Good morning. Welcome to our day two of the Cantor Fitzgerald Healthcare Conference. My name is Li Watsek, a biotech analyst here at Cantor Fitzgerald. It's my great pleasure to welcome our next company, Faeth Therapeutics. Anand, I would love to turn it over to you to walk us through the story. Yeah. Thank you very much, everyone. Faeth is a company focused on multi-node inhibition of crucial cancer pathways. We're starting with the PI3K/AKT/mTOR pathway, the most frequently mutated pathway in all of cancer, where we have two oral small molecules targeting PI3K-alpha, TORC1, and TORC2. We've seen a 47% overall response rate in our phase I-B, including some complete responses with good tolerability as well, particularly along the key dimensions of hyperglycemia and stomatitis. We're currently ongoing with a phase II in endometrial cancer, which I'm sure we'll talk about, and phase I-B, phase II in breast cancer as well. We're well-funded. We recently raised $200 million in a PIPE and have over $186 million in cash as of Q2, and focused firmly on the future. Mm-hmm. That's great. Maybe let's start with PIKTOR. Obviously, it's very exciting times for multi-node inhibitor. We talked about PIKTOR's differentiation versus gedatolisib. Then we're talking about maybe lower stomatitis, its ROA, and the PK profile is more favorable. How is it that that's possible that PIKTOR can achieve all these attributes? Yeah. It's always a question that I get, which is, how can you have such low stomatitis, low hyperglycemia? The real answer is, our route-of-administration advantage, being oral, also confers a PK advantage. If you think about an intravenous drug, an intravenous drug, by necessity, is dosed once weekly usually, right? When dosed, you must give the entire bolus of drug at the beginning of the week. That leads to a very high Cmax. Then quickly falling below IC90, in gedatolisib's case, in about 14 hours-15 hours in a given week. Because we're dosed orally- every time we dose, which is Monday, Tuesday, Wednesday, we don't have as quite of a high of a peak, not even close. They're 50X IC90. We're 2-3X IC90. But we are staying in that efficacious range for longer. Greater target coverage without the peak means less stomatitis. The hyperglycemia is really related to multi-node inhibition and pulsatile dosing, both of which we share with gedatolisib. Mm-hmm. I know, Anand, you recently published some pretty interesting skin biopsy data and PK/PD modeling. I wonder if you can just walk us through that data, which I thought was pretty interesting, and maybe connect the dots for us, how should we think about PK/PD and ultimately how that might translate into the clinical outcome? Yeah. Maybe I'll link it back to your last question, which is Yeah how could you see such low rates of AEs? One of the bear cases that I always heard on Faeth was, well, the doses are too low. They're placebo. Yeah. That was one of the reasons why we put out the PK/PD poster. The poster that Li Watsek referring to is a poster we put out at the STOP Cancer conference that showed skin punch biopsies in clinical subjects showing full pathway shutdown at the 200 mg, 3 mg doses that we've chosen in our phase II in endometrial cancer. What that poster shows is whether you look at human skin punch biopsies, whether you look at tumor in vivo levels of inhibition, or you look at IC90, all three of those kind of metrics all triangulate to a similar zone. In either one of those three, we are above those thresholds for significant periods of time. I think it conclusively showed that we're not at a placebo dose, that the dose is indeed active, that it is indeed shutting down the pathway in many patients, and that we're excited to see what that results in the endometrial study. Okay. That's great. I know gedatolisib is approved right now in second-line breast cancer. What do you think of the unmet need still is, and then what the degree of differentiation that you guys have to show, just given you're probably several years behind here? Yeah, great question. I think whenever you talk to KOLs Yeah you hear that breast cancer is an oral space. When you dive into this a little bit, you have to understand the treatment paradigm for these patients. Many times they've been on adjuvant therapy for years. They've stopped adjuvant therapy, and then they recur. If all of a sudden they're in an infusion chair for several hours a week, that's a big shift for these patients who have really had no treatment, or limited treatment for many years. So going from all oral sort of light touch treatment to in the infusion chair regularly is quite a shift. Add on top of that, the tolerability burdens around stomatitis and the prophylaxis regimen required with everolimus four times a day, dexamethasone mouthwash. You