Xencor, Inc.

Good afternoon. Thank you for standing by and welcome to Zencore's fourth quarter and year-end 2022 conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. Please be advised that this call is being recorded at the company's request. Now, I would like to turn the call to your speaker today, Charles Lyles, Head of Corporate Communications and Investor Relations. Sir, please go ahead.

Thank you, and good afternoon. Earlier today, we issued a press release which outlines topics we plan to discuss today. The press release is available at www.zencore.com. With me on the call are Basil Zahief, President and Chief Executive Officer, Alan Yang, Chief Medical Officer, John Deserlais, Chief Scientific Officer, and John Cush, Chief Financial Officer. After we make a few comments, we will then open up the call for your questions. Before we begin, I would like to remind you that during the course of this conference call, Zencore Management may make forward-looking statements, including statements regarding the company's future financial and operating results, future market conditions, the plans and objectives of management, future operations, the company's partnering efforts, capital requirements, future product offerings, and research and development programs. These forward-looking statements are not historical facts, but rather are based on our current expectations and beliefs and are based on information currently available to us. Outcome of the events described in these forward-looking statements are subject to known and unknown risks, uncertainties, and other factors that could cause actual results to differ materially from the results anticipated by these forward-looking statements, including but not limited to those factors contained in the risk factor section of our most recently filed annual report on Form 10-K and quarterly report on Form 10-Q. With that, I'll pass the call over to Basil.

Thanks, Charles, and good afternoon, everyone. We've used our array of modular protein engineering tools to create our internal development portfolio in oncology and autoimmune disease and we use the breadth of this portfolio to take multiple simultaneous shots on goal in the clinic. Our intent is to use proof-of-concept data from our early-stage studies to guide which programs we advance, which we terminate, and which we partner so that we can use our resources on programs with the greatest potential for success and make room in our portfolio for the next wave of XMAP bispecifics and engineered cytokines. In addition, we use revenues from our partnership portfolio to support our development. Here's a few pipeline highlights from 2022. For Vudalamab, we continued our Phase II study in metastatic castration-resistant prostate cancer in combination with standard chemotherapy or PARP inhibitor, and we initiated a monotherapy Phase II in MCRPC and in gynecologic tumors, which are just some of the tumor types where PD-1 and CCLA-4 bispecifics have potential. And in November, we reported encouraging single ascending dose data for XNAB564, a regulatory T-cell-targeted IL-2 for autoimmune disease, particularly the strong durability of Treg expansion. As a consequence, we've started the multiple ascending dose study in atopic dermatitis and psoriasis patients to explore extended dosing regimens. We hope to have the psoriasis arms of the study finished by early 2024. And we started phase one studies for two novel T-cell engaging bispecifics. The first was XMAB819, which targets CD3 and ENPP3, an antigen and renal cell carcinoma that was built with our And we built the molecule with our 2 plus 1 format for improved tumor selectivity. We believe 819 offers a new mechanism against a barely explored target with a high unmet need in second and later line RCC. The second T cell engager to start clinical studies was XMAB 808, our first CD28 targeting bispecifics. It co-stimulates T cells when it's bound to its tumor target, B7H3, a widely expressed solid tumor antigen. Exciting early data for CD28 bispecifics has increased our already high enthusiasm to develop this new class of immunotherapies. And we're continually building the next wave of drug candidates with our engineering tools and try to tackle new or hard-to-address biology with them. Two such programs are advancing this year, led by the expected Phase I initiation for our third reduced-potency cytokine, XNAV662, an engineered IL-12, and followed by IND filing for XNAV541, a 2 plus 1 CD3 bispecific targeting Clouden 6 for ovarian cancer. With the well-balanced portfolio of late and early stage programs in development that we can potentially advance to approval and ultimately the market if the data supports it. Our development pipeline gets strong support from our broad alliance portfolio, not just from the revenues it generates, but also from the resources of our co-development partners, those programs that we have partnered. Now, the last of my remarks is that we are in the midst of completing our laboratory and office relocation to Pasadena, where our new facility can accommodate our expanded R&D efforts and will help keep us at the cutting edge of protein engineering. With that, I'll turn the call over to Alan Yang, our Chief Medical Officer, who will review recent updates from a few of our ongoing clinical studies for wholly owned programs.

