SNSE Study update

I am Anand Parikh, CEO and Co-Founder of Faeth. Thank you for joining us for this important milestone in Faeth's history. Today, we are very pleased to present phase II data for PIKTOR in advanced endometrial cancer. Before we start, today's presentation includes forward-looking statements. Please see this slide and our SEC filings for the full risk factors. Here is the agenda for the next 30 minutes. I will share the headline results and frame the opportunity for PIKTOR, both broadly and in endometrial cancer. Dr. Debbie Chirnomas, our Chief Medical Officer, will cover the disease, the trial design, efficacy, and safety. Then Dr. David Starks, the Principal Investigator on PIK-201, will join for a guided Q&A on what these results mean for patients in the clinic. I will then conclude the prepared remarks with a review of the data and upcoming company milestones, and then we will open for questions.

Let me start with high-level takeaways. At Faeth Therapeutics, we are developing multi-node inhibition of crucial cancer pathways, beginning with PI3K/AKT/mTOR, or the PAM pathway. Today, we are announcing a significant leap forward for our first program, PIKTOR, in endometrial cancer. First, PIKTOR is now the leading oral PAM pathway inhibitor to show evidence of durable activity in endometrial cancer, the deadliest of all gynecological cancers. Second, efficacy. PIK-201 delivered a 33% confirmed overall response rate and a disease control rate of 83% in all evaluable patients. Among patients with PIK3CA mutations, with or without concurrent PTEN loss, the response rate was 44% and DCR 81%. In all patients, median PFS, a Kaplan-Meier estimate, is 7.4 months. This is nearly double what would be expected from standard of care chemotherapy rechallenge and is as good or better than second-line options, including ADCs and pembrolizumab lenvatinib.

This is despite a more heavily pretreated population and a still maturing dataset. Third, tolerability. Treatment-related discontinuations were just 5%. The two toxicities that have held this entire drug class back, hyperglycemia and stomatitis, were 12% and 21%. At grade 3, one patient each. Other agents in this class routinely require anti-diabetic drugs or steroid mouthwash prophylaxis. We use neither, and in a patient population that is about as metabolically challenging as it gets. Finally, phase III. Plans are now underway for a pivotal trial, and we recently completed a Type B meeting with the FDA. We also believe PIK-201 de-risks our aspirations to test PIKTOR in breast cancer, for which the phase I-B PIK-101 trial is ongoing. Why do we believe endometrial cancer is the perfect proving ground for our multi-node approach?

Endometrial cancer has the highest incidence of PAM alterations, but there's never been an FDA-approved treatment for the PAM axis. In the bar chart to the left, you can start to understand why. Only a small percentage of patients carry an isolated single PIK3CA mutation, which could, in theory, be treated with a single-node PI3 kinase inhibitor. However, PI3 kinase is involved in a majority of endometrial cancer patients, but most carry concurrent pathway mutations downstream of PIK3CA, which generally cannot be addressed by single-node inhibitors. We believe multi-node inhibition is the solution for all of these endometrial cancer patients. Full suppression of the pathway and elimination of the escape routes, that's how we designed PIKTOR.

As you can see from the figure on the right, PIKTOR consists of two drugs, serabelisib, an alpha-selective PI3 kinase inhibitor, and sapanisertib, an mTORC1 and two inhibitor, dosed in combination to fully disable the PAM pathway. With this slide, I want to quickly highlight that we are targeting large markets, starting with presenting data for endometrial cancer this year and breast cancer next year. Based on the clinical evidence to date, we believe that PIKTOR has potential in other indications as well. But today, the focus is on endometrial cancer with PIK-201. With that, I'll hand over the reins to Dr. Debbie Chirnomas. Debbie is a friend, a wonderful oncologist, and our Chief Medical Officer. She joined us from Arvinas, where she led oncology clinical development, and before that, she held clinical development roles at Gamida Cell and Pfizer, and she was on faculty at Yale.

Debbie has run PIK-201 from the start.

Debbie, over to you. Thank you, Anand, and good morning, everyone.