start to see this kind of, not burden of disease in the traditional sense but the burden of your disease in a more mental sense. I think is what we hear again and again from KOLs, that this is going to be difficult to keep patients on. We think that what we have to do to win is really three dimensions. So efficacy, tolerability and route of administration. If we can win on any two of those three, I think we become the most widely used drug in the space. Now, I've given you reason to believe why we can win on all three. So efficacy, we have greater target coverage. We'll also show some more preclinical data at ESMO that hopefully should reinforce that case. We also have, on the tolerability side, we've already released data at these doses that demonstrates really good tolerability along the key dimensions of hypoglycemia and stomatitis. Then with our endometrial data, you'll see more. The route of administration is self-evident. We're oral, not intravenous. So I really think we've got a great shot here to improve the standard of care for patients and physicians. Mm-hmm. I wanted to follow up on this efficacy point, right? So we've been getting some questions from investors, and they're really trying to put pieces together. We have some monotherapy activity from PIKTOR, and we have the PK/PD, and we know the coverage is great. Then we also have some early data in endometrial cancer. So how should we just put everything together and think about the potential of PIKTOR in breast cancer? How confident are you that this can perform just as well as gedatolisib? Yeah. So maybe I'll separate how I talk about this into two buckets. Let's think about the disease, and let's think about the combination partner. So when we think about the disease, endometrial cancer, you have five-year mortality that is about 85% compared to about 50% in breast cancer, HR-positive, HER2-negative breast cancer. Then when you look at the metabolic dysfunction, which obviously for a PI3 kinase agent is very important because the most prognostic factors for hypoglycemia are BMI, HbA1c, and fasting blood glucose. In endometrial cancer, 90% of the patients are obese, pre-diabetic or diabetic. Not true in breast cancer. So it is endometrial cancer for PI3 kinase agents or PAM agents is a harder disease. I fundamentally believe that. Just because the pathway biology, the patient population being so metabolically dysregulated, and just the history of failure of PI3K agents, and the increased mortality. When we think about the treatment partner, in endometrial cancer, we're pairing with paclitaxel, right? Because it's the backbone there. I think we all would agree that generally chemo is a tougher regimen and is going to cause greater tolerability issues than targeted therapies like CDK4/6 and fulvestrant or oral SERDs, which are standard of care in breast. For all of those reasons, and the fact that endometrial cancer is a very hormonally driven cancer, like breast cancer- we believe that there's significant read-through- from endometrial to breast, and really that in many ways endometrial is going to be the tougher disease. Mm-hmm. Now, maybe we can talk a little bit about your phase II endometrial cancer data. I believe you're going to present by the end of the year. First of all, can you just remind us of what you guys have showed in endometrial cancer patients before, and maybe set the expectations for us in terms of what to look for in the data update later this year, and what would constitute good data? Yeah. In our phase I-B, which was a mix of advanced solid tumors- we had five endometrial cancer patients. Of those five patients, we had three complete responses, one partial response, and one patient with progressive disease. It's a small data set, right? Admittedly. And those patients were heterogeneous. Not all had received IO. One of them hadn't received taxane, so it's a mix. Our phase II will be more homogeneous, where everyone will have received carboplatin, everyone will have received IO. We are really looking forward to that data set, especially when you consider that there is a significant unmet need in this disease. In terms of expectations, the likely comparator in a phase III is paclitaxel re-challenge. Paclitaxel re-challenge in the KEYNOTE-775 study, which was in an IO-naive population, showed about 15% response rate, three to four months PFS. We will need to do is to beat that, likely in a phase III. Anything that shows significant differentiation above that, I think is going to look winnable. To give you an example of another data point that has recently come out, sacituzumab govitecan, in its phase II China-only study, showed a 30%-35% response rate, six to seven months PFS. That announced that in their phase III now that that was a positive trial, and they