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

Thank you for standing by, and welcome to the Aadi Bioscience's Conference Call. [Operator Instructions] As a reminder, today's program is being recorded. And now I'd like to introduce your host for today's program, Marcy Graham, Senior Vice President, Investor Relations and Corporate Communications at Aadi Biosciences (sic) [ Aadi Bioscience ]. Ms. Graham, please go ahead.

Thank you. Good morning, and welcome to the Aadi Bioscience conference call to review the results of initial data from the ongoing PRECISION 1 tumor-agnostic trial evaluating nab-sirolimus in patients with TSC1 or TSC2 inactivating alterations. Joining me on the call today is Dr. Dave Lennon, our President and CEO; and our Chief Medical Officer, Dr. Loretta Itri. We will open the line for questions at the end of the call following closing statements. A quick reminder that statements made on the call today will include forward-looking statements. Actual events or results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties and other factors, including those set forth in the Risk Factors section of our annual and quarterly reports filed with the Securities and Exchange Commission, which can be found at www.sec.gov or on our website at www.aadibio.com. In addition, any forward-looking statements made on this call represent our views only as of today, December 13, 2023, and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update or revise any forward-looking statements, except as required by applicable law. I will now turn the call over to Dave for his opening statements. Dave?

Thank you, Marcy. It's an exciting day for us as we're sharing the first look at early data for nab-Sirolimus from our PRECISION 1 trial. As a reminder, at Aadi, we are developing nab-Sirolimus in a portfolio of oncology indications. Along with the approval of nab-Sirolimus or FYARRO and PEComa, we are developing this product for tumors harboring TSC1 or TSC2 in activating alterations in the PRECISION 1 trial, which we'll discuss more on today. But I also want to point out we're developing nab-Sirolimus in endometrial cancer, neuroendocrine tumors, lung cancer and other solid tumors. Today's focus is on the reporting of initial interim results for the first 40 patients of the PRECISION 1 trial. Next slide. As a reminder, TSC1 and TSC2 form an important complex coordinating a number of signaling pathways important to cell energy regulation and cell growth. In cancer, when this pathway is disrupted, my mutations in TSC1 or TSC 2 genes, the mTOR complex becomes activated, leading to unregulated cell growth, resulting in cancer progression. Inhibition of mTOR activation by oral mTOR inhibitors has previously been shown to have potent cancer activity across a wide variety of cancers. But disappointingly, oral mTOR inhibitors have shown only limited effectiveness in cancers with specific TSC1 or TSC2 mutation. And today, there is no approved treatment for these types of cancers. Next slide. As you can see on Slide 5, this is an area of large unmet need. TSC1 or TSC2 pathogenic mutations occur across 2% of all cancers, resulting in 16,000 new cancer cases each year. Occurrence is roughly split between mutations in each gene, leading to sizable unmet needs in the cancer community. TSC1 and TSC2 alterations occur in a number of common cancer types and tend to aggregate in the areas of thoracic, gastrointestinal and general urinary tumors. Next slide. In an exploratory analysis of our trial in PEComa patients, the AMPECT study, we have previously shown a high association of nab-Sirolimus responses with TSC1 or TSC2 alterations in patients with PEComa. Our hypothesis was our unique nanoparticle technology in nab-Sirolimus could lead to greater inhibition of mTOR pathway at the site of tumors with harbor pathological TSC1 or TSC 2 alterations and thereby improve on the low response seen with oral mTOR inhibitors. This and other data became the basis for the PRECISION 1 trial to test the potential utility of nab-Sirolimus as a single agent across different tumor types that harbor these TSC1 or TSC2 in activating alterations. We're delighted to be at this point to share the first interim analysis from this tumor-agnostic trial. For that, I'm going to turn it over to Loretta.

