All right. Good morning, everyone. I'm Li Watsek, a biotech analyst at Cantor. Welcome to our Fireside Chat with Akrivon, and we have CEO Peter Blume-Jensen with us today. It's a pleasure to have you, Peter. I guess before we get to your ESMO data, which is quite interesting, maybe just tell us a little bit about, you know, Akrivon, what you're working on, and what's coming up.
Yeah, thank you so much. So Akrivon is a next-generation precision medicine company, and it's centered around its platform called AP3, which stands for Akrivon Predictive Precision Proteomics. So we are a clinical stage biotech company. We have now two assets in the clinic, and but the most differentiating feature that's probably not fully appreciated is our AP3 platform. It's a decades-long vision and commitment to execute on an orthogonal approach to precision medicine, where we are looking at the disease-driving mechanisms in a diseased tissue, whether it's inflammatory tissue or cancer tissue, and then we can directly match the mechanism of action with a compound with those disease-driving mechanisms, and we have pioneered the underlying technologies. There are two.
One is mass spectrometry-based phosphoproteomics, which we do at very high resolution, and that's with our academic co-founder, Jesper Olsen, who runs the Novo Nordisk Foundation Center for Protein Research in Copenhagen. And then we've also pioneered the quantitative multiplex protein-based biomarker platform, and we've worked on that since 2010, together, focusing on that day in, day out, as one team, and have now successfully generated prospective validation for our approaches. What it opens up for is to match the exact drug effects inside a cell and match that and look at how it quenches or inhibits the disease-driving perturbed signaling mechanisms, completely agnostic to genetic alterations, transcriptomic alterations, and that's what makes it so powerful.
And we make it actionable, so we can generate drug-tailored predicted biomarker signatures, which we are using now in our registrational intent phase 2 trials, and we also use it to do indication finding. For example, endometrial cancer was screened preclinically and identified with our method, and we have now proven that that's particularly sensitive in the clinic. So it has a lot of potential, and we intend to have that as an engine that every single compound we generate or in-license go through this indication finding. We generate these so-called OncoSignature tests that are able to predict patient sensitivity to the drug and aim for, in oncology, the accelerated pathway.
Okay, great. And I saw your lead program, 368, is sort of the initial proof of concept for your approach. So let's talk a little bit about that. I mean, give us a background of this molecule, and then how you apply. You mentioned OncoSignature to sort of predict tumor responses. I thought that was-
Yeah
... a very cool idea.
ACR368, also known as prexasertib, is a balanced CHEK1 and, very importantly, CHEK2 inhibitor. As far as we know, it's the only CHEK inhibitor that has demonstrated single-agent response activity in the clinic. We in-licensed it from Eli Lilly exclusively with worldwide rights, and it was based on a target product profile, which included, importantly, durable single-agent activity at recommended phase 2 dose across tumors, solid tumors, and a huge drug safety database. But the only thing missing was a way to identify patient responders, and that was the conclusion. They were in over one thousand patients, were excited about this single-agent activity they saw, which was usually durable, but there was no method that worked based on state-of-the-art genetics-based methods. We in-licensed that.
We had already profiled ACR368 at the time when we talked to Lilly, and could demonstrate with our OncoSignature at the time, which is the same we're using in the clinic today, without any changes, that we could identify sensitive tumor types and also show them which ones they should probably not have worked on, which included squamous non-small cell lung cancer at the time. So that one is the one that we brought in with one aim, to go for indications where there is single-agent activity and aiming ultimately for the accelerated pathway. And endometrial cancer now, as we announced at the R&D event this Saturday, is obviously the one where we think we have the potential for an accelerated approval first.
Okay, great. So I do wanna stay with your ESMO data a little bit, and endometrial cancer data looks very, you know, compelling to me, very high response rate. So maybe walk us through the data. What is new here?
Yeah
... and what is sort of the big takeaway?
