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Yeah.
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All right. Thanks for joining the 46th annual TD Cowen healthcare conference. I'm Marc Frahm from the biotech team here at TD Cowen. Very pleased to have the next session here, Acrivon Therapeutics, with the CEO and President, Peter Blume- Jensen, who we're gonna kinda walk through their mostly on their lead program with CHK1, ACR-368, but also a little bit on the pipeline deeper behind that. Maybe to start off with, Peter, This would be even higher level than the programs themselves. Do you wanna kinda walk through the AP3 platform, kind of what it is, and give us a sense of kinda how that platform runs through everything you do from targeted discovery all the way through to that lead optimization and ultimately the conduct of the clinical trial.
Yeah. Thank you, and thank you for inviting us here today. We have a proteomics-based precision medicine platform that's driven by generative AI. We use it in a different way, and we could have a whole separate day about the AP3 platform and what we use it for, but we are laser focused on using it to advance our clinical assets towards approvals and also for drug discovery. Two, we have just brought our first internally developed dual WEE1 PKMYT1 inhibitor into the clinic, developed for superior single agent activity, and these are some of the deliverables of the platform.
It's based on unbiased assess how a drug acts on the signaling pathways inside a cell, and you can then design molecules based on optimal pathway effects, and you can also design it to inhibit pathways that drive survival in cells, et cetera, et cetera. It's a pathway-based approach and we are now applying it to both our two clinical assets and our preclinical pipeline.
Okay. Maybe with 368 specifically, last week, you know, you did show to the clinical community, kinda the latest data and review with them at ESGO, of course hosted a KOL event that was more investor-facing. You know, what do you think were the main takeaways from that meeting? I think what do you think investors are missing or have misunderstood about 368's potential?
Yeah. Thank you for that. In fact, I can forward the slide here. We had an outstanding expert panel at the ESGO meeting last week, and they're shown here, Dr. Coleman, Eskander, Becchetta, Larusso, and Brian Slomovitz. World-leading experts behind a lot of the guideline-changing therapies in endometrial cancer and other gynecological cancers over the last 30 years. Basically, the panel expressed very strong enthusiasm for our data, especially the impressive clinical activity we have observed of our lead asset, ACR-368, our dual CHK1/2 inhibitor in the highest unmet need form or type of cancer called serous endometrial cancer. The reason for that excitement. Oops. There's a slide missing here. Oh, okay. I'll just talk to it.
The reason for that excitement is that Serous endometrial cancer contributes to 50% of all mortality of endometrial cancer, and it's very aggressive. Most of them are P53 mutated and pMMR, so there are very few treatment options. There's only modest benefit from immune therapy, which is a new frontline therapy introduced actually by Dr. Eskander and our CMO, Mansoor Raza Mirza, two back-to-back New England Journal of Medicine papers. In second line, we have the KEYNOTE-775, Vicky Makker study with Pembrolizumab showing a 15% response rate in second line and higher, and it's really only chemo. The exception is a very small fraction where you can use HER2-targeted agents, HER2 3+, which is where the approval is.
Besides, from that small fraction, there's really nothing to offer these patients. Our drug is very, very active in that type of cancer, which is extremely deadly. The survival is shortest. The overall survival is only about three years. As I said, while it's a small incidence, it contributes to about 50% of mortality. It's a type of endometrial cancer that's responsible for most deaths of all types of endometrial cancer. I think maybe that's not fully acknowledged by the community, by investors, how serious the unmet need is in serous endometrial cancer. I encourage everyone to go to our webcast and see that for themselves and the enthusiasm expressed was really strong, as I said. I think that's what I'll say.
Yeah. Then maybe, you started touching on it a little bit with the answer in response to that, but can you walk through kinda the standard of care, first line, second line, third line? 'Cause I think a lot of investors, part of what they struggle with is they've never really done that much work on endometrial cancer in general.
