Hello, everyone. Welcome to the Jeffrey's Global Healthcare Conference. It's a pleasure to be here with Dave from Whitehawk Therapeutics. Hi, Dave. Could you introduce yourself and your company?

Yeah, for sure. So, hi, everyone. Dave Lennon. I am the CEO of Whitehawk Therapeutics. We're an ADC-focused company. I'm currently developing three ADCs with two that have entered the clinic earlier this year. We recently announced a financing of $87.5 million that extends our runway into 2028 as we pursue each of those programs through dose escalation findings in Phase 1. We have our third program going into the clinic in Q3 this year, and we look forward to provide data updates in the first half of 2027.

Awesome. Thank you, Dave. And, you know, you have an exciting pipeline, three ADCs, These two, they're going to have data in the first half of 27. And now when we think about those two, the Hawk 007 and the MUC 16, you know, we get questions and we're curious about what do you think, like, say the day after the data, what would get you excited about what kind of signals you'd like to see from here? What matters most to investors?

So we have two programs. Hawk 007 is a PTK7-directed ADC, and Hawk 016, which is a MUC16-directed ADC. Each of these ADCs is based on the same linker payload technology, which is based on a linker payload called CPT113 and a bioconjugation process called carbon bridge cysteine repairing. It's quite a unique platform for an ADC. It provides ultra-high stability for each of our ADCs, which we think will translate into greater potency and, importantly, greater tolerability due to both the stability I mentioned as well as the nature of our TOPE1 inhibitor payload. For each of the programs, there's different indications that we're pursuing. So in HAWC007, we're pursuing non-small cell ovarian cancer and endometrial cancer. It's actually a focused phase one dose escalation program that really targets our ability to show differentiation versus other ADCs that are competitive in this field, in those indications. When we think about data that gets us excited, or our hypothesis is, that we can achieve the high levels of efficacy, particularly on ORR rates initially in dose escalation, that ADCs have been achieving to date while improving the overall tolerability of our ADCs, and we would plan to demonstrate with that within the dose escalation. We're currently, we've enrolled already a 2 mg cohort, which is a relatively high starting dose for DOC007, and are enrolling a 4 mg cohort today. Ultimately, we see an efficacy bar in lung cancer of about 40% of ORR and 50% of ORR in gynecological cancers as an efficacy bar, and we anticipate tolerability, particularly heme-sparing effects of our payload to come through with relatively low grade three based AE events with this program. That's what I think gets investors excited around this core program. MUC16 is similar in its construct and what we're trying to achieve, and that program focuses on ovarian cancer and endometrial cancer with the same expectations for benchmarks of what we potentially can achieve.

Thank you for that overview. And you mentioned again a little bit on the differentiating safety profile, I was wondering if you could kind of walk us through a little bit more kind of how, you know, you have preclinical data, de-risking, kind of indicating that, you know, you've built around stability, this low free payload and the tolerability you've shown in NHP studies. So, again, what should we think about in terms of, you know, when we start your dose escalating and what would be like a dose limitation or something, a signal to watch?

Sure. So, as you mentioned, we had preclinical data at AACR this year where we showed HNSTD for all three of our ADCs off of this platform that achieves 60 milligrams per kilogram, which is relatively high in the ADC field. That gives us confidence about the potential therapeutic index that we can achieve with this and the relative tolerability that we're seeing, not only for that absolute number, but the types of events which were relatively minor that we saw within our Sinotox studies. Importantly, there is a parallel program that's being developed by our partner in China, where one of the folks who originated the CPT113 linker payload, and they reported some data on a CD56-directed ADC at ASCO this week. And so we can see in about 100 patients' worth of safety data there, the hematological heme-sparing effects that I talked about before, where they had zero grade 3 neutropenia, very low rates of thrombocytopenia, and about 18 percent grade 3 anemia, which is considered really low for the context of a TOPE1-based inhibitor, and that's while showing very promising efficacy signal in small cell and non-small cell patients in that trial. Now, that was all China data. It's not our programs directly. There are some small modifications that we made in development of our ADCs, which moved from their program, which is a DAR4 to a DAR6. So there's some variability in the translation potential of that data, but we think it provides some good clinical support, along with our NHP data, for a really clean tolerability profile for, relatively speaking, for an ADC. What we'll be looking out for, of course, as we dose escalate is those stochastic events that occur that can be due to injury within patients on different dimensions. I think in general, though, what you're seeing with the ADCs these days, it's less about actual DLTs that get developed and more about the overall tolerability profile relative to the risk-benefit that you're seeing in efficacy. So we don't expect anything particular to hold us back as we dose escalate, but we will be testing how much efficacy gain do we get at each dose relative to the cumulative toxicity that we generate.

