All right. All right, welcome, everyone, to day one, Jefferies Healthcare Conference, in London. So our next presenting company is, Aadi Bioscience. Welcome, Dave and Scott.
Good morning.
Thanks, Roger.
Awesome. Yeah. So, maybe we start from the overview. You know, if people are new to Aadi's story or know you for a while but haven't really followed for the recent updates, what is your updated elevator pitch for the investors?
Yeah, sure. Thanks, Roger. Thanks for allowing us to attend today at Jefferies, and welcome, everyone. Thank you for coming. So we're Aadi Bioscience. I'm the new CEO, Dave Lennon. I joined in the beginning of October, and have been delighted to be sharing the story of Aadi, since then. We are a single-asset company developing nab-sirolimus, which is a technology between delivery, a technology that was utilized in Abraxane previously with sirolimus, which is a potent mTOR inhibitor. Combination of that allows us to deliver this product IV and improve bioavailability and inhibition of the mTOR pathway, key pathway in precision oncology and oncology indications in general. Our technology initially has been approved for use in PEComa, which is a rare soft tissue sarcoma, and that's under the brand name FYARRO.
And we announced last quarter, we sold about $6 million, and $18 million year to date in that product. Importantly, we're developing that product for a tumor-agnostic indication for a series of mutations that impact the mTOR pathway and cause overactivation of the pathway. Those are so-called TSC1 and TSC2 mutations, and that trial is called PRECISION1. We've been enrolling that trial since 2022, and are on good track to share an initial interim data on the first one-third of patients enrolled in that trial in the middle of December. We also have trials in endometrial cancer, neuroendocrine tumor, and in lung cancer in combination with Mirati's KRAS inhibitor.
Ultimately, we see this product as a multi-indication, multi-billion-dollar opportunity in precision oncology, and we're continuing to pursue and develop various opportunities with nab-sirolimus as the core for the Aadi platform. Thanks.
Excellent. All right, so it is single asset, but it's a product in your pipeline, so with the many different opportunities and in pretty diverse and kind of orthogonal indication-
Mm-hmm
... potential. So but I understand the investor absolutely going to focus on the precision, the pivotal TSC1 and TSC2 inactivating tumor in your tumor-agnostic kind of a pathway. And you just mentioned you're gonna read out the first interim data, which is early interim analysis upcoming by the end of this year. So what should we expect from there in terms of patient number-
Sure
... and what are the data we're gonna see? What do you consider a winning scenario for you?
Sure. So Precision is, as Roger mentioned, it's phase II registration-enabling trial testing both TSC1 alterations and TSC2 alterations in various tumor types because it's tumor agnostic. Each of those arms will read out independently, so we basically have two different opportunities to identify positive responders to nab-sirolimus. The trial is meant to enroll 120 patients in total, 60 in each arm. This first interim, which we'll read out in mid-December, will be 40 patients or 20 patients in each arm with four and a half months of follow-up. Importantly, the question will be: what does good look like within this context? And ultimately, I'm not gonna give you the number because I don't know it yet, but the when you look at-
You know we can ask it.
Yeah, of course. When you look at comparables, tumor-agnostic studies, products that have been approved to date have been anywhere from 29%-76% response rate. Importantly, when you look at prior tumor-agnostic trial with other mTOR inhibitors, it was everolimus trial that actually showed 7% response rate overall. So, you know, improvement upon the prior studies or or on the prior study or finding response rates in the range of what we saw before, we would consider success at this point in time.
Okay, awesome. And those patient at least they will have a 4.5 months follow-up. How many scan they will have, and how much durability data we're gonna see?
Yeah. So patients will have a minimum of two scans post-baseline. Most will have three scans post-baseline. We look to try to provide as much durability as possible, but obviously, it'll be an ongoing trial.
Yeah. Yeah. Okay, so that's the first interim. It, it is not like a formal statistical analysis, so you won't claim this a success or failure, anything like that?
Yeah. I should have said it's a investigator-assessed overall response rate, so it's not our primary endpoint. We do have a second interim planned with 2/3 of patients enrolled, for Q3 of next year. That will be based on the centrally reviewed scans.
Yeah. And then that, that is the second prepared pre-planned interim analysis, 80 patients, 2/3, and all of them will have, like, around 6 months follow-up.
That's correct. 6.
So how should we think about that data readout? And I believe this is, you have some formal statistical plan there, so in terms of futility, utility, and maybe stop and maybe even modify the study.
