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spk02: Thank you for standing by. This is the conference operator. Welcome to ZymeWorks first quarter 2024 results conference call and webcast. As a reminder, all participants are in listen only mode and the conference is being recorded. After the presentation, there will be an opportunity to ask questions. To ask a question, press star one one on your telephone keypad. To withdraw your question, please press star one one again. I would now like to turn the conference over to Shrinal in Updar, director of investor relations. Shrinal, please go ahead.
spk01: Thank you, Operator. Good afternoon. I'd like to welcome you to our first quarter 2024 results conference call. Before we begin, I'd like to remind you that we'll be making a number of forward looking statements during this call, including without limitation, those forward looking statements identified in our slides and the accompanying oral commentary. Forward looking statements are based upon our current expectations and various assumptions and are subject to the usual risks and uncertainties associated with companies in our industry and at our stage of development. For discussion of these risks and uncertainties, we'll refer you to our latest SEC filings as found on our website and as far as with the SEC. In a moment, I'll hand the call over to Ken Galbraith, our chair and chief executive officer. We'll be discussing recent corporate updates along with our financial results for the first quarter 2024. Following this, Dr. Paul Moore, our chief scientific officer, will talk about recent data shared at the annual American Association for Cancer Research or AACR meeting and key takeaways. At the end of the call, Ken, Paul and Bijard Si, our VP of finance and strategy will be available for Q&A. As a reminder, the audio and slides from this call will also be available on the DesignWatch website later today. I'll now turn the call over to Ken.
spk08: Thank you, Chanel. And thanks to everyone for joining us today on our first quarter 2024 earnings call. With that, I'll begin today's update with an overview of key achievements from our development programs, as well as our financial results. We're pleased to be reporting on another busy quarter where we've had a chance to present some really interesting data from our R&D team, which showcased the capabilities and internal expertise we have in screening and optimizing our candidates as presented at AACR, which Paul will speak to later in this call. Beyond that, we've also made progress on the clinical development readiness of our teams, including conducting steering committee meetings and various regulatory agency consultations to fine tune our clinical strategy for our two upcoming investigations on drug applications or INDs and foreign equivalents coming up this year. We've also been strengthening our presence in key locations to carry out a broad phase one clinical trial program in North America, Europe, and Asia Pacific, with the majority of our patients in our upcoming phase one studies expected to be recruited outside the United States. And I look forward to talking more about our plans in the near future when we've posted our respective study protocols publicly on the clinical trials website and are actively recruiting in the dose escalation stage of our phase one studies. To support this continued growth, we've brought in Dr. Neil Gallagher to join our experience board. His experience in leadership and leading multiple development programs through the global regulatory approval will support our efforts to rapidly advance our five by five programs into clinical studies and our continued pipeline expansion of novel antibody drug conjugates and multi-specific antibodies in the years ahead. Dr. Gallagher is in very good company and will provide complimentary guidance along with the new and longer serving members of our board. I'm very confident that these advances, coupled with R&D reprioritization and some difficult but necessary personnel decisions over the past two years will position us for success as we approach pivotal milestones for design works this year and in the years ahead by focusing our resources and energy on our most advanced and highest potential clinical value drivers. On our latest data set, we're very pleased that JAZZ has completed its BLA submission seeking accelerated approval for Xanadatamab in second line biliary tract cancers or BTC in the United States as monotherapy. Yesterday, JAZZ also guided that their plans to submit a marketing authorization application or MMA to the European Medicines Association for Xanadatamab are proceeding. Similarly, Beijing is expecting to submit their BLA for Xanadatamab with the National Medical Products Administration in China during the second half of this year. JAZZ also initiated a phase three confirmatory trial for Xanadatamab as first line treatment in BTC in combination with the current standard of care and enrollment for this trial is ongoing. JAZZ has also noted that they expect to present updated data with longer follow-up, including overall survival findings from the phase two B Horizon BTC01 trial at the 2024 ASCO annual meeting. Additionally, JAZZ is targeting the top line PFS data readout from the pivotal phase three trial presented data map in first line gastroesophageal adenocarcinoma or GEA in late 2024. Furthermore, JAZZ announced they expect to initiate a phase three trial anticipated for the second half of 2024 for Xanadatamab in and HER2 experienced patients with HER2 positive breast cancer. We sincerely appreciate the progress achieved and commitment shown by our partners JAZZ and Beijing in leading Xanadatamab towards commercialization, initially in BTC, and then with additional clinical development investment for potential label expansion, including in GEA and metastatic breast cancer. Turning now to our financial position this afternoon, Ziemark's reported financial results for the first quarter of 2024. Ziemark's net loss with a three month ended March 31st, 2024 was $31.7 million or 42 cents loss per diluted share compared to a net loss of 24.4 million for the same period in 2023. The increase in net loss was due mainly to a decrease in revenue, which was partially offset by a decrease in operating expenses and an increase in interest income. As reported, our revenue for the three months ended March 31st, 2024 was $10 million compared to $35.6 million for the same period in 2023. Revenue for the three months ended March 31st, 2024 included $9.9 million for development support and drug supply revenue from JAZZ and $0.2 million from our partners for research support and other payments. Revenue for the same period in 2023 included $34.4 million in revenue for development support and drug supply payments from JAZZ and $1.2 million from our partners for research support and other payments. The decrease in revenue from JAZZ was the result of a transfer of responsibility for certain clinical trials regarding ZendataMAP to JAZZ for our transfer agreement and amended collaboration agreement with JAZZ. Overall operating expenses were $47.8 million for the three months ended March 31st, 2024 compared to $62.9 million for the same period in 2023, representing a decrease of 24% year over year. The decrease in overall operating expenses resulted from a decrease in both research and development expense, as well as a decrease in general and administrative expense. The decrease in R&D expense was primarily due to a decrease in expenses for ZendataMAP as a result of a transfer of responsibility for the program to JAZZ for our transfer agreement and amended collaboration agreement. This decrease compared to the same period in 2023 was partially offset by an increase in preclinical expenses, primarily with respect to the preclinical product candidates ZW171, ZW191, and ZW220. Salaries and benefit expenses decreased compared to the same period in 2023 due to a lower headcount in 2024, which was partially offset by an increase in stock-based compensation expense in 2024. The decrease in general administrative expense was primarily due to a decrease in expenses related to external legal spending and insurance expenses compared to the same period in 2023. As of 30th, 2024, we had approximately 70.7 million shares of common stock outstanding and approximately 5.1 million shares of common stock issuable under pre-funded warrants. As of March 31st, 2024, we had 420.5 million of cash resources consisting of cash equivalents and marketable securities as compared to 456.3 million as of December 31st, 2023. Based on our current operating plans, we expect our existing cash resources as of March 31st, 2024 when combined with a receipt of certain anticipated regulatory milestone payments will enable us to fund planned operations into the second half of 2027. For additional details on our quarterly and year-end results, I encourage you to review our earnings release and other SEC filings as available on our website at .zymeworks.com. With respect to our SEC filings, you may notice that our current shelf registration statement expires later this year, and as a matter of good financial housekeeping, we've filed an automatic shelf registration statement today to take advantage of our new well-known season issuer or WICC status. This automatic shelf registration statement, like our existing ATM equity program, provides us with flexibility to consider various financing operatives in the future, as other biotechnology companies do, but does not commit us to raise any new equity capital. As further financial housekeeping, you may see some further upcoming filings with the SEC to bring our existing prospective supplement filings regarding our exchangeable shares and our ATO program under our new WICC automatic shelf registration statement. Starting with slide seven, our strategy of refocusing the business and building a diverse clinical stage product pipeline of anybody drug conjugates and multi-specific anybody therapeutics continues to provide a solid foundation helping to achieve our long-term goal of identifying additional product candidates and seeking valuable partnership options where appropriate to assist in global development and commercialization. Our strong financial position of $420 million in cash resources as of March 31st, 2024, together with certain anticipated regulatory milestones payments, gives us an expected runway into the second half of 2027. We may also be able to extend this runway or fund an expanded R&D scope through potential regulatory approval milestone payments in connection with our existing partnerships with JAZZ in Beijing or new partnerships and collaborations, which we may choose to form. In addition, pending regulatory approval, we are eligible to receive commercial milestone payments based on annual sales of Zena DataMap and tiered royalties between 10 and 20% on JAZZ's annual net sales and between 10 and .5% on Beijing's sales. With that, I'd like to hand over to our Chief Scientific Officer, Dr. Paul Moore, who will talk more about the really interesting work our team presented at AACR on our ADCs and Multicivic Antibody Therapeutics. Over to you, Paul.