Thank you for that. Yes, we have a master guidance protocol. It was cleared by FDA in 28 days, which actually cleared our recommended phase 2 dose, which was part of our strategy and quite unique in the DDR field, we think, during Project Optimus. So that was a door opener for us to go fast. We got recommended phase 2 dose clearance, not only for ovarian cancer, which is the tumor type where there have been observed activity, but also in endometrial cancer and bladder cancer, which were two predicted tumor types predicted to be sensitive with our AP3 indication finding, and we also got clearance for using our OncoSignature test prospectively for patient selection, which is what enable us to have a registration intent trial. Otherwise, it would be a retrospective exploratory biomarker pursuit. Endometrial cancer is one of the three tumor types.
The data have matured very fast and very promising. We had an R&D update all a quarter before this Saturday, so in Q2 in April, and since then, the data have matured very, very rapidly. We have a confirmed overall response rate in the indication, which is high-grade, locally advanced or metastatic recurrent endometrial cancer that must have progressed on anti-PD-1 with a lower bound of the confidence interval of 30.4%, and very importantly, there are 23 efficacy evaluable patients now. We demonstrate that we can segregate the responders from the non-responders in the biomarker positive and negative with a significant p-value of 0.009 in that patient number.
We have 35 patients now safety evaluable, and it's a very encouraging safety profile, with just limited to mechanism-based hematological adverse events that are reversible and transient. No non-hematological adverse events of note. So with that, we are moving fast. We also have now the duration of response maturing. All the confirmed responders, which they all are, are... Meaning, at least two scans on treatment with confirmed response, are the duration of response has not yet been reached. They're still on therapy, and that's now 6 months already, so very, very exciting for us.
I guess in this tumor type, in OncoSignature-positive patients, so you have eight, and you show, like, 63% response rate, right? Maybe just put that data into context for us a little bit. Obviously, the treatment landscape is evolving rapidly in endometrial cancer.
Mm-hmm.
How should we think about the response rate that you've shown, and how should we think about that compares to some sort of, I guess, the benchmark here?
Yeah. No, that's exactly right. The treatment landscape has changed drastically and very rapidly in endometrial cancer. Until recently, the frontline was carboplatin with paclitaxel, and then followed by pembrolizumab and then nivolumab in second line. But a couple of New England Journal of Medicine papers at the end of 2023 by Mansoor Raza Mirza and Ramez Eskander established a new frontline therapy with anti-PD-1 plus chemo, carboplatin and paclitaxel in high-grade advanced stage endometrial cancer, and regardless mismatch repair status, meaning both the 20% or so that are mismatch repair deficient and the high unmet need group, if you want, of 80% or so of pMMR. This means this is a long treatment.
There are six cycles every three weeks of chemo plus immune checkpoint inhibitor, followed by up to 14 cycles every six weeks of the anti-PD-1 only. So if you put that time together, and there's very long duration of response, that means you're on anti-PD-1 almost two years or about two years, and that means you exhaust the opportunity to use pembro plus lenvatinib in second line. This now leaves what many call the big gap in second line, where the best comparator for what the standard of care is there is a control arm in the former pembro lenvatinib study, which showed a response rate in 300-400 patients.
It was a huge study, Vicky Makker, New England Journal of Medicine, of fourteen point seven percent and a PFS of about, I think, six months. Sorry, three point eight months. It's pembro lenvatinib that has the six months. So three point eight months of PFS and fourteen point seven percent response rate is now kind of the chemo standard of care in second line because of the new front line. This opens up an enormous opportunity. The only thing that currently is approved there is trastuzumab deruxtecan, which is approved for HER2 three plus, and that's estimated to be about 10%-15% of those patients. The remainder of that group, which pretty much all of those that are recurrent, locally advanced or metastatic high grade, they only have the chemo option.
So with the lower bound of the confidence interval over 30%, you can see why we are excited and why key opinion leaders are excited about this. So, I think that's it. It's an increasing incidence tumor type. It's. There's actually I think it's underserved in many ways. There's a lot of focus on platinum-resistant ovarian cancer. The mortality is slightly more patients per year than ovarian cancer, about 13,200 versus 12,700 or so. The prevalence is enormous, 860,000+ patients. This is all U.S. numbers and about, estimates would say that it's about the double of the mortality that are high grade, locally advanced or stage 3, 4 of these tumors across all histopathologies and subtypes. And, that includes the locally advanced that recur.