Yeah. No, it's good. It's a good question. I think, you know, an important part of understanding this trial is the fact that we are, you know, in many ways, we're learning a lot about the performance of the product in the context of TSC1 and TSC2 mutations within this trial. We didn't conduct a phase I for this program, and the phase II is really our first exploration of this indication. So this first interim gives us some indication of where we are. The second interim is more traditional interim point, where we're looking at the efficacy with six months of full follow-up on 40 patients in each arm. That point in time, we'll be able to actually look at the statistics of where we are with the program overall.
Importantly, I think the opportunity then to assess, do we need to adjust the trial, increase sample size at all to improve its robustness, or, if we can stop the trial early for potential efficacy and filing with the FDA. I think importantly, we would, you know, want to embark upon that discussion with the FDA once we have that data in hand.
Okay. So before the final data, after the two-thirds of the patient, you will have a conversation with the FDA to talk about how should we proceed, the study?
I mean, always open to what the actual data tells us at that point in time, but I think our plan would be to do that.
Got it. Okay. And then interesting, so maybe let us know what is your enrollment trajectory right now, and what's the goal to complete the enrollment? And you mentioned in that second interim analysis, potentially you can modify the study, either upsize...
Mm-hmm
... the study. How, procedurally, are you gonna achieve that?
Sure. So enrollment has been going extremely well. We're really happy with where we are with enrollment. We project that we will complete the full 120-patient enrollment by the spring of this year, and ultimately, the trial will be completed by the end of 2024, with data at the end of 2024 or early 2025 on the full trial. The adjustments we could make at the interim, including enrollment or stopping early - sorry, were, you know, will be dependent on the data at that point in time. And... Sorry, your question was?
Yeah. So if you decide to upsize or-
Oh, if upsize, yeah.
Well, procedurally, how are you gonna do that?
Yeah, I think it's a good question operationally, if we can kind of complete the 120 enrollment in the spring. I think importantly, you know, we have developed a system to activate sites just in time. And we have over actually 150 active sites within the U.S. We've been able to stand up sites within, with less than two weeks, and it's required in a tumor-agnostic study because we're not targeting a particular subspecialty. We are targeting many subspecialties. And therefore, you know, we have this ability to kind of ramp up and ramp down extremely quickly, and if we need to enroll more patients, we feel comfortable we'll be able to do that.
Got it. Okay, so you know I'm gonna ask you this question. You are not gonna be able to give me the answer today, but how are you gonna help us contextualize the data you see? I believe you give us some number, 27, 27 to-
Yeah
... 60, 70, each for the tumor-agnostic label, approve the drug, and then the previous mTOR in the tumor-agnostic, at 7%, and, somewhere in between?
Yeah.
How and maybe also when you will help us to contextualize, you meet the statistical hurdle with the FDA or even just, some of the benchmark you provide?
Yeah
... to the FDA say, "Okay, that's the, that's the target we wanna-
Yeah. You know, I think it's always important to step back and understand that tumor-agnostic studies are not, you know, as easy to interpret from the outset as more traditional indication-based studies. Because the underlying data supporting the discussion around statistics is unknown to us until we actually enroll the trial. We don't know the tumor types that are enrolled until we actually enroll the trial. We don't know the line of therapy that we're enrolling until we see the trial data. Importantly, that means that we have a heterogeneous mix of tumors that all have different trajectories and different underlying standards of care that may have been applied to those patients.
In that context, it's important then to understand what we're seeing holistically across the whole population, but also, what are the individual patient responses that are occurring, and which tumor types they are occurring in. And those are all important considerations we know with the FDA. When we present an early data set, we know that we're missing, you know, roughly probably half of the tumor types that we may eventually see within the trial. And, we, you know, the full population mix won't be transparent to us. So we can give an idea of where we are in this first interim. I think the second interim is much more predictive in that sense-
Mm
... because it would be more representative of the ultimate population that enrolls in the trial, and obviously just has a greater weight of patients at that point in time.
Got it. Yeah, so yeah. So I think the tumor types you enroll or the three in the trial are absolutely gonna dictate what's the real bar for the approval. So would you be able to tell us the kind of a benchmark at the second kind of interim, or you will wait for the final and even maybe after discussion with the FDA, so investor will have a little bit clear view-
I-
... where you're gonna heading to?
Yeah, I think the second interim will be much more informative from that perspective. Again, I think it, we will have, at that point, generated the likely understanding, not just of the enrollment we have of the patients, in that two-thirds, but we'll actually have the demographics of the full enrollment at that point in time because we'll have completed the 120 patients by the spring. And so we can not only give a, an update on the interim, but we can potentially give an update on the demographics of the entire population-
Mm
... which allows us then to think about prediction of what the right efficacy bar is for that population... that makes sense.
Yeah, that makes perfect sense.
Yeah.
Yeah. So absolutely, the second one will-
Sometimes when you're talking, you don't understand if you make sense.