spk18: Thanks, Cain. As you said, we were pleased to be able to showcase some of these capabilities at AACR and provide insights into how these technologies can be applied to the screening and optimization of our preclinical development candidates, keeping the specific targets and patient populations in mind with the aim of de-risking clinical development efforts. Posters presented on our multispecific antibody therapeutics focused on our Tri-TCE CoSTEM platform, a next generation tri-specific T-cell engager with integrated CD28 co-stimulation. We presented data on the platform itself and in the context of two tumor targeting antigens, highlighting enhanced mechanistic and anti-tumor activity compared to clinical benchmark CD3 bispecifics targeting the same antigens. By providing balanced activation of both signal one through CD3 and signal two through CD28 in a single molecule, Tri-TCE CoSTEM molecules have the potential to induce more sustainable T-cell responses in the tumor microenvironment beyond that achievable with conventional bispecific T-cell engagers that only engage CD3 or CD28 alone, providing a potential therapeutic modality to treat solid tumors with low T-cell infiltration and poor T-cell function that are underserved by existing immune-based therapies. On slide 10, summarizes the first Tri-TCE CoSTEM presentation which utilizes CLAWDN 18.2 as a model tumor target. And it focused on the various design features optimized through protein engineering and reiterative functional screening to enable certain key functional properties desired in the platform. This includes conditional binding of CD28 contingent on CD3 binding, obligate -T-cell binding of CD28 and CD3 with no T-cell cross-linking between CD3 and CD28 on separate T-cells, and with T-cell activation contingent upon tumor antigen engagement. In the presence of tumor cells expressing CLAWDN 18.2, the simultaneous engagement of CLAWDN 18.2 on tumor cells with dual CD3 CD28 co-engagement on T-cells is anticipated to yield higher functioning T-cells capable of driving more durable T-cell responses, culminating in sustained anti-tumor activity. As shown in the left, we tested this hypothesis in an in vitro serial repeat challenge assay with results demonstrating superior T-cell viability, T-cell proliferation, and tumor cell cytotoxicity over time with the lead CLAWDN 18.2 TRITC molecule relative to clinical stage benchmark bi-specifics from AMGEN and Nostellus. On the right-hand side of the slide, you can see that this also translates into enhanced anti-tumor activity in established gastric cancer models. Building on data shared in prior presentations on the platform demonstrating lack of systemic cytokine release, we also continue to characterize the safety profile of the platform. In pilot NHP studies, CLAWDN 18.2 TRITCE CoSTEM was well tolerated upon repeat dosing at three megs per kick with mild changes in peripheral cytokines and noticed pathological changes observed in the stomach where CLAWDN is expressed. Taken together, we view these results as very encouraging, further validating the potential of the TRITCE CoSTEM approach and supporting continued evaluation against additional tumor targets. The second TRITCE CoSTEM presentation described the design and characterization of a DLL3-targeted TRITCE CoSTEM module, again incorporating balanced CD3 and CD28 T-cell activation to enhance cytotoxic T-cell responses against DLL3-expressing tumor cells, beyond that achieved with benchmark DLL3 CD3 bispecifix. As described in the presentation, molecule selection was achieved through a rigorous evaluation and functional screening of various formats, geometries, and paratope affinities, while also leveraging advances in the platform described in the CLAWDN .2-based poster. This slide shows a subset of data from the poster. On the left, we show example in vitro cytotoxicity results performed at low ET ratio, demonstrating favorability of DLL3 TRITCE CoSTEM relative to benchmark clinical stage DLL3 CD3 bispecifix, such as AMG757 or Trilatumab and HPN328 from Harpoon. In additional experiments reported in the poster, we further demonstrated that the DLL3 TRITCE, as by design, improves T-cell proliferation and survival, resulting in more sustained T-cell cytotoxicity than re-challenge experiments relative to benchmark TCEs, while maintaining desired T-cell engagement properties, such as conditional binding to CD28, that requires co-engagement of CD3. Similar to our CLAWDN 18.2 TRITCE, the novel geometry that prevents binding of the CD28 parotope in the absence of CD3 binding reduces the potential of cytokine release syndrome as tested using a predictive in vitro model through monitoring cytokine release. Finally, as shown in the right-hand side of the slide, in vivo studies using a high-bar, established small-cell lung cancer humanized xenograft model, comparing the DLL3 TRITCE to the AMG75 benchmark demonstrates tumor regression with the DLL3 TRITCE not observed with the benchmark control. Taken together, we feel both AACR posters describing the TRITCE specific T-cell engager platform illustrate our ability to engineer T-cell engagers to supplement CD3 activation with CD28 co-stimulation to enhance T-cell responses and anti-tumor activity, while maintaining a desired tolerability profile, paving potential opportunity to expand and enhance therapeutic responses in solid tumor patients beyond that achieved thus far with T-cell engagers. Slide 12, as you are no doubt aware, the appeal of incorporating CD28 co-stimulation into T-cell engager strategies is also being pursued by others in the industry, as shown in gray on this slide, highlighting the exciting potential of CD28 co-stimulation to augment T-cell based therapeutic strategies. DesignWorks approach highlighted in green, however, differentiates from these competitive approaches in several key features. First and foremost, we have designed tumor targeted T-cell engagers that incorporate both CD3 and CD28 co-engagement in a single molecule, engineering balanced CD3 and CD20 activation to enable an optimal level of T-cell activation through signal one and signal two. This differs from companies developing CD28 bi-specifics alone or in combination with either anti-PD1 or with CD3 bi-specifics. While others have developed CD3 CD28 based tri-specifics, in contrast to their approach, we have been very careful to engineer conditional CD28 binding and activation contingent with CD3 binding to offset the potential for T-cell engagement and peripheral T-cell activation. Designed data maps advancement to regulatory review marks a significant milestone and validates our protein engineering expertise, including the isometric platform, also a core component of our multi-specifics used in the next generation T-cell engager, said W171, alongside our latest tri-PCE custom candidates. Much like our design and optimization of Xani as a next generation anti-HER2 agent, we anticipate our protein engineering expertise and attention to design features of next generation T-cell engagers will likewise provide enhancements in therapeutic benefits beyond the limits of first generation T-cell engagers. And we look forward to nominating a tri-PCE molecule at the end of this year as the final molecule of our five by five strategy.
spk17: From our ADC team,
spk18: we had three posters. For ZW191, our folate receptor alpha targeting antibody drug conjugate, we shared additional preclinical data that's demonstrating its differentiated profile relative to other folate receptor targeting ADCs, its strong anti-tumor activity across an expanded set of folate receptor alpha tumor indications, and its favorable tolerability and repeat those non-human primate studies. On this slide, we highlight a few of these results. On the left, we demonstrate the relative internalization, payload delivery, and tumor spheroid penetration supported by ZW19 folate receptor alpha MAV compared to folate receptor alpha targeting antibodies incorporated in four other ADC programs. As you can see, ZW191 MAV in blue, in dark blue, demonstrated higher levels of internalization, spheroid penetration, and payload delivery compared to the MAVs from Elahir, Morab 202, Stroh 002, and Pro 1184. This observation is consistent with our decision to select the ZW191 MAV from a larger pool of folate receptor alpha antibodies based on its optimal ability to deliver payload through enhanced internalization, and consistent with our care in factoring in all components of the ADC when designing our candidates. On the right hand side of the slide, we demonstrate ZW191 anti-tumor activity in a range of PDX models. Consistent with prior data, we saw greater total activity of 191 compared to MERV with ZW191 demonstrating activity in folate receptor, a high, medium, and low models of ovarian cancer. We also reported promising results in folate receptor alpha expressing non-small cell lung cancer, endometrial, and triple negative breast cancer models with representative examples of responses shown. Further for ZW191, we disclosed updated data from our GLP toxicology studies supporting our IMD filing where we reported the highest non-severely toxic dose in non-human premix was 60 mgs per kig, presenting a compelling profile for potentially efficacious dosing. Beyond the ZW191 poster, our ADC team also presented development of a novel tumor spheroid model system applicable to multiple cancer types to aid in the screening and characterization of our ADC molecules, including topo-based ADCs that is more predictive of anti-tumor activity in vivo than traditional 2D cell line models. It also aids in the detection of ADC mechanism of action, such as the tumor spheroid penetration data shown in the ZW191 presentation. Finally, we also shared progress made on the design and functional screening of high-specific ADCs to identify those optimally formatted in affinity, valency, and design to overcome challenges associated with tumor heterogeneity associated with targeting a single tumor antigen. And we look forward to presenting more data from that novel technology in the future, including applications to additional tumor target pairs. In addition to today's updates, we anticipate further opportunities to showcase our progress for both our preclinical and clinical milestones at upcoming conferences in 2024, including the nomination of our final product candidate within our -by-five portfolio. Our commitment to innovation and mission to provide effective treatment options for patients remains at the heart of what we do at ZymeWorks. We're actively exploring alternative mechanisms of actions and harnessing new modalities to optimize efficacy while minimizing toxicity, ultimately with the aim of raising the bar for the standard of care, particularly in challenging to treat diseases. We're excited about the journey ahead and remain dedicated to advancing transformative therapies. Ken, back over to you. That's great, thank you,
spk08: Paul. In summary, as mentioned earlier, we're very pleased with the BLA submission seeking accelerated approval for ZendataMap in second-line BTC in the United States having been completed. And we continue to work very closely with our partners, JAZZ in Beijing, to achieve key near-term milestones. We're encouraged by our progress to date in 2024 and as excited as ever about the future of ZymeWorks. As we prepare to enter multiple phase one trials in the next coming 24 months, our commitment to advancing innovative solutions remains evident with more preclinical data for our early stage pipeline to be presented throughout 2024. Beyond that, we wish to further build upon and leverage the differentiated platform at ZymeWorks to generate continued long-term R&D productivity with the ability to expand our therapeutic focus and research scope beyond the current pipeline with the potential for two new INDs annually from 2027 onward. Our cash runway remains on track to support the development of our 5x5 product pipeline and invest in our long-term R&D strategy called ADVANCE. While we approach milestones that may result in the further extension of this runway or allow us to expand our R&D scope, we remain diligent in efficiently managing our operating expenses as we continue to execute on the strategic clinical development plans for our assets. We look forward to reporting our continued progress against our key priorities during the remainder of 2024. With that, I'd like to thank everyone for listening to our call. I'd like to turn the call over to the operator now to begin the question and answer session. Operator?
