Hi everyone, welcome to TD Cowen's 44th annual healthcare conference. I'm Tara Bancroft, a senior analyst here, and I'm happy to welcome Aadi Bioscience today, and we'll have Dave Lennon speaking today. Come on up.
Thank you.
Thanks, Tara, and thanks to Cowen for hosting the conference and inviting us to speak today. I'm going to talk to you about Aadi Bioscience. I'm Dave Lennon. I'm the CEO here at Aadi, joining last October, and really excited to talk to you about our story and what we're doing to advance really exciting molecule for rare types of cancer. So I won't spend too much time on the forward-looking statements, just to say that there might be some and you should look out for those. Our vision at Aadi is to make bold choices in applying technology to efficiently deliver improved precision oncology therapies for people living with hard-to-treat cancers. It's a mission we take very seriously, and we really focus on understanding our customers well and applying different types of technology to the problems that they face.
The area we're focused on currently is really unlocking the power of mTOR inhibition, which is a really important pathway in cancer. Previously it's been shown that direct mTOR inhibition can lead to a lot of advances in a number of different cancers, but that category has been plagued by the fact that there were limitations in our ability to really inhibit mTOR as a pathway. We saw relatively low response rates in monotherapies, poor pharmacokinetics, as well as variable oral absorption of those molecules that led to a relatively narrow therapeutic index for prior molecules that looked to inhibit the mTOR pathway in cancer. We at Aadi actually combine novel nanoparticle albumin-bound technology that allows us to modulate the impact and the utilization of mTOR inhibitors to generate a novel way to treat cancer.
Our nab technology leverages albumin as a delivery vehicle, that induces stability, improves solubility, and better targeting of medicines to cancer of interest. And we've combined that technology with sirolimus, which is a relatively, established, mTOR inhibitor that, allows us to deliver but allows us to deliver that technology directly into the bloodstream and thereby, deliver better, kinetics for patients. What that leads to is more complete mTOR, target inhibition, greater tumor suppression, a wider therapeutic index, which allows us the flexibility to think about novel combination strategies, for this established pathway. Importantly, we're a commercial-stage, precision oncology company, and we've actually demonstrated that this approach can work in a rare subset of sarcomas called PEComa.
We've actually generated $33 million in sales since launch in that indication, and I'll talk a little bit about the impact that that's having for patients, with the rare sarcoma called PEComa. We're also advancing a pipeline of multiple different tumor types that we're looking to address with nab-sirolimus, which is a brand name called FYARRO. Most importantly is our PRECISION1 registration-directed tumor agnostic trial, for patients harboring TSC1 and TSC2 inactivating mutations. We also have two phase II single indication trials in endometrioid-type endometrial cancer, as well as neuroendocrine tumors, that we kicked off last year and are currently ongoing. Finally, we have a collaboration established with Mirati, to combine, well, I guess now BMS, to combine their KRAS inhibitor in non-small cell lung cancer and other tumors, that is also ongoing.
We have an experienced management team that has led the commercialization and development of this asset, and, as of Q3 in 2023, $119 million in cash, which allows us a cash runway that extends us well into 2025. Our approach actually utilizes our nab technology and sirolimus to address two different categories of mTOR-driven disease. The first one is TSC1 and TSC2 genetically driven tumors. These are tumors that are impacted by the loss of the tumor suppressor genes, TSC1 and TSC2, which leads to downstream activation of mTOR. Inhibition of TSC1 and or sorry, of mTOR, in TSC1 and TSC2 driven disease, is thought to potentially lead to a new therapeutic modality.
Those mutations account for 2% of all solid tumors today, and importantly, those mutations also already are captured on existing NGS panels, which allows us to use them to identify patients across a broad range of tumor types. We also are addressing what we call mTOR-sensitive tumors, which are tumors where mTOR is an important, the signaling pathway through mTOR is an important component of the cancer progression, and we know mTORs have activity, but where it might have been limited by prior ways of delivering oral mTORs. And in that series of tumors, we are addressing neuroendocrine tumors, endometrioid cancers, as I mentioned, and utilizing our ability to be utilized in combination with an excellent safety profile to treat these otherwise difficult tumors.
