Morning, everyone. Tara Bancroft here. I'm one of the Senior Biotech Analysts at TD Cowen. Thank you so much for joining our seventh annual Oncology Innovation Summit. For our next session, we have a Q&A with Whitehawk. It's my pleasure to introduce Dave Lennon, who is the President and CEO. It's a privilege to have you here, Dave. Thank you so much for joining me. Before I get started on Q&A, for anyone listening, please feel free to email me questions at tara.bancroft@tdsecurities.com. If you have anything that you want me to get asked, I will be sure to do so. Also have to say, as you all may know, Extel voting kicks off today. The TD Cowen biotech team would really appreciate your support if you feel that we have earned it.
That being said and done, let's get into questions. Dave, I want to give you the opportunity to maybe start with some high-level thoughts, if you have any, before we get into more details.
Well, thanks, Tara, and thanks TD Cowen for hosting this set of sessions again. It's our second year participating out of the seventh year, really exciting moment always right before ASCO to catch up on different topics. We're excited about the progress we're making on our ADC portfolio, as well as some recent announcements over the last couple of weeks around financing and new deals. I'm happy to get into all of that today as we get going here.
Awesome. I feel like it might be a helpful place to start, kind of at a high level, talking about the platform. Can you maybe walk us through, you've acquired these really exciting assets. There's really interesting platform technology. Maybe you could just tell us a little bit more about how the linker payload and conjugation approach are translating into meaningful differentiation and especially versus first-generation Topo 1.
Yeah, happy to. We are an ADC company. We founded the company around a three-asset ADC deal we did at the end of 2024, and we've been progressing those three assets through initial preclinical studies, and now in the clinic on the first two assets, as of earlier this year, with the third program coming into the clinic in Q3. Really three shots on goal with three different ADCs. All of them rely on the same linker payload and bioconjugation technology that we think is truly differentiated in the field. It is a Topo 1-based linker payload system called CPT113, and CPT113 is quite unique because it actually used a paired linker approach, meaning that there's two linkers that are conjugated together that act as a pair when added onto the antibody.
That pair linker system induces great stability onto the ADC itself, and allows for the very specific release of our proprietary Topo 1 inhibitor inside of cells at the site of tumors, with a stability that we think is unparalleled in the industry and certainly top of class in terms of what we've been able to benchmark. This should lead to greater potency of the ADC overall and really a much-reduced toxicity profile, particularly because we pair that stability with a novel payload, Topo payload, that we think will be heme-sparing, reducing the particular cytopenias that you would often see with Topo 1-based ADCs.
Now we're starting to see all of this come into fruition as we progress in the market, but also as a partner that we've been working with for a while, who's the originator of this linker payload, has also been progressing their program in the clinic, and we're excited to see that data presented at ASCO Monday this week. That'll be an exciting update, and we think very validating for the clinical potential of this linker payload system. We're so confident in the payload system, we've actually re-upped with our partner company and have now an option agreement to do up to five additional ADCs, development of five additional ADCs on this linker payload system, and that includes dual and novel payload variations that we think will be the next generation of this entire category.
Okay. I do want to get into asking you a little bit more about what to expect at ASCO.
Yeah
We should be looking for. I know it's targeting a different target than what you guys are, but I think before we get into that, it might be more helpful. You guys just put out a whole bunch of data at AACR last month, and so maybe you could recap maybe the top one or two highlights from each program. You had so much from each of these different pipeline programs that you guys have, so that would be really nice to just kind of hear at a high level what we should be taking away from that.
Right. I was describing the differentiation we have with this platform, which is foundationally about stability of our linker payload system. We saw that carry through in all of our preclinical programs, which we presented at AACR last month. Our first program is HWK-007, our James Bond program against PTK7, which we think is a really exciting target. What we show there is we have great potency of the molecule down to 1 mg per kg in xenograft studies, which we think will be the minimally effective dose in humans. An HNSTD of 60 mg per kg, which is the highest dose we tested in non-human primates. That therapeutic index, the safety over the efficacy window, is really a great ratio, which we think will translate into a broad therapeutic window for this program.
We're already seeing that in the clinic. We actually have completed our first dosing cohort at two mg per kg and cleared DLTs. We've completed enrollment of our second cohort at four mg per kg. We already started above that 1 mg per kg level, which we think is active, and we believe we're in the active dose range for this program already in the clinic. AACR provided a great platform for differentiation, and we're already kind of seeing that pull through, both in our strategy of aggressive dose escalation within phase I, but also in the safety profile we're seeing so far. I should say I mentioned maybe the other program. HWK-016.