spk02: Thank you. At this time, we will conduct the question and answer session, and as a reminder, to ask a question, you will need to press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we
spk04: compile the Q&A roster. Our first
spk02: question comes from the line of Stephen Willey of Stifle. Your line is now open.
spk16: Yeah, good afternoon. Thanks for taking the questions. It'd be just a couple of zany questions for me. So Ken and perhaps Paul, just curious as to your thoughts regarding Merck's disclosure of the OS benefit that was seen in Keynote 811. I know that there was some suggestion that this could be the case per the interim analysis that we saw at ESMO back in October, but just wondering if you think that if this changes the longer term competitive dynamic at all in frontline GEA and if that now kind of raises the bar for perhaps what the triplet arm meets the show in the Horizon Trial.
spk08: Yeah, thanks for the question, Steve. I mean, obviously we don't know much more than what was put in the press release about the OS outcome. There's no actual data there, so it's hard for us to comment further about the strength of that data, the consistency across the patient population. Obviously the OS was determined on ITT as it needs to be across the population. Obviously the previous PFS result was not across the entire patient population, but only in the P01 positive stratified part of that study. So until we see the actual data presented, until we understand what's on the label, it's difficult for us to evaluate your question about the attractiveness of that regimen versus our own. And I think for us and JAAS in Beijing, we're focused on completing the Horizon GA01 study and we're more focused on seeing the results of our own combinations, Zani plus chemotherapy and Zani plus chemotherapy with TISLA and how that compares to our own active control arm. Trazin chemo in the patient population we're studying, which remember is different than the Keno 11 patient population just because of the inclusion of the esophageal adenocarcinoma patients. So I think we're more interested in the patient recruitment in our study, understanding the PFS results and continuing to follow the patients. And I think once we have more data available on our study and the other study, then it'll be probably a little bit easier to understand the competitive environment for everyone.
spk16: Okay, I guess that's fair. And then, I know JAAS obviously has outlined plans to pursue registration in post and HER2 metastatic breast. And I think there was some KOL discussion on their call regarding the need for prospectively generated data in this patient population. But just curious, given that most KOLs think and HER2s going to become frontline standard of care, I'm just kind of interested in your thoughts regarding the relevancy of this trial. With respect to gaining utilization in the second line setting, if indeed that in HER2 upstream move into frontline occurs. And I guess from a relevancy perspective, I'm just questioning the thought, right, that one would need to assume that the Cleopatra regimen and Cat's Isle are kind of completely displaced and not repositioned as later line treatment options post and HER2. So just kind of curious as to your thoughts there.
spk08: Yeah, I mean, I think JAAS indicated in their call, so they're gonna talk more about that study design in the second half of this year when it's initiated. So I don't wanna get ahead of that. I'll say from our own perspective, we obviously did a number of studies in different combinations in the metastatic breast cancer setting. And you can certainly see the potential for Zani in combination with other agents, just because if it's tolerability nature makes it a great combination with other agents as we're doing in GEA and as we'll seek to do in bilaterally cancer. So you can certainly see the potential for Zani to find a place in the treatment paradigm for metastatic breast cancer. And I know from the KOL work that we did when I got here before the JAAS transaction, there was certainly a need for something in a post and HER2 environment where patients may have got a response, but then progressed. And I think there was some sense that maybe having a different mechanism than another ADC at that timeframe might be something that might be attractive. So obviously looking at Zani being a unique bispecific antibody in the HER2 space surrounded by a wave of different ADC formats, including TdxD, might be a really attractive proposition provided you could find the clinical and regulatory pathway to that type of label. And I think we'll let JAAS describe their study in more detail when they initiated the second half this year to see if you can understand more of the clinical and regulatory pathway that they intend to pursue, but from a commercial opportunity, it was evident to us that that was something that was very attractive. Obviously we just didn't have the capital to pursue that on our own, and one of the benefits of the JAAS transaction for us is that they do have a capital that they could put to work beyond what we could do on our own in attractive opportunities beyond ability to track cancer and GEA, and that's what they've announced they intend to do, and that's fantastic. All
spk15: right, thanks for taking the questions.
spk02: Thank you. One moment for our next question. Next question comes from the line of Yigal Nocemovic of Citi. Your line is now open.
spk07: Hi guys, this is Ashok Mubarak on Vyagal. Thanks for taking my questions. I just have one operational question and one scientific question. First on the sort of financing, you're guiding to cash runaway in the second half of 2027, including some regulatory milestones. I'm just kind of wondering if you could give us a little color on what of that runway or how much of that runway is being contributed to from potential milestone payments. Are you able to break those out in more detail?
spk08: Yeah, not beyond the guidance that we've previously given, and again, not all of the milestones that we may be entitled to for approval from our current fields of JAAS imaging are included in that. So there's some element, but not all of it. I think we feel comfortable with our current financial position and current financial outlook that we can fund the R&D strategy that we have right now through the second half of 2027 in a number of different scenarios. So I think we feel we have a very strong financial position, a good outlook for the business. Obviously a number of other biotechnology companies in our sector went and accessed additional equity capital through offerings, R&D, in the first quarter of this year. We were not one of those, because I think we feel very confident in our current financial position and our runway and the outlook for the business, and that's why we chose not to do so. But I can't go beyond the details we've previously provided until all the milestones start to be received, and then we'll obviously be in a position to announce those.
spk07: Okay, that's understandable. Maybe one more. On the TRITCE platform, which you shared to ACR, I thought that was pretty interesting. I'm just curious if you could tell a little more about how you expect in the clinic the CRS profile might be differentiated compared to a more traditional CD3, bi-specific. I think you alluded to the idea that peripheral cytokines might be less, but I'm just curious if you think the improvement could be meaningful enough in something like CRS that there may be practical differences in terms of maybe less steroids or less step dosing, or maybe potential to be in the outpatient setting versus continuous IV, et cetera. I'm just curious what you can comment from maybe a practical potential standpoint.
spk18: Yeah, sure, good question. Let me clarify that a little bit. So for the TRITCE, something that we were very careful of was actually the level of interaction with T cells that could trigger T cell activation. So we are actually using a lower affinity CD3, and the CD28 binding is actually quite weak, but upon ability binding through CDC-D28, we get engagement of T cells when we co-engage with a tumor target. So the amount of binding, say, in the periphery is very low, only when we engage the target and then engage the T cells do we see this nice ability-powered CD28-CDC activation. So that, we feel, is important as something we've also embedded in the ZW171 program, where we're using a lower affinity novel CD3 epitope that so far, when we've modeled that in preclinical studies, both in vitro and non-human primates, does not support the level of T cell activation we see with other CD3s. So that's kind of how far we can take it. Obviously, we'll need to see a lot of it. A lot of the T cell activation that you see in the clinic will also be driven by the target that you pair with the T cell engager. So that's also a factor that we consider. But overall, we've done what we think to engineer peripheral cytokine activation that's independent of tumor engagement.
spk07: Okay, okay, maybe the last question for me. I'm just curious, I mean, I think you said that the final program in the -by-five will be one of these Tri-TCEs. I'm just wondering if it potentially might be the DLL3 or the quad in 18.2 programs you kind of outlined, or could it be something else entirely?
spk08: Yeah, I mean, we obviously have a pretty broad program in both the Tri-TCE with the COSTEM, but also other tri-specific formats that we've been working on research, so we haven't disclosed yet. I think we have published data preclinically around the quad in 18.2 and DLL3, because those were good programs to work on to benchmark ourselves against other product formats and understand what that Tri-TCE COSTEM might give you that you don't see in another bi-specific antibody or an ADC or just a simple antibody approach. I think we will make a nomination of the candidate we wanna move forward with as our fifth later this year, but I don't wanna speculate as to whether it's one of the two that we published data on or something else that we still continue to work on as a part of our broad portfolio approach there. That's beyond those two, and you just have to wait until we nominate it to see that, and that will be this year.
spk02: John, thanks very much. Thank you. One moment for our next question. Our next question comes from the line of Akash Tewari of Jeffreys, your line is now open.
spk10: Hi, this is Phoebe on for Akash. Thank you for taking your question. So, profound bio was recently acquired by GenMab, which is lead molecule, RINA-S, which is a folate receptor alpha targeting with a topo ADC that is ahead of time with encouraging initial human data. I guess, where do you think you can differentiate with DW-191, and what is your approach here that's different than RINA-S? Thank you.
spk08: Yeah, again, we don't know enough about that molecule, I think, to do a proper comparison, and whether it's encouraging or not, I guess it was acquired, so it must be encouraging, but I don't know how to speculate on data that's publicly available versus public data that GenMab may have had available to it. So, I can really only comment on our own program and approach with DW-191, and I think that's reflected in data we've previously published, and also at AACR, where I think, you know, we think there's a lot of differentiation in what we're doing around the payload. So, we did disclose earlier this year our proprietary payload 519, which was through a significant medicinal chemistry effort to find a payload that was a campus-based analog but proprietary to us, and with properties that we believe are ideal to be used in an ADC, including in the indication of interest in folate receptor alpha. I think from the standpoint of the antibody, we think we have made some innovations around how optimization of an antibody can make an ADC more effective, and obviously that was the purpose of one of our publications at AACR, was to focus on not just binding, but internalization and tumor penetration as a way to get efficiency out of a payload with maybe less tolerability given up to get that activity. And so, we're really interested to put that, put that to the test in clinical studies, and it won't be too long from now, and I think then we'll understand the characteristics of our own molecule. We definitely have some differentiated features in there from any of the other folate receptor alpha ADCs, including the one you mentioned, but I'm more interested in looking at our own data to understand the activity that can be generated, find a dose, understand the tolerability of that agent, and then be able to understand where we can create clinical differentiation against a host of competitors, and it's just difficult for us to try and make a comparison at this point between any of the other agents.