Thank you, Dave. Next slide, please. This slide contains an overview of the design of the PRECISION 1 trial. Importantly, this trial was designed to assess inactivating alterations in either TSC1 or TSC 2 through 2 independent study arms; Arm A, TSC1 and Arm B, TSC2. The subsequent slides contain data from a preplanned interim safety assessment after enrollment of 40 patients in total between the 2 arms. While the primary endpoint for this study is ORR by independent radiology review, this interim contains results based on investigator-assessed ORR, which is an exploratory end point of the study. Next slide, please. This slide contains the demographics of the efficacy-evaluable population from the initial 40 patients enrolled in the study. Originally, 22 patients were enrolled in the TSC1 arm and 18 in the TSC2 arm. 3 patients in the TSC1 arm were unable to be assessed because they did not have post-baseline scans due to early progression in all cases. They were, therefore, considered invaluable and are not included in this analysis. The efficacy evaluable cohort therefore, consisted of 19 TSC1 patients and 18 TSC2 patients. Arms A and B are similar in age and sex distribution and both arms enrolled patients who had a significant number of prior therapies. Approximately 80% of patients in each arm had at least 3 prior lines of therapy. Notably, 25% of patients in Arm A and 50% of patients in Arm B had at least 5 prior lines of therapy. Each arm enrolled a significant range of different tumor types. Arm A showed a distribution of 9 tumor types and Arm B enrolled 13 different tumor types. Next slide, please. This slide shows the distribution of histologies and roles in each arm of the study. The most common tumor types enrolled were ovarian, bladder, colon, Leiomyosarcoma of any organ and breast. The distribution seen was highly representative of the most common TSC1 and TSC2 tumor types in the general population. And we believe this bodes well for meeting the tumor distribution requirements for a tumor-agnostic registration program. Next slide, please. Results for Arm A or TSC1 are shown on this slide. 5 of 19 patients achieved an investigator-assessed partial response for a 26% overall response rate. An additional 3 patients had stable disease for longer than 6 months, resulting in a clinical benefit rate of 42%. Importantly, responses occurred rapidly with a median time to response of 1.4 months. This is similar to what was observed in the AMPECT study in PEComa. 4 responses were ongoing at the time of data cutoff with more than half already longer than 6 months. Next slide, please. This slide shows a swimmer's plot of TSC1 patients enrolled in this interim cohort. 6 of 19 patients are currently continuing on therapy in the trial, 5 of whom have had partial responses, all of which are ongoing. 2 of these patients have achieved responses that approach 1 year in duration. Next slide, please. Results for best overall response show that the majority of patients had some degree of tumor shrinkage upon treatment with nab-Sirolimus. Impressively, we are seeing more than half of the responders achieving a greater than 50% reduction in tumor volume by Kaplan-Meier estimates, including 1 patient with a near 90% tumor volume reduction. Next slide, please. We find the 26% overall response rate in the TSC1 population to be encouraging. And without revealing specific tumor types, we would highlight that responses occurred in 4 different epithelial carcinoma. We are seeing high-quality responses to nab-Sirolimus that were achieved within weeks of treatment initiation, often resulting in greater than 50% tumor volume reduction. All responses were ongoing with some extending past 9 months. Next slide, please. Results for Arm B, TSC2 are shown on this slide. 2 of 18 patients achieved an investigator-assessed partial response for an 11% ORR. An additional 3 patients had stable disease for longer than 6 months, resulting in a clinical benefit rate of 28%. Two of these patients are near or beyond 1 year on treatment and more continuing therapy at the time of data cutoff. Next slide. This slide shows a swimmer's plot of TSC2 patients enrolled in this interim cohort. 4 of 18 patients are currently continuing on therapy. Interestingly, 2 patients have achieved long-term stable disease and have continued to benefit from therapy for nearly a year or longer. 1 partial response patient progressed and stopped therapy after 7 months. Next slide, please. Results for best overall response show that similar to TSC1, the majority of patients had tumor shrinkage upon treatment with nab-Sirolimus with a few ongoing patients having a reduction in tumor volume that approach the PR threshold. Next slide, please. The 11% ORR in the TSC2 population is clearly lower than what was observed in Arm A and was rather surprising giving the preliminary genomic profile from the AMPECT study, which suggested that patients with TSC2 alterations would be more likely to respond. Interpretation of these data is additionally complicated by the fact that 50% of patients in Arm B have received 5 or more prior lines of therapy for their respective cancer diagnosis. The heavy pretreatment in this cohort may limit our ability to fully test the utility of single-agent nab-Sirolimus in the TSC2 arm at this point in time. Next slide, please. Across both arms, safety findings were consistent with prior nab-Sirolimus safety data and other mTOR inhibitor therapies. There were no Grade 4 treatment-related adverse events and no new safety signals were observed. 1 patient discontinued study due to Grade 2 pneumonitis that completely resolved after discontinuation of therapy. I'll now turn it back over to Dave.

