SNSE KOL event

Please go ahead, Anand. Good morning, everyone, and thank you for joining our inaugural analyst and investor event.

My name is Anand Parikh. I'm Co-Founder and CEO of Faeth Therapeutics. Next slide. We will be making forward-looking statements in this presentation, so please refer to this slide for appropriate disclosures. Faeth was founded at the intersection of cancer biology and metabolism with the goal of broadly enabling multi-node inhibition of crucial cancer pathways. We began by attempting to solve the PI3K/AKT/mTOR conundrum. That is how to effectively drug a pathway crucial to the livelihood of both cancerous and healthy tissue. Our work began in the lab of Lou Cantley, discoverer of the PAM pathway. Research by Lou and Dr. Marcus Goncalves, who you'll hear from later, paved the way for our multi-nodal approach, which we call PIKTOR.

As the industry doubled down on novel ways to target PI3 kinase, most recently with mutant selective inhibitors, our resolve in multi-nodal inhibition never wavered. With the recent approval of Celcuity's REVTORPYK, we believe that multi-nodal PAM inhibition is now a validated pillar of cancer care. Our work here is just beginning. Ultimately, we would like to get PIKTOR into the hands of nearly half of all cancer patients who have a PAM pathway alteration, starting in endometrial and breast cancers. Next slide. Here is our agenda for this morning. I'll start with an introduction into Faeth's history and strategic direction. Marcus will then provide you with an overview of the company's scientific foundations, which include several Nature publications.

Oliver, our Chief Scientific Officer, will then discuss preclinical and translational data that we believe supports selection of the dose that we've chosen for our phase II trial in endometrial cancer, PIK-201. Debbie, our Chief Medical Officer, will then walk through some of the clinical data that have gotten us to this point, preview PIK-201's data, and why we believe there's read-through from PIK-201 to our ongoing efforts in breast cancer. Brian, our Chief Financial Officer, will wrap up with the market opportunity for endometrial and breast cancer indications. Analyst Q&A will follow. By the end of the event, I hope to convince you that our approach is grounded in strong science and that multi-node inhibition of the PAM pathway is the solution to finally unlocking the true potential of PAM inhibition. We can completely disable PAM. Single-node inhibitors, no matter the dose, cannot. Next slide. Here's a pipeline overview.

We are currently exploring PIKTOR in two clinical trials. PIK-201, which is in endometrial cancer, is currently in phase II. We look forward to that readout at the year-end this year. PIK-101 is a phase I-B trial exploring PIKTOR in breast cancer, which will read out at year-end next year. Next slide. Our scientific co-founders include some of the world's preeminent cancer biologists and endocrinologists, including Lou Cantley, the discoverer of the PI3K pathway, Dr. Sid Mukherjee, Dr. Karen Vousden, and Dr. Scott Lowe. The provenance of the PIKTOR molecules comes directly from Kevan Shokat, one of the world's leading medicinal chemists. Next slide. The PI3 kinase/AKT/mTOR pathway, or PAM, probably needs no introduction to this audience. It's altered in up to half of all solid tumors. PAM regulates cell growth and division. It also regulates glucose metabolism. That combination is not a coincidence.

Cancer is a disease of growth. Growth takes energy. A tumor that alters PAM gets both at once, the signal to grow and the fuel to do it. Next slide. Here you can see how frequent PAM alterations are in cancer. In terms of sheer prevalence, endometrial tops the list at over 80% PAM altered, with breast cancer coming in a close second. Next slide. The prevalence made PAM a priority for drug development. It has also made it one of the harder pathways to drug multiple regulatory loops, and those loops are what defeat single node inhibition. Block one node, and the pathway compensates by upregulating another, like a game of Whac-A-Mole. This is exactly the case for hitting more than one node at once. Exactly what PIKTOR does. Next slide. This has been the crux for drug developers for decades.

Single-node inhibitors, which now include alpha-selective PI3K inhibitors, mutant-selective PI3K inhibitors, AKT inhibitors, and single-node mTOR inhibitors, all fail to completely disable PAM. Increasing the dose of single-node inhibitors will dampen the pathway, but it's never completely shut. At those higher doses, on-target toxicities, such as hyperglycemia and stomatitis, quickly become untenable. Our approach is different. We combine inhibitors at three nodes, each at a lower pharmacologic dose. We get deeper pathway suppression than either agent achieves alone at exposures that are more tolerable than maximizing either one. As you'll see in Oliver's presentation, translational data that we have in-house shows complete shutdown of the PAM pathway at the doses being tested in PIK-201. Next slide. We call our multi-noded approach PIKTOR. It combines serabelisib, an alpha-selective PI3K inhibitor, with sapanisertib, an inhibitor of both mTORC1 and 2.