spk09: Okay, understood, thank you.
spk02: Thank you, one moment for our next question. Next question comes from the line of Brian Chang of JPMorgan, your line is now open.
spk14: Hi Ken and team, thanks for taking our questions today. We're seeing some excitement around the application of T cell engagers in the autoimmune space, like Skiriderma and Myosinogravus, just these recent weeks. Just curious if you have any interest or whether you have any potential ability to, whether you see any potential ability to disrupt that space with your Tri-TC platform.
spk08: Yes. No, thanks Brett, no, it's obviously, you know, Zymmerx has never been exclusively an oncology company, we have been working in autoimmune and inflammatory and dermatology indications for some time period. We just decided when I got here not to focus on it, because we wanted to have a focused R&D program for the 555, but we definitely have some platforms and capabilities and experience in that area, given things we worked on pre-clinically, and if you look at the folks who I've added since I got here, including Paul, we do have a number of folks who have some great experience in commercializing in the autoimmune and inflammatory space. So I think as we think about going beyond the five by five, we definitely have an interest in understanding of some of our platforms and assets can be really differentiated from what we see from others and be applicable to a patient population beyond oncology. And I think we haven't talked a lot about that. I think by the time we get to our R&D day in Q4 this year, you should probably expect it will outline some more thoughts around assets and approach and differentiation against others who are in that space. So the answer, yes.
spk14: Okay, great. And then maybe just a follow-up. On your prepare remarks, you talk about, you mentioned partnership, and I think past partnership had always been a core part of your approach. We're about halfway through the year, so just curious if there's also a particular direction that you're looking at from a partnership standpoint. And then on top of that, are you looking for a partnership to kind of accelerate your development on autoimmune side? Just any color they can provide would be super helpful.
spk08: Yeah, I think clearly partnership is a part of our strategy for a number of reasons. One is obviously access to capital, and it's no surprise that transactions in both ADCs and T-cell engagers have gotten to a much higher valuation at an earlier time point in development. We also look at partnerships and the ability for us to accelerate and compete. And obviously with the acquisitions which have occurred over the past period of time in both ADCs and T-cell engagers, we find ourselves against larger and more formidable competitors. And with the potential for broad applications, especially in 191 and 171 going to the clinic first in both mesothelin and folate receptor alpha, those targets are of interest in a pretty broad patient population. I think we learned from Zany that there was a certain breadth of opportunity to Zany, which was probably beyond the reach of ourselves on our own, and completing the Jazz Partnership, as you see with their subsequent developments, may allow them to pursue that, where we couldn't do that on our own. And hopefully we structured that in a way that allows us to continue to share in a good portion of success for that. So that's a good learning for us to look at. But we've also been very clear with Zany being partnered exclusively with Jazz in Beijing, that for our follow-on agents in five by five, we would like to have the ability and the opportunity to build a future late stage development and commercial opportunity for ourselves. And we've talked about it as a USXUS potential partnering strategy. There's other forums we could do, but we'd obviously like to, if we're fortunate, to find another agent in our five by five, which has the potential that Zany seems to have in a peak sales potential, which Jazz guided on, that we'd like to be able to keep some of that for ourselves and not look at a fully licensed strategy going forward. So obviously there's a substantial amount of interest, as you know, in innovative products in both ADCs and T-cell engagers, which gives us good optionality for potential partnerships and collaborations and the timing of those. But we also have a strong balance sheet, and talent pool in the company, which allows us to execute those five by five programs in the early clinical data without requiring partnerships or collaborations as part of that. So I like the position we're in, where we have optionality and not a requirement to partner. I think there is considerable interest in both of these spaces, as well as autoimmune. So I think we'll continue to consider interest and have discussions, but make sure we can meet the requirements we might have for future capital, folks to help us accelerate and compete against larger competitors, as well as retaining rights and commercial opportunities for ourselves. And until we find the right partnership, I'm unwilling to give up the optionality that we have by having a host of unencumbered assets, which are really interesting to us when we're just going into clinical studies over the next 24 months for all five of
spk13: them. Great. Thanks, Ken.
spk02: Yeah. Thank you. One moment for our next question. Our next question comes from the line of John Miller of Evercore. Your line is now open.
spk06: Hey, guys.
spk02: Thanks
spk06: for taking the question. I wanted to ask a question on the trispecific stuff that you presented at AACR. In particular, in addition to the reduced CRS or cytokine release, purple cytokine release that you already touched on, I also noticed was interested by improved T-cell survival or what would look like improved characteristics of the stimulated T-cells that are coming from those reduced affinity CD3C28 binders. Obviously, you have the spider plots in the -to-day, and those were up there at AACR, but do you have evidence that improving T-cell health means that you get continued stimulation? I mean, that is to say, as you get in longer and longer in timeline, do you see the ability to generate stimulated T-cells further on into treatment after continuous treatment than you would with a CD3 bispecific alone? If that question makes sense. Did you buy more T-cell activity by using these binders? In terms of durability, not in terms of potency.
spk18: Yeah, sure enough. I'm glad you brought that up because I think that's an important point that what we're trying to do here is by having that CD20 co-stimulation, we're generating T-cells that are more durable and don't become exhausted. And that they then provide enhanced anti-tumor activity. So, it's a little... We've done some modelling of the sustainability of the response in vitro where we can do these kind of repeat challenges where we take the T-cells and continue to re-stimulate them. And we can see that under those conditions that we can maintain response for much longer if we challenge them with the trispecific, with the CD28 compared to the CD3. So, that's consistent with what you would expect by having, you know, thinner T-cells and that was described in the poster. And then when we've gone in vivo, what we have seen is we've reported this in some studies that we do see, you know, more T-cell... We look at T-cell infiltration in the tumours, we see evidence for that. But I think what was very clear in the one example I showed today was that we were seeing responses, tumour responses or anti-tumour responses with the Tritce platform that you don't see with the bispecific CD3. So, that suggests to us that in the tumour microenvironment, not only this, you know, enhanced durability and sustainability, we're seeing better activity and responses where you don't see responses without CD3 bispecifics... You don't see it with CD3 bispecifics alone. So, that tells us that we are indeed doing something in the tumour microenvironment in an animal model, albeit that is supportive of our hypothesis and we then, of course, you know, anticipate that that hopefully will translate in the clinic to better responses.
spk05: Now, that makes sense.
spk06: I guess one more on a related topic. If... Obviously, the CD3 bispecifics are active drugs, they're used to great effect in many indications. Do you expect the sort of trispecific platform that you're talking about to be a fully generic improvement that is, you know, is this going to be better in every case? Or are there certain indications of tumour antigens where you would expect this to be, this sort of technique, to be relatively most important or give you the relatively best benefit versus the CD3 bispecifics?
spk18: Yeah, that's another great question. I think we do anticipate that overall this should yield better responses. You know, even where CD3 bispecifics work, I don't want to be too hypothetical, but I think when you think about the CAR T-space, without co-stimulation on those T cells, the responses were not as generally as good without it. So, you know, you needed that co-stimulation. So there's a potential that, you know, we could have broader overall better response with this. And I think that's why other companies are pursuing CD28 co-stimulation as well. It's fundamental T cell biology. But I think where we see, you know, maybe the biggest need is in solid tumours where low T cell infiltration or, you know, T cells are already anergic, need a little bit more than just CD. That's where you could really see, you know, the greatest, you know, potential impact. And so that's part of the design feature and the thinking behind, you know, developing this type of technology.
spk04: Thanks, Dan. Thanks so much. Thank you. One moment for our next question. Next
spk02: question comes from the line of Derek Artilla of Wells Fargo. The line is now open.
spk12: Hi, this is Sevan for Derek. Thanks for taking our question. A quick one from us. Can you share how the IND filing activities are progressing for .9.1 and .7.1? And what are we expecting? Are you expecting to initiate phase one studies? Like I'm just trying to understand, like, is this like a 2024 event for any of these molecules?
spk08: Thanks. Yeah, we previously got it. It was our intention to file INDs and commence first in human studies for both .7.1 and .9.1 this year. We haven't given any more guidance specifically to that. And I won't on the call today. I think once both of those studies are up on QMTrials, which means we've initiated our first site, then we'd be happy then to talk more about the details of the study design and timing that's available on QMTrials. I think once you see them up there, we'll be happy to publicly comment on them. But until then, we're on track. We're a little bit ahead of schedule where we might have been. And hopefully we can keep that a little bit ahead of our schedule and be discussing those in the near future. But until we have those publicly disclosed and initiated, we won't be talking about them further.
spk04: Okay, thanks. All right, thank you. As a reminder,
spk02: to ask a question, you will need to press star one one on your telephone and wait for your name to be announced. Please stand by while we
spk04: wait for additional questions. Okay, one moment for our next question. Our next question comes from the line of John Miller of Evercore.
spk06: Please go ahead. Hi, thanks for letting me hop in the queue again. One thing that you mentioned that, Prepare to Marks, I just want to get a little bit more color on. You mentioned that you expected that your phase ones would have mostly XUS, it would be global studies, but mostly XUS patients. Obviously, you're not commenting on the specifics of trial design at this point, but I would love to hear you talk a little bit more about strategy on where you're running, where you anticipate running the studies and what the pushes and pulls are in terms of where you're getting your patients from.
