Whitehawk Therapeutics, Inc. (WHWK) Earnings Call Transcript & Summary

Great. Good afternoon, everyone. My name is Frank Tang, and welcome to the Morgan Stanley Healthcare Conference. So this is the fireside chat for Aadi Bioscience, and I'm joined on stage by Founder and CEO, Neil Desai; COO, Brendan Delaney; and CFO, Scott Giacobello. So before we get started, I'd like to read a quick disclaimer. For important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative.

So Neil, to kick things off, it would be great if we could spend a few minutes at the beginning for you to give us an overview of the exciting Aadi story, maybe specifically the FYARRO asset and then your precision medicines approach and then the nanoparticle albumin technology.

Yes, sure. Thanks for the invitation, by the way. So the story really started back in the Abraxis BioScience space where we developed the platform of the albumin technology binding to drugs and show that -- proof that with the first drug Abraxane that was approved that you could get high tumor drug levels because of the albumin platform and the mechanisms that albumin brings. And so subsequent to that, we were working on other molecules with the same technology and sirolimus or rapamycin as it was formerly known, an mTOR inhibitor is the one that we're working on now. What we did was then take sirolimus into this platform and then develop it for the specific mutational population. And our first indication there was PEComa, which I'm sure we'll talk about it later. But the reason for that was because of the high prevalence of mTOR pathway mutations in PEComa and it worked remarkably well. And that's -- the big driver there is the albumin technology, which carries a lot of drug into the tumor. And we published on this previously and really overcomes a lot of the limitations of the other mTOR inhibitors, which can't effectively suppress the mTOR target.

Yes. So speaking of that, I think it would be good to get a brief overview of the limitations of the currently approved mTOR inhibitors and then the need for better therapies?

Yes, sure. mTOR is a very central target in biology and in cancer, in particular, and there was a lot of excitement about that many years ago. The drugs that were approved for mTOR inhibition were sirolimus, everolimus, et cetera. And however, these didn't prove to be as sort of widely accepted as once was promised and thought about. And the limitations there are primarily driven by poor PK, the pharmacokinetics, poor absorption, so highly variable absorption, narrow therapeutic index; so you can't really shift the dose to get a more optimal amount of drug into the tumor and poor target suppression. And that's really the key limitations that have, we believe, prevented the broader use of mTOR inhibitors. And so, with this new drug, FYARRO or what we call nab-sirolimus, we're able to overcome all of those limitations because we can get very high drug levels into the tumor and have a very wide therapeutic index and therefore, great target suppression and better efficacy.

Great. I guess, could you elaborate on the clinical PK profile that FYARRO has been able to demonstrate versus other mTOR inhibitors?

Yes, sure. So there are some key differences. We have a very long half-life, unlike the mTOR inhibitors. We have, at the tumor level, much higher tumor penetration or the order of magnitude higher. And then at the target level, so we look at targets -- downstream targets of mTOR like phosphor-S6 and 4EBP1, we have almost complete suppression of those targets, which is not possible to achieve with the other mTOR inhibitors. So that's the big differentiators there.

No, that's great. Okay. So maybe moving on specifically about the indication that FYARRO's going after, specifically malignant PEComa. So congratulations on the FDA approval in early this year. So this is obviously a disease that's not received a lot of attention, and there aren't any standard treatment options for the disease. So could you give us an introduction to the disease and specifically, the causes, prevalence and then current treatment paradigm?

Sure. Yes. So malignant PEComa is a very rare form of sarcoma and the prevalence numbers are probably in the 100 to 300 range, -- or I should say incidence, not prevalence. And so that's the new patients with these advanced PEComas every year...

In the U.S.?