Yeah. Yeah. I unfortunately missed a slide that would have shown this so elegantly. It's in our deck, but I will see if maybe we can do something about that. Basically, as I said, there's about 14,000 deaths per year in the U.S. from endometrial cancer, and about 8,000 of them are from serous endometrial cancer. The frontline therapy now is for all patients with stage three, four, or locally advanced. That's the combination of immunotherapy with platinum-based chemotherapy introduced by Dr. Eskander and Dr. Mirza. After that, you really are seeing it's a very, very revolutionary treatment. About 20%-25% of all endometrial cancer patients are what is called dMMR, mismatch repair deficient, and they benefit enormously from immunotherapy and chemo.
We are basically seeing cures. It's, it's kind of a revolution in endometrial cancer care. The 75% or so that progress, out of those, about 50%, and that came out at the panel as well, about 50% of them are serous, already in second-line. There are not really studies on the serous subgroup. It tends to be, as I said, P53 mutated and very, very aggressive. The, the median survival is about, t he median PFS is about 3.4 months as well. Having the activity we are seeing in patients, so far in our trial is pretty spectacular. The standard of care is HER2-targeted therapy for the 8%-10% that are HER2 3+. Some doctors also use it in HER2 2+, which is about 15% more, but it's not approved there.
It's under NCCN guidelines. Otherwise, it's really single-agent chemotherapy for that group, and there's just nothing really to offer. There are emerging therapies. Obviously, ADCs are getting a lot of attention, but I think we have a very competitive profile, not only on a response rate that's about 50% in serous endometrial cancer, second and third line, but also with a favorable AE profile. We don't see interstitial lung disease, et cetera, and I have a slide on that later. I could go through quickly the data.
Yeah, yeah. Maybe before we get into the data itself, do you wanna talk about the diagnosis trends of endometrial? I think that's also a little bit different than a lot of other tumor types.
Basically, it's routine pathology is to subtype endometrial cancer. You typically by routine H&E staining, you always type them based on whether they are serous, endometrioid, carcinosarcoma, clear cell, et cetera. It's part of a routine assessment. In a way, it can be used as a lineage biomarker, and we've just seen that if you are serous, you have a very high sensitivity to the drug.
Yep. Maybe if you wanna review the data 'cause I think maybe some people may not be familiar.
Yeah, I think I need to quickly go through. It was based on an analysis of our ongoing trial, a registrational intent phase II trial. First here you're seeing arm one, which is our OncoSignature, which is our protein-based functional biomarker driven trial where we prospectively predict response or benefit to ACR-368, where we have seen a 44% confirmed response rate. There were two that were not confirmed at the time of analysis. We see that the biomarker, the OncoSignature, is working. This is in all subtypes. This is not just serous. This is an all-comer study where we simply say, if you're OncoSignature positive or biomarker positive, we predict benefit to ACR-368. We've also, with our platform, uncovered that ultra-low dose of gemcitabine, ULDG, can sensitize to ACR-368 if you're resistant to that, and we are seeing some signs of that.
We basically completed arm two, and achieved what we wanted, which was to assess. This was an exploratory arm, while arm one is registrational intent, which was to assess whether ULDG can contribute. A further analysis of that ongoing trial uncovered this very, very significant response rate that we could see in serous patients. This is all patients, serous versus non-serous in our trial. First of all, you can see that the serous subgroup, just like I said, actually constitutes quite a lot of all patients in second and third line. Here we have about 35%-40% of them are serous. We see that regardless biomarker status, we have about 50% response rate confirmed. You can see the depth of the responses. We have confirmed response.
We also have very, very deep responses based on the waterfall plot here. Clearly, serous is a very, very sensitive subtype. We think this is a very competitive response rate compared to also what's emerging. The only one we are aware of that has been in that neighborhood of response, but not specifically in serous cancer, is ARENA-S from Genmab in Copenhagen, which has had close to 50% response rate. It's an ADC. Otherwise, we're not aware of any other ADCs. They tend to be more in the 30% response rate. This is a very competitive profile for endometrial cancer, and especially the serous subtype. This has to be paired with a very favorable safety profile. We only see hematological AEs. They are transient, and they are mechanism-based, dividing cells.