spk08: Yeah, absolutely. I think we took a decision a while ago that we could go faster and potentially get a higher quality, more diverse set of patients, even from the very first dose escalation cohort, if we structure ourselves to be able to globally recruit patients. So you should see in our phase one studies not just IMD filings, but foreign equivalents very quickly thereafter, so that we can get up a pretty global program which encompasses sites in Europe, North America, and Asia pretty concurrently, so that we can recruit in all those jurisdictions even from the early dose escalation cohorts. And I think that this allows us to go quickly, get high quality and diverse patients from the start. And more importantly, if we see data that looks pretty interesting and compelling, we can go further, faster to follow those data signals in a broader phase one program as we move from dose escalation to expansion cohorts and eventually the combination cohorts and eventually beyond phase one. So I think we've thought a lot about how we would execute this. I think we structured our groups internally and externally to be able to do this. And the hope is that we can go fast with high quality, diverse patients. So the data that comes out of that will come to us faster and also in a way that allows us to interpret it in a more significant way. So we will have U.S. Vice, but I would expect the majority of patients in both those studies in phase one, the vast majority will be recruited outside the United States. And hopefully we structure ourselves and made those decisions to accomplish what we want, which is a faster phase one study and clearer data and a more diverse data set by recruiting patients globally. So we'll have to see if we can do that, but that is the goal and hopefully you'll see evidence of that pretty soon.
spk06: Thanks so much.
spk02: All right, thank you. There appear to be no further questions. I'd like to turn the conference back over to Ken for closing remarks.
spk08: No, thank you very much. And I really appreciate everyone taking time today to listen to our call and ask the questions. Hopefully we're able to answer them fully. If there's any follow-up questions, please don't hesitate to reach out to us. We're happy to address any questions or clarify anything in the call. Hopefully you can see we're very excited about 2024. This is getting very interesting for us this year and next year. And we are all in on executing the plan in front of us in the best way possible and look forward to reporting the results of that execution to you as we move forward through 2024. So thank you for everyone for listening today.
spk02: This concludes today's conference call. You may disconnect your lines. Thank you
spk04: for participating and have a pleasant day.
spk00: Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank
spk02: you. Thank you for standing by. This is the conference operator. Welcome to ZymeWorks' first quarter 2024 results conference call and webcast. As a reminder, all participants are in listen-only mode and the conference is being recorded. After the presentation, there will be an opportunity to ask questions. To ask a question, press star 1-1 on your telephone keypad. To withdraw your question, please press star 1-1 again. I would now like to turn the conference over to Shrinal Inupdar, Director of Investor Relations. Shrinal, please go ahead.
spk01: Thank you, Operator. Good afternoon. I'd like to welcome you to our first quarter 2024 results conference call. Before we begin, I'd like to remind you that we'll be making a number of forward-looking statements during this call, including without limitation those forward-looking statements identified in our slides and the accompanying oral commentary. Forward-looking statements are based upon our current expectations and various assumptions and are subject to the usual risks and uncertainties associated with companies in our industry and at our stage of development. For discussion of these risks and uncertainties, we'll refer you to our latest SEC filings as found on our website and as far as with the SEC. In a moment, I'll hand the call over to Ken Galbraith, our Chair and Chief Executive Officer. We'll be discussing recent corporate updates along with our financial results for the first quarter 2024. Following this, Dr. Paul Moore, our Chief Scientific Officer, will talk about recent data shared at the annual American Association for Cancer Research or AACR meeting and key takeaways. At the end of the call, Ken, Paul and Bijard Si, our VP of Finance and Strategy, will be available for Q&A. As a reminder, the audio and slides from this call will also be available on the DesignWatch website later today. I'll now turn the call over to Ken.
spk08: Thank you, Chanel, and thanks everyone for joining us today on our first quarter 2024 earnings call. With that, I'll begin today's update with an overview of key achievements from our development programs as well as our financial results. We're pleased to be reporting on another busy quarter where we've had a chance to present some really interesting data from our R&D team, which showcase the capabilities and internal expertise we have in screening and optimizing our candidates as presented at AACR, which Paul will speak to later in this call. Beyond that, we've also made progress on the clinical development readiness of our teams, including conducting steering committee meetings and various regulatory agency consultations to fine tune our clinical strategy for our two upcoming Investigative on Drug Applications, or INDs, and foreign equivalents coming up this year. We've also been strengthening our presence in key locations to carry out a broad Phase 1 clinical program in North America, Europe, and Asia Pacific, with the majority of our patients in our upcoming Phase 1 studies expected to be recruited outside the United States. And I look forward to talking more about our plans in the near future when we've posted our respective study protocols publicly on the clinical trials website and are actively recruiting in the dose escalation stage of our Phase 1 studies. To support this continued growth, we've brought in Dr. Neil Gallagher to join our Experience Board. His experience in leadership and leading multiple development programs through the global regulatory approval will support our efforts to rapidly advance our 5x5 programs into clinical studies and our continued pipeline expansion of novel antibody drug conjugates and multispecific antibodies in the years ahead. Dr. Gallagher is in very good company and will provide complimentary guidance along with the new and serving members of our board. I'm very confident that these advances coupled with R&D reprioritization and some difficult but necessary personnel decisions over the past two years will position us for success as we approach pivotal milestones for ZymeWorks this year and in the years ahead by focusing our resources and energy on our most advanced and highest potential clinical value drivers. On our later stage of ASAP, we're very pleased that JAZZ has completed its BLA submission seeking accelerated approval for Xanadatamab in second line biliary tract cancers or BTC in the United States as monotherapy. Yesterday, JAZZ also guided that their plans to submit a marketing authorization application or MMA to the European Medicines Association for Xanadatamab are proceeding. Similarly, Beijing is expecting to submit their BLA for Xanadatamab with the National Medical Products Administration in China during the second half of this year. JAZZ also initiated a Phase 3 confirmatory trial for Xanadatamab as first line treatment in BTC in combination with the current standard of care and enrollment for this trial is ongoing. JAZZ has also noted that they expect to present updated data with longer follow-up including overall survival findings from the Phase 2B Horizon BTC01 trial at the 2024 ASCO annual meeting. Additionally, JAZZ is targeting the top line PFS data readout from the Pivotal Phase 3 trial presented data map in first line gastroesophageal adenocarcinoma or GEA in late 2024. Furthermore, JAZZ announced they expect to initiate a Phase 3 trial anticipated for the second half of 2024 for Xanadatamab in in her two experienced patients with her two positive breast cancer. We sincerely appreciate the progress achieved and commitments shown by our partners JAZZ and Beijing in leading Xanadatamab towards commercialization initially in BTC and then with additional clinical development investment for potential label expansion including in GEA and metastatic breast cancer. Turning now to our financial position this afternoon, Ziemark's financial results for the first quarter of 2024. Ziemark's net loss for the three months ended March 31st 2024 was $31.7 million or 42 cents loss per diluted share compared to a net loss of $24.4 million for the same period in 2023. The increase in net loss was due mainly to a decrease in revenue which was partially offset by a decrease in operating expenses and an increase in interest As reported, our revenue for the three months ended March 31st 2024 was $10 million compared to $35.6 million for the same period in 2023. Revenue for the three months ended March 31st 2024 included $9.9 million for development support and drug supply revenue from JAZZ and $0.2 million from our partners for research support and other payments. Revenue for the same period in 2023 included $34.4 million in revenue for development support and drug supply payments from JAZZ and $1.2 million from our partners for research support and other payments. The decrease in revenue from JAZZ was the result of a transfer of responsibility for certain clinical trials regarding Xanadatamab to JAZZ for our transfer agreement and amended collaboration agreement with JAZZ. Overall operating expenses were $47.8 million for the three months ended March 31st 2024 compared to $62.9 million for the same period in 2023 representing a decrease of 24% year over year. The decrease in overall operating expenses resulted from a decrease in both research and development expense as well as a decrease in general and administrative expense. The decrease in R&D expense was primarily due to a decrease in expenses resented data math as a result of a transfer responsibility for the program to JAZZ for our transfer agreement and amended collaboration agreement. This decrease compared to the same period in 2023 was partially offset by an increase in preclinical expenses primarily with respect to the preclinical product candidates ZW-171, ZW-191, and ZW-220. Salaries and benefit expenses decreased compared to the same period in 2023 due to a lower head count in 2024 which was partially offset by an increase in stock-based compensation expense in 2024. The decrease in general administrative expense was primarily due to a decrease in expenses related to external legal spending and insurance expenses compared to the same period in 2023. As of 30th 2024 we had approximately 70.7 million shares of common stock outstanding and approximately 5.1 million shares of common stock issuable under pre-funded warrants. As of March 31st 2024 we had 420.5 million of cash resources consisting of cash equivalents and marketable securities as compared to 456.3 million as of December 31st 2023. Based on our current operating plans we expect our existing cash resources as of March 31st 2024 when combined with the receipt of certain anticipated regulatory milestone payments will enable us to fund planned operations into the second half of 2027. For additional details on our quarterly and year-end results I encourage you to review our SEC filings as available on our website at .zymeworks.com. With respect to our SEC filings you may notice that our current shelf registration statement expires later this year and as a matter of good financial housekeeping we've filed an automatic shelf registration statement today to take advantage of our new well-known season issuer or WICC status. This automatic shelf registration statement like our existing ATM equity program provides us with flexibility to consider various financing alternatives in the future as other biotechnology companies do but does not commit us to raise any new equity capital. As further financial housekeeping you may see some further upcoming filings with the SEC to bring our existing prospective supplement filings regarding our exchangeable shares and our ATO program under our new WICC automatic shelf registration statement. Turning to slide seven our strategy of refocusing the business and building diverse clinical stage product pipeline of anybody drug conjugates and multi-specific anybody therapeutics continues to provide a solid foundation helping to achieve our long-term goal of identifying additional product candidates and seeking valuable partnership options where appropriate to assist in global development and commercialization. Our strong financial position of 420 million dollars in cash resources as of March 31st 2024 together with certain anticipated regulatory milestones payments gives us an expected runway into the second half of 2027. We may also be able to extend this runway or fund an expanded R&D scope through potential regulatory approval milestone payments in connection with our existing partnerships with Jazz in Beijing or new partnerships and collaborations which we may choose to form. In addition pending regulatory approval we are eligible to receive commercial milestone payments based on annual sales of Zenadatamap and the tiered royalties between 10 and 20 percent on Jazz's annual net sales and between 10 and 19.5 percent on Beijing's SIPs. With that I'd like to hand over to our chief scientific officer Dr. Paul Moore who will talk more about the really interesting work our team presented at AACR on our ADCs and multi-specific antibody therapeutics. Over to you Paul.