Thank you, Loretta. On Slide 19, we have a summary. We'd like to reiterate that TSC1 arm results are encouraging. The response rate is in the range of our expectations and in indirect comparison, these results are demonstrably better than results seen with oral mTOR inhibitors in earlier tumor-agnostic studies. It is really important to note that in a single-arm study, these ongoing responses were robust in a heavily pretreated population. We saw onset of response in the first few weeks, deep tumor reductions often with greater than 50% reduction in tumor mass. As you may recall from the waterfall plot, we even had 1 patient approaching an impressive 90% tumor volume reduction. Importantly, all responses were ongoing at the time of data cutoff. With these responses occurring in multiple different epithelial carcinomas representative of common TSC1 mutated tumors, we believe we're on the right path to meet FDA requirements for a tumor-agnostic label in TSC1. The TSC2 overall response rate is more complicated to interpret, especially in this heavily pretreated population. The arm was potentially impacted by the very late-line nature of the population, where 50% of patients received 5 or more prior therapies before being dosed with single agent nab-Sirolimus. As mentioned, we have previously seen positive association between TSC2 and responses to nab-Sirolimus in PEComa patients. So ultimately, it is unclear if TSC2 alterations are truly behaving differently or if it is just too early in a study to understand the impact of nab-Sirolimus in TSC2-related disease. We look to understand this better as the study matures. Finally, I want to highlight an enrollment update for PRECISION 1. Through the work of our team and in partnership with PRECISION investigators, this trial is enrolling extremely well. In fact, we have now enrolled 80 patients in the trial and this is an important milestone because it is required number of patients for our 2/3 interim analysis and puts us on track to report that data in Q3 of next year based on this much larger group of patients. So, if we get the last slide. As we look forward, we're excited about the milestones and catalysts the next year can bring for the PRECISION 1 trial. For 2023, we met our stated objectives, brought the interim 40 patient report out today and can now report reaching the important milestone of 80 patient enrollment. As we look forward, we believe that there are a number of important milestones for PRECISION trial in 2024, including our expectation to have the trial fully enrolled in the spring and a 2/3 interim readout in quarter 3. We anticipate that, that next interim based on 80 patients will include analysis of the primary endpoint, overall response rate by independent radiographic assessment with a minimum of 6 months of follow-up. It is at this interim that we can make adjustments for the size of the study or consider the potential for early submission. As previously stated, we plan to complete PRECISION 1 by year-end 2024, with full results expected in 2025. We believe this is an exciting data and that it bodes well for an exciting year for Aadi in 2024. With that, we'll take questions. Operator?

[Operator Instructions] And our first question comes from the line of Roger Song from Jefferies.

A couple of questions from us. The first one, I just want to confirm, Dave, on the call, you mentioned assuming the ORR for the TSC1 and 2 replicate what you have right now, 26%, you are confident the FDA will likely approve the TSC1 cohort. So, maybe just how confident you are and what is the key evidence giving you this confidence the 26% is sufficient for approval for TSC1?

The TSC1 responses, we find are encouraging. This is an early point in the trial, but a 26% response rate in a patient population where we are treating patients on average in fourth-line therapy with a single agent nab-Sirolimus, we think is really impressive overall response rate. Maybe more impressive within that context is the fact of the quality of responses that we're seeing on these patients, both in terms of the rapid onset of response within the patients at 1.4 months. The deep responses we're seeing with patients -- most of the patients achieving greater than 50% tumor reduction and ultimately, the duration we're seeing with most of the patients out past 6 months now and some patients approaching 9 months in a year. That put together gives us a lot of confidence that not only are we seeing a response rate that's important in the context of [ baseline ] TSC1 disease, but we're also seeing an opportunity that we're having really high-quality responses we know the FDA values when talking about tumor-agnostic labeling. And importantly, these are occurring each in different types of cancers. And that, again, bodes well for our tumor-agnostic approach. So, we put these things together, we're very confident that the agency will have a very positive discussion with the agency if this data holds as we go throughout this the rest of the TSC1 arm enrollment.

And then so on the TSC2 [ received ] response surprisingly and even lower than compared to what we've seen before and your expectation. My question is what could make the TSC2 arm efficacy overall response rate will be better from here because we do see you have a few ongoing stable disease? Will they kind of convert to response later? And also, you highlight 50% of the patients, they are fifth-line, prior lines and how this will play into the response rate in the later data cutoff.