Thanks, Basil. Vidalimab is our most advanced dual checkpoint inhibitor. We've designed the class of bispecific to bind T cells that express both targets, in this case, PD-1 and CTLA-4, with the intent to limit the exposure of the molecule, to control and improve tolerability, and yet still hit the cells that are going to be the most active against the tumor. Two ongoing Phase II studies are looking for clinical signals that would prompt us to invest in registrational studies. At the CITC meeting in November, we reported the first data coming from our first Phase II study in combination with chemotherapy in patients with late-line metastatic castrate-resistant prostate cancer, a very high unmet need population. Given the changing treatment landscape in prostate cancer, we designed the study to address several groups of prostate cancer patients, including aggressive variant, PARP actionable, PARP inhibitor relapse, and MSI, and a biomarker negative group. We designed each arm to receive Vudalamab and in combination with a standard therapy if warranted. For chemotherapy eligible subjects, we originally designed the study to use Taxane Platinum Doublet based on a previously reported study that showed a high response rate in order to maximize potential efficacy. In the first patients, we saw multiple PSA50 drops in three of eight patients, and one of these eight patients had a durable partial response. We also saw toxicity related to the intensive chemotherapy combination, but without a consistent type of AE among all the patients. However, we modified the chemotherapy dosing regimens, keeping budalimab dosing as planned, and we're rolling again into the chemotherapy combination cohorts of the study. The second phase two study is evaluating budalumab monotherapy and additional high-risk populations of prostate cancer as we continue to search for a defined subpopulation that we could advance quickly towards registration. This study is also enrolling patients with gynecological tumors where we also saw good activity. And finally, this study introduces the flat dosing and more convenient schedule. Now, as we continue to enroll these patients, we see a lot of opportunity for the program, as emerging data across the class provides us signs for broad utility across additional solid tumor types. Now, secondly, XMAP808 represents a new class of bispecific antibody targeting the CD28 pathway, and Zencore is among the first companies to enter the clinic with a molecule in this space. Clinical data beginning to emerge have indicated dramatically enhanced activity of a checkpoint inhibitor in prostate cancer, where previously checkpoint inhibitors have had limited activity. So we're seeing the case that a targeted CD28 bispecific, in this case PSMA, markedly increased the activity of a checkpoint inhibitor and serves as an important validation for the class. We find the data encouraging enough to accelerate our own program targeting B7H3, an antigen heavily expressed in multiple tumor types, including prostate cancer, renal cancer, lung cancer, and many others. As B7H3 is also expressed at low levels on some healthy tissues, we've incorporated our 2 plus 1 bispecific technology into XMAB808 to potentially increase the therapeutic window. And we're moving rapidly with XMAB808. The first patient in our phase one dose escalation study was dosed last year. And following initial doses of XMAB808, we add pembrolizumab as combination therapy. We believe we are well positioned in the CD28 bispecific space, especially as there becomes increasing recognition that this class holds a lot of opportunity and is really starting to eat up. Not only with our XMAP 808, but as our research teams advance more CD28 programs through preclinical development, we hope to share more in the coming months. With that, I'll now hand over the call to John Desjarlais, our Chief Scientific Officer, to review two programs we plan to bring forward into clinical development this year, our IL-12 cytokine XMAP662 and CLADEN6 by CD3 bispecific XMAP541.

Thanks, Alan. So, the key to all of our cytokine programs, including XNOV662, is that we reduce the potency, dialing down the receptor binding affinity to smooth out the activity profile observed in wild-type cytokines, which are natively very hot and administered systemically can generate a lot of immune toxicities and get cleared quickly. Now, IL-12 is a different kind of cytokine compared to IL-15 and IL-2. Instead of expanding T cells and NK cells, IL-2 promotes high levels of interferon gamma secretion, which increases the cytotoxicity of T cells and NK cells and makes tumor managers more visible to the immune system. So, XMAP662 is a reduced-potency IL-12 engineered with an XMAP-biospecific FC domain enhanced with our X10 technology to further duration of action. And in preclinical testing, this reduced-potency FC fusion compared to a native IL-12 FC fusion demonstrated an improved pharmacokinetic profile in the therapeutic window with superior exposure, a more gradual dose response, and more sustained interferon gamma response. Our IND application was recently submitted and allowed by the FDA, and we look forward to initiating a phase one study in patients with advanced solid tumors mid-year. Finally, XMAP541 is a Clouden 6 by CD3 biseptic antibody built with our XMAP2 plus 1 format for improved tumor selectivity. and we are developing the molecule for patients with ovarian cancer. We are wrapping up IND-enabling studies. We plan to submit an IND later this year. Now, a quick refresher on the XMAB 2 plus 1 format, where we build a bispecific or multispecific using two tumor-binding arms and one T-cell binding arm. This is the approach we use to address a frequent observation of tumor targets that are also expressed on normal tissues. For therapies intended to address solid tumors, off-target effects can lead to high toxicity. By having two antigen-binding domains, we can tune the affinity for tumor antigen and bias the molecules to cells that have a lot of the antigen expressed over normal cells that have lower antigen expression, where it's just harder to stick. We believe XMAP2 plus 1 can be generally applicable to biospecific antibodies against solid tumor targets and hope it opens the doors to bringing more CD3 cytotoxics and CD28 co-stimulators into development. Now, with that, I'd like to hand the call over to John Cush, our CFO, to review our financial results. John?