Yeah, right.
It is our MUC16 program. At AACR, we demonstrated similar potency, one mg per kg, same HNSTD as 60 mg per kg. We demonstrated that we can get around an antigen sink, which has plagued the MUC16 field for a long period of time. We've designed a specific antibody that bypasses a cleaved portion of MUC16, which has been prohibitory in addressing this target in the past. Why do we go through the trouble to do that? Well, because MUC16 is the highest expressing ovarian cancer target that's known. It's maybe three to 10x more highly expressed than FR alpha or CDH6 or other high potential targets within the gynecological space. We think this is really one of the best targets to go after.
We have a novel way to go after it, and we demonstrated that pre-clinically, we can generate a great potency with this molecule. We are testing that molecule. We've started this program actually at 2.5 mg/kg in our initial dose escalation. Again, a dose range we think is already going to be active for patients in our dose escalation studies. Our third program, HWK-206, is against a CNS-originated protein called SEZ6. It gets upregulated in neuroendocrine tumors, like small cell lung cancer and other neuroendocrine neoplasias, things like prostate neuroendocrine cancer, for example where we really think there's a really unique opportunity to go after this target, which has been validated actually by an AbbVie program called ABBV-706. That program has shown some really promising efficacy signal, but really hasn't balanced the safety signal with that.
We think we have an opportunity here with this program to target this antigen in a better way. Here, we're using a biparatopic antibody, which outperforms the AbbVie antibody. We've conjugated that into this highly stable platform, which we think can be best in class from a tolerability perspective. We do think we can improve both on the potency and the safety of AbbVie's program, which is ahead of us against this target. Really three exciting demonstrations of differentiation against three really unique targets that go after different segments, but still very sizable opportunities for each one in the cancer space.
Okay, awesome. Thank you. Just to go back to what you said in the beginning when you were talking about differentiation of the platform, I want to go back to this ASCO data set that's coming up for the CD56 targeting ADC, and any other programs that are in the clinic using this same linker payload platform, the CPT113. Can you maybe just give us a little bit more specifics on how you guys are thinking about read-through of those data sets to your programs?
Yeah. CPT113 is the linker payload system that we utilize. It's from a company called Hangzhou DAC. Hangzhou DAC has a CD56 targeting ADC that's called DXC-006. That's like my tongue twister for the day. A lot of Ds and Cs in there. In any event, DXC-006, a CD56 ADC, has been internally developed by Hangzhou and has been in clinical trials in China in small cell lung cancer, non-small cell lung cancer and neuroendocrine neoplasias. They will be presenting data, which has already been partially released in the abstract. What they showed is a very high response rate, in the high 60s of overall response rate in small cell lung cancer, 50s overall response rate across all the cancers, 45% in non-small cell lung cancer. These are sizable patient populations. There were 79 trial patients in the trial overall.
We're seeing some really promising efficacy out of this linker payload system. The other part we're really excited about is we're seeing great safety. The tolerability profile of this asset shows less than 30% treatment-related AEs, Grade 3 treatment-related AEs overall, and the cleaner hematological toxicity profile that we expected from this payload, in particular, without the Grade 3 neutropenia that can be really problematic, especially for most Topo 1-based ADCs. Also, no ILD so far, no DLTs in the dose escalation. Really a very tolerable program relative to in the ADC field. We're really excited about that data. There'll be an update on that data. We know Hangzhou has conducted a new data cut, and that'll be updated in their Monday presentation. We expect it to be in line given the kind of sizable data they already had to date.
We're really excited to have that presented at this point in time, because it gives validation for CPT113, which is the linker payload. I will comment that we use a slightly different bioconjugation approach with the same chemical structure to achieve a DAR6 versus a DAR4 that Hangzhou had been utilizing, and while maintaining the same tolerability. We actually improved the overall HNSTD in monkeys, and demonstrated greater potency with this revised bioconjugation method that we developed alongside WuXi Biologics, who we licensed this program from. All of this points to the fact that we now have clinical validation on this linker payload system. We have an improved version that we're taking into the clinic on our programs, and we think really a nice read-through for Whitehawk and the three assets we have.