In the U.S. alone, so similar numbers elsewhere. Now the unique part of PEComa is that the name PEComa actually comes from perivascular epithelioid cell tumor. So by that definition, they occur near blood vessels, so they're perivascular, but they can occur at pretty much any location in the body. The greater prevalence is in -- the highest prevalence, by location, is in the uterus, in the abdominal cavity, in general, but it can be on the colon. It can be in the brain, it can be anywhere as the site of origin. So it is a form of sarcoma, which has a specific characteristic that's identified through immunohistochemistry and morphological characteristics. And there's no prior approvals for PEComa. mTOR inhibitors have -- there were some case reports out there that showed prevalence, -- not prevalence, but really activity of mTOR inhibitors in isolated cases. And that's really what sparked the interest for us several years ago to pursue this as a registration indication for our drug.

Yes. Great. And given the approval, could you give us an overview of the registrational data that led to the approval and how that data is now able to offer this treatment option for patients?

Sure. So we did a trial which we had prenegotiated with the FDA for about 30 patients. Being such a rare disease, 30 patients was a sufficient population for approval. We designed the trial to have a 30% response rate as the hurdle bar for approval, which the FDA agreed to. We ended up with a 39% response rate that was independently reviewed. We published this in JCO last year. And the striking result, other than the response rate, was the duration of response was phenomenal. It was in excess of 36 months, and the median was not reached with the PFS, median PFS of about 10.6 months and survival of about 41 months. So all in all, a good data set for approval. Since then, of course, we've commercialized the drug and the drug is now on the market as of February of this year.

That's great. So on that topic, could you comment a bit on the continued commercial launch and progress at that one?

Yes I'll ask Brendan Delaney, who has handled our commercial aspect to comment on that.

Yes. So as Neil said, we made drug available in the market as of February. And since then, the drug -- the launch has been off to a very strong start. I would say the acceptance of the clinical profile of the drug, which Neil just detailed has been very strong across the oncology community in the United States. So obviously, the overall response rate at 39% is impressive. But what's most differentiating and impressive about the product in the eyes of oncologists is the durability of responses. You don't necessarily see that type of durability with other first-generation mTOR inhibitors. So you're getting that type of efficacy with a safety profile that's predictable and manageable. A lot of the oncology world is familiar with managing mTOR inhibitors. So overall, the profile has been very well accepted. I would say we've had a strong kind of tailwind from the very beginning with an early NCCN recommendation as the only preferred treatment option in PEComa. That's obviously fueled prescribing and adoption, but also has helped on the market access side with coverage policies and reimbursement coming on board a lot quicker than I've seen with other launches. So that's been very encouraging. On some of the metrics that we've provided through Q2, we've seen north of 60 accounts ordering a drug, which is a loose kind of proxy for the number of patients that have been put on therapy. We've said that the reorder rate for those accounts is north of 80%. I think that's the closest with an IV drug. You don't get patient-level data, but that's a good approximation of the -- starting to see that durability of response in the real world, right? We have more than 80% of those ordering accounts reordering and assigned patients are continuing on therapy. I think another encouraging indicator is the adoption in the community setting. We said that as of Q2, north of 40% of the prescribing accounts, so ordering accounts represent the community oncology setting, and that's highly encouraging, a lot stronger than I would have predicted and very encouraging, I think, for the long-term prospects for the drug.

Yes. And just as a quick follow-up, is the durability that's seen in the data affecting how you guys are viewing the prevalence of, I guess, the disease?

I think we'll just have to see how it kind of plays out over time. Duration of therapy evolves after launch, right? You're getting patients in an early launch at where they are in their treatment journey and that could be second, third line, right? You may not see the early duration. But I do think based on the data, you do have a number of patients or a segment that are considered long runners, right, that just continue on and on. And I think that's where -- as that starts to mature, you'll start seeing that compounding effect of duration in the market to your point.

Yes. Absolutely. Okay. Great. So maybe if we move on from PEComa. Could you give us an overview of the rationale for moving on and thinking about targeting TSC1-TSC2 mutation?