Thank you, Dave. And when we talk about ASCO, again, saw updates across the space. And then just regarding this asset, Hangzhou's DAC, again, similar, if you could just talk to us a little bit about that linker payload. Yeah. And then kind of on top of that, you have some additional differentiation with your conjugation, if you could just walk us through that.

Yeah. So as I mentioned, we think we have a unique linker payload system that we have that was developed by Hangzhou DAC, which is a Chinese-based company. If I step back for a second, the vast majority of ADCs today are made with what we call single-chain malamide-based bioconjugation. It's malamide-cysteine-based bioconjugation, I should say. And what happens in that process is that the disulfide bonds that exist between heavy and light chains of an antibody, and there are four of those within an antibody, are reduced to free up cysteines, whereby we then add the chemical linker payload structure onto those antibodies to produce ADCs. That can happen at four sites of disulfides or eight cysteines overall, and that's how you typically generate single-chain Dar8-based ADCs. The big difference for Hangzhou and our approach is that we actually use a paired linker system whereby linkers are actually conjugated together and then added on to the antibody as a pair. It's quite a unique bioconjugation approach or unique structure overall and a unique bioconjugation approach. What it does is actually reestablish the disulfide bonds or reestablish or replace the disulfide bonds that were typically there for the antibody and imparts a greater stability to the ADC overall, something that can't be replicated by single chain based bioconjugation with almost every other competitor uses so it's quite a unique platform uh that that uh and a unique chemistry that hong joe built we then improved upon that by moving uh from a dar4 to a dar6 that improves the overall potency of each adc while maintaining tolerability in hnstd as i mentioned before that um in addition to a couple other confidential steps in which we take technical know-how to improve stability of the ADC overall. It gives us a version two of this platform for ADCs. And so we really look at that DXC006 data that I mentioned earlier from Hangzhou as kind of the floor of what we may be able to achieve with this asset. And that update at ASCO had overall response rates for that target, which we're going into small cell and non-small cell in the high 50s and high 40s ORR respectively for each of those indications showing that the protogram is and the platform is already very competitive in those spaces and those are kind of very stellar results given the tolerability that we're seeing with that platform thank you and then regarding PTK7 you know we do have some precedent for other ADCs in this space.

How do you think about your asset and how differentiating it is?

Yeah, so the PTK7, the great thing about PTK7 is that it's actually one of the most broadly expressed tumor targets that's really yet to be exploited in the ADC field. So it's present in up to about 70% of tumors. So this is a really interesting target to go after. And there was a Pfizer and AbbVie co-development program called Cofituzumab-Pelidotin that looked to target PTK7 with a first-generation ADC based with an MMME payload. That program actually was tested in non-small cell cancer, ovarian cancer, and triple negative breast cancer, where it showed some initial efficacy signal anywhere from 20 to 40 percent ORR in a small group of patients across those indications. Ultimately, the program was discontinued probably because of the confluence of tolerability that was challenging with that MME-based payload, a lot of class toxicity associated with that and the fact that it existed in a co-development between two large farmers which were headed in different directions at that time with their adc commitments so that program was discontinued but it provides the foundation of efficacy of the relatively limited potential on-target talks that could exist with ptk7 and really opened up the opportunity for people to go after this target so now there are a couple of competitors that are also now have switched over to the topo one based um adc platforms uh

along with us going after ptk7 so lily kibu biosciences uh and day one pharmaceuticals to name a few yeah thank you and um again uh we have uh your o7 trial in a few indications non-small cell ovarian endometrial we did see again some other assets in that space as well feels like it's almost getting crowded how do you think about the signals in that space how do you rank the importance by indication of some of those tumors and again if you could just share a little bit more because again the topo one space we saw you know 200 different payload you know 200 different assets there. Again, if there's something that we should think about how 07 improves that therapeutic index, potentially the link or stability, the FC, things like that. Sure.