That program is captured in the pipeline slide you see here, with FYARRO, approved in the PEComa indication, as well as being developed in our PRECISION1 trial for TSC1/TSC2 inactivating mutations, and then being developed across a range of tumors that I mentioned previously. Importantly, as a program, this is all built off of a single molecule, but with multiple phase II arms and individual programs, we have the opportunity to generate a large amount of data over the coming year. So as mentioned, FYARRO is approved for advanced malignant PEComa. This is an ultra-rare sarcoma estimated to impact 100-300 patients per year in the U.S., so really one of those ultra-rare cancers. There was biological evidence that mTOR pathway activation was important in this, and that formed the foundation for us to look at this indication utilizing nab-sirolimus.
Importantly, these patients have a very poor prognosis, originally with 12-16 months potential survival at median. These types of tumors can arise at almost any site, but are commonly occurring in the viscera, retroperitoneal, and abdominopelvic area, with a predominance in females of about four to one These are mesenchymal tumors, consisting of the perivascular epithelioid cells, distinctive cell type that is associated with blood vessel walls, leading to a large degree of complications in looking at and how these tumors developed and are treated. Ultimately, our product was approved back in 2021 and launched in early 2022. We generated $6 million in sales in Q3 of 2022, and we've seen that be a sustained growth overall in the penetration of the molecule across sarcoma centers in the U.S., with over 180 ordering accounts and a 90% account reorder rate.
Importantly, while this is largely a business that's concentrated in sarcoma centers, we do see increasing adoption within the community, and utilization amongst rare patients who show up in the community setting. Importantly, this is the preferred treatment for sarcoma or preferred guideline for sarcoma includes FYARRO, as the only preferred treatment for malignant PEComa. Importantly, we have established commercial infrastructure to support this product right here in the US. FYARRO approval was based on the AMPECT trial, a registrational trial that was a single-arm study that looked at treating PEComa patients with nab-sirolimus. You can see in this study we had an overall response rate of about 40%, with some really deep responses and two complete responses in this relatively small group of patients.
We saw median overall survival of 53 months amongst these patients, and if you compare that to what has been seen historically, it's a dramatic improvement in the outlook these patients potentially have upon treatment with FYARRO. Importantly, our safety program or our safety profile of the product in this trial was very similar to what we saw with prior oral mTOR inhibitors, demonstrating our hypothesis which were getting improved mTOR inhibition while maintaining a similar safety profile to prior therapies. When we look at this data also by its genetic profile, we see this is the same efficacy data now presented with indication for TSC1 or TSC2 inactivating alterations that were assessed within these patients. You can see in the yellow bars here, these are TSC2 positive patients, a high correlation of response rate between PEComa patients and their TSC2 status as mutant.
We also saw that with TSC1, although there are fewer, many fewer TSC1 patients in this population, and overall we saw an enrichment of response rate, dependent on genetic status, in this population, which led us to the hypothesis that potentially, our product could address TSC1 and TSC2 activate inactivating alterations across a broader, set of tumors. Just to step back and give you a sense of what the unmet need is within this population, TSC1 and TSC2 inactivating alterations occur in about 2% of all known tumors. We did a large survey of the Foundation Medicine database looking at over 440,000 cancer patients, which gave us this incidence rate. And that those tumors with TSC1 or TSC2 inactivating alterations typically cluster into the thoracic cavity, genitourinary or GI tract.
Ultimately, that leads to approximately about 16,000 patients in the U.S. each year that have either TSC1 or TSC2 inactivating alterations, and those are roughly split between, sorry, roughly evenly split between TSC1 and TSC2. So we designed the PRECISION1 trial, which is a registration-directed trial, to look at the tumor agnostic oh, sorry, registration-directed trial, in the tumor agnostic setting. I mean, we enroll any and all types of patients into this trial, as long as they have a positive TSC1 or TSC2 inactivating alteration. This sets up a very complicated trial, which requires us to partner very intimately with the test sites, and those providers of NGS testing like Foundation Medicine and Tempus, as well as US Oncology Network to identify very unique patients within each of these different tumor types that may enroll.