hit the first interim OS look and hit on PFS as well. Now we'll see that data at ESMO in Madrid, but I think it gives you a good sense of what good looks like. If we're seeing response rate kind of in the 30% and PFS looking like six months, you're going to win in a phase III, an all-come win. So for this data read out, by the end of the year, you're going to be sharing response rate. Are we going to see PFS or it's too early? Yeah, it's a little early for PFS. You will see response rate. You'll see adverse events of special interest. Yeah discontinuation. We'll also try to give you a read on durability. So landmark analysis, some other measures that allow you to see durability in these patients as well. Mm-hmm. Anand, you mentioned sacituzumab govitecan's phase III data will be presented at ESMO. Do you think that is going to set the bar for second line? Yeah. It is a great question. They are moving forward into a first-line maintenance study, TROPiCS-03, already. The treatment paradigm in endometrial cancer is carboplatin plus PD-1 in first line. That is a limited duration treatment, and now they are planning a maintenance treatment with sacituzumab govitecan afterwards. Second line after first line maintenance is going to be wide open, and unfortunately, will be paclitaxel rechallenged. That is something that we think we can really bring to patients so they are not left with that option in second line. What's your expectation for the control arm in that study, given I think it's going to be probably the most contemporary benchmark for you guys? Yeah. Just to give a little more context, the KEYNOTE-775 arm, which was their control arm for pembrolizumab and nivolumab trial was, as I mentioned, 10%-15% response rate, three to four months PFS. That trial was in an IO-naive population. sac-TMT will be in an IO-experienced population. That's the major difference. I would anticipate something similar. That's generally the best guess I have. You may see a slight decrement because of IO experience or just as a function of more lines of therapy, but hard to really guess. Yeah Right now my default is that it's going to be similar. The KOLs I talk to sort of agree with that. Anand, as you talked about maybe sacituzumab govitecan is going into frontline maintenance therapy, obviously we are looking at evolving treatment landscape. Yeah. You talked about the second line is wide open and maybe there is some potential for a combination. How are you thinking about, after your phase II data, the development path going forward? In endometrial? In endometrial. Yeah. Yeah. I think as we think about moving forward in endometrial, the real unmet need is really in pMMR patients, which constitute about 75% of the patients. Right now they are getting carboplatin plus PD-1 in the first line. There are good response rates, but the PFS could be improved upon. It is about 12 months for many of the patients. What I think would be interesting personally is in gynecologic cancers where we are seeing all these ADCs coming to the forefront, is if we can already pair with paclitaxel- then what are ADCs but more targeted chemo, right? If we can pair with an ADC, and given what we know thus far- our toxicities don't appear to overlap. We don't have ocular tox, we don't have the ILD. Our stomatitis is much lower. That's a potential combination that I think could be very interesting in first line, or even as a way to differentiate some of these ADCs. Right now, a lot of these ADCs, it's a knife fight, right? Yeah. They're all Topo I payloads, and you can't rechallenge Topo I after Topo I as far as we know. The exclusion criteria in almost all of these trials is no prior Topo I exposure. I'm not sure what you're going to do if you're the third or fourth ADC, however good your data is. Yeah If patients have already received Topo I. I think what we have is the ability to help some of these differentiate, particularly in gynecologic cancers, where we know the burden of pathway mutations in both endometrial and ovarian is relatively high. Mm-hmm. That's a good point. Just curious for your phase II study, have you enrolled any patients that had prior ADC exposure? I believe so, but I am not 100% confident. I try not to bother my CMO Yeah. on a too regular basis, otherwise she slaps my hand. So, yeah. Okay, I guess we will just have to see when you Yeah present the data. I know we talked in the beginning, you said endometrial cancer, just from a biology perspective, is a more challenging histology relative to breast cancer. We have seen PAM inhibitors being tried in this setting, and we have not seen a ton of success. What makes you think that PIKTOR will be different? My second question is, can you just remind us of what gedatolisib has showed in endometrial cancer? Yeah. What makes