spk18: Thanks Cain. As you said we were pleased to be able to showcase some of these capabilities at AACR and provide insights into how these technologies can be applied to the screening and optimization of our pre-clinical development candidates keeping the specific targets and patient populations in mind with the aim of de-risking clinical development efforts. Posters presented on our multi-specific antibody therapeutics focused on our Tri-TCEQoSTEM platform, a next generation tri-specific TCL Engager with integrated CD28 co-stimulation. We presented data on the platform itself and in the context of two tumor targeting antigens, highlighting enhanced mechanistic and anti-tumor activity compared to clinical benchmark CD3 bi-specifics targeting the same antigens. By providing balanced activation of both signal 1 through CD3 and signal 2 through CD28 in a single molecule, Tri-TCEQoSTEM molecules have the potential to induce more sustainable T cell responses in the tumor microenvironment beyond that achievable with conventional bi-specific T cell engagers that only engage CD3 or CD28 alone, providing a potential therapeutic modality to treat solid tumors with low T cell infiltration and poor T cell function that are underserved by existing immune-based therapies. Slide 10 summarizes the first Tri-TCEQoSTEM presentation which utilizes Clawdon 18.2 as a model tumor target. It focused on the various design features optimized through protein engineering and reiterative functional screening to enable certain key functional properties desired in the platform. This includes conditional binding of CD28 contingent on CD3 binding, obligate cis-T cell binding of CD28 and CD3 with no T cell cross-linking between CD3 and CD28 on separate T cells and with T cell activation contingent upon tumor antigen engagement. In the presence of tumor cells expressing Clawdon 18.2, the simultaneous engagement of Clawdon 18.2 tumor cells with dual CD3 CD28 co-engagement on T cells is anticipated to yield higher functioning T cells capable of driving more durable T cell responses culminating in sustained anti-tumor activity. As shown in the left, we tested this hypothesis in an in vitro serial repeat challenge assay with results demonstrating superior T cell viability, T cell proliferation and tumor cell toxicity over time with the lead Clawdon 18.2 tritce molecule relative to clinical stage benchmark by specifics from AMGEN and Nostellus. On the right-hand side of the slide, you can see that this also translates into enhanced anti-tumor activity in established gastric cancer models. Building on data shared in prior presentations on the platform demonstrating lack of systemic cytokine release, we also continue to characterize the safety profile of the platform. In pilot NHP studies, Clawdon 18.2 tritce-CoSTEM was well tolerated upon repeat dosing at 3 mgs per kig with mild changes in peripheral cytokines and no histopathological changes observed in the stomach where Clawdon is expressed. Taken together, we view these results as very encouraging, further validating the potential of the tritce-CoSTEM approach and supporting continued evaluation against additional tumor targets. The second tritce-CoSTEM presentation described the design and characterization of a DLL3 targeted tritce-CoSTEM molecule, again incorporating balanced CD3 and CD28 T cell activation to enhance cytotoxic T cell responses against DLL3 expressing tumor cells, beyond that achieved with benchmarked DLL3 CD3 bispecifics. As described in the presentation, molecule selection was achieved through a rigorous evaluation and functional screening of various formats, geometries, and paratope affinities, while also leveraging advances in the platform described in the Clawdon .2-based poster. This slide shows a subset of data from the poster. On the left, we show example in vitro toxicity results performed at low ET ratio, demonstrating favor activity of DLL3 tritce-CoSTEM relative to benchmark clinical stage DLL3 CD3 bispecifics such as AMG757 or Trilatumab and HPN328 from Harpoon. In additional experiments reported in the poster, we further demonstrated that the DLL3 tritce as by design improves T cell proliferation and survival, resulting in more sustained T cell cytotoxicity and re-challenge experiments relative to benchmark TCEs, while maintaining desired T cell engagement properties such as conditional binding to CD28 that requires co-engagement of CD3. Similar to our Clawdon 18.2 tritce, the novel geometry that prevents binding of the CD28 paratope in the absence of CD3 binding reduces the potential of cytokine release syndrome as tested using a predictive in vitro model through monitoring cytokine release. Finally, as shown in the right-hand side of the slide, in vivo studies using a high bar established small cell lung cancer humanized xenograft model comparing the DLL3 tritce to the AMG75 benchmark demonstrates tumor regression with the DLL3 tritce not observed with the benchmark control. Taken together, we feel both AACR posters describing the trispecific T cell engager platform illustrate our ability to engineer T cell engagers to supplement CD3 activation with CD28 co-stimulation to enhance T cell responses and anti-tumor activity, while maintaining a desired tolerability profile, paving potential opportunity to expand and enhance therapeutic responses in solid tumor patients beyond that achieved thus far with T cell engagers. Like 12, as you are no doubt aware, the appeal of incorporating CD28 co-stimulation into T cell engager strategies is also being pursued by others in the industry, as shown in gray on this slide. Highlighting the exciting potential of CD28 co-stimulation to augment T cell-based therapeutic strategies. DesignWorks approach highlighted in green however differentiates from these competitive approaches in several key features. First and foremost, we have designed tumor targeted T cell engagers that incorporate both CD3 and CD28 co-engagement in a single molecule, engineering balanced CD3 and CD20 activation to enable an optimal level of T cell activation through signal 1 and signal 2. This differs from companies developing CD28 bispecifics alone or in combination with either anti-PD1 or with CD3 bispecifics. While others have developed CD3 CD28 based trispecifics, in contrast to their approach, we have been very careful to engineer conditional CD28 binding and activation contingent on CD3 binding to offset the potential for T cell engagement and peripheral T cell activation. The Xani DataMaps advancement to regulatory review marks a significant milestone and validates our protein engineering expertise including the azometric platform, also a core component of our multi-specifics used in the next generation T cell engager ZW171 alongside our latest Tri-PCE co-stim candidates. Much like our design and optimization of Xani as a next generation anti-HER2 agent, we anticipate our protein engineering expertise and attention to design features of next generation T cell engagers will likewise provide enhancements in therapeutic benefits beyond the limits of first generation T cell engagers. And we look forward to nominating a Tri-PCE molecule at the end of this year as the final molecule of our 5x5 strategy.
spk17: From our ADC team,
spk18: we had three posters. For ZW191, our folate receptor alpha targeting antibody drug conjugate, we shared additional preclinical data that's demonstrating its differentiated profile relative to other folate receptor targeting ADCs, its strong anti-tumor activity across an expanded set of folate receptor alpha tumor indications, and its favorable tolerability and repeat dose non-human primate studies. On this slide, we highlight a few of these results. On the left, we demonstrate the relative internalization, payload delivery, and tumor spheroid penetration supported by ZW191 folate receptor alpha MAB compared to folate receptor alpha targeting antibodies incorporated in four other ADC programs. As you can see, ZW191 MAB in blue and dark blue demonstrated higher levels of internalization, spheroid penetration, and payload delivery compared to the MABs from Elahir, MoRAP202, Stroh002, and Pro1184. This observation is consistent with our decision to select the ZW191 MAB from a larger pool of folate receptor alpha antibodies based on its optimal ability to deliver payload through enhanced internalization and consistent with our care in factoring in all components of the ADC when designing our candidates. On the right hand side of the slide, we demonstrate ZW191 anti-tumor activity in a range of PDX models. Consistent with prior data, we saw greater total activity of 191 compared to MERV with ZW191 demonstrating activity in folate receptor high, medium, and low models of ovarian cancer. We also reported promising results in folate receptor alpha expressing non-small cell lung cancer, endometrial, and triple negative breast cancer models with representative examples of responses shown. Further, for ZW191, we disclosed updated data from our GLP TOCS studies, toxicology studies, supporting our IMD filing where we reported the highest non-severely toxic dose in non-human premix was 60 mgs per kick presenting a compelling profile for potentially efficacious dosing. Beyond the ZW191 poster, our ADC team also presented development of a novel tumor spheroid model system applicable to multiple cancer types to aid in the screening and characterization of ADCs that is more predictive of anti-tumor activity in vivo than traditional 2D cell line models. It also aids in the detection of ADC mechanism of action such as the tumor spheroid penetration data shown in the ZW191 presentation. Finally, we also shared progress made on the design and functional screening of high specific ADCs to identify those optimally formatted in the ZW191. We look forward to presenting more data from that technology in the future, including applications to additional tumor target pairs. In addition to today's updates, we anticipate further opportunities to showcase our progress for both our pre-clinical and clinical milestones at upcoming conferences in 2024, including the culmination of our final product candidate within our -by-five portfolio. Our commitment to innovation and mission to provide effective treatment options for patients remains at the heart of what we do at ZymeWorks. We're actively exploring alternative mechanisms of actions and harnessing new modalities to optimize efficacy while minimizing toxicity, ultimately with the aim of raising the bar for the standard of care, particularly in challenging to treat diseases. We're excited about the journey ahead and remain dedicated to advancing transformative therapies. Ken, back over to you. That's great. Thank you,
spk08: Paul. In summary, as mentioned earlier, we're very pleased with the BLA submission seeking accelerated approval for ZEN data map in second line BTC in the United States having been completed. And we continue to work very closely with our partners, JAZ and Beijing, to achieve key near-term milestones. We're encouraged by progress to date in 2024 and as excited as ever about the future of ZymeWorks. As we prepare to enter multiple phase one trials in the next coming 24 months, our commitment to advancing innovative solutions remains evident with more pre-clinical data for our early stage pipeline to be presented throughout 2024. Beyond that, we wish to further build upon and leverage the differentiated platform at ZymeWorks to generate continued long-term R&D productivity with the ability to expand our therapeutic focus and research scope beyond the current pipeline with potential for two new INDs annually from 2027 onward. Our cash runway remains on track to support the development of our 5x5 product pipeline and invest in our long-term R&D strategy called ADVANCE. While we approach milestones that may result in the further extension of this runway or allow us to expand our R&D scope, we remain diligent in efficiently managing our operating expenses as we continue to execute on the strategic clinical development plans for our assets. We look forward to reporting our continued progress against our key priorities during the remainder of 2024. With that, I'd like to thank everyone for listening to our call. I'd like to turn the call over to the operator now to begin the question and answer session. Operator?
