Good afternoon, everyone. Tara Bancroft here. I'm one of the senior biotech analysts at Cowen. Thank you very much for joining TD Cowen's Fifth Annual Oncology Innovation Summit. For this session, we have a fireside chat with Aadi, and it's my pleasure to introduce Dave Lennon, who is the President and CEO of Aadi. So Dave, it's a privilege to have you here, and thank you so much for joining me. I do wanna note that before we get started, for everyone who's listening in the audience, please feel free to email me any questions, or submit questions through the link that was provided. So, Dave, to start, before we dive into more specific questions, can you provide an overview of Aadi and a general update to kick things off?
Sure, happy to. Thanks, Tara, for hosting the summit. Thanks to Cowen for that, and thank you for inviting us to share our story today. Aadi is a commercial-stage biotech company that's developing a next-generation mTOR inhibitor we call nab-sirolimus, for application against a variety of tumors. Nab-sirolimus, also known as FYARRO, is an improved product for an ultra-rare soft tissue sarcoma that we currently had about $25 million in sales for last year. But we're also developing this compound in a subset of mutation-driven cancers, as well as neuroendocrine tumors and endometrial cancer, as a next-generation mTOR inhibitor to further advances of treatment for patients with those different types of cancers.
Okay, great. So actually, let's start with PEComa. So, you know, you've had pretty steady sales and, you know, growth throughout the launch of it. But, you know, and a very slight decline in Q1. Can you maybe provide some context for Q1 sales and what you anticipate to see throughout the next several quarters in 2024?
Yeah, for sure. So PEComa, a rare soft tissue sarcoma, you have about 300 patients in the US each year, and that's where we're approved and currently sell FYARRO for this indication. We did see a bit of a decline in Q1. It was really impacted by two issues that we see as transitory in nature. So one was a bit of a change in distributor buying patterns that led to a drawdown in inventory, which we expect to reverse out of into normal levels in the coming quarters. And at the same time, we saw a dip in some of our new patient starts at the end of Q4, and that bled into Q1.
You know, interestingly, this was correlated or occurred at some of our largest accounts, where we have a large overlap with our clinical trial sites of our ongoing PRECISION trial. We suspect that some of this may have been just some cannibalization across those. Even though we don't have patient-level data, we know there's the potential that that was occurring. As we mentioned, we only have about 300 patients each year in the US that we treat. We had over 80 patients recruited in the last nine months in our clinical trial, so a large proportion, very similar kind of proportions between the clinical trial and our commercial sales.
Overall, what I think is important to take away is we do expect a return to growth in Q4, as both of these trends reverse now that the clinical trial's over, and we're already seeing inventory pick up. In terms of sales guidance, you know, we've mentioned a number of times that we're highly penetrated in the PEComa market. We have 70% first-line usage, very high awareness among key prescribers within the PEComa and sarcoma area. And we anticipate that any growth that we generate here is really incremental in terms of finding new patients to put into the funnel, in this very rare indication. I think one of the key things is getting patients diagnosed into the right centers, where they can utilize FYARRO for those patients.
Okay, and just to clarify, you said you anticipate a return to growth in Q4, or-
Sorry, I-
Q2
... Did I say Q4? I meant Q2.
You did. We miss nothing here.
Yes.
Okay, great. And, okay, so then I guess, do you have a global commercial strategy for FYARRO? Like, are there any plans underway for filing in the EU or other markets, anything like that?
We do. We've been looking at where else we can launch and support FYARRO. Our core focus has been getting the results from PRECISION1 to drive that strategy. Whether or not we lead with an ultra-orphan indication like PEComa, which is quite rare, to stand up the commercial infrastructure for the handful of patients that may be available in each country might be difficult. And so we're looking first at making sure we understand the potential for each of those markets with PRECISION1 in combination with PEComa before we launch into those other markets. But certainly it's on the horizon now, especially as we look at Q3 for our PRECISION1 next interim readout, helping us determine the trajectory of that strategy.
Okay, and when thinking about growth going forward, not just in 2024, but beyond, are there any other barriers or concerns that you're all mitigating or at least keeping visible amongst yourselves, like generic entry or manufacturing? Anything to consider that could impact in future years?