So the space is, I don't think it's almost getting crowded. It's definitely getting crowded. There's a lot of competition within our target, but also within indications across different targets. We tend to think about really a couple generations of what's happened. So I mentioned kind of first generation programs with MME payloads. Well, a lot of people have switched over to the topo field. And generally you're seeing that there's significant gains in efficacy, improved tolerability when you switch over topos. But not all topos are created the same. And I think what we really spent a lot of time doing is optimizing each technical parameter to get the highest performance out of our adc so the first thing um is the antibody itself so we use high affinity antibodies against ptk7 they're really strong internalized it's a really strong internalizing antibody that can target ptk7 and outperforms on an antibody level copituzumab pellet and pfizer so we benchmarked that performance versus the prior generation product and improved upon that with our antibody design in addition we attenuate the fc region of the antibody itself. Attenuation of FC limits the uptake of the antibody and ultimately the ADC by FC receptor-mediated endocytosis, which can occur in inflammatory cells and is actually in the topo field thought to contribute to high rates of ILD that we've seen with topo. So abrogation of that binding of specific uptake by immune cells by limiting the FC receptor allows us hopefully to minimize the ILD impact that topos can have and then I went through the conjugation chemistry and the linker stability elements that are now optimized and we have benchmark we actually generate the best in class stability within the field we cannot find a program which produces better stability for us and that allows us to really limit free payload release into circulation and limit the payload related toxicity mainly in the hematological compartment. We also use PEG-based masking which helps hydrophobicity of the antibody and hydrophilicity of the antibody I should say and avoiding the hydrophobicity of the payload and improve circulation and PK which allows us to achieve very long half-life of our product and very long half-life of an ADC is important because topoisomerase damage actually needs time to accumulate within cells to drive cell killing as opposed to being directly cytotoxic so we've optimized that component pk component to get really long exposure of adc and that's achievable because of the high stability and limited free payload release if you have a high uh unstable linker payload you need to go to shorter half-lives because you don't want to generate that exposure to the bone marrow and you need that period of recovery and then finally we We use a proprietary cleavage and payload system. It's a triple alanine-based cleavage system that results in a proprietary exotecan analog being released into the circulation, or sorry, into the tumor, I should say, not into the circulation, at the site of tumor. And that payload is actually designed to be less heme-toxic because it doesn't cross the cell membrane as easily and really stays retained within the tumors itself allowing it to focus its effect at that point. So when you go through the entire technology stack that accumulates as you build an ADC we've optimized every component to really drive for potency which we've seen within our animal models we're active around one mg per kg in animal models and we know that translates directly into about a human minimally effective dose. So we have one mg per kg as our kind of minimally effective dose in human. We already started our trials and are starting to clear doses at two and four mg per kg, which we know, which we think will be active for efficacy. So we're not spending a lot of time through dose escalation within the trial. And we have that great HNSTD we're working with, high bar. We could potentially dose up to 8, 10, or 12 minks per kg in humans to generate a very large therapeutic index to explore and determine where our best dose will be.

Dave, thank you. That was such a thoughtful walkthrough of some of the differentiating aspects of your pipeline. And then I'm just curious, you know, through this learning process, you know, and you have some other early pipeline that have TOPA1 plus N-DISCO's assets, how do you see some of the learnings that you've gone through and the differentiating aspects of your assets reading through to other parts of the pipeline?

Yeah, it's a great point. I mean, obviously, we'll learn a lot about DOS from our first program, and that can translate directly into kind of the next two programs that we have. But as part of our recent financing, we actually signed an extension deal with Hangzhou DAC for up to five additional ADCs that we can put into our pipeline. And we're really thinking very thoughtfully about how we bring those programs forward. These will not be your traditional single-target, single-payload-based ADCs. We're looking consciously about which indications really have still opportunity where it's not yet as competitive or where we think there's unique solutions that ADCs can bring to particular indications in the field. And how do we do that by selecting the right target or the right targets in combination in bispecific formats to improve upon the selectivity against the tumor relative to healthy tissue and side effects, as well as thinking about payload combinations. So the TOPE-1 CPT113 linker payload will be the backbone which we utilize within any of our new ADCs, but we're also looking at how we combine that with orthogonal cytotoxic agents or other novel payloads to create the next generation of ADCs, which we think will be, you know, potentially even more impactful and also overcome, you know, what will be a growing problem of resistance to first, well, to the top one-based ADCs that you mentioned. Yeah.

Thank you. And then going back to the PTK7 asset, again, you mentioned a little bit about, you know, what we might be able to see. So just going back there, and in those indications, I mean, is there any thoughts on what would signal going into a particular one of those indications from that early data?