It's a great set of questions and I can't predict the outcomes here. But a couple of things that are encouraging to us, I think you're already pointing out. I think the first is, it was a very late-line population. So, we are intervening as the sixth therapy for over half or for half of the patients in this trial. And so a very high bar in terms of a single-agent activity for a cytostatic agent like nab-Sirolimus, so very high bar there. And so that makes us question, right? Have we really tested this product fully yet in this population? And the second thing, as you point out is we did have some very long-lasting stable disease patients. We had 2 patients who didn't reach the criteria for progressive -- sorry, for partial response yet, but actually have stayed stable with their disease out to 12 -- nearly 12 and in over 15 months in those 2 cases. Both of those things give us pause to reflect on this data and look and make us very interested in what we'll see in the next 20 patients, if enrollment changes as we move through the trial maturity and if any of these potential long-term responses converts to a partial response. So, I think you're spot on in where the opportunity for improvement is in the overall response rate for TSC2. At the same time -- sorry, Roger. At the same time, I'd say we recognize that 11% overall response may not be what's -- is likely not necessary for -- to reach approval and we'll be monitoring this very closely as we go forward.

Maybe just lastly, very quick. For your second interim third quarter next year, maybe just remind us, what would be the patient pool you will report, how long is the follow-up? More importantly is how you will disclose the regulatory strategical hurdle to let the U.S. know, okay, if you are hitting the bar or not?

Yes. So the report out will be an efficacy interim based on the primary endpoint, which is ORR by independent radiological assessment with a minimum of 6 months of follow-up and therefore, will be a regulatory endpoint in the sense of what's required for approval. In terms of disclosure around where that falls from a statistical plan, we'll tackle that when we come to that point in Q3.

[Operator Instructions] Our next question comes from the line of Joe Catanzaro from Piper.

Maybe just 2 for me. It sounds like if I read correctly in the press release, you've indicated the potential expansion of the current registration. I was wondering if you could just elaborate what you mean by that, what would trigger that and how that could prolong time lines around the full top line and potential registration. And then I guess along those lines, can you remind us of your cash runway and how that aligns with the potential time line? And I have one follow-up.

To be clear, we have no current plans to expand enrollment of the trial. This is a 120-patient trial as designed and we're on track to deliver on that recruitment by the spring of next year. What I did mention is that at the point of the interim, the statistical plan allows for adjustment of the enrolled population if we find that necessary. But at this point, we don't have any plans to expand enrollment.

And then I'm just wondering if you could speculate a bit on why the TSC2 cohort was -- it seems like meaningfully more heavily pretreated. Was that driven by the tumor types that cohort involves anything else? Just wondering if you have any thoughts there.

Yes. It's an interesting question, Joe. And I think I'll just say that I think the reality is that we're dealing a little bit in the law of small numbers at this point in the trial. Remember, this is only the first 1/3 of the patients that enrolled in the trial. It's not uncommon to see late-line patients enroll in the earlier stages of a trial given sometimes there have been awaiting treatment or waiting for treatment to come in or the trial to open. And this could change over the course of the next 2/3 of the trial that's still set to enroll. But we don't have a particular insight into why that occurred. It's likely just the law of small numbers at this point in time and maybe a little bit unlucky in terms of the stage of patients that enrolled. But Loretta, if you have any other things to add around it, please feel free.

No, I would say, though, that I think there's an interesting difference between Arm A and Arm B. If you look at Arm A, you see that there are more multiples of the same tumor type, whereas in Arm B, we have a lot of single tumor types, which may suggest that these were patients who are being followed for a long period of time have run through everything. And then when this study came available, they were rolled over on to it. So, it would not surprise me if all of the different tumor types of which there were many singlets might, in fact, have contributed concurrently with the heavy pretreatment to the lower response rate. I've got to believe that there's an interplay between those factors.

[Operator Instructions] Our next question comes from the line of Ahu Demir from Ladenburg.

A couple of questions from us. Looking at the Arm A and Arm B, TSC1, the Arm A, it looks like half of the patients were followed up longer than 6 months compared to Arm B, TSC2 patients were followed up, about 1/4 of them followed up longer than 6 months. Just curious if that was driven by slower enrollment on TSC2 and do you think longer follow-up could lead to higher response rates with more mature data?

Great question. I'm going to let Loretta speculate on that insight.