Thank you, John. CENCOR's broad portfolio of partnerships, collaborations, and licenses continue to generate strong cash flow to support our operations. In 2022, we received $198.7 million in royalties and milestone payments, which helped fund our investments in our portfolio by CIVIC and cytokine drug candidates. Total proceeds received in 2022 offset a substantial amount of our operating expenses, and we ended up 2022 with cash, cash equivalents, receivables, and marketable debt securities of $613.5 million compared to $664.1 million at the end of 2021. Based on current operating plans, we expect to have cash to fund research and development programs and operations through the end of 2025. And we currently estimate we will end 2023 with between $425 and $475 million cash equivalents, receivables, and marketable debt securities. I refer you to our press release this afternoon and our 2022 Form 10-K filing for further information about our recent financial results. With that, we would now like to open up the call for questions. Operator?

Thank you. As a reminder, to ask a question, please press Star 1-1 on your phone and wait for your name to be announced. To withdraw your question, please press Star 1-1 again. One moment, please, for our first question. Our first question will come from Mara Goldstein of Mizuho. Your line is open.

Great. Thanks for taking the question. You know, I wanted to ask a question on 564 and, you know, the program there. And I'm really trying to understand, I guess, maybe when in looking at atopic dermatitis and psoriasis, you know, what you think the benchmarks for success are going to be in terms of being able to advance that product forward.

Yeah, thanks for us right now. There's 2 goals from this phase phase 1, be multiple ascending dose study that we're doing 1st and foremost is establish a dosing regimen. that we can move forward with. And that means someone that's safe and one that gives us good coverage of the target or rather a good biomarker movement of the Tregs for the duration of, you know, our dosing interval. So that's step one. And I think those two indications are great indications for that because you can see, looking at skin, how the disease readout's doing in parallel with your biomarkers. So that's goal one. I think the second goal addresses your question, which is what's the benchmarks for success? I would say in both of those indications, they're generally high. I will say that the thing we're going to be keying off of is looking at how durable and how long of an effect we can have with the agent. Does this have new biology by attacking Tregs that you can extend response time even beyond dosing duration? That was seen with some competitor programs, glimmers of it. And how long of a dosing interval can we get? Can we build a best-in-class Dosing interval extending beyond every 2 weeks that that a lot of the competing programs seem to have settled into. So, I think those are the questions that we want to address with this early study. And then I think after that, there's, there's good benchmarks for Cassie and for for easy scores.

Okay, and if I can just ask on the Vidalimab, the discussion around reengaging the child now that you've finished modifying the protocol, can you talk a little bit about just the enrollment characteristics for that program?

You mean how well it's enrolled?

And what those dynamics have been. Yeah, what those dynamics, like what you can expect going forward. Do you think it will go back to sort of baseline where you were?

I don't know. Alan, you want to comment on that?

Yes. So just to be clear, Merle, we have two phase twos. We have a monotherapy phase two, which explores a sort of new flat dosing and schedule. And that we've clinically defined sort of an aggressive type of prostate cancer. And then we have the first phase two, which actually molecularly defines different subgroups of prostate cancer. This data is available, but we have an aggressive variant subtype. We have a PARP-enabled, sort of a PARP-actionable subtype, a PARP inhibitor, sort of relapsed refractory group, microsatellite, unstable group, and then finally everybody else. And I guess what you're asking is how they're enrolling now that we've, you know, we had to pause to adjust the chemotherapy groups, and that was, you know, three of the groups. But the other groups continue to enroll, and now we've opened up the other arms with chemotherapy, and we've modified the chemotherapy for two of those groups.

All right. Thanks so much.

Yeah. Thank you. One moment, please, for our next question. Our next question will come from Edward Pentoff of Piper Sandler. Your line is open.

Great. Thank you very much. I appreciate you taking the question. So I wanted to get a sense, again, to the extent you can share, sort of how the profile of the CD28 is differing from CD3. And as you sort of, you know, advance down the pipeline, How do you see, you know, prioritizing one mechanism versus the other? Are there places where one may make more sense?

There's multiple facets to that one. John, why don't you take the point about, you know, refreshing on the differential biology, CD28, CD3, and what we can do with that, and, you know, maybe I'll jump in on the second one.