Myeloid progenitors will be suppressed, but it's typically in the first cycles. It's a lab abnormality. Unless you get febrile neutropenia, which is a very small % shown down here, you don't have any symptoms. This is obviously also in stark contrast to other types of agents. We have a notable absence of all the nasty AEs that we are aware of from other therapies like GI. We have no GI toxicities, interstitial lung disease, which can be grade five and can lead to death, stomatitis, ocular toxicity, and peripheral neuropathy, et cetera. All in all the benefit risk profile, the response rate is very competitive in second line, where, as I mentioned, the standard of care is about 15% and three months PFS.
Our disease control rate and clinical benefit rate is listed here at 65% for more than 16 weeks. Two thirds have more than 16 weeks of either PR, CR or stable disease. It compares very favorable.
Okay. Maybe based on this now you are adding an arm three. Can you maybe walk through the arm one, two, three, kinda how they're different, and how the hypothesis particularly for arm one versus three.
Yes
Is a little bit different.
Maybe I can use this one here. Basically based on the observation of the high response rate in serous endometrial cancer, you can see here we have now three arms. We have our arms one and two, of which arm one is registrational intent, ACR-368, a monotherapy based on being biomarker positive. The biomarkers basically predict whether there's an addiction to check one, check two, whether it's driving DNA repair, and we have shown it works. We've had several prospective cuts and as I showed, we have a response rate that's over 40% here. This is all endometrial subtypes, and it's up to three prior lines of therapy. On the right side, you see that arm two, as I mentioned, is exploratory and basically completed now.
We wanted to assess the contribution of ULDG when you are resistant to ACR-368, something we also uncovered with our AP3 platform. On the right side we have the new arm, and we have actually now opened up and expanded that trial without the need for a pretreatment tumor biopsy. It's very easy to do a global expansion. We are rapidly now initiating sites in four major countries in Europe. We are anticipating completion of enrollment of up to 90 patients by beginning of Q4 this year. That's a very powered study. We actually think if the response rate holds up just somewhat that an interim read much, much earlier will be very informative. Obviously, we are in active dialogue with the FDA.
Great. Okay. I mean, you started to touch on it just then, but just the importance of the pretreatment biopsy and maybe, you know, we've seen an enrollment base that is what it is within arm one and two. How, how should we think about that, the enrollment pace that arm three is gonna be able to do because of the lack of pretreatment base?
It makes an enormous difference. In Europe it's very difficult, especially with our OncoSignature, which is a new type of biomarker. It's three protein-based biomarkers, quantitative read of those, and one needs a minimal threshold. When they're above that threshold, there's an addiction to CHK1, CHK2, as we've shown. In Europe, introduction of such biomarker approaches and companion diagnostics is very time-consuming. Having the ability to use Serous as a lineage biomarker, basically a type of endometrial cancer that tells us when you have Serous endometrial cancer, you are very sensitive, is an enormous advantage. That allows us to enroll very, very rapidly. You can see here we are anticipating that being completed beginning of Q4 this year. Arm one, we are enrolling aggressively there.
That's only in the U.S. as well, but we do have a pretreatment tumor biopsy. The value of keeping arm one is, first of all, the OncoSignature is working, the biomarker is working. We have up to three prior lines of therapy. The more lines, the more amenable patients and physician would be to take that pretreatment tumor biopsy. Also it's all histopathologic. If anything, it's kind of an expansion of our label opportunity to do that.
Yeah. You mentioned both arm one and arm three, yeah.
Are registrational intent. Yeah.
have registrational intent.
Yeah.
What do you think those arms need to show in terms of efficacy?