I'm Debbie Chirnomas, Chief Medical Officer at Faeth. Thank you for joining us. Over the next several minutes, I'll cover four topics: why the PAM pathway matters in endometrial cancer, how we designed PIK-201, and the efficacy and safety top-line results. These data are still maturing, and I'll be clear about what is still developing. Next slide, please. Endometrial cancer is the most common gynecologic cancer in the U.S., with about 68,000 cases a year. Unlike most cancers, over the last decade, the incidence is up 26% and mortality is up 36%. It is now the deadliest gynecologic cancer for women with metastatic disease. Five-year survival is only about 20%-25%, and there are no approved targeted therapies. Chemotherapy is still the backbone, with very limited second-line options.

It's also a deeply metabolic disease tied to obesity and diabetes, which is exactly why our approach is so compelling. The biology speaks for itself. 80%-90% of these tumors carry a PAM pathway alteration, with no approved agent targeting that pathway. We will touch base on why that might be a little bit later. This is a large, growing, underserved population where we think we can make a real difference. Next slide. Endometrial cancer can be divided into two main groups. About 80% are endometrioid endometrial cancer, hormone-dependent, estrogen-driven, ER/PR positive, and the PAM pathway is altered in over 80% of cases. That's the population we are targeting. The other 20%, serous and clear cell, tend to be not estrogen-driven, often are P53 mutated, and rarely carry PAM alterations. By focusing on endometrioid, we go exactly where the biology and our mechanism line up.

While the subject of today's call is our endometrial program, I do want to highlight that the same crosstalk, as you can see on the right, between the PAM pathway and estrogen signaling that we also see in breast cancer. Therefore, we believe these data incrementally de-risk our ongoing development of PIKTOR in breast cancer. Next slide. This is a quick overview of the treatment landscape for advanced endometrial cancer. First-line therapy consists of carbo/Taxol plus immunotherapy. That's pretty much it. In second line, the only approved therapies include pembrolizumab plus lenvatinib and single-agent chemotherapy, like paclitaxel. Luckily for patients, ADCs are coming, but they are not here yet. It's important to remember that even though the ADCs, there are quite a few of them, the Topo 1 payload may unfortunately limit them to only one ADC.

If you look on the bottom, if you include the recent phase III data from TroFuse-005 that read out at ESMO, the benchmark for second-line therapy is a median PFS of seven months. That includes pembrolizumab plus lenvatinib at 7.3 months and sacituzumab tirumotecan at 7.2 months, compared with 3.8 months for weekly paclitaxel. We are studying PIKTOR in the second line and beyond setting, and as ADCs move earlier, we believe an oral targeted option could offer physicians a meaningful alternative. Next slide. PIK-201 is an open-label, single-arm phase II conducted in partnership with GOG. We enrolled patients with advanced endometrioid endometrial cancer and a PAM pathway alteration who had progressed after platinum chemotherapy and a checkpoint inhibitor. Patients received sapanisertib three milligrams and serabelisib 200 milligrams once daily, three days on and four days off, alongside standard weekly paclitaxel.

We are reporting on 42 patients who have been treated on study. The primary endpoint is overall response rate, and key secondary endpoints include PFS, CBR, DOR, and overall survival. Next slide. Here are the demographic data. The median age was 65. Over a third of participants had more than two prior lines of therapy, and 12% had four prior lines. All patients had at least one prior taxane, and 38% had more than two. 98% had prior immunotherapy, and 10% had a prior ADC. Nearly half the patients had diabetes or pre-diabetes, and the median BMI is 29, indicating that most patients were overweight or obese, and 76% had distant metastases. These are heavily pre-treated patients, and approximately a third of whom, based on publicly available criteria, would not have been eligible for TroFuse-005. Next slide. Here is the waterfall plot showing the best percent change in the 36 RECIST evaluable patients.

As of the October 30 data cut, the confirmed objective response rate is 33%, or 12 of 36 patients. We also had a single patient with an unconfirmed partial response that had clinical progression prior to the next scan. The disease control rate is 83%. The black diamonds denote patients who are still on study. Seven patients with stable disease remain on treatment, and these patients could deepen their response over time, as we have seen in several of our current responders. Next slide. Here's the same waterfall plot split by PIK3CA status. Patients with a PIK3CA mutation are shown on the left and have an overall response rate of 44%. Patients with wild type are shown on the right.