In addition, there is a big pharma partner that Hangzhou has been working with for a number of years, which is J&J. J&J disclosed at AACR that they are actually making an ADC version of amivantamab, which is their key lung cancer, EGFR/c-Met, bispecific lung cancer drug. That ADC version will also utilize CPT113 in the DAR4 format, the Hangzhou bioconjugation process. Again, just another kind of validating a vote of confidence in this linker payload and its ability to differentiate that J&J would entrust such an important part of their portfolio to this otherwise novel linker payload system.
Awesome. That's really comprehensive. Appreciate that. One of the things that I want to go back to, which I think is interesting, and especially for us, we're super interested in the science of how this actually works for ADCs. I think it's still this mysterious thing to some extent, but you made a point how, of course, with these programs, the linker payload is the same, but the conjugation is different. Your DAR-6 is differentiated, especially in terms of safety versus the DAR-4. Can you explain for us how conjugation actually contributes to having a different safety profile versus another type of conjugation method? I think that it's important to distinguish, right?
Yeah. Conjugation can involve a number of steps, and particularly when we talk about maleimide cysteine-based conjugation, which is the most common utilized bioconjugation method for ADCs today. There are some tricks to ensuring that you generate the most stable profile with your asset. The first is almost everybody uses a single chain-based bioconjugation, which means that there's a single bond that is utilized at the site of cysteines, which are normally bound across disulfide bonds within interchain monoclonal antibodies. Those are reduced and released and opened up for bioconjugation with single chain-based linker payload systems. That bioconjugation can be inherently unstable, and so it's prone to break down when in circulation. It can be attacked by different reactions within the blood, and outside of tumors releasing linker and ultimately payload into the circulation.
As I mentioned, we use this paired system, which gives us two points of attachment for our linker onto the antibody versus relative to the one, which is inherently more stable because you need two attacks to actually release any linker payload into the blood. The second component, there are additional steps you can take to improve stability of your linker payload, particularly hydrolysis of maleimide rings. For those who want to get into biochemistry, that's a particular part of the process, which if not done, can lead to what's called retro-Michael reactions, which release linker payload into the system. That issue has plagued a lot of first generation ADCs who didn't take that additional step in the process to impart further stability. I think it is more common in the next generation of maleimide cysteine-based chemistries.
All of these components added together, there's some smaller other things that you can do within that context of bioconjugation, all contribute to increasing stability and cumulative stability of the ADC, particularly in circulation, which is what we're trying to do here. The last step is often around masking and masking techniques using either polyethylene glycol or polysarcosine or carbohydrate extensions with on the antibody, which help cloak and mask the linker payload while it's in circulation and prevent unwanted deconjugation. All three of these components, whether it's our particular proprietary dual-based addition, hydrolysis maleimide rings, and masking, all help support improved stability of the ADC in circulation. It's really the cumulative effect that allows us to get down to levels now that when we release free payload, we're not generating free payload that gets above the therapeutic index of the free payload itself.
That really limits exposure to healthy tissues and the side effect profiles that have plagued a lot of those first-generation topo programs.
Okay. Perfect. I thank you for indulging my inner nerd there.
Dude, I love the inner nerd.
Don't we all? Okay. Let's start with the PTK7. Really, there's so many PTK7s in development now, right? You had Dawn, which was acquired, Pfizer, which had clinical data already. Sutro has a dual payload PTK7. There's several others out there as well. Maybe it would be really wonderful to hear how you're learning upon Pfizer's old experience with their auristatin. Genmab had one too, right?
Yes.
Also auristatins. How you're learning from that experience and then differentiation amongst the other clinical stage candidates, especially as you're thinking towards your first proof of concept data that you're expecting?
Yeah. We anticipated that PTK7 would be an explosively growing target because it is the last large target that's yet to be exploited. By large, I mean, it covers up to 70% of cancers out there, and when you look at patient numbers, which makes it a huge opportunity on the scale of a Trop-2 or HER2 or Nectin-4, some of the most successful drug targets in the ADC field. That's why you're seeing multiple folks go after this now. A lot of that's based on some early learning from Pfizer, which was a discontinued program, but did show some early efficacy in non-small cell lung cancer, breast cancer, and ovarian cancer. We think we can build upon that by moving from the auristatin-based payloads to topo. I think everyone's betting on that transition.
Our belief is that given the competition, we need to show that our molecule is best in class. We took a very focused approach within our dose escalation. We're only focused on non-small cell ovarian and endometrial cancer, where there are clear benchmarks for what good looks like with an ADC. We're not pursuing 12 different indications in all solid tumors, because we believe that if we can't show we're best in class, then we shouldn't be trying to find a small target that will eventually get taken over by another. Our goal is really that focus in effort and execution, and we anticipate our ability to demonstrate that best-in-class profile will really then drive the opportunity to expand into other indications when we think about dose expansion down the road. That's our strategy overall.