I mean
Accelerated approval? Is it the same bar for both of them? Is it different because, you know, the patient population will be slightly different?
It's pretty much the same. In Serous for sure in Serous endometrial cancer with up to or including two prior lines of therapy, we can have, I think, a significant reduction of the response rate in the prospective enrollment we are doing now and still have a very significant separation from the standard of care. In fact, I think we had the. Yeah, we have the lower bound of the confidence interval here is 33%. Combined with the favorable safety profile, this is obviously more than twofold better than the standard of care of about 15%. We can degrade quite a lot from there, especially as we get more patients inside our confidence intervals.
Combined with that favorable safety profile, we think that this the bar is easily met with, say, 35 maybe +% response rate and the durability we have seen already. In arm one, it's gonna be similar, especially in up to three prior lines of therapy across subtypes, because there you're also running into a similar response rate, again, driven by the, as was witnessed in the KEYNOTE-775 study of about 15% there.
You touched on it a second ago there, but just durability, the durability that you think you need to show, not just the response rate, obviously.
The durability in second line serous is about 3.4 months. Again, that was a Keynote study by Vicky Makker. Those patients at the time had not even had prior IO, so they were less heavily pretreated, and that was 3.4 months. We are seeing, as I showed, a clinical benefit rate over 16 weeks of 65%. Durability is also similar, approaching 6 months. That should be very sufficient for me think for approaching for filing with that data.
Okay. How do, in your KOL conversations that you were having around ASCO, just, there's the regulatory bar that you just walked through, but, how, if at all, does the kind of commercial adoption bar differ than that regulatory bar?
Again, it's the highest unmet need. I think the enthusiasm expressed by the treating doctors, they are all treating physicians on the expert panel, is driven by the fact that you stand with a patient that serious, they have only modest benefit from the new frontline therapy of IO and platinum-based chemo. I think the adoption should be very aggressive and positive. Again, I encourage everyone to go and listen to the panel. In fact, at the panel, the specific question was asked if the data hold up somewhat, what percentage of patients would you use this drug for? It was mentioned at least 75% in second line and 100% in third line.
The 75% is probably because of the HER2 3+ and 2+, that we typically would give in second line, and that's why we allow up to two prior lines of therapy so we can come in after that. In fact, we mandate HER2 targeted agent has been given if you're HER2 3+. The question was asked, what percent of patients are serous in second line and third line, and it's about 50%, just like the mortality contribution. They're the ones that progress. The dMMR kind of get the front line and many of them are being cured, it looks like, which is great news for patients.
Yep. Okay. If you do hit those bars over the next year or two as you enroll in it and read out the data, that would be for an accelerated approval, right? What do you need to do from a phase three perspective, from a you know, confirmatory trial to ultimately support?
We have submitted already a protocol, a design, with an SAP for a phase III based on our synergy we have observed. There's both a strong rationale, and we've seen complete regression and permanent immune memory by combining ACR-368 with immunotherapy in competent, syngeneic competent mouse model studies. It's preclinical data, but there's a lot of rationale and also a lot of other studies from outside with, specifically with ACR-368. We think that synergy can be leveraged for frontline, for moving frontline into what is called a maintenance, switch maintenance therapy, where immunotherapy is combined with ACR-368 after the frontline chemo with IO of six times three weeks. There's a long maintenance phase after that, where we think you'll benefit significantly more from the combination with 368. There's also a very strong synergy.
Again, there's both preclinical studies and that from outside laboratories, as well as our own phosphoproteomic data showing synergy with Topoisomerase I inhibitors, which is the main payload in a vast majority of ADCs. One of the things that also came out of the panel was once you're given an ADC with that payload once, you cannot come in a second time. There's built up resistance. What is interesting is that the resistance mechanism to that topo one is actually the check one two checkpoint. It's kind of a synthetic lethal opportunity. When you treat with Topoisomerase I inhibitors, there's DNA repair kicking in, driven by check one two. That's a vulnerability. Once that resistance is there, you can come in with ACR-368.