So 30,000 per year of those is the estimates based on our blind and market research we did up to the R&D event. With that number, and 90% of them going to second line, and with the bar being about 15% response rate and a PFS of 3.8 months, there's really a huge unmet need. It's about, it's a tumor type that increases with about 1% to 3% every year. Really an underserved, high unmet need cancer compared to many others, and less emerging therapies, actually. There are some Trop-2 directed ADCs entering there, but right now the lower bound there is down around the standard chemo, and obviously they have different, AE profiles.
So, that's, we think this is an exciting opportunity for patients and for Akrivon with this asset.
Now, Peter, you mentioned, sort of the benchmark or the bar here, so to speak, is response rate about, you know, 15%-ish. I mean, is that the bar, in your view, that the FDA will look at? Or do you still have to sort of align with the FDA in terms of what the data that they need to see to give you, accelerated approval pathway?
So the typical primary endpoints for accelerated approval are duration of response and overall response rate, while for confirmatory trials, it's typically progression-free survival and overall survival, as you know. So yes, they do look at that, and because if 85% or so of patients don't respond, that means they need something else. Obviously, for confirmatory trials, it's about quality of life and getting progression-free survival and ultimately also overall survival up. We have a registrational intent trial, single agent, single arm, open label, Simon two-stage. We've shared in our S-1 filing, the exchange with the FDA and comments like there might be a discussion about what patient numbers will ultimately be needed. But typically, what you want to do is separate.
A great example is mirvetuximab, which had accelerated approval in the folate receptor high population of ovarian cancer, about 30-35% of them, with the lower bound was, I think, about 7% higher than the standard of care of 12% or so in the second and third line setting. That's a typical approach. We have set a target product profile here or a target profile for what's needed of 20-25% response rate and a duration of response of five and a half months. We are obviously already separating extremely well from that with the lower bound and the ongoing duration of response.
So with that, the opportunity is there, I think, to get an approval in such a setting, and then you'll want to follow up with a confirmatory trial as soon as you can. And obviously, we have already shared and discussed some different ideas about how we can move towards a potential label expansion with that in both front line and second line, more towards an all-comer setting.
Okay, so let's stay with the AA path. Obviously, you have eight patients right now in OncoSignature positive patients, which I thought was pretty nice, 63% response rate. Obviously, you have a pretty big delta versus the benchmark. I guess, how many patients do you need before you can go to the FDA and ask for AA and any plan for breakthrough designation?
So our ambition is to now, with the data we have, you could argue you should you have enough to really obviously have a dialogue with FDA. We have, as I mentioned, been treated very well with the clearance in 28-day originally. We have two Fast Track designations for endometrial and ovarian cancer. We have a breakthrough device designation for our device, and we just had another clearance of our new asset, internally developed 2316 and dual WEE1 PKMYT1 inhibitor in less than a month, which is also pretty unusual in these times. So we have already a very good relationship with FDA, and you can imagine that now with the data we have, we wanna move towards discussing with them you know numbers of patients.
There's a huge drug safety database, so in contrast to most agents that go the route of accelerated pathway, we actually have a huge drug safety database we can point at that's very, very consistent with what we've seen. Actually, it's over 600 patients at RP2D single agent across tumors, and it's the same mechanism-based hematological reversible AEs. So with that, we hope the number can be on the smaller end and be driven more just by the pure statistics, with the lower bound of the confidence interval and the duration of response. So we have already achieved different designations from FDA. You can imagine that a company like ours would start moving towards a breakthrough therapy designation. It's such a high unmet need, and further open the door for getting priority review and so forth. But...
This, we will update on that at a future date, but this is our ambition to go as fast as possible. We've been ahead of the timelines for most things, including our recent entry into the clinic with twenty-three sixteen. So we don't just rest on the laurels, but move as fast as we can.
For OncoSignature-positive patients, so that's about 30%-ish?
Yeah, 30, 30-35%.