As I mentioned, I think one of the core pieces of differentiation is obviously our stability. I mentioned our payload, and the reason our payload is important, particularly against other PTK7s, is because every PTK7 we're aware of at this point that's being developed in the U.S., uses exatecan as a payload. We know that exatecan is a potent payload, but it also comes with a high degree of GI toxicity and hematological toxicity in particular. We've seen a number of programs that need to utilize GCSF or just have to deal with high rates of grade 3 neutropenia, in particular, anywhere from 25%-50% sometimes. That, we think, will be a limitation relative to our program, which is, as I mentioned in the beginning, much more heme-sparing.
This will give us a better tolerability profile, and that becomes really important when you think about where you want to go with these programs, which is into first-line combinations or earlier-line combination studies, where a hematological toxicity profile that exatecan is showing may be problematic for certain additions with bevacizumab, with IO, with others. We think that clean tolerability profile, along with best-in-class efficacy, will really allow us to move up in regimens and fully maximize the PTK7 opportunity.
Awesome. Okay. I still want to get to the other programs, let's now switch to MUC16. I know you already mentioned that you get improved target engagement because you have this membrane-proximal binding strategy and the difference between circulating antigen and target shedding. All really, really interesting stuff. Maybe you could put it into context with what has been done and what's currently out there and what you're expecting to see translate into clinical data when you have it.
Yeah. I covered it really quickly before.
Yeah
The shedding of the antigen has really been problematic. MUC16 is shed into a circulating antigen. It's actually recognized as a blood-based biomarker called CA 125, which folks familiar with the gynecological space will know this is a really highly utilized blood-based biomarker in that space. MUC16 and CA 125 are two sides of the same coin. Really high expression, but you have to target around that, which we did. Now, we really believe this is a great target because we know if you target MUC16, there was a Genentech program that did that, you can actually get really high response rates. It's just that if you don't target the right part of it, you have to dose really high to achieve those response rates, and that led to a side effect profile. That was intolerable.
Genentech had that program 40% overall response rate in their initial MMAE-based program, but really high side effects because they had to dose really high to overcome that. We've redesigned the molecule, as I mentioned, to get around the antigen sink effect. We have also switched to a topo. We think that can actually lead to potential efficacy we haven't seen before, potentially greater than 60%, although clearly the benchmark now in the space is in the 50s, against gynecological cancers. That's what we'll be looking to achieve within our first-generation program, is a differentiated profile, again, with the tolerability profile I mentioned before, but with that efficacy that tops out potentially above 60% in terms of ORR, initially in our phase I dose escalation.
That would be really exciting because I think it would be a breakthrough for this category, utilizing a marker that we can potentially enrich for patients through circulating CA 125 identification.
Okay. Awesome. Okay, in the last remaining minutes, I do want to get to SEZ6 because especially from us, of course, in our inner nerds, we love a good novel target. This one is a more underexplored target, especially compared to PTK7 and MUC16. I was hoping maybe take a step back a little bit. Can you explain a little bit more of the rationale for going here with this particular target and any kind of validation that you have that supported advancing this one into the clinic? Not just in terms of the pre-clinical data that you've already discussed, but just on a higher level.
SEZ6, there's a number of targets that are upregulated in neuroendocrine-based cells. DLL3, B7H3, are common ones that are being explored in the space today. What we really like about SEZ6 is two things. One, it's actually one of the most highly overexpressed tumor targets in neuroendocrine or small cell lung cancer, and that's data we're actually presenting at ASCO next week. That gives us a great starting point for addressing this tumor target or these tumors because we have a very highly expressed tumor target, the most highly expressed tumor target. That was one reason we really like this target overall. I mentioned we're using this biparatopic approach that will hopefully improve engagement upon this target and really give us that opportunity to differentiate against all the targets that are out there.
We really think this is the best-in-class target for these types of tumors, and it's why we went down this road. We think AbbVie's data to date validates that from a target perspective, and we think we can build upon that to improve and make a better asset.
Okay, awesome. Well, I found this to be a very fun and exciting conversation. It's unfortunate that we're out of time, Dave, but I really appreciate you taking the time to chat with us on this and enlighten everyone on everything that you're doing and your exciting strategies. I appreciate your time and everyone for listening.
Thanks, Tara.