Yeah. So, okay, so that's very good, and, you know, it's good. That's a recent update from your earnings. You say you will have the second one, second interim analysis, and then we will know a lot more about the potential bar-
Yeah
... for the trial. Okay, and then another topic investors also are very interested is the how likely you're gonna be able to file TSC1 and TSC2 independently, depending on the data.
Yeah.
You know, we hope you hit both, but, yeah, what if you have one but miss the other one, how you're gonna handle the filing? I think we discussed earlier-
Yeah
... in terms of biology, underlying biology, maybe start, we start from a regulatory kind of a hurdle-
Sure
... and then we tie back to the biology.
Biology, yeah.
Yeah.
Yeah, so importantly, you know, when we talked to the FDA, the FDA was really keen to understand if there were differences between TSC1 and TSC2 type mutations in different tumor types. And this is important 'cause the underlying biology, while we often talk about it being connected, there's some potential that it could be different. So TSC1 and TSC2, scientifically or biologically, act as a complex, and therefore, loss of either protein leads to overactivation of the mTOR pathway. So they are inhibitors of the mTOR pathway, and therefore, inactivation of either gene often leads to activation of the pathway.
It's therefore thought that the biology isn't terribly different when we think about knocking out either one of these genes, and that they would act very similarly in the sense of conditions, and we see that across genetic disease and across tumor types.
Mm.
So the FDA was still, though, keen to understand that independently, and the trial is actually set up for us to actually be able to. And it is set up to independently look at each arm, and each arm can be filed independently as its own indication. So therefore, a win in either arm is a win for the product and a win for patients in the sense that we'll be able to treat that portion of patients effectively.
Got it. Let's say if you have 60 patients for TSC1 or TSC2, how should we think about the safety database and the exposure to that population? I understand you have approved the drug, but, you know-
Yeah
... overall, the package will, if we just have one population.
Yeah. So the safety population will always be the full trial.
Mm.
So you'd have to still consider the full population, safety in the full population overall. You know, importantly, mTOR inhibitors, in general, have been utilized for a long time and with a known safety profile for the class. Our product hasn't demonstrated any significant differences from the known safety profile for the class, and we're really confident that we're not gonna generate anything new at this point.
Yeah. Got it. So a lot of the investors are asking me, you know, how big the market really is for the TSC1 and TSC2. You have been publishing quite a lot epidemiology and based on the genetic mutations-
Yeah
... kind of testing. So maybe just elaborate on how big the market will be and how practical you can capture those patients in the real world.
Yeah. You know, the trick always with tumor-agnostic studies is then how do you think about commercialization of those studies? So TSC1 and TSC2 mutations occur across the gene. There's no single point mutation, et cetera, that we're focused in on. And we test today through NGS, so we utilize next-generation sequencing to identify largely, fully inactivating or fully altering mutations. So these are mutations which fully knock out the protein expression, so things like frameshift mutations, stop codon, splice site mutations are incorporated within this context. We've done a large analysis both with Tempus and with Foundation Medicine that demonstrates that pretty consistently, about 2% of all tumors have either a TSC1 or a TSC2 mutation. They roughly split equally between the two genes.
And we've then looked at, given the rates of mutation in each of the tumor types, how does that apply to the overall potential population that's out there? And what you see is about 16,000 patients overall, who have either TSC1 or TSC2 mutations each year within the U.S. alone. About 8,500 of those are on the TSC1 side, 7,500 on the TSC2 side. While they occur across all different tumor types, they tend to cluster in a few areas. So about a quarter of those patients are gonna be lung or thoracic patients. About a quarter are going to be in the GI space or GI tract. About a quarter are general urological type conditions, so a kidney to bladder connection.
And about 12% are in the gynecological and breast cancer space, and then you have a long tail of other stuff. So while there's many tumor types that are involved in the treatment of, that are evolved from TSC1 and TSC2 mutations, they do consolidate in a few of these areas, and that's how we would focus commercialization, is really thinking about the customers that we're going after, and educating them about the space.
I don't believe you have disclosed exactly what are those TSC1 and TSC2 inactivating kind of mutations?
Mm-hmm.
But you have a set of the mutation. I think you used to call it definite-
Yeah
... kind of impact, population. So are all of those mutations are readily available in the commercial, NGS, and, how much additional work those physicians need to do to identify those, mutations?