Overall, we've activated over 150 sites associated with the trial, and that can give you a sense, given that there's only 120 patients in the trial, how much activity that we've actually generated, around this program. The study, in essence, was designed as a two-arm oh, sorry, a single-arm study, but with two arms, one each independently to assess TSC1 or TSC2 mutations. This is important because, the FDA wanted to us to evaluate each of the impacts of these loss of these proteins independently, even though they form a complex, in the pathway, upstream of mTOR.
We have enrolled over 80 patients total in this trial as of December, and we had enrolled 40 patients and chose to take an interim look at with 4.5 months of follow-up in those initial 40 patients enrolled in the trial, and that data was released in December of last year. There we saw some durable responses that were observed in a really heavily pretreated patient population of patients where we saw a median of three prior lines of therapy before exposure to single agent nab-sirolimus. Here you can see each of the arms evaluated for efficacy in this initial population, 19 in the TSC1 arm and 18 in the TSC2 arm.
Here you see initially, I want to point out that these patients had a number of prior lines of therapy, so three in the case of TSC1 and 3.5 in the case of TSC2. In fact, in the TSC2 arm, 50% of patients actually had five or more prior lines of therapy. So these are really end of the end of therapy type of patient, and that is dictated by the trial where patients have to have failed on all prior available therapies for their individual indication before enrollment in the trial. So very stiff bar for us to be evaluating then the single agent nab-sirolimus in these patients. With all of that said, we saw a 26% response rate in the TSC1 arm, 11% in the TSC2 arm in this initial early population of heavily pretreated patients.
Importantly, in the TSC1 arm, we saw a really rapid response in the patients who did respond, and an overall clinical benefit rate of 42%. Importantly, there were no new safety findings in these patient populations. Here you can then see the waterfall of that data, and I'll focus a little bit on the TSC1 arm because that's the most interesting of these. You can see the five responses that are recorded on the right-hand side of the TSC1 chart. All of those responses were ongoing at the data cutoff, indicating their robustness, and some of them had reached nine and 12 months of time on therapy. Importantly, we also saw some really deep responses here with 78% and 90% response rates in our two most deeply responding patients.
Overall, we're really encouraged by the activity that we're seeing with nab-sirolimus in this patient population. The TSC1 arm was a little bit lower, obviously, in response rate and depth of response, but with a number of patients ongoing, we still haven't fully evaluated what that might look like once we have those patients out at a longer time point. Ultimately, taken together, our interim analysis, we see as the TSC1 arm being very encouraging with response rates that were in the range of our expectations, and we believe would be, if held up, would be appropriate for potential approval discussions with the FDA. We do see those responses as deep and durable, and that forms the foundation, I think, of a robust discussion about approvability.
Importantly, we saw those responses across different tumor types, which is supportive of our tumor agnostic indication that we're pursuing through this trial approach. The TSC2 arm, overall, the responses were lower, but we believe this is a little bit complicated to interpret at this point, just given the small sample size and the fact that 50% of the patients received five or more prior lines of therapy, which is potentially an issue in trying to evaluate really how bioactive this drug is in this patient population. Importantly, our two-thirds interim enrollment has been completed. We did that in mid-December, which will allow us another interim efficacy readout in Q3 of this year. Overall, we anticipate being able to complete the PRECISION1 trial by the end of 2024 and results in early 2025 with an associated submission if that's appropriate.