Yeah, I mean, you mentioned how crowded it is, and we look at each indication independently across the entirety of what is there, and so when we focused on non-small cell, we actually picked a subset of that, which is EGFR wild type adenocarcinoma, And the reason we did that is twofold. I think one is we wanted as homogeneous a population as possible. So as we accumulated patients, there was real clarity about what we were achieving within a population. And secondly, we thought that's where the main opportunity lies within the non-small cell space, where ADCs up until this point have really topped out around 30% ORR typically in these types of patients, and where we already saw 20% to 30% with COFIP. Now, if we can build upon that, generally in these transitions from MME to topo, you gain anywhere from 15 to 30 points of ORR. That puts us in that 35 to 50 percent range, which we think could be really impactful for patients. And we know that's what KOLs are looking for in terms of achieving differentiation on efficacy in the small cell EGFR wild type population. So that's our bar and what we expect to hold ourselves to as we accumulate patients in dose escalation and backfill cohorts that we are utilizing early in our program to generate that bolus of patients. Along with that, we are actually requiring tissue in our non-small cell lung cancer patients and screening those for PTK7 expression so that we can retroactively look and stratify potentially results by PTK7 expression. And importantly here, if we want to achieve some of these high ORO rates, it may be a requirement that we actually have selected patients down the road. But, of course, we'll let the data drive whether or not that's actually the case.

Yeah, thank you. And then, you know, ASCO, going to, you know, we saw a couple of these MUC targets as well. So could you just, again, just introduce us a little bit more to the MUX16 for those that are new to the story and kind of how we see that in endometrial and ovarian cancer compared to some other, like, targets, folate, you know, and then some of the B7 stuff, yeah.

So the ovarian and endometrial cancer group is, you know, a smaller set of patient numbers than what you see with non-small cell. It's also a more homogeneous population across each of those indications, although there is stratification of different resistance mechanisms and mutation patterns within each of those patients. With all of that said, there are also a lot of targets which can be very specifically addressed within the ovarian space, which are upregulated uniquely within gynecological cancers, like you mentioned, FR-alpha and others. MUC16, we think, is probably the best target to go after for ovarian cancer and endometrial cancer because it is so highly expressed. And we know this because MUC16 is actually cleaved into the circulating biomarker called CA125. And CA125 is the most common blood-based biomarker utilized by gynecological oncologists to monitor progression and response to therapy for endometrial and ovarian cancer. And so MUC16 is the originating molecule for that, and it actually gets cleaved at the surface of the cell and releases CA125 into the blood. And it does so at such high levels that it's often used as a measure of disease progression, as I mentioned. The challenge has always been with targeting MUC16 is that circulating CA125 creates a huge antigen sink in the circulation for patients. So if you target MUC16, particularly epitopes in that C125 region, you have to dose really high to overcome the circulating epitope that exists within the blood to actually get your ADC or monoclonal antibody or TCE to the site of the tumor. And so recently we've been taking a strategy along with a couple others to actually target only epitopes that are not part of that cleaved portion. so they are actually below the cleavage site in the juxtamembrane region of the molecule, and they bypass that circulating CA125 antigen. Well, why go through all this work if this antigen is such a difficult one? Well, it's because it's so highly expressed. So MUC16 is often 3 to 10 times more highly expressed than common markers like you mentioned, FR-alpha, CDH-6, B7H4, NAPI-2B, some of the things that have gotten a lot of attention recently. So we think as a starting point, MUG-16 is probably the best target we can go after. We've developed a clever way to get around the circulating CA-125 issue that has plagued And then we bring along all of the benefits I mentioned with HAWCO-07 for our linker payload system, high potency, high stability, and high tolerability.

Thank you. And then thinking about, you know, we have another story that we want to share on the SCZ-7 and, sorry, SCZ-6, and you are going to clinical entry next quarter. You recently shared at ASCO some of the real-world characterization of this particular target, And I was wondering if you could just walk through some of that and, you know, why this is a relevant target to look at.