Okay. And then, I thought was interesting is that in negative patients, it seems like you can sort of explore maybe a combination strategy with low-dose GEM. So maybe talk a little bit about the rationale there and whether you can sort of expand the patient population.
Yeah. So with our AP3 platform, one of the lowest hanging fruits is in every single experiment we do, which are very, very high resolution experiments. We generate 150 million quantitative data points every 12 days or so for every experiment in quadruplicates. We're able to see drug-induced resistance mechanisms. Every time one treats a tumor cell or an inflammatory cell with any asset, any compound, any modality, you inevitably see upregulated drug-induced resistance mechanisms, which we directly identify and quantify in the intact cell with our approach. And one of those resistance mechanisms turned out to be nucleotide synthesis pathways that could be overcome with nucleotide synthesis inhibitors and restore DDR stress around the CHEK1/CHEK2 axis. But our OncoSignature is not tailored for predicting that combo efficacy. It's the platform that we uncover that with.
So that's why that part of the study is an exploratory phase 1b study, and what we have reached now is an RP2D for that, and we are exploring the potential benefit of that. It's a modest, very modest RECIST response rate we get there in those that otherwise would be non-responsive. But we do get some initial disease control that's quite increased, that potentially could be a value in a confirmatory setting by when endpoints become PFS and OS. But this is truly exploratory right now, and we don't have the full data yet to see how much benefit we get from the low-dose GEM.
Now, in terms of the confirmatory study, sounds like you may have some options here, and we know for the FDA right now, if you want to get AA, obviously, you have to align on confirmatory study, and probably you have to enroll decent amount of patients before they give you the approval. So just talk a little bit about the options that you guys are looking at, and it sounds like you may not even need a biomarker here.
Yeah, so we shared that at the R&D event as well, this Saturday. What we are seeing is we believe we have efficacy across the four dominant subtypes, histopathologies, which is serous, clear cell, endometrioid, and carcinosarcoma, a very aggressive subtype, and also regardless MMR status. We do see that we have most of the frequency of MMR, pMMR and dMMR is very similar to the distribution in that group 80/20. And what we see is that the best response in the last prior line of therapy before our agent was primarily progressive disease. Not just the overall response, but the best overall response, meaning best tumor shrinkage, and that's where we have the efficacy, and they tend to be predominantly pMMR. We also have a confirmed complete responder in dMMR, so again, it's irrespective of that.
But it's particularly interesting that in pMMR, where anti-PD-1 works less efficiently, that we have such a deep response across the board with the confirmed PRs. So the idea is that in that phase of frontline, the new frontline, the 14 cycles every six weeks where you have anti-PD-1 only, one could, in a confirmatory setting, test the idea of randomizing that against anti-PD-1 plus ACR-368 and leverage that delta benefit you would get just from single agent ACR-368 alone, when most of the patients in the prior line had had pembro and nab-paclitaxel. So meaning, when anti-PD-1 didn't work at all there, it wouldn't have worked in frontline is the notion. And so this gives us an opportunity to test the contribution there.
On top of that, there are several high-impact preclinical studies from leading laboratories, Bob Weinberg, MD Anderson, et cetera, showing at least three mechanisms by which there's synergy with ACR-368 and anti-PD-1, including upregulation of PD-1, PD-L1, upregulation of cGAS-STING pathways, and double-stranded breaks inducing very, very significantly enhanced immune responses. So on top of that, if we could bring that synergy in, we think we have a really good opportunity here to consider a potential label expansion, all-comer in the frontline, what is called, maybe I don't like that word, but one word for it would be switch maintenance. So after the six cycles of chemo plus anti-PD-1, go over to anti-PD-1 with the ACR-368.
The other more natural, more conservative would be a second line with an all-comer leveraging the boost we get from ultra-low dose of GEM. But I think the most exciting is the opportunity to move further, for the potential to move further, front, more frontline.
... So I guess in terms of, you know, these options, some, you know, make a lot of sense. But I guess would you approach the FDA to align on the confirmatory study when you go to them with the single arm study? Is that the time point that you could potentially have that discussion?
That is definitely a great time to do that, where you have the attention and where they're expecting that you have thoughts about it. So I would say yes, that's a very, very good time to do that.