Yeah, sure. Yeah, thanks for the question, Ted. So, The way we think about the CD3s versus CD28s is with the CD3s, it's basically more of an artificial immunity where you're just taking advantage of any T cell around, engaging it through CD3 and recruiting it to attack the tumor cells. With the CD28, because it's just providing signal 2, that's equally intriguing biology because now that signal 2 has to build off of an endogenous signal 1. which comes from a neoantigen, you know, T cell recognition by the T cells. And of course, when you're applying the CD28, in order to fully open up that signal one, you're generally going to be combining with PD1 checkpoint blockade. So, and then that's sort of the third arm of that is we also see, you know, really interesting opportunity for combining the CD3s with the CD28s. And that's one of the reasons we chose B7H3 as our our sort of flagship CD28 program, because it's expressed in so many different histologies, it could be sort of a one-size-fits-all combination partner for our CD3s or other people's CD3s.

Great. That's very helpful. Thank you. Go ahead, Abbas.

Sorry. Go ahead, Ted. Did you get all your answers, or do you need me to address your other point?

No, please. I was saying go ahead, Abbas. Thanks.

Yeah, so regarding how we view the different MOAs and think about them in different indications, some of it depends on target availability. You know, is there an opportunity to improve response for targets that have been tried that have promising biology but didn't work out? I think that's the case where the combination of a CD28 with a checkpoint inhibitor could be very attractive. I think we've seen that from, you know, competitor programs and prostate cancer with that early glimmer of data. And then philosophically on, you know, targets that you can – you have a good, nice differential of expression, healthy to normal tissue, you know, hitting it with that direct attack of a CD3 could make sense more, right? So that's generally how we think about it as we explore, you know, the initial biology of the CD28s over the next year or two. Great.

Thanks, guys. Excited for more data this year. Thank you. Thank you.

And one more please for our next question. Our next question will come from Dane Leon of Raymond James. Your line is open.

Hi, congrats on all the progress and thank you for taking our questions. I just wanted to get your take on maybe some of the earlier programs that you have emerging now. Firstly, maybe we'd like to hear your updated thoughts on the IL-12 approach. There seems like there's been maybe a few more discontinuations from peer programs. Curious to hear your thoughts on how you're differentiating to create a therapeutic index, essentially, out of a difficult cytokine. And then maybe on targeting with B7H3 versus maybe another emergent approach of using B7H4 would be interesting as well. Thank you.

So on the IL-12, I think it comes down to our reduced potency design is something that has given us significantly improved tolerability profiles versus wild-type level activity cytokines for IL-15 and IL-2 programs. So I think that's what we're banking on. Maybe, John, if you want to touch briefly on the preclinical profile and not even primate data we have for X9662 and how that, we believe, differentiates it.

Yeah, yeah. In fact, thanks for the question, David. So we... You know, we actually compared a wild-type IL-12FC fusion to our XMAB662, which, again, is around 100-fold potency reduced. And recall, the problem with these cytokines is when they signal, they actually get cleared through the receptors. And so when we look at monkeys at a wild-type IL-12FC, we dose it, you know, as high as we can in terms of tolerability, and it's gone in about, you know, one or two days. In contrast, XMAP662, because of its potency reduction, actually has a, it looks incredibly like an antibody. It's got a half-life of 14 to 20 days in the monkeys. That's likely to extend out even further. So that's one aspect. Basil also mentioned that, you know, when you have the potency reduced version, you have much greater tolerability. And then the thing in the monkey studies that kind of inspired me the most is when we put in the wild-type IL-12 at a range of, you know, a 30-fold differential dose range, and every one of those doses, those levels, gave the same exact initial peak of interferon gamma response, irrespective of the dose. The only thing that changed when you dosed more was because you get a little more exposure, you broaden out that peak in terms of time. In contrast with 662, we actually saw a really nice, gradual increase of the dose response as we, you know, up the dose. And I think that is going to give us a lot more flexibility to really zero in on the optimal dose and therefore therapeutic index.

And regarding the B7H3 versus B7H4, I think we'll focus on what we find attractive about B7H3. It's expressed in multiple tumor types. It has a good differential across multiple tissues for tumor versus normal tissue. You know, it's absent or very undetectable expression, I should say, in certain problematic tissues like the central nervous system, brain, and nerves. So I think that makes it very attractive. You know, B7H4 is a target I'm starting to see pop up, and I think there's very little data to comment on it.

Do you view B7H3 in a different light when using a COSTM approach like CD28 versus the past attempts that have used ADCs?

I think it could be very, very different. An immunotherapy approach versus directly delivering a cytotoxic could be profoundly different. And so I don't know how much read-through we get other than that you have clearly enough of that target around tumors that an ADC can provide activity. Beyond that, there's such different mechanisms that I don't know anything we can glean.

Excellent.

Thank you.