There's nothing at risk in the short term, for sure. We believe we have patent protection all the way out to potentially 2040 with this molecule. And in addition, this is not an easy program to make, so we use the nanoparticle albumin-bound technology that allows us to specifically target the tumor, and allowed us to deliver sirolimus through an IV formulation. That manufacturing technology is nontrivial, and therefore, you know, requires significant investment in specialized equipment and technology to actually produce, and puts up some barriers to entry for manufacturers, particularly generic manufacturers, to come into this space.
... Okay, great. Let's move on to PRECISION1.
Mm-hmm.
Can you start, just walk us through the design of that maybe, and what the primary objective and rationale for that trial was?
Sure. PRECISION1 is a really, an interesting trial, an innovative trial, because it is a true tumor-agnostic trial. So this trial is actually set up to identify patients who have either a TSC1, TSC2 mutation in their cancer. These are mutations that are known to modulate the mTOR pathway, and activate mTOR, because they are traditionally tumor suppressors. And so their loss leads to mTOR activation, and our belief, and the hypothesis we're testing in this trial, is inhibition through nab-sirolimus could be beneficial for patients who have these types of tumors. The trial design is actually two arms, so one for each mutation, and there's 60 patients in each arm. So we have a TSC1 arm with 60 patients and a TSC2 arm with 60 patients.
This is important because it allows us to independently assess the ability of nab-sirolimus to combat either mutation. We don't necessarily expect there to be a difference between these two mutations from a biological perspective sense, but we always wanna make sure that that is clinically true and valid. The outcomes for the trial are overall response rate as a primary endpoint, as evaluated independently in radiological review. And we read out some early interim data on the first 20 patients in each arm, or 40 patients overall, back in December, and we'll read out on 80 patients, or about 40 patients per arm, in Q3 of this year. We intend to complete the trial by the end of 2024 and look for results in early 2025.
Okay. Actually, can we go to that first interim and, you know, can you start by... I mean, just summarize for us what you saw in each arm, TSC1 and then TSC2?
Sure. In the TSC1 arm, Arm A of the trial, we saw a 26% overall response rate in patients who had an average of three or more prior lines of therapy. This, that was in the efficacy-evaluable population, so this was within the 18 patients who had more than one scan post-baseline. So overall, in a very late-line patient population, we saw a reasonable response rate, which we think, if it holds true for the full population, would be allow us a path to approval, or filing and submission and approval for the TSC1 indication. In the TSC2 arm, in the efficacy-evaluable population, again, it was about 18 patients, we saw two responses in that arm. It was a lower response rate than we had seen in the TSC1 arm.
The interesting thing there was these were even later-line patients that were in, and we actually had 50% of the patients in that population who had five or more prior lines of therapy, and so the expectation for response is, you know, even lower, potentially, in those patients overall. Our view is that this is still a very early read, and we'll see how the remaining two-thirds of the trial really matures over the next number of months as we further evaluate and continue to enroll, and now have completed enrollment of this trial.
So what do you think, if you had to explain it, what caused the difference in responses seen between the two different mutation types? Was it due to indication-specific differences or something else? Is there inherent differences in those mutations or what?
Yeah, it's a great question, and certainly one we get quite often. Biologically, TSC1 and TSC2 act as a heterodimer, so a mutation in either, and loss, and we're looking at mutations that lead to full functional loss of the proteins should actually impact the pathways in the same way. And so biologically, there isn't an obvious reason why you'd get a difference. So we really look at then the clinical parameters that we've achieved so far to see if there's a kinda difference in those populations. And the thing we point to is, first, we did look across indications. There is a different mix of indications within each of those populations, but nothing obvious that would point to why you'd see a difference in those initial outcomes.
The real thing, which I mentioned before, which we think is potentially the real, the potential underlying cause, is just the difference in line of therapies that the patients have been exposed to. And in each of the group, with the TSC2 arm, having that large portion, at least half of the patients, who had five or more prior lines of therapy, and that could just set a different expectation for what you'd see. We anticipate that those things will average out over the course of the remainder of the enrollment, and it may have just been too early in the trial to really assess the difference. So we don't put a lot of stock in the difference at this point in time, and anticipate that it could change as we enroll more patients in the trial.
Okay, great. So then, I guess, let's go back to, you know, you mentioned the full data reading out. So as we think about what you already have shown, that you just discussed, and what will be shown, what would you consider to be the, like, the minimum threshold for what you consider to be a good result, and then what would you hope to see?