Yes, sure. This actually evolves from our PEComa experience. The reason we went into PEComa in the first place was because there was a high percent of the PEComa patients that had these type of mutations, TSC1 and 2 in the case of PEComa, over 50%. Now the mutation now exists across all tumor types. If you average them out, it's roughly about just under 2% of all tumor types. So that ends up with a fairly large population on an annual basis, about 12,000 new patients with advanced cancers in the U.S. alone. So that's a significantly large opportunity. We have been -- besides our PEComa data, we had the subset of TSC1 and 2 patients within the PEComa study that had a very high response rate, much higher than the overall. We've had data from a few other types of tumors that we presented at ASCO, which also had a very encouraging response rate outside of PEComa. And then we also reproduced this in a set of become patients who had been previously pretreated and failed other mTOR inhibitors. And even those patients with the mutations had a good response. So putting all of that together, that formed the rationale of going after patients with other tumor types that have these mutations. Now as I mentioned, the population is pretty large about 12,000 patients. And so we've initiated a new trial. It's a tumor-agnostic trial called PRECISION 1 and focusing on those patients.

And you mentioned there are a large number of cancers with TSC1-TSC2 mutations. How do you think about prioritizing which of those? I know it's early days, but how do you think about selecting maybe a framework of which ones you want to focus on?

Well, I think our trial, the way it's designed, it's tumor agnostic. So all comers, all tumor types will end up in the trial. So right now, we are pursuing broadly all indications within the same trial as has been done with other tumor-agnostic therapies. Now in terms of patient subpopulations of different tumor types, there's obviously higher prevalence in certain amounts -- certain tumor types than others, like for example, bladder cancer is relatively high. The absolute numbers of lung cancer patients with the mutation is also high. You have hepatobiliary cancers, liver cancer, for example, that's high, endometrial cancers, et cetera. So there are several cancers that fall into this category. And by themselves, they could be a market within these other cancer types as well.

I guess when you think about selecting these, how do you think about choosing which indications to focus on given kind of the competitive nature of oncology? How do you think about the treatment paradigm of each of those particular cancers? And would you want to be trying to move early in line or just wherever you're seeing the efficacy? How are you thinking about that?

Yes. At this stage, like I mentioned, we're going tumor-agnostic, so not focusing in on a particular indication. The requirement there is like in other tumor agnostic trials as well is that the patients should have been exposed to some prior standard therapy or approved therapy. So we expect most of these patients to come in second line, third line, fourth line depending on which indication they come from which tumor type. So at this point, again, the focus is on all tumors as opposed to narrowing down one particular tumor type.

Okay, absolutely. And you mentioned the kind of the encouraging data that we saw in TSC1 and 2. Can you give us an overview of that kind of data?

Yes, sure. So we had presented at ASCO last year, a series of about 7 or 8 patients, and these were all patients with extensive prior therapy included patients like ovarian cancer patients, endometrial cancer patients, some other sarcoma subtypes, different from PEComa, like angiosarcoma and others. And in this patient, the common thread was, of course, they had to have a TSC1 or a TSC2 mutation. We had 5 out of those 8 or so patients have very good responses in that subset. So that was a good indication that the drug can work outside of PEComa as well provided we have the right type of mutation. Within PEComa itself, we talked about that. So we had about 14 patients who had TSC1 and 2 mutations in our trial. We had a response rate of about 64% in that subgroup with just the mutations. And so that was also a very encouraging data and again, these data form the basis of our push in the tumor-agnostic mutation.

You mentioned that you saw responses even for those that were not mTOR naive. How do you think about -- how does that factor into your development strategy as you're looking forward to the current trial and future trials?

Yes. I think more so in other trials, probably factors in because mTOR inhibitors are known and they're approved for certain indications, for example, like kidney, breast, et cetera. And that data is very important where we saw responses after another mTOR inhibitor had failed to really show that differentiation, that the drug can -- is truly inhibiting the target at a much greater level than the other prior mTORs could. And so that sort of sets us up nicely to think about other indications, maybe where mTORs have been used. Now we haven't said publicly that we're going to focus on those but that's amongst the things that we're looking at that we could potentially do in the future.