Thank you. One moment for our next question. Our next question will come from Esther Darroch of BMO Capital Markets. Your line is open.

Great. Thanks for taking the questions. First one is a few things going on in prostate. Just wanted to know if you had any updates on AMG-509, the steep one, two plus one, any updates here from Amgen on the development. And for XMAP-808, just wondered, you know, for that program, the, you know, start of the sort of combo trial with pembrolizumab is That's just kind of based on literature examples and or sort of preclinical data on the synergies or if that's something where you've seen something in the clinic that sort of prompted the combination with Pembroke. Thank you.

Great. Regarding Amgen's AMG 509 program, which is licensed, you know, they licensed all the tools and technologies from us to build it. The only information we can share is what they publicly announced. I think they did it at their earnings last month, and it's that they expect to have initial data presentation in the second half of this year, and that they're pursuing a quite broad phase one program looking at both combinations, monotherapy. They've got a subcutaneous formulation in addition to their IV. So they're putting a lot of resource behind it. That's all we can share publicly. But we're certainly encouraged by the effort and by the initial data we saw a year ago. For 808, I think that there is a very strong theoretical reason, in fact, the fundamental basis for why you want to use a CD28 bispecific for combining it with either a checkpoint inhibitor or, say, a CD3 bispecific, because that completes the circle of getting the CD28 to give you that potent signal-2 inhibitor activation and maintenance of activation, while the other side, signal one, initiates that T cell movement. And so PEMBRA is based on very strong theoretical data for that combo for why you want to combine a checkpoint inhibitor with a CD28, for that CD28 to put the checkpoint inhibitor over the hump when it's in a nominally cold tumor.

And Basil, just to put a finer point on that, You know, there's some pretty strong literature that the dominant mechanism of action of PD-1, the checkpoint itself, is to directly inhibit CD28 signaling, and most people also think it inhibits the signal 1. And so the idea is that the B7H3 CD28 by itself is going to be hindered unless you can also block PD-1 at the same time.

Great. Thank you.

Thank you. One moment, please, for our next question. And our next question will come from David Dye of SMBC. Your line is open.

Great. Thanks for taking my questions and congrats on the progress. So I have two questions. First, it's just on Vidalumab. We have seen some competitors showing PD-1 times CTLA-4 as a positive antibody. It has some pretty intriguing data in metastatic prostate cancer at ASCO-GI. Could you maybe compare and contrast your Vidalumab-struck profile versus the competitor PD-1 CTLA-4 positive antibody?

Sure. So I guess for starters, I guess we'll say there's a lot of movement in the PD-1, CTLA-4 class that's starting to happen, all still based on very early studies. And, you know, we're very encouraged by how that is reflecting on now the potential for these dual checkpoints as we start to sort out how to use them. I'll start out by saying that the relevant comparison is the monotherapy data from our Phase I expansion cohorts that we presented a while back. compared to what was presented at ASCO-GU. So it's that monotherapy-monotherapy comparison. So I don't know. Alan, did you want to touch on that? Yeah, sure. I will be happy to.

I mean, I think the data at ASCO-GU sort of validates the class in prostate cancer. And, you know, it's difficult to compare the data between our data and theirs. You know, what we reported is a PSA response rate of about 20% in a heavily pretreated U.S. population, U.S.-only population, where the median number of therapies was five. You know, the other data that was reported at ASCO-GU reported a response rate, a PSA response rate in the high 20%, but, you know, a less pre-treated population where the median number of treatments was only two. So, again, I think it's interesting data. It supports the idea of doing these PD-1, CTLA-4s in prostate cancer, and we already believe that, and that's why we've started two Phase II programs and are moving aggressively to try to figure out a registration pathway.

Got it. That's really helpful. And just another question on the Plumatumab. I know you're currently developing a Step Q version of the drug. Could you maybe talk a little bit more about the status of the Step Q formulation, and when should we expect to see data from that program?

So we initiated clinical studies, that is dose patients with the sub-Q formulation last quarter, and that is a dose escalation-based study so we can figure out the sub-Q regimen, priming dose and step-up doses. We, of course, have all the information we have from the IV that we think is going to greatly accelerate that process relative to what we had to learn from the IV. And of course, we're doing this in collaboration with our partner Janssen. So that's going forward as part of the whole package of our B-cell collaboration with Janssen, which also incorporates our CD28 bispecifics, where we just this quarter announced that we have achieved the candidate selection milestone. So we've delivered the B-cell targeted CD28 that ultimately when it gets to the clinic would be combined with Pembro, sorry, with Plamo, Plamodimab. So that's the sort of general context. You know, we'll guide on data as we go forward with the caveat that, of course, Janssen has to be party to wanting to disclose data. Got it. Thank you so much.