Right. Well, we always hope to see better than the minimum, for sure. But, I think, you know, importantly, I mentioned this in the beginning, this is an innovative tumor-agnostic trial. The number of true tumor-agnostic trials that have been run in mutation-driven cancer is actually very small. Typically, people have used cohort studies to actually enroll different cohorts of indications, group those together, and then seek a tumor-agnostic approval. In the past, that has often worked, but usually requires large numbers of patients. Here, we took a very prospective approach in taking all comers into the trial.
That led to over 20 different tumor types that have now been enrolled into each arm of the trial, and so a very broad distribution of different tumor types that are in the trial in a truly, truly tumor-agnostic setting, which also requires that each tumor type has gone through its standard of care, meaning that all of these patients are essentially last-line patients. The expectation in last-line therapy, when you're talking about third, fourth, fifth-line therapy, is actually very low. Typically, when you think about historical comparisons, you're talking about single-digit, low double-digit response rates that might be expected within those patients. And so when we saw 26% overall response rate in these types of patients, we think that's a material and clinically meaningful difference that we're generating for these patients.
And experts we have talked to have agreed, in that regard, that this is a meaningful difference that we're generating for patients with these diseases. These patients really go from having no chance at potential therapy to, you know, one in four, one in five potentially responding to that. And I think that is the bar that we have for ourselves as we look at this data, is getting to that, you know, where our lower bound of the analysis would be above what might be expected in the single-digit range for these late-line patients. And, you know, our belief is that the FDA will view this data positively, given the construct of this trial.
Okay, so you mentioned up to 20 different tumor types being enrolled in this trial. So, I mean, obviously, that means not very many patients per tumor type, but... Regardless, in the data, do you plan to report how many patients of each tumor type and maybe even, you know, which ones responded? Just-
For sure.
To-
I think it's important, you know, well, you know, to give transparency into the data. At the end of the day, it's not, you know, we don't think that that's where the FDA will focus, is the tumor type distribution, other than to say it's representative of what TSC1 and TSC2 patients that are out there in the community. And we know that by design, the trial is meant to be looked at in aggregate of all of those different tumor types, and the overall response durability of response, and quality of response will be what's important when we think about the review of this indication. But we will present the breakdown by tumor types and kind of where we saw responses in particularly.
Yeah. Is there, I guess, is there one tumor type that's particularly enriched for these mutations?
It's a very-
Yeah.
You know, it's interesting. TSC1 and 2, there's about 2% of all cancers or 1.9% of cancers, if we're being specific, that we think harbor a TSC1 or TSC2 mutation. They roughly split equally between them, which means there's about 8,000 patients in TSC1 and another 8,000 patients in TSC2 that have these mutations each year. Interestingly, they're quite distributed across different tumor types, and we see that in the clinical trial enrollment, but you also see that in the large NGS data sets that we've investigated around this in partnership with Foundation Medicine and Tempus. It does...
There are a couple of areas where you see the, you know, contribute more because they are larger, so, lung cancer, genito urinary cancers of bladder and renal, GI cancers, anywhere really along the GI tract, as well as, endometrial, ovarian, and breast cancer contribute, differentially to TSC1 and TSC2 mutations, and that's typically where you see, patients, come up. But they really can exist, pretty much all over, and, they do, you know, present, through a variety of different, tumor types. Importantly, all of these mutations are already screened on NGS testing today, and are readily available on the panels that are out there for, diagnosing genetic mutations for patients.
Great. Hmm, so, all right, following this other, the next interim update, how do you plan on moving forward? Would a filing be possible on that outcome? Do you have to wait for a final readout? What's the plan there?
Well, I think it would be important for us to review this information with the FDA. And so our first plan of attack is to, you know, have a discussion with the FDA about what we're seeing with this second interim. Importantly, the second interim data is built off of the planned primary endpoint, which is independent radiological assessment of response rate. And we'll have sufficient follow-up for us to have initial comments on durability of therapy, 'cause each of these patients in that interim will have at least six months of follow-up, which is longer than we had in the first interim. So with those components together, it gives us a good platform for a discussion on potential route to submission with the FDA. It certainly could file on that data.
You know, importantly, the full data set is coming shortly thereafter, so we have... You know, we had a significant ramp-up in recruitment for this trial over the last 9 months. We closed the second interim enrollment in December, and we closed the full enrollment in April. So there's really only a 4-month difference between our second interim and then the full data. And so the ability for us to file quite quickly as we get into 2025 is there in front of us, and that's our plan, assuming the data hold as we expect.
