

That's an important fact because when we see the activity that we've seen, and which I will further demonstrate, this explains why the tolerability is also so beneficial for patients and physicians. In that phase Ib, we saw a 47% overall response rate with three complete responses, four partial responses, and four patients with stable disease. When we look at those patients who had stable disease on the swimmer plot, we can see that that stable disease was sufficient to qualify also for clinical benefit. These patients had endometrial, ovarian, and breast malignancies, and on average, had four prior lines of therapy. It's notable that all of these patients, except for one, had prior taxane. This was taxane rechallenge. In that setting, taxane rechallenge in advanced solid tumors, we would expect a 10%-20% overall response rate with about four months PFS.

This data appears to be outpacing that significantly. I also want to discuss the mutational landscape. When we look at the mutational landscape here, you can see classical PIK3CA mutations in green, PI3K pathway mutations without PI3K PIK3CA mutations in red. mTOR, AKT, PIK3R1, those kinds of mutations, those are in red. Patients without any pathway mutation in black. It's notable to see that we had activity across all three different mutational subtypes. Also, if we look to the VIKTORIA-1 study, which was undertaken by Celcuity, the data that got a positive market response was actually in wild-type patients. That means patients who had an absence of a PIK3CA mutation. In this study, that would be all patients denoted in the red or the black. All those patients would be considered PIK3CA wild-type under the VIKTORIA-1 stratification.