Thank you. And one moment for our next question. Our next question will come from Charles Zhu of Guggenheim Partners. Your line is open.

Hello, everyone, and thanks for taking the questions. I have one question that's essentially a follow-up to something that Etzer had asked. But regarding XMAP-808, you know, encouraging to see that you guys are combining this with PEMBRO. Perhaps given you have other pipeline assets in the clinic that are also going after prostate cancer with similar mechanisms, such as Vudalamab, how are you gauging the potential to, I guess, co-develop with Vudalamab as opposed to an external asset, and how should we think about that? Thank you.

We think that's a great idea and a great approach. We absolutely have it in our in our minds as we escalate with 808. We want to obviously do that very quickly, and we have to start from relatively low levels because, of course, regulators are cautious with new immunotherapies. So as we escalate, we have, you know, in our minds how we can quickly flex in with our own pipeline agents, such as Vudalamab, or perhaps even CD3 biospecifics, as some of our CD3 biospecifics that could overlap with the expression patterns that 808 will hit are moving forward. For example, XMAP819, our EMPP3. So absolutely, I think the key here is get rolling fast. try to understand data in light of a well-understood standard, PEMBRO, where enrollment, frankly, is greatly facilitated by its broad use, and jump in once we've gotten a little further.

Got it. Great. Thanks for taking the question.

Thank you. And one moment for our next question. Our next question will come from Bill Morgan of Kennecott Genuity. Your line is open.

Hi. Good afternoon. Thanks. So just looking at the cash guidance for this year and thinking through the fact that Sotrovimab is still available in some ex-U.S. jurisdictions, how much Sotrovimab are you expecting this year in that guidance? And then I'll have a follow-up.

Twenty-three?

Yes.

Twenty-three, zero. It's been coming down since Q1, and they lost their U.S. authorization Q1, so it's just been ex-U.S. So going forward, anything we get is found money. We have no expectations of future revenue.

Great. And then on your 2 plus 1 T cell engagers, so understanding that the differentiated mechanism allows you to go after something like a CD28, Do you see room to improve on more well-worn targets like CD3 over products that are later in development and kind of come in behind them and still share with a better version of what's already kind of making it to market?

Absolutely. We have all of that kind of consideration in mind, and we watch very carefully any CD3 programs that are advancing into the clinic. I would say it's still early days in the whole CD3 world, so there's not a lot of late-phase CD3 work yet outside of the heme malignancies. They'll do the CD20, CD3s, and BCMA CD3s dominating. And those don't strike us as maybe fruitful avenues to use this plan of attack because those are not solid tumors. But absolutely, we look at potential fast follower approaches with the 2 plus 1 carefully. I think the opportunity space is still just emerging, so that's why we haven't declared any yet.

Great.

Thank you. Thank you. And one moment for our next question. Next question will come from Michael King of E.F. Hutton. Your line is open.

Thanks, guys. Can you hear me okay? Yep. Okay. Just maybe pick up where Dane left off on aisle 12. I just wondered, just as far as the cytokine space is concerned, sort of writ large, I'm a big fan of the engineered cytokine space, but I just wonder if we know enough, either as antagonists or agonists, you know, what the real correlates or the real clues are to clinical success. You know, it's nice to see gamma and the furon levels go up in response to IL-12, but do we know, you know, what the meaning of that is? And I think it's kind of... again, especially important to think about in light of some of the recent developments, both in IL-12 and the IL-2 world. I just saw, as this call, literally as this call started, Nectar indicated that it's ResPeg, Aldis, and had some activity in SLE, but did not achieve, you know, a clinically relevant STAT-SIG result. So, do we... Do we know enough about this class to really put them in the clinic without further sort of preclinical exploration? Thanks.

Oh, there's no doubt that we don't have perfect knowledge about what it's going to take to succeed in cytokines. So I would say that's the case for pretty much almost any drug. I think with cytokines, we do know that a lot of the approaches that have been tried in the past have been challenged and have not worked. And so I will say that we are taking a specific approach. We are putting a bet down on reduced potency cytokines which inherently because of that reduced potency gives you longer action and a lower peak punch, which so far with two programs out of two has reduced tolerability issues but still given us profound biomarker movement. So we think that's a great start. Does it answer the question fully? Are we out of the risk window? Absolutely not. We're optimistic our IL-12 will share those kinds of properties on the biomarkers and the tolerability, but we're going to see. if our preclinical data plays out in humans. We'll start seeing that later this year. So we don't have the answers, but we've got a bet that so far is performing as it should, this reduced potency, and we think the opportunity is enormous if we could be among the first to crack that code. So it's absolutely a bet we think is worth taking. And I think the one thing we can hang our hat on is if you can see the immune markers of activity, that certainly ties in better to whether you're going to have success. We know wild-type IL-2, proleukin, creates all sorts of immune markers to IL-2 activity, most of them toxic, but it also, in a small number of patients, can cure them. So I think that's all we've got, and I think how we position ourselves is really strong. And I will say, referencing some of the recent RESPAG news, I will say that lupus is an area where many successful drugs – have had unsuccessful clinical trials, and it's a challenging development space. Certainly, Vencor in its past has had some experiences with tricky, conflicted Phase II data in lupus, and so we'll dig into that more, but it's a hard read-through on a lupus Phase II really to anything, I would say.