Hmm. Since you mentioned it, actually, do you know why you had such a significant pickup in enrollment?
I think it's execution of our team. The team-
Cool
... did an excellent job, really, getting putting in place the things that are necessary for this kind of trial. So if you can imagine, if you're doing a lung cancer trial, you go to the lung cancer centers, and you talk to lung cancer KOLs, and you put those folks in place, and they know how what to expect in terms of patients coming through the door that might be able to enroll into the trial. In tumor-agnostic setting, you don't have the same luxury. And what we had to establish was what we call just-in-time readiness and screening processes in partnership with NGS providers that allowed us to flag centers and patients who could be eligible for treatment and then establish those where they were actually getting care.
So it's often that meant setting up sites, just in time. We had actually over 150 sites that we ended up activating for this trial, just to enroll the 120 patients. And obviously, that ability to kind of get to that scale took some time, which we really accomplished in the first half of 2023, and we saw, you know, rapid pickup, starting over the summer of last year and really throughout the rest of this year.
Okay, so next market, I guess the trial design kind of answers this for us, but really, how would you expect this to be positioned relative to standard of care drugs? Is this essentially last-line therapy for any TSC1 or TSC2-expressing solid tumor?
I think the trial establishes the potential of this to act upon actionable mutations. And I think what you'll see in terms of and when we've talked to physicians about how they might use the drug, the trial forms the basis for how you might think about putting this in standard of care. The label will not be specific to line of therapy, obviously, because it's not specific to any particular indication. And what we typically see is you know, physicians working through a standard of care that they might have in first line, even in second line for certain indications, but then really looking for solutions from an actionable mutation perspective, and that varies by different tumor type.
Certainly, when you're talking about non-small cell lung cancer, where physicians are regularly doing mutation screening, this comes up higher or earlier in the treatment, decision-making. In certain other indications where they're not doing that kind of testing regularly, you wouldn't potentially see that, come up as early. So we think this will really be a tumor by... or physician-by-physician decision about in terms of how they choose to use this. But we think that this, the, impressive results we're seeing in these late-line, therapies will translate into earlier usage, once people recognize the actionability of these, of these mutations, for their patients.
All right, so we have four minutes left here, so I want to make sure that I give you a chance to give us some context and update on NETs and endometrial. So anything you could say here in four minutes, that would be great.
Yeah. Well, I, I'll do it in less than four minutes just for you. The opportunity here, you know, we think is great. You know, there's a mTOR inhibitors have been traditionally used within endometrial cancer, or neuroendocrine tumor. They're approved, and there's good data to support their use in endometrial cancer. We've actually think that nab-sirolimus is potentially best-in-class neuroendocrine mTOR inhibitor, and therefore could be an improved solution for neuroendocrine tumors, or as a in combination with letrozole for endometrioid-type endometrial cancer.
We believe that these are early phase II data, which we should read out later this year, will give us initial indication if we're really seeing that kind of best-in-class efficacy that could allow us to supplant the use of a traditional mTOR, oral mTOR inhibitors in each of these indications.
What would the bar for that be, to call it best in class?
I think it's... You know, we'll have early data, maybe 10 patients, later this year. I think what we're expecting to see is improvement in ORR in the neuroendocrine space from the single digit that you see today with typical oral mTOR inhibitors. So that could be anywhere 15%-30%. And similarly in the endometrial space, we would expect ultimately to be reaching areas of 30%-40% to have an impact in that area as a potential key to superiority 'cause these are not head-to-head studies yet.
Yep. Okay, I guess now we have a minute, so I do wanna ask you, from your perspective running the company, what do you think is the most underappreciated aspect of the Aadi story by investors?
Well, I think the reality here is we're a small biotech, where we have an improved product on the market that sells today, and we're actually pursuing indications which are just add-on to that. And the opportunity here, really for sNDA submissions with the FDA on a known pathway and a known compound with a known safety profile, really means that we have a very high probability of success, assuming our clinical data pulls through. And I think the value of that de-risked story is often underappreciated by investors who, you know, maybe not seeing the opportunity here that they have for Aadi to actually quickly add indications onto our portfolio and ultimately deliver a kind of a robust sales growth over the next few years.
Yeah, agreed. There's a lot of exciting updates coming up, and, with that, you know, we're up on time. But Dave, I really appreciate-