Ahu, it's a very interesting question. But what I can tell you is that the 2 arms accrued relatively equivalently. So, we would put on a TSC1 and the next day, it would be a TSC2. So, at no point during the recruitment in this study was 1 arm more than 2 maximum 3 patients ahead. So, patients were enrolled relatively evenly. So that does not explain the differences.

And what is the reason then in that case, they are not followed? Is it more of the discontinuation rate or the patients were not on treatment longer?

Again, I think this is, first of all, very small numbers that we're looking at, but patients come off pretty much when they progress. We did not lose many patients because of adverse events. We lost patients because of progression of disease, which, frankly, is not hard to believe when 50% of your patients are already fifth-line coming into study or sixth-line coming into study. It would kind of make sense that they might progress more rapidly. And that's the primary reason they came off study.

And another question I have is when we look at the EAP program, we did see multiple ovarian cancer and endometrial cancer responses and you had about 8 patients in that category. Any comments on why these patients may not have responded? Was it related to their prior treatments or any other comments, any other color that you could provide?

I mean, I think -- yes, go ahead Loretta.

First of all, we've not provided any guidance about which tumors have responded or not, Ahu. And we have to be very careful about that because we cannot introduce bias into the study, okay? That has to be our primary concern. So, we're remaining quiet on what tumor types responded and did not respond. So, I really can't say a whole lot more at this point about that. And Dave, I don't know if you want to address that.

And I think what I would point out, which I think is what you're hitting on is the difference between what we saw when we came into the trial in the AMPECT study and the EAP program, which was generally higher response rates to TSC2 positive disease. And the expectation that if any arm was going to perform better would be that one. And so we are equally curious about what could be these drivers. And we're digging into the data to understand that. Clearly, there's this later-line of therapy enrollment with a large part of the population. But I wouldn't discount the fact that we are seeing some stable disease that where people are clearly seeing tumor reduction, just not reaching the PR status and then that going on for a long period of time, those patients -- some of our long risk patients in our trial are those patients in that TSC2 population. So, there's clearly a benefit that's occurring there. We're just not seeing it. At the same overall response rate we see in the TSC2 category. And so while it makes it harder for the TSC2 category to be hit that overall response rate we'd like to see, it does make us quite confident about the TSC1 arm and what we're seeing there in terms of the quality of response and the overall response rate in these later-line patients.

[Operator Instructions] Our next question comes from the line of Boris Peaker from Cowen.

This is Hangfei Fu for Boris Peaker. Did you see any correlations between number of prior lines of therapy and the response as you alluded to that the TSC2 arm performed worse than TSC1 because potentially have more prior lines of therapy? And I have a follow-up question.

There's no particular correlation in that we did see responses across different lines of their prior therapy in the patients. It's too small a sample size though to project if that's a real trend at this point in time or there's any trend or there's not any trend at this point in time, given the small numbers. But we would say we've seen responses in various lines of prior therapy in the study so far.

So my follow-up question is on those stable disease with longer than 6 months of benefit, have you seen a pattern to tell how likely they will be converted to PR?

We -- no. So I would say, Hangfei we have not seen any pattern yet that would articulate an ability to say whether or not those will convert to a PR.

This does conclude the question-and-answer session of today's program. I'd like to hand the program back to Dave Lennon for any further remarks.

Thank you, Operator, and appreciate everyone for your questions and joining the call today to hear more about our interim data from the first 40 patients in the PRECISION 1 trial. I want to remind everyone that we are excited about this data and really encouraged by what we saw in the TSC1 arm in the trial where we had a 26% overall response rate in efficacy-evaluable population and saw rapid, deep and durable responses across a range of different tumor types, which is the type of data we really like to see. We know we want to see to move this program forward with the FDA. With TSC2, we're obviously -- the response rate is lower and is complicated by the fact that we had many late-line patients and we look forward to learning more as we enroll -- further enroll the study. Ultimately, we think this puts us on a great path towards our milestones for next year and we look forward to the continued rapid enrollment within the study. And I would highlight that we now have actually formally enrolled 80 patients into the study, which allows us to hit the milestone of delivering our next interim on 2/3 of patients and the primary endpoint in Q3 of next year. Thank you for taking the time today and best of holidays to everyone out there. Thank you.

Thank you, ladies and gentlemen, for your participation in today's conference. This does conclude the program. You may now disconnect. Good day.

Bye.