And Basil, if I can, I'll just follow up on that question about the interferon gamma. So the reason interferon gamma is so important is it does a couple of things. You know, first and foremost, it can have a direct tumorocidal effect. But probably more intriguingly is the most famous thing it does. It does two famous things to tumor cells. It upregulates class I MHC, and that's what the T cell receptors are looking for to recognize the tumor cells. So that's a really desirable activity. And then the other famous thing it does is upregulate PD-L1. And that's exactly why, you know, combining an IL-12 with febrolizumab or other checkpoint inhibitor makes a lot of sense.

Can I ask you, why did you guys choose to develop an IL-2 agonist? Why did, you know, first as opposed to having it go in the autoimmune direction rather than oncology?

Well, we think that that was a great hypothesis, and we already tried Treg boosting for autoimmune, and we already have our IL-15, which addresses much the same pathway that we think with a better-suited natural precursor molecule for our engineering. So it would have been redundant to do an IL-2 given XMAP-306 and the really promising Phase I data we've seen with it so far.

Okay, appreciate the answers. Thanks, guys.

Thank you. One moment, please, for our next question. One moment. Our next question will come from Brian Chang of J.P. Morgan. Your line is open.

Hey, Basel. How are you? Thanks for taking my question. Just going back to VodaloMap, We're curious if there's any strategic shift in your way of thinking around the development of Vidalimaps since Astra is planning to start five phase three with their own site by specific later this year. And I have a follow up. Thank you.

Yeah, we're certainly aware of that data from Astra and think that it's very promising. We know that our molecule, XMAB, oh, God, I was about to call it XMAB717, Vidalimab, shares a very similar design, monomeric binding to both targets, essentially very limited CTLA-4 binding without PDLA, a PD-1 binding, so it's very conditional binding. And so we think that's a really interesting comparison set there. We're looking very hard at that. We're thinking through possible game plans and hope to be able to guide on that really soon. So, yes, it's a very relevant point. And I think the key element there is their willingness to combine with highly active chemo regimens in frontline lung, where you really, I think, have to have chemo as part of your backbone, given that the comparator is a chemo PD-1 combo. I think that, you know, that's a really intriguing synergy with our thinking around using aggressive chemo and prostate cancer and some of the experience we gained there. So more to talk about that later, but it's something that's definitely on our radar.

Great. And just related to 662, are there any learnings from other interleukin approaches in the past that give you a better sense of what's the low-hanging fruit here for 662 in terms of the solid tumor type? that you think could be most sensitive to the IL-12 approach?

Hey, John, do you want to tackle that one?

Yeah. I mean, you know, I would build off of my response a second ago about, you know, we expect 6.2 to, you know, submit, you know, a lot of interferon gamma, upregulate class 1 MHC. And so probably the low-hanging fruit, as you put it, would be to go after you know, the more immunogenic tumor types, like, you know, melanoma, places where checkpoint inhibitors have already worked. There's, of course, certain practical synergies with that approach as well. But, you know, maybe the slightly higher hanging fruit would be to go after histologies that have struggled a little bit, shown, you know, simple signs, like a little bit of evidence of activity with checkpoint inhibitors. But if we can make those tumors more immunogenic, with an IL-12, then that's a whole new opportunity space.

Great. Thank you, John. Good luck on the move. Thank you.

Thank you. And one moment for our next question. Our next question will come from the line of Peter Lawson of Barclays. Your line is open.

Hi. This is Shay for Peter. Thanks for taking our question. We were hoping to get an update around your ENPP3 program, 819, and how the progress is there and how we should be thinking about timing for initial data and for the recommended phase 2 dose, whether that might be something we see in 2023.

You know, we could just barely hear you just from a volume perspective. If you could speak up. We know you're asking about 819.

Oh, apologies. Is it better now?

Yes, that is.

Okay, perfect. We were just hoping to get an update on your 819 program, so the ENPP3, and just how progress is going there, and if we could see initial data and maybe recommend a Phase 2 dose in 2023. And then just secondly, how we should be thinking about how this will compare profile-wise to Stella's ENPP3 ADC program. Any color, that would be great. Thank you.