me think that it would be different- Yeah is that prior attempts have often, not entirely, but often focused on single node inhibition. This is fundamentally the problem that we think is pervasive within the entire PAM field. My co-founder is Lewis Cantley, the guy that discovered the PI3K pathway. When you only hit one node in what is a very plastic pathway, you get reactivation. You give a PI3K-alpha inhibitor, and what you see is PTEN mutating and resistance occurring. If you have a multi-node inhibitor that hits the pathway at the top and the bottom, at PI3K-alpha and TORC1 too, you are actually preventing that treatment resistance. In a disease like endometrial cancer, where PTEN mutations are pervasive- pervasive, giving a single node inhibitor is like It just doesn't make any sense to me. It sort of drives me slightly crazy, that the biology is so obvious, it's standing in front of us and people are still pursuing single node approaches. Yeah, anyway. You asked about inavolisib's monotherapy activity. Inavolisib, in the del Campo study, showed about a 16% monotherapy ORR in a staph mid enriched population, which was lightly pretreated. Then they also showed in a taxane naive population, I believe, one response out of four with carboplatin. Those are the two datasets we have with inavolisib. Okay. Maybe switching over to the breast cancer trial. You guys are doing combination with fulvestrant. Give us an update on where you are with this study. Yeah. So, in our breast cancer study, we have fully enrolled cohorts at a dose escalating with fulvestrant. We have begun enrolling cohorts that are dose escalating with fulvestrant and palbociclib. As those cohorts continue to enroll, we will test a variety of doses. Some lower and some higher than the current doses in endometrial cancer. Our belief is because of the general greater robustness of breast cancer patients, we may be able to push dose a little bit in breast cancer, but that remains to be seen, and we will do what is best for patients in the future of the program. We are excited. We have a wait list, which is one of the first times in my career I can say that we have had a wait list for enrollment. I think it speaks to the demand Yeah amongst physicians and patients for oral options. Yeah. That is great to hear. It sounds like you guys are already in the triplet dose escalation portion. When would you be able to select a dose based on what you are seeing right now? Yeah. We are trying to do so expeditiously but also judiciously, right? We've seen a lot of drugs in breast cancer fall down by not taking enough time in that dose escalation period. We wanna make sure that we get good durability data. You don't wanna have to go back and do dose escalation again, right? This is something that we saw with some SERDs, which shall remain nameless. But you wanna make sure that you do that right, that you give patients on those dose cohorts a little bit of time to mature and not just one month, great, move on to the next dose cohort. One month, great, move on to the next dose cohort. Really give those dose cohorts a little bit of time to mature. and see what are you seeing in terms of both activity but also tolerability for these patients over time. I don't have any strict timelines that I can give you, but I can say that we are moving as quickly as humanly possible with a lot of excitement about this program. What's your criteria to pick the optimal dose? I know you said maybe you guys can push the dose a little bit, but then you have to balance with tolerability, and you also want to show some durability. Walk us through your thought process on how the team is internally thinking about how to pick the right dose. Yeah. It's an art as well as a science, as you know. Yeah. I think what we know about breast cancer is it's slightly more indolent tumor than endometrial typically. We want to make sure that we have a tolerability profile that allows patients to stay on this- for extended periods of time. Also, as we look forward in the future to potential first-line settings, we have doses that are tolerable in those settings as well. This is going to be potentially a doublet or even a triplet Yeah combination, with PIKTOR. We really want to make sure that that burden of toxicity is approachable for patients and gives them good quality of life. Yeah. That is definitely number one. Then, because if you cannot stay on the treatment, how are you going to drive durability, right? Yeah. I think that's first and foremost. But then we've got to look at the activity as well. Are we seeing different activity at different dose levels? That means we should favor one or the other. It's multifactorial. I'm probably not telling you anything that is too surprising. But, yeah, we're trying to look at it from all