We've also seen synergy, that opens up also for a second frontline therapy opportunity. We haven't designed a protocol for that yet, that's another opportunity.
The main protocol that you have submitted, I guess, can you explain how in practice it could serve as a confirmatory trial for both either arm one or arm three? Since they're, you know, those are different hypotheses that are kinda running in parallel in the second
Yeah. So, you know, a confirmatory trial is basically to, for ultimately for label expansion, moving more frontline. We have submitted the protocol based on IO. When we submitted it was before we had the insight on the serous sensitivity. With that insight, it's possible that we would modify the protocol to first have a hierarchical testing of serous, the serous subtype, and then followed up by the old comma. We are focusing on pMMR, the 75%-80% of patients that benefit least well from immune therapy, and to get that boost from the combination.
You know, since that protocol is kind of, because the standard of care in frontline it does involve PD-1 therapy. What do you need to do in order to kind of support opening that from a safety perspective? You know, 'cause as of today, you haven't dosed on top of PD-1, right?
Yeah. The AEs are completely non-overlapping as you saw. This is not AEs you see with immune therapy. The AEs are completely non-overlapping. We have designed it for with a safety run-in followed by the actual maintenance phase 3 trial. That's how the protocol has been designed.
Okay. What is gating to starting that trial?
We have right now we have publicly said that we will have trial readiness mid-year. You can imagine for a company like ours, we are also talking to big pharma with immune therapy agents about such a trial 'cause it's many patients. That's what I can say about that right now, but there's obviously strong interest in that.
Okay. We're starting to get a little close on time, so maybe we'll move to the deeper pipeline. With 2316, the WEE1 PKMYT1, asset. Just you wanna maybe give a high-level overview of the status update of that phase 1 trial with the dual WEE1 PKMYT1?
Yes. Thank you for asking. That's the compound that has been designed with our AP3 platform, specifically based on optimal pathway effects. We uncovered the main resistance mechanism to potent WEE1 inhibition, and that's driven by PKMYT1, maybe not surprisingly. We can see that based on the phosphoproteomic data and the activity readouts. Based on that, we build in the ability to quench not only WEE1 potently, but also inhibit in a balanced manner PKMYT1. That was with the purpose of achieving superior single-agent activity. We also, based on the pathway insights, were able to optimize the leads that will lead to activation of PLK. PLK1 is a driver of mitosis. It's essential for mitotic execution.
What we have achieved is the most potent, tumor cell death, pro-apoptotic tumor cell death of all the agents that we have been able to compare head-to-head with that are in the clinic of both WEE1 and PKMYT1 inhibitors. We have all that data on our, in our corporate deck. We get complete regression across all models tested to date, which we haven't been able to see with benchmark, clinical benchmark competitors and are excited about that having translated to the clinic already during dose escalation. Is that the updated deck?
No, it's that one.
Oh, yeah, it works. It works. Oops.
It just happens on a pop-up.
All right. Sorry. already doing, here was the slide I was looking for earlier with the unmet need. Let's go forward to
It's just its own slide.
Okay. If you, kindly go forward.
If you wanna go swap it. Okay.
What we've seen already is that that has translated to the clinic with activity in tumor types that have not previously been sensitive to WEE1 inhibitors or PKMYT1 inhibitors. There might be one exception for adenocarcinoma with one study where there was one responder. That is we predicted with our AP3 platform that we would see sensitivity in small cell lung cancer and squamous non-small cell lung cancer. We saw that already during dose escalation. You steer it? If you go to-
Do you wanna? This is its own slide. Do you just wanna see this?
No, I wanted to advance it. Can I control it with?
Yeah, you can. You can from this.
Yeah, okay. It just doesn't work for some reason.
No, wait. No.
Oh, yeah, it does. Okay. I have it. Thank you.
Okay.