Got it. And I believe the registrational trial was initiated in the first quarter of this year.

That's right.

So when do you expect initial data to be read out for that trial?

Yes. So our plan for that is in the first half of '23, we should release some preliminary data on the trial, whatever number of patients has been enrolled up to that point. And we expect to talk about response rates, maybe some duration depending on how much duration of therapy we have at that time, the different tumor types that have been treated and maybe some safety information. So that will be the first piece of information from that new registration trial. The final data, of course, will be in 2024 after we complete enrollment. We have a total of 120 patients, 60 patients per arm, 60 patients for TSC1 and 60 patients for TSC2.

Great. This one might be a bit difficult to give, but do you have -- what do you hope to see for the initial data?

Well, of course, we hope to exceed the bar that we've set with the FDA, and we're pretty confident on that based on the data that we've seen so far already with our studies and Expanded Access Program. And so we're expecting a positive study, but we have to wait and see like everybody else.

Absolutely. Are you able to give us an update on the status of enrollment?

We can talk not about specific numbers, but our focus now, we've sort of initiated the trial in the last several months. And the focus is really getting a whole bunch of centers up and active so that they can enroll. We, of course, are enrolling patients, but we're in the early phase where we haven't reached a steady state. So talking about enrollment, it's better to wait until later to be some steady states of enrollment. But we anticipate a good enrollment rate. And the reason I say that is that we're not only looking at the large academic centers for this trial, but we also engaged the NGS providers who do the TSC1 and TSC2 testing and through their networks, we can do just-in-time enrollment. So if they find a patient with TSC1 and 2, we are contacted and then we know where that patient is and then we can activate their center very quickly after that. And so this sets up a whole network throughout the country of how we can find these patients. So that will help enrollment. In addition, we have -- we're partnering with U.S. Oncology, which is the largest community network in the country. And so -- we're using the same mechanism there, we should be able to reach out to as many patients as there are.

Okay. Great. That's good to hear. Moving back a little bit, I missed this point. In terms of the timing for the data, would you be looking to present it at scientific conferences or is that still kind of to be determined?

Yes, to be determined either at a scientific conference or in a company type event. So we'll have to determine that a little bit later.

Great. Maybe we'll move on to a few corporate and financial questions. Could you remind us of your cash position, current runway? And then any key upcoming milestones beyond the TSC1/2 data that we just talked about?

Yes, I'll start with the cash. As of our most recent quarter ended June, had about $119 million in cash. So we're well capitalized. And that cash will take our runway into 2024 and allow us to continue to fund the FYARRO launch in malignant PEComa as well as fund the PRECISION 1 trial, which Neil was talking about. And I'll turn it back to Neil for...

Yes. So the new things we're looking at in '23-'24 timeframe are really expansion of the indications for FYARRO. Now this is beyond the TSC1 and TSC2 trial. So there's several potential indications we could go after such as those that are related to the mTor pathway. So the combination with targeted therapies that as their targets feed into the mTOR pathway, it could be Ras, Raf, MEK, there's a whole bunch that makes a very good rational sense to combine with mTOR because mTOR signaling becomes a resistance pathway for those drugs. And so this will be a very good rational combination. So we're looking at all of those, exploring those. And with the intent that maybe by next year, we should start kicking off some new trials, particularly in combinations.

Great. So on that point, with specifically the combination strategy side, what are some gating items to come to those decisions?

I think it's just the evaluation that we're going through right now, and we probably complete that evaluation by end of the year and then take some calls on which trials make the most sense for us to pursue either as company sponsored, some could be investigator-sponsored trials. So we have to come to that decision.

Understood. That's perfect. That's all I have for the prepared questions. Maybe now I'd like to open it up briefly to see if we have any questions on the floor? Well if not, I'd like to thank Neil and the team for joining us today, and we look forward to your continued progress.

Thank you very much, Frank.

Great. Thank you.