angles, as well as the PK/PD angle. In case there are any differences in breast vis-a-vis endometrial. For the data update that is going to come next year, can you set the expectations? My understanding is that you want to present a fulsome set of data. The second question is, what should be the bar? Should we look to VIKTORIA-1 as the right benchmark that you want to beat, get at? I think the bar is every patient population is different. If we enroll a higher proportion of patients who have had chemo or patients who have had bone-only disease, that bar changes. depending on that. It's hard for me to put any particular line in the sand on that. But I think, in breast cancer, typically CBR16, CBR24- Yeah have been important markers. I think we'll look to those to see the efficacy of the regimen as well. That's really what we're looking at. Response rate, of course, in breast cancer has generally been predictive. Things with kind of 25%+ ORRs have generally done relatively well. When you look at the PIKTOR 1 wild-type cohort, you saw on an ITT basis about a 25% ORR. I think it's a reasonable benchmark. Do you want to wait for median PFS or you think not necessarily? I would love to wait till median PFS. I'm not sure whether the markets will give me that time. I think we'll look at the dataset and try to put out what we think is a meaningful and fulsome data readout. Yeah by year-end of 2027. Okay. We want to give people that signal that they can have confidence in enrolling in a larger study, a potential phase III in 2028 or, yeah, soon thereafter. In terms of a potential phase III trial, you talked about you may not move the triplet regimen into the phase III. What are the alternatives that you guys are thinking about? Yeah. I think when you say the triplet regimen, you're saying fulvestrant- Fulvestrant And palbociclib. Palbociclib, yeah. I think what we've seen in breast cancer is an evolution of the treatment paradigm. If you think about breast cancer, there are three pillars of breast cancer. You have hormone therapy, you have CDK, and now you have multi-node PAM. Those are the only things with labels all the way across HR+ HER2- breast cancer. I think about picking what is the most modern forward-facing regimen in each one of those buckets. Starting with second line and then thinking about first line, that's the framework that we are thinking through all of our clinical development decisions. When we look at the hormone therapy bucket, for example, while fulvestrant still has a label all the way across, I think we look at oral SERDs, we look at the data there, both in the ESR1 mutant. Yeah ESR1 wild-type populations and say, in the wild-type populations, oral SERDs look as good as fulvestrant. They don't look any worse. The kind of difference in the PFS curves can't quite put a finger between, right? It generally shows superiority, but not enough separation. What we want to do is, ideally, when you think about the ESR1 wild-type population, why are they not showing that separation? Many of those patients have PI3 kinase pathway mutations that appear to be the driver in that setting. We think we could help an oral SERD potentially demonstrate activity in ESR1 wild type patients as well. When it comes to that hormone therapy bucket, we would like to help the field move away from fulvestrant. We think that's something that we can help bring. The oral SERDs are favored generally by physicians and patients. Who wants an intramuscular injection in your butt every month, right? Doesn't sound great to me. I don't think it's great to patients either. Maybe just lastly, on contribution of components, because we got that question from investors a lot. Anything you can share in terms of the FDA feedback, just on this issue? Any gaps that you guys would need to address? Yeah. First of all, PIKTOR is two small molecules, serabelisib, which hits PI3K-alpha, sapanisertib, which hits TORC1/2. Contribution of components will be necessary. In endometrial cancer, that we've already demonstrated the contribution of sapanisertib to paclitaxel. We will have to answer the question of serabelisib plus paclitaxel. In prior conversations with the agency, that's been really focused on 20 patients- 40 patients' worth of data. Now, we'll reconfirm that at our end of phase II meeting. That's our belief at this point, is that that could be folded into a phase III, and that question could be answered with 20 patients- 40 patients with an inbuilt futility analysis. It will not need to be stat sig, probably a qualitative analysis. That's our belief at this time, yeah. In breast cancer, we think that question is already solved with prior work that Takeda has done. Okay, great. Thank you so much, Anand. I enjoyed our discussion. Yeah, thank you. Thanks again for the time.