Yeah, so SCZ6, seizure protein 6, is a protein that's expressed in certain neuronal cells and massively upregulated in neuroendocrine tumors, like small cell lung cancer and other neuroendocrine neoplasias. SCZ6, you may get the story now. We spend a lot of time thinking about what's the best target for a particular indication. And with SCZ6, it's really the highest expressed target in this somewhat smaller category of neuroendocrine tumors. And the prototypic one so far has been DLL3. And SCZ6 is expressed at least as high as DLL3, if not higher, and therefore forms a foundation of a great target to go after for this class of molecules and can potentially be combined with DLL3 therapies. We did some work to show kind of that across subsets of small cell lung cancer, across progression of lung cancer, so SCZ6 is very stably expressed regardless of stage of disease and metastatic potential, and we think really establishes SCZ6 as a great target to go after. It is validated because there's a program ahead of us from AbbVie, which forms the foundation then of this being highly expressed and clinically validated target to go after with an ADC.

Yeah, thank you. And we saw some early data, or we saw some data also at ASCO in neuroendocrine and small cell lung cancer from the 706 asset. Any thoughts on how we should interpret any read-throughs from that to your asset?

So AbbVie 706 is the SEZ6 targeting ADC that they've developed, showing some really promising FC signal, greater than 50% ORR in small cell lung cancer. I think what's interesting with that program, so AbbVie has built a platform on a payload called Adizatecan. Adizatecan is a super potent payload, so it really does very well in driving efficacy of ADCs. The challenge is it also comes along with a lot of toxicity, particularly heme toxicity. As an example, in their expansion dose within small cell, they generated 40 percent grade three anemia in that program, which is really difficult for patients to deal with overall. So very potent molecule, validates the target, but we would think really a lot of opportunities to improve tolerability for patients with that. And by improving tolerability, we can actually increase dose intensity, which should allow us to achieve even better, greater efficacy than the AbbVie program. We use a very unique antibody here. We use a biparatopic antibody against this target and we know this antibody is actually about two to three times more potent in terms of internalization and cell killing than the AbbVie antibody and so again we've taken every step to design a molecule that it really can be best in class against the SCZ6 target.

Thank you and as we prepare for the clinical entry of this, could you walk us through some of the design and how you've thought about the best way to show some early signal here and what we expect to see. Yeah.

So this program will go in the clinic in Q3 of this year. I just want to reiterate that's three clinical shots on goal over the next 12 months to look out for and really an opportunity for us to hit on any one of those being a major value inflection, if not all three. The SCD6 program will target small cell lung cancer initially, and we expect to see data in the second half of next year from that program and dose escalation. We will limit that program initially to small cell lung cancer and then look for expansion in neuroendocrine tumors and other places as we go forward, again, with the demonstration that we really have a best-in-class asset driving that decision to bring the program and expand the program further.

Thank you. And as we continue to get more data, you know, and congrats on the three shots. You know, that was, I remember, like, last year in November we were talking and we're here, and it's just, it's been great to see the execution there. Regarding just, like, the PK and biomarker readouts, like, the way that we should think about the PK package for some of your platform, what are maybe some things we should expect to see regarding just some of the PK metrics like your ADC, your total antibody, things like that, exposure response? Yeah.

Yeah, so we'll really be looking at, you know, the half-life that we've seen in replicating half-life initially of this. We saw a very long half-life within monkey studies. We'll be looking for that in our human studies in PK. And then from a stability profile, we always look at what is that free payload that's being released and we you know benchmark that stability in our human pk data overall ultimately what we expect to see is half-lives that extend beyond a week to 10 days for each of our programs and that stability profile that keeps free payload release under the therapeutic limit of our payload which is a couple nanograms per mil Thank you.

And one more question on, so you have optionality for five additional CPT 113 ADC programs. How do you think about that optionality? And then how do you think about partnering also, if I can ask a combined question? Sure, sure.

That's kind of two ends of the spectrum in terms of how we bring new assets in and how we might develop assets going forward. You know, in terms of bringing assets, new assets in, we're really selective about what we want to bring in. we're not trying to fill the pipeline to fill the pipeline. We're really looking for unique value-creating opportunities that add to what we're doing versus our three assets that we already have, which is already a good foundation to build on from a value perspective. And so you'll see us make very deliberate decisions about new programs that we initiate. Our expectation is we wouldn't have, those programs would come in the second half of 2027, so also would come after data release on our first two programs and would be also somewhat momentum-driven at that point in time based on our learnings from those programs. In terms of partnering, I think right now what we're focusing on is execution of our programs and getting to those clinical inflection points. We'll tackle partnering after we have data. Thank you, David.

That was fantastic. Thank you, everyone, for joining us. Thanks, Jeffords.