spk02: Thank you. At this time, we will conduct the question and answer session. And as a reminder, to ask a question, you will need to press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, please press star 1-1 again. Please stand by while we compile
spk04: the Q&A roster.
spk02: Our
spk04: first
spk02: question comes from the line of Stephen Willey of Stifle. Your line is now open.
spk16: Yeah, good afternoon. Thanks for taking the questions. Maybe just a couple of questions for me. Ken and perhaps Paul, just curious as to your thoughts regarding Merck's disclosure of the OS benefit that was seen in keynote 811. I know that there was some suggestion that this could be the case per the interim analysis that we saw at ESMO back in October. But just wondering if you think that if this changes the longer-term competitive dynamic at all in frontline GEA and if that now kind of raises the bar for perhaps what the triplet arm needs to show in the Horizon Trial.
spk08: Yeah, thanks for the questions, Steve. I mean, obviously we don't know much more than what was put in the press release about the OS outcome. There's no actual data there, so it's hard for us to comment further about the strength of that data, the consistency across the patient population. Obviously the OS was determined on ITT as it needs to be across the population. Obviously the previous PFS result was not across the entire patient population, but only in the PL1 positive stratified part of that study. So until we see the actual data presented, until we understand what's on the label, it's difficult for us to evaluate your question about the attractiveness of that regimen versus our own. And I think for us and Jazz in Beijing, we're focused on completing the Horizon GA01 study, and we're more focused on seeing the results of our own combinations, Xani plus chemotherapy and Xani plus chemotherapy with TISLA and how that compares to our own active control arm. Traxin chemo in the patient population we're studying, which remember is different than the Keno 11 patient population just because of the inclusion of the esophageal adeno carcinoma patients. So I think we're more interested in finishing recruitment in our study, understanding the PFS results and continuing to follow the patients. And I think once we have more data available on our study and the other study, then it'll be probably a little bit easier to understand the competitive environment for everyone. Okay, I
spk16: guess that's fair. And then Jazz obviously has outlined plans to pursue registration in post and HER2 metastatic breast. And I think there was some KOL discussion on their call regarding the need for prospectively generated data in this patient population. But just curious, given that most KOLs think and HER2 is going to become frontline standard of care, I'm just kind of interested in your thoughts regarding the relevancy of this trial with respect to gaining utilization in the second line setting if indeed that HER2 upstream move into frontline occurs. And I guess from a relevancy perspective, I'm just questioning the thought, right, that one would need to assume that the Cleopatra regimen and Cat's Isle are kind of completely displaced and not repositioned as they're going to be.
spk08: And I think Jazz indicated on their call, they're going to talk more about that study design in the second half of this year when it's initiated, so I don't want to get ahead of that. I'll say from our own perspective, we obviously did a number of studies in different combinations in the metastatic breast cancer setting. And you can certainly see the potential for Zani in combination with other agents just because of its tolerability nature makes it a great combination with other agents as we're doing in GEA and as we'll seek to do in biliary tract cancer. So you can certainly see the potential for Zani to find a place in the treatment paradigm for metastatic breast cancer. And I know from the KOL work that we did when I got here before the Jazz transaction, there was certainly a need for something in a post and HER2 environment where patients may have got a response but then progressed. And I think there was some sense that maybe having a different mechanism than another ADC at that time frame might be something that might be attractive. So obviously looking at Zani being a unique bispecific antibody in the HER2 space surrounded by a wave of different ADC formats including TdxD might be a really attractive proposition provided you could find the clinical and regulatory pathway to that type of label. And I think we'll let Jazz describe their study in more detail when they initiated the second half this year to see if you can understand more of the clinical and regulatory pathway that they intend to pursue but from a commercial opportunity. It was evident to us that that was something that was very attractive. Obviously we just didn't have the capital to pursue that on our own. And one of the benefits of the Jazz transaction for us is that they do have the capital that they could put to work beyond what we could do on our own in attractive opportunities beyond ability to track cancer and GEA. And that's what they've announced they intend to do. And that's fantastic.
spk15: All right. Thanks for taking the questions.
spk02: All right. Thank you. One moment for our next question. Next question comes from the line of Yigal Nocemovitz of Citi. Your line is now open.
spk07: Hi guys. This is Ashok Mubarak on Vigal. Thanks for taking my questions. I just have one operational question and one scientific question. First on the sort of (?) thought process for moving on in 2017, including some regulatory milestones. I'm just kind of wondering if you could give us a little color on how much of that runway is being contributed to from potential Milestone payments. Are you able to break those out in more detail?
spk08: Yeah and not beyond the guidance we've previously given. And again not all of the from our current deals with Jazz and Beijing are included in that. So there's some element, but not all of it. I think we feel comfortable with our current financial position and current financial outlook that we can fund the R&D strategy that we have right now through the second half of 2027 in a number of different scenarios. So I think we feel we have a very strong financial position, a good outlook for the business, obviously a number of other biotechnology companies in our sector went and accessed additional equity capital through offerings, rate games in the first quarter of this year. We were not one of those, because I think we feel very confident in our current financial position and our runway and the outlook for the business and that's why we chose not to do so. But I can't go beyond the details we've previously provided until the milestones start to be received and then we'll obviously be in a position to announce those.
spk07: Okay, that's understandable. Maybe one more. On the TRITCE platform, which you shared ACR, I thought that was pretty interesting. I'm just curious if you could tell a little more about how you expect in the clinic the CRS profile might be differentiated compared to a more traditional CD3, bi-specific. I think you alluded to the idea that peripheral cytokines might be less, but I'm just curious if you think the improvement could be meaningful enough in something like CRS that there may be practical differences in terms of maybe less steroids or less step dosing or maybe potential to be in the outpatient setting versus continuous IV, et cetera. I'm just curious what you can comment from maybe a practical potential standpoint.
spk18: Yeah, sure, good question. Let me clarify that a little bit. So for the TRITCE, something that we were very careful of was actually the level of interaction with T cells that could trigger T cell activation. So we are using a lower affinity CD3, and the CD28 binding is actually quite weak, but upon a bit of binding through CD28, we get engagement of T cells when we co-engage with a tumor target. So the amount of binding, say, in the periphery is very low, only when we engage the target and then engage the T cells do we see this nice ability-powered CD28, CD3 activation. So that, we feel, is important as something we've also embedded in the ZW171 program, where we're using a lower affinity novel CD3 epitope that so far, when we've modeled that in preclinical studies, both in vitro and non-human primates, does not support the level of T cell activation we see with other CD3s. So that's kind of how far we can take it. Obviously, we'll need to see a lot of it, a lot of the T cell activation that you see in the clinic will also be driven by the target that you pair with the T cell engager. So that's also a factor that we consider. But overall, we've done what we think to engineer peripheral cytokine activation that's independent of tumor engagement.
spk07: Okay, okay, maybe the last question for me. I'm just curious, I mean, I think you said that the final program in the five by five will be one of these Tri-TCEs. I'm just wondering if it potentially might be the DLL3 or the CLAWDN 18.2 programs you kind of outlined, or could it be something else entirely?
spk08: Yeah, I mean, we obviously have a pretty broad program in both the Tri-TCE with the COSTEM, but also in the TCE with the TCE-1. We also have a couple other tri-specific formats that we've been working on in research so we haven't disclosed yet. I think we have published data pre-clinically around the CLAWDN 18.2 and DLL3 because those were good programs to work on to benchmark ourselves against other product formats and understand what that Tri-TCE COSTEM might give you that you don't see in another bicific antibody or an ADC or just a simple antibody approach. I think we will make a nomination of the candidate we want to move forward with as our fifth later this year, but I don't want to speculate as to whether it's one of the two that we published data on or something else that we still continue to work on as a part of our broad portfolio approach there. That's beyond those two and you just have to wait until we nominate it to see that and that will be this year.