Okay. So besides endometrial, obviously, you've shown some signal in ovarian cancer as well. So maybe talk a little bit about that and when should we see, I guess, next, data, update?
Yeah. So, we remain completely data and science driven, and unless there are conclusive material changes in response rates and in clinical activity, we don't update on anything. It's quite unusual for a public company like to have two quarters in a row to have interim updates on registration on 10 trials, as you might know. So, we will update on ovarian and bladder, so there's nothing materially different from what we reported in the April R&D event. We are noting that the excitement about endometrial cancer is not only the things I said, the much, much higher, we think, market opportunity, high unmet need, but frankly, also ovarian cancer now in the third line, because second line is becoming exhausted. There's we count 11 emerging therapies there, mirvetuximab covering a third of those.
And so with numbers down, there's a mortality of 12,000 and about 90% progress to second-line, 65% to third-line. We are down in numbers 8,000-9,000 that have to split a lot of emerging therapies in third-line. So the numbers are night and day versus 27,000, we think, in a second-line endometrial. So as a still small public biotech company, we, of course, want to try to generate and create value, maximal value as quickly as possible when it's clear to us that we are closest towards a potential approval in endometrial, and the market size, market opportunity, we think, is in the order of five- to eightfold bigger, just even in second-line.
Okay, great. So in the interest of time, I do want to spend some time on your second program, WEE1, and congrats on your IND approval. So tell us a little bit about, you know, this program, what is the cadence for clinical data update, and what are the tumor types that you're looking at?
You mean the dual in the-
Yes.
Yeah.
Yes, dual.
We have, in a very, very short amount of time, generated what we think is an optimized dual WEE1/PKMYT1 inhibitor. One of the unique things we can do with the AP3 platform is, as I mentioned, it's in the intact cellular setting, and we can directly measure the activity states upon compound treatment of tumor cells and look at what's upregulated, what's downregulated, directly, quantitatively. It's called substrate consensus motif analysis. With that, we can design compounds, not just to be very selective. We do cocrystallography in all our programs and are right next door to the world's brightest synchrotron, MAX IV, in Lund, where we do all drug discovery, and we can also optimize based on the pathway effect.
What we wanted to do here, generate a compound with superior single agent activity and highest possible selectivity to expand the therapeutic index, and we think we've achieved that. Based on the data we have, we maximally activate not only CDK1 and 2, the two on targets for WEE1, but also PLK1. We not just don't inhibit it, but we activate it. It's the third most activated kinase. We also, undisclosed, have inhibition of some kinases that are believed to be key players in resistance to DDR inhibitors, all in one molecule. Our GLP-enabling tox shows reversible, transient, mechanism-based AEs only, and we have dosing tolerance. We have the same complete tumor regression across daily, on/off regimens, weekly dosing.
The GLP-enabling tox studies are completed at the dosing regimen we have brought into the clinic now and are having flexibility there to also all of that. We are very excited about that molecule, as you can hear. We intend to move fast there. We will use our biomarker expertise to look at drug target engagement, and we believe we can back off from an MTD to achieve superior anti-tumor efficacy. We've done head-to-head studies with all the leading WEE1 and PKMYT1 clinical inhibitors.
Okay, so maybe just last, quickly, it seems like you can leverage your platform beyond oncology, and I thought inflammatory diseases are, you know, very interesting space. So tell us a little bit about that and, you know, potential for partnership.
Yeah. So, the platform, obviously, because it's looking at the functional disease-driving mechanisms, independent genetic alterations, is particularly attractive outside oncology, and we have both inside, and external interest in going into the inflammatory fibrotic area. And we have, we are conducting and have conducted a very thorough target hunt in that space using our AP3 platform on actual disease tissues, which is one of the advantages of that. So we intend to go in there, and we are committed to develop internally, because of the value creation, but obviously, we are getting a lot of interest from the outside, so and talk to parties there as well. But right now, with the way things are going, we are very capital efficient. We certainly intend to keep building out internally, towards commercialization.
Okay, great, Peter.
Thank you.
Thanks so much.
Thank you so much.