Yeah, so, for the most part, the algorithms we used are aligned, very much aligned to the algorithms that the various providers of NGS testing utilize to identify TSC1 and TSC2 inactivating alterations. It's important to note that actually, there's about 5%-6% of all tumors have TSC1 or TSC2 mutations that accumulate, but only 2% are what we would call likely or pathologically inactivating tumor mutations that it impact the tumors. And so we're really focused, and there are clinical trials focused on those that are really known to be or very likely to be pathological mutations. But there is a whole host of opportunity to explore whether or not some of these other type of point mutations or missense mutations are really contributing to TSC1 or TSC2-driven cancers.
Okay, awesome. So yeah, I think we spent a fair amount of time on the precision as expected.
Mm-hmm.
But you do have some indication expansion to add the combo, add the mono into endometrial and NEC, NET, and then the KRAS. Maybe tell us a little about the status of that.
Yeah
... and what's the rationale behind those, indication expansion?
Sounds good. So, as I mentioned, endometrial cancer, neuroendocrine tumors, and lung cancer and other cancers are areas that we're exploring, either on top of standard care monotherapy or in combination with novel agents. And each of those is a unique opportunity, but really, a really exciting one. So in endometrial cancer, we think there's a really key opportunity within second-line endometrial cancer with IO plus chemotherapy now being moved into first line, to provide a alternative combination package that could service patients. And here, we're looking at combination on top of standard of care for the estrogen receptor inhibition pathway. And that trial has just started over the last quarter, and we're really looking forward to sharing more of an update in 2024.
Similarly, with neuroendocrine tumors, I think we have an interesting proposition there in that neuroendocrine tumors are a known target for mTOR inhibitors. There's approved molecules within the space, but the response rate, traditionally in mTOR inhibitors, for neuroendocrine tumors has been very low. So while patients who do generate a response actually have a very long PFS within that context, we think improving response rates with nab-sirolimus, which we anticipate is a more potent mTOR inhibitor, could be really promising. Then we have this combination with Mirati's agent in lung cancer, looking at building upon the opportunity for KRAS inhibition with kind of a known escape mechanism that occurs through mTOR, the mTOR pathway, and we think that's a promising, potentially synergistic combination to utilize within those patients.
Excellent. Okay, so we have been talking about this, you know, in development, indication, but, FYARRO is approved-
Mm-hmm
... as a brand name. So maybe tell us, what is the current kind of sales trajectory look like? I believe last quarter, a little bit flat. So how do you think about - how should we think about the PEComa overall opportunity for FYARRO? But we know the larger opportunity-
Yeah, sure
... indication. Yeah.
Sure, but it's still important to have that base of business that we operate from with FYARRO, which is approved in PEComa, a rare soft tissue sarcoma. These patients, performance there has been really strong as the uptake in the academic centers and centers with sarcoma has been excellent. We believe we're capturing over 80% of patients first line in PEComa when they're diagnosed. There's just not very many of them. There's about 100-300 patients in the U.S. each year. You're finding needles in a haystack, even in very targeted sarcoma centers, they might see only one or two patients a year. And therefore, we are, you know, consistently looking to think, "How do we grow outside of the core centers?
How do we generate and make sure all patients are getting diagnosed, and then getting triaged into the right places so they can get treated?" We have seen growth was flat over the course of last quarter, and I think this indicates, you know, our penetration in those key centers. But we do believe still there's an opportunity to grow outside the core centers in the more community setting.
Mm-hmm. In terms of the real world, how is the duration of treatment line, if 80% of the first line-
Yeah
... in those core centers, so what is the line of therapy, line of treatment you are getting for the patient in them compared to your clinical trial, which is, you know, pretty robust?
Yeah. I mean, the clinical trial data was 6-7 months of duration, and we're seeing something that's very comparable within the real-world setting.
Awesome. Okay, great. So lastly, what's your cash position? And maybe just recap the upcoming catalyst, which will be pretty eventful for the next 12-18 months. Yeah, so from-
Sure. Well, I brought Scott for a reason. He has to-
Yeah.
- can answer the cash question.
Yeah, good.
Yeah.
Yeah, so as of the end of the third quarter, so September, we had $119 million in cash and short-term investments, and we said that takes our runway into 2025 and also contemplates the completion of the PRECISION1 tumor-agnostic trial. And I'll turn back-
Yeah, and just to, to highlight the catalyst, so we mentioned mid-December for early interim data. Importantly, though, next year, I think, becomes really pivotal for the precision trial. So we'll have complete enrollment in the spring of next year for the full 120 patients. We'll read out our second interim update in Q3, and we plan to complete the trial by the end of 2024, with data sharing at the end of 2024 or early 2025.
Awesome. It's a long wait, but it's kind of worth this wait for the precision. Anything else we haven't talked that you wanna impress upon us?
I think you've done a great job, Roger, hitting everything, so thank you.
Appreciate it. Okay, thanks for the time, and thanks, everyone.