Moving on from PRECISION1 , we also have the work we're doing in endometrial cancer as well as neuroendocrine tumors. We kicked off both of these studies last year. We believe the opportunity is really great in endometrial cancer and establishing a new preferred combination with anti-estrogen therapy in this case, which we know from prior studies with mTORs is an area where we've seen signal inactivity between with that combination in this tumor type and where we believe, given the recent changes in first-line therapy that we're seeing with chemo and IO combination, really creating an opportunity for an effective combination to be utilized in second-line therapy. Overall, this population is about 7,000-10,000 patients that we could be addressing each year, and we hope to have data around the initial patients enrolled in the phase II trial later this year.
And then, on the neuroendocrine side, mTOR inhibitors have a long history of being utilized within neuroendocrine tumors, but importantly, we've seen very low response rates within these tumors, which are more indolent, and most of the approvals or the approval that occurred within the mTOR prior mTORs have been based on PFS. So here we're looking at the potential that nab-sirolimus could be best in class in the neuroendocrine setting, with a better response rate and deeper responses that we project based on our preclinical models. Ultimately, we're on the path to become a leading precision oncology company, using nab-sirolimus as a foundation.
This is important to remember, this is an approved molecule with commercial sales, and we are building off of that initial PEComa indication, as we drive our PRECISION1 trial forward this year with multiple readouts, and completions and milestones that we anticipate from PRECISION1, as well as introducing, hopefully, new data from our neuroendocrine and endocrine sorry, and endometrial studies. Ultimately, 2025 will be the opportunity for us to read out the full trial PRECISION1 and look for submission at that point in time for that indication. So, as I said, we're really excited about the opportunity we have for new data within 2024, and thank you for taking time to listen to us today. Questions from the audience, but I have, of course, my own questions if we don't have any.
So obviously in the initial PRECISION1 data, the follow-up was really early still, and you didn't have half of the patient population enrolled. And so I was wondering to what extent you think that efficacy could actually improve over time, either at the second look or at the full data, what once you reach that. Yeah. So interestingly, this, the, class is known as cytostatic agents, and therefore rapid responses are usually not what you might expect within this. And we did see rapid responses, so that's encouraging to us in the first instance, because we do project that durability should be an important component of, the profile of nab-sirolimus, and we saw that within the AMPECT trial.
So it's wholly possible that as we see the program develop, we could see more responses within that context, and there are a number of patients who showed tumor reduction, but were still ongoing on therapy at the time of this cutoff, and we'll see how that data. I wouldn't speculate other than to say we'll see how that data comes out. Are you familiar with exactly what the FDA would like to see? I mean, perhaps not exactly, but a general range of what they'd like to see to support approval. Right. This is always the million-dollar question around what we're looking at. This is a single agent, single-arm trial, in a tumor agnostic setting, which there are very few benchmarks for, in terms of what the FDA actually expects from this.
What we think is important and what we know the FDA focuses on is, in a tumor agnostic setting, did we have a range of tumors that we've enrolled in the trial? Are we seeing responses across tumor types? When you look at the responses, do they do is there good quality of those responses? So do you see depth of response? Do you see responses that are durable? Those are the components that come together that we know that the FDA will look at for the program. There are a number of variables that come together then, in terms of what makes a good program and what makes a good outcome from approvability. With all of that said, we believe our data in the TSC1 arm, if it was to hold up, would be a robust discussion for approvability with the FDA.
Can you tell us, of the new patients that are enrolled up to the 80 that you've disclosed, what % are TSC1 versus TSC2? Like, have you really filled out that TSC2 arm? Yeah, so they're both, we had 22 patients and 18 patients originally in the first interim. It's actually exactly flipped in the second interim, and we have 20 in each sorry, 40 in each category now. Great. So kind of going back to what we were talking about with what does the FDA need to see? Often, what we find, especially in these rarer tumors and in any indication where there's a large unmet need, KOLs will often even use a drug that is generally, quote, "under the bar," because the bar is usually low in these really high unmet need indications. Yeah.