So I guess on the update, we're about six months in or seven months into the phase one dose escalation. And I think one thing we'll say is that investigators in renal cell carcinoma are very enthusiastic to have the option of a CD3 and therefore have been great collaborators and we've been accruing patients really well. So I think that's all we can say about that yet. We don't have a timing on data guidance. And we'll do that as we advance in cohorts and understand better the regimen when we would guide on how we're seeing dose. We're not giving a timing update on that yet, other than saying, you know, the accrual has been going really, really well. You know, the profile of a CD3 versus, in particular, a 2 plus 1 CD3 versus an ADC, you know, we hope would have a completely different kind of side effect profile that offers something that physicians don't have right now, and, you know, compared to salvage chemo. I mean, any comments there, Alan, in that particular space?

Yeah, you know, renal cancer has been one of those tumors that are traditionally immunoresponsive. And so we think that, you know, the immunotherapy would hopefully have an advantage. But, you know, it's still early days. And as Basil said, we have high investigator interests that are really hungry for this MOA and this disease type. And so, you know, we're very excited. I also will add, you know, we can't sort of predict what our recommended phase two dose will be and how many cohorts we need to get there. But along with investigator interest, the trial design is fairly novel in terms of how we're escalating without disclosing our strategy there that allows us to sort of aggressively pursue the recommended phase two dose, both in the priming dose and the actual step-up dosing, as well as the final highest dose as well.

Thank you. One moment please for our next question. And our next question will come from Gregory Renta of RBC Capital Markets. Your line is open.

Yeah, hi guys. It's Anish on for Greg. Congrats on the progress and thanks for taking my question. Just on the ExMab 2 plus 1 design for 819 and AMG 509, being armed with the knowledge of these compounds, what's the ultimate effect on the development and future of the 1 plus 1 class, so the future of Plumodimab and 968? Thanks so much.

I'll let John handle that and give a thoughtful response, but I will just tell you 1 plus 1 has plenty of roles to play if you know how to pick properly.

yeah i i yeah i think the easiest way to think about that is you know one plus one worked really well for plomodemab because it's it's very well established you can you can get rid of all your b cells um and include hopefully including the lymphoma b cells and and that's that's an on target off tumor toxicity that is that is you know it's fine to live with that when you go into the solid tumor setting you've got to be a little more careful. And a lot depends on the target and the selectivity of the, you know, selectivity profile of a target, how well it's overexpressed and selectively expressed in the tumor versus normal tissue. Also would depend to some extent on which of the normal tissues is expressed in, because some are a little bit more dangerous to attack than others. So in general, we don't see a downside to using the two plus ones. And so we'll likely use that for most of our solid tumor targets, but there could be exceptions.

Great, thanks so much.

Thank you. And one moment please for our next question. Our next question will come from the line of Jonathan Chang of SVB Securities. Your line is open.

Hey guys, this is Matt Calferon for Jonathan Chang. Thanks for taking my question. I know you said that the PSMA CD28 data were validated to the class kind of broadly, but You know, looking at the data, it didn't have, like, the cleanest AE profile, particularly with regards to immune-mediated responses. So just kind of wanted to get your thoughts on how you're thinking about the AE profiles for this class, you know, sort of in light of what we've seen with PD28 monotherapy approaches, and then sort of maybe discuss how your approach might mitigate some of these effects.

Thanks. Yeah, I think that the choice of co-target, we believe, is going to be very important. It was interesting that some of the AEs, the most dangerous AEs that were seen, were ones that are not typical for a PD-1 inhibitor alone. Because remember, that study was done combining it with the PD-1 inhibitor simiplumab. And you saw, in particular, central nervous system involvement in a couple of patients, peripheral nerve involvement in a couple of patients, or in one patient. And it's notable that the target choice, PSMA, outside of prostate, has among its brightest expression in brain and nerve. So I think there is a quite reasonable hypothesis there that you're activating immune response against the target and the tissues that have that target. And, in fact, I think that, you know, the sponsor of the study emphasized that they saw those AEs in patients that responded. Very early data, and it's hard to make too much of it, but I think the idea that CD20s can greatly activate the immune system in cold tumors has been pretty convincingly demonstrated. Now the question is, can, by prudent choice of target, we make a great drug? We're exploring that, but we're excited by the prospect.

Got it. Makes sense. Thank you so much.

Thank you. I see no further questions in the queue. I would now like to turn the conference back to Basil Darrap for closing remarks.

Thanks, everyone, for joining us today, and we look forward to updating you throughout the year. Have a great evening.

This concludes today's conference call. Thank you all for participating. You may now disconnect, and have a pleasant day.