Both agents are oral, taken with food each morning, Monday through Wednesday, then off for the rest of the week. That intermittent dosing is part of how we get suppression without the toxicity that comes with continuous exposure. Next slide. In terms of its reach, multi-node broadens the treatable landscape relative to single-node approaches. For example, in the graph below, you'll see that single-node inhibitors, such as PI3K alpha-selective inhibitors or even mutant-specific inhibitors, can only target the yellow space, a small fraction of the overall PAM alterations in solid tumors. We can target the yellow and green and potentially beyond, as REVTORPYK has demonstrated. As mentioned earlier, endometrial has the highest incidence of PAM alterations of any cancer.

However, you can see here only a small percentage of the PAM alterations in endometrial cancer are purely PIK3-related, meaning that the majority of PAM alterations in endometrial cancer cannot be served by a single-node inhibitor. Next slide. PIKTOR is the culmination of decades of research into drugging the PAM pathway. Early work conducted by Lou and then Marcus found that certain low-carbohydrate diets could blunt the impact of PI3K to the insulin feedback loop, improving the efficacy of early PI3K inhibitors. The company was founded on this trailblazing research, which was published in Nature in 2018. It also led us to seek out a PI3K inhibitor of our own, and in 2021, serabelisib was in-licensed from Petra Pharma via Takeda. We later found that combining serabelisib with an mTOR inhibitor could recapitulate much of that prior diet-based work. This was the birth of Faeth's multi-nodal strategy.

Sapanisertib was subsequently in-licensed in 2023 from Calithera Biosciences, leading to PIKTOR as we know it today. Next slide. Sapanisertib and serabelisib were both initially developed by Kevan Shokat at UCSF and subsequently put into a company he co-founded called Intellikine. Intellikine was subsequently acquired by Takeda. Takeda mainly developed these 2 drugs as monotherapies and sometimes in combination with fulvestrant or paclitaxel. Takeda did do some subsequent work combining serabelisib and sapanisertib, testing different doses and different dosing schedules. That work gave us a strong foundation from which to build our ongoing programs in endometrial and breast cancers, which Oliver and Debbie will describe later. Next slide. This table summarizes much of what I've already talked about on the advantages of multi-node inhibition relative to single-node inhibitors that are currently in development.

It also compares us to gedatolisib, which as I mentioned, was recently approved under the trade name REVTORPYK. Next slide. While we believe that multi-nodal PAM inhibition has been validated, there are several ways we believe that we can improve upon it. First, PIKTOR is orally available, adding the convenience of a daily pill versus a weekly infusion. Secondly, our safety profile thus far looks quite tolerable relative to other options, with a specific emphasis here on hyperglycemia and stomatitis. Stomatitis in particular, which we believe is more of a Cmax-driven event, we believe is derived from gedatolisib's IV formulation. We'll touch on PK in more detail on the next slide, but the bottom line is that PIKTOR spends around 2 to 3x more time above IC90 than gedatolisib in a given week.

As many of you know, usually in cancer drug development, greater time above IC90 generally correlates to more efficacious drugs. Debbie will highlight some of those safety differentiations as well in detail later. Next slide. Here we outline our PK in more detail. The blue curve is gedatolisib. What I hope stands out for you is that relative to gedatolisib, we're relatively similar. We believe that gedatolisib has demonstrated that pulsatile dosing of the PAM pathway is feasible and delivers a clinical benefit relative to incomplete inhibition of PI3K or other nodes of the pathway on a daily basis, which we see with alpha and mutant selective PI3 kinase inhibitors. However, as an IV formulation, gedatolisib has a much higher Cmax, which we believe contributes to greater stomatitis. But overall, we both cross IC50 around the same time.

Finally, note that PIKTOR spends around 2x to 3x more time above IC90 than gedatolisib in a given week. This is my last slide, beginning with our most advanced indication, endometrial cancer, and then translating to breast cancer and beyond. Oliver will explain to you why we believe that PK development has set us in good stead for PIKTOR's development in endometrial cancer. Debbie will then walk you through prior clinical data with an eye towards our first public readout, or our first readout as a public company later this year. She'll also tie in why PIK-201 should provide relevant read-through to our ongoing development in breast cancer. But first, I'll hand it over to Marcus, who'll walk you through more of the rationale behind multinodal inhibition of the PAM pathway.