So what is the KOL feedback that you're getting on this? I mean, do they find it meaningful already, and are they excited about seeing what the updated data could bring? Yeah, it's a leading question because if I don't say yes, then that's weird, right? No, of course, yes, they do. No, I mean, I think it's a great question because I do think it points to the fact that you shouldn't apologize. Sorry, it points to the fact so I'll go back to it. So there is a benchmark you could look at with everolimus that there was a study, a two-center study in Boston, in New York that looked at, the utilization of this against that program against TSC1 and TSC2 mutant cancers. That response rate was 7% in those patients.
And so when you start to see and it was kind of similar lines of therapy, similar distribution across different tumor types. So when you start to see things that are at 26%, like four times the number that you saw with everolimus, the physicians do get excited, and it's in many ways, it's beating their expectations, which maybe they were lower, of what the product could potentially do. And certainly, our investigators in the study have not slowed down at all in enrollment. They're really excited about continuing that, and we've seen that. We've had some of our best enrollment runs most recently in the study, so the data is not discouraging to the KOL community, well, at least our investigators at all. And certainly, the KOLs we've talked to have been encouraged by the potential that this could be meaningful benefit for those patients.
Okay, so in the next readout in Q3, are you going to be breaking out tumor types or still keeping it under wraps? I understand you. That's a good question because we get it we get it all the time. People want to know the tumor types. So, to be clear, right, we didn't reveal tumor types in our first interim because we were still enrolling in the study. We didn't want to bias the study by demonstrating zeros or multiple responses in any particular tumor type. And certainly, we're cognizant that the FDA thinks about bias, very intimately, and we've seen that with other programs in a similar vein. So, with all of that said, we will complete enrollment in the spring.
And so by the time Q3 rolls around, we will be able to reveal tumor types in our next interim analysis that we have for y'all. But the hope is tumor agnostic label. The program is designed only as a tumor agnostic label. It would be difficult for us to think about an indication specifically just given the lower numbers of individual tumor types that are enrolled across the entire trial. Okay, so let's see. We have a couple minutes left. So can you next walk us through how you're developing the nab-sirolimus? Nab-sirolimus. We're both stumbling on our words today. Sirolimus plus letrozole trial. How is that designed and, yeah. Yeah, so that I mean, that's an early trial.
So what we've seen, historically, there's been, as I mentioned, good activity seen between anti-estrogen type therapies and rapalogs like sirolimus, in terms of efficacy in those types of patients, endometrial cancer, ovarian cancer, breast cancer. And this has been demonstrated to be bioactive. And the question is, you know, how can we effectively utilize this combination in endometrial cancer, in ER-positive endometrial cancer? And how can we, so we think there's a great opportunity to utilize this combination in that setting. Importantly, we also have seen that if you have too many rounds of chemotherapy, mTOR inhibitors aren't necessarily as effective in that scenario.
And so we've really designed a trial that allows us to be utilized really in first or second line in the endometrial cancer setting, particularly endometrioid endometrial cancer, so that we can avoid the ability of chemo to kind of limit the mTOR inhibitor effectiveness. And that we think is really a winning strategy in this approach and will allow us to really evaluate this novel combination relative to anti-estrogen therapy alone. Any specific plans to go into ovarian and breast? And actually, yeah, data too. Yeah, let me say, so it's a single-arm phase II study that's evaluating the potential in this. Well, we have an initial group of patients enrolling in that trial. We hope to read those out later this year.
And certainly, if that is demonstrating the potential, not only in endometrial cancer, it is a kind of a window into potentially extending that into ovarian and, maybe, breast cancer. I think it's more competitive in that dynamic, and the side effect profile may not be as appropriate just given the number of options that breast cancer patients have today. Anything else in the pipeline that you'd like to highlight for us, or what's exciting that we haven't talked about yet? I think we've hit on all the exciting stuff. I mean, the most exciting things and most pressing things to us, obviously, are executing on this PRECISION1 trial. I would highlight that execution. I mentioned the enrollment's gone really well, really excited about closing out our 120 patients in the spring, and getting on keeping on track to finish the trial this year.
Great. Well, thank you for coming, and thanks, everyone, for being here.
Thanks, Tara.