Let's go to that. No, it's not the right deck. All right. Never mind. We have, as I said, seen very, very strong activity in tumor types like lung cancer where other WEE1 inhibitors haven't been sensitive. And that's with a disease control rate of 80% already during dose escalation in the active doses at 120 milligrams and above, and also with, we have 9 out of 20 patients, I think there were, with tumor shrinkage. We are very excited about that single agent
Okay
Across all the tumor types.
We started comparing a little bit of the clinical activity you've seen versus some of those other molecules that have hit at least one of the two pathways. Can you just talk about biochemically the level of pathway engagement you're getting on.
Oh, so
The WEE1 access
Yeah
One way, but also the PKMYT1 relative to what either of those
Yeah
Are being inhibited.
We have several also posters at ACR and tri-meetings, et cetera, showing the potent inhibition of both on target of WEE1, balanced inhibition of PKMYT1, but also the pathway suppression leads to much more potent readouts of, as I said, pro-apoptotic tumor cell death, biomarkers, pharmacodynamic biomarkers, et cetera. It's a very, very potent molecule. It's highly selective, so again, we have a very desirable AE profile there as well. We basically only see neutropenia, transient neutropenia, which is extremely encouraging. And this is something where we are very excited about that obviously and that opens up also for a lot of both combination opportunities and single agent opportunities with the lung cancer activity.
You mentioned some of the activity you're seeing in the early parts of the dose escalation there. Just. Can you walk through the focus, tumor types as of now that you're planning to do the expansion work in?
Yeah.
Maybe frame up, I think there's a data update expected later this year. Just frame up, how investors should.
We have.
About patient numbers, follow-up, that type of thing.
Yeah. Yeah. We have developed two weekly oral dosing regimens already very quickly, and we're also working on a bi-weekly schedule based on the mechanism-based transient adverse events in the bone marrow of myelosuppression. If you have a hard hit with 2 days on, we think that the bone marrow will recover each 14 days. As I mentioned, it's a lab abnormality. With the neutropenia, you don't have patient symptoms or anything. It's truly just numbers that drive the max dosage. With the two on, 12 off, where you'll typically see routine sampling of blood before the beginning of each cycle, we actually think you can hit much, much harder, and we are working on that now. We will probably expand.
We'll expand into one of the three regimens, either one of the two weekly oral or the one we are finalizing now, the bi-weekly. In tumor types that we think are uniquely sensitive, and it could be that it could be lung cancer, we go into for the expansion phase. I anticipate that that would make a lot of sense based on what we're seeing of activity. The unmet need is enormous there as well. For example, Small Cell Lung Cancer. The patient we had there had been treated more than the median survival of 13 months with several rounds of immunotherapy, chemotherapy, and T-cell engagers. Also, we came in after a very short last line and have stayed on for quite a while in both of these tumor types.
Maybe, I know we're running up on time, but maybe quickly just earlier this year you did disclose kind of the next target that's ready to go towards the clinic, an asset targeting CDK11. Just, you know, why is CDK11 a particularly attractive target? Then maybe what, you know, what needs to happen between now and getting to an IND?
Yeah. Thank you. We've just declared the development candidate also developed with the AP3, the Acrivon Predictive Precision Proteomics platform. It's an inhibitor, a potent inhibitor of CDK11. As far as we know, that's also a potential first-in-class program. There are no known clinical programs for sure. There have been some preclinical efforts. It's actually a master regulator of the cell cycle. It has the broadest regulatory role of global transcription, of cell cycle progression of all CDKs. While CDK2 and four and six and so forth, they have much more specific roles in the cell cycle. This here is a very broadly acting regulator and we are in IND-enabling studies now.
In the tox studies in rodents, we've seen very encouraging safety so far and plan to have that IND ready by the end of the year.
Unfortunately, we're over time, so I think we're gonna have to cut it off there. Thanks, Peter, and thanks everybody for joining in the room.
Thank you.
Or online. Thank you.