spk02: John, thanks very much. Thank you. One moment for our next question. Our next question comes from the line of Akash Tewari of Jeffreys, your line is now open.
spk10: Hi, this is Phoebe Onforakash. Thank you for taking our question. So, profound bio was recently acquired by GenMab which is lead molecule, RINA-S, which is a folate receptor alpha targeting with a topo ADC that is ahead of time with encouraging initial human data. I guess, where do you think you can differentiate with DW-191 and what is your approach here that's different than RINA-S? Thank you.
spk08: Yeah, again, we don't know enough about that molecule, I think, to do a proper comparison and whether it's encouraging or not, I guess it was acquired, so it must be encouraging, but I don't know how to speculate on data that's publicly available versus public data that GenMab may have had available to it. So, I can really only comment on our own program and approach with DW-191, and I think that's reflected in data we previously published and also at AACR, where I think we think there's a lot of differentiation where we're doing around the payload. So, we did disclose earlier this year our proprietary payload 519, which was through a significant medicinal chemistry effort to find a payload that was a campus-based analog but proprietary to us and with properties that we believe are ideal to be used in an ADC. Including in the indication of interest in folate receptor alpha. I think from the standpoint of the antibody, we think we have made some innovations around how optimization of an antibody can make an ADC more effective, and obviously that was the purpose of one of our publications at AACR was to focus on not just binding, but internalization and tumor penetration as a way to get efficiency out of a payload with maybe less tolerability given up to get that activity. And so, we're really interested to put that to the test in clinical studies and it won't be too long from now, and I think then we'll understand the characteristics of our own molecule. We definitely have some differentiated features in there from any of the other folate receptor alpha ADCs, including the one you mentioned, but I'm more interested in looking at our own data to understand the activity that can be generated, find a dose, understand the tolerability of that agent, and then be able to understand where we can create clinical differentiation against a host of competitors, and it's just too difficult for us to try and make a comparison at this point between any of the other agents.
spk09: Okay, understood, thank you.
spk02: Thank you, one moment for our next question. Next question comes from the line of Brian Chang of JP Morgan, your line is now open.
spk14: Hi Ken and team, thanks for taking our questions today. We're seeing some excitement around the application of T cell engagers in the autoimmune space, like Scuriderma and Myosinogravus, just these recent weeks. Just curious if you have any interest or whether you have any potential ability to, whether you see any potential ability to disrupt that space with your TRITC platform?
spk08: Yes. No, thanks Brian, no, it's obviously, Zymrx has never been exclusively an oncology company, we have been working in autoimmune and inflammatory and dermatology indications for some time period. We just decided when I got here not to focus on it, because we wanted to have a focused R&D program for the 555, but we definitely have some platforms and capabilities and experience in that area, given things we work on, pre-clinically, and if you look at the folks who I've added since I got here, including Paul, we do have a number of folks who have some great experience in commercializing in the autoimmune and inflammatory space. So I think as we think about going beyond the five by five, we definitely have an interest in understanding if some of our platforms and assets can be really differentiated from what we see from others and be applicable to a patient population beyond oncology. And I think we haven't talked a lot about that, I think by the time we get to our R&D day in Q4 this year, you should probably expect that we'll outline some more thoughts around assets and approach and differentiation against others who are in that space. So the answer, yes.
spk14: Okay, great, and then maybe just a follow-up. On your prepare remarks, you talk about, you mentioned partnership, and I think, past partnership had always been a core part of your approach. We're about halfway through the year, so just curious if there's also a particular direction that you're looking at from a partnership standpoint, and then on top of that, are you looking for a partnership to kind of accelerate your development on autoimmune side, just any color they can provide will be super helpful.
spk08: Yeah, I think clearly partnership is a part of our strategy for a number of reasons. One is obviously access to capital, and it's no surprise that transactions in both ADCs and T-cell engagers have gotten to a much higher valuation at an earlier time point in development. We also look at partnerships and ability for us to accelerate and compete, and obviously with the acquisitions which have occurred over the past period of time in both ADCs and T-cell engagers, we find ourselves against larger and more formidable competitors, and with the potential for broad applications, especially in 191 and 171 going to the clinic first, in both mesothelin and foliar receptor alpha, those targets are of interest in a pretty broad patient population. I think we learned from Zany that there was a certain breadth of opportunity to Zany, which was probably beyond the reach of ourselves on our own, and completely the Jazz Partnership, as you see with their subsequent developments, may allow them to pursue that, where we couldn't do that on our own, and hopefully we structured that in a way that allows us to continue to share in a good portion of success for that, so that's a good learning for us to look at. But we've also been very clear with Zany being partnered exclusively with Jazz in Beijing that for our follow-on agents in five by five, we would like to have the ability and the opportunity to build a future late stage development and commercial opportunity for ourselves, and we've talked about it as a USXUS potential partnering strategy. There's other forums we could do, but we'd obviously like to, if we're fortunate, to find another agent in our five by five, which has the potential that Zany seems to have in a peak sales potential, which Jazz guided on, that we'd like to be able to keep some of that for ourselves and not look at a fully licensed strategy going forward. So obviously there's a substantial amount of interest, as you know, in innovative products in both ADCs and T-cell engagers, which gives us good optionality for potential partnerships and collaborations and the timing of those. But we also have a strong balance sheet, and talent pool in the company, which allows us to execute those five by five programs in the early clinical data without requiring partnerships or collaborations as a part of that. So I like the position we're in where we have optionality and not a requirement to partner. I think there is considerable interest in both of these, in both of these spaces, as well as how to immune. So I think we'll continue to consider interest and have discussions, but make sure we can meet the requirements we might have for future capital, folks to help us accelerate and compete against larger competitors, as well as retaining rights and commercial opportunities for ourselves. And until we find the right partnership, I'm unwilling to give up the optionality that we have by having a host of unencumbered assets, which are really interesting to us and are just going to clinical studies over the next 24 months for all five of
spk13: them. Great, thanks, Ken.
spk02: Thank you, one moment for our next question. Our next question comes from the line of John Miller of Evercore, your line is now open. Hey guys, thanks for taking the question.
spk06: I wanted to ask a question on the trispecific stuff that you presented, AACR. In particular, in addition to the reduced CRS or cytokine release, purple cytokine release that you already touched on, I also noticed was interested by improved T cell survival or it would look like improved characteristics of the stimulated T cells that are coming from those reduced affinity CD3C28 binders. Obviously, you have the spider plots in the day to day and those were up there at AACR, but do you have evidence that improving T cell health means that you get continued stimulation? I mean, that is to say, as you get in longer and longer in timeline, do you see the ability to generate stimulated T cells further on into treatment after continuous treatment than you would with a CD3 bispecific alone? If that question makes sense, did you buy more T cell activity by using these binders in terms of durability, not in terms of open C?
spk18: Yeah, sure enough, I'm glad you brought that up because I think that's an important point that what we're trying to do here is by having that CD28 co-stimulation, we're generating T cells that are more durable and don't become exhausted. And that they then provide enhanced anti-tumor activity. So it's a little, we've done some modeling of the sustainability of the response in vitro where we can do these kind of repeat challenges where we take the T cells and continue to re-stimulate them and we can see that under those conditions that we can maintain response for much longer if we challenge them with the trispecific, with the CD28 compared to the CD3. So that's consistent with what you would expect by having better T cells and that was described in the poster. And then when we've gone in vivo, what we have seen is we've reported this in some studies that we do see more T cell, we look at T cell infiltration in the tumors, we see evidence for that. But I think what was very clear in the one example I showed today was that we were seeing responses, tumor responses or anti-tumor responses with the Tritce platform that you don't see with the bispecific CD3. So that suggests to us that in the tumor macroenvironment, not only this enhanced durability and sustainability, we're seeing better activity and responses where you don't see responses without CD3 bispecifics, with CD3, you don't see it with CD3 bispecifics alone. So that tells us that we are indeed doing something in the tumor macroenvironment in an animal model, albeit that is supportive of our hypothesis and we then of course anticipate that that hopefully will translate in the clinic to better responses.
spk05: Now that makes sense.
spk06: I guess one more on a related topic. If, obviously the CD3 bispecifics are active drugs, they're used to great effect in many indications. Do you expect the sort of trispecific platform that you're talking about to be a fully generic improvement that is, is this gonna be better in every case? Or are there certain indications of tumor antigens where you would expect this to be, this sort of technique to be relatively most important or give you the relatively best benefit versus the CD3 bispecifics?
spk18: Yeah, that's another great question. I think we do anticipate that overall this should yield better responses. Even where CD3 bispecifics work, I don't wanna be too hypothetical, but I think when you think about a CAR T-space, without co-stimulation on those T-cells, the responses were not as generally as good without it. So you needed that co-stimulation. So there's a potential that we could have broader overall better response with this. And I think that's why other companies are pursuing CD28 co-stimulation as well. It's fundamental T-cell biology. But I think where we see, maybe the biggest need is in solid tumors where low T-cell infiltration or T-cells are already on energy, need a little bit more than just CD. That's where you could really see the greatest potential impact. And so that's part of the design feature and the thinking behind developing this type of technology.
spk06: Thanks,
spk04: X. Thanks so much. Thank you. One moment for our next question.
spk02: Next question comes from the line of Derek Artilla of Wells Fargo. The line is now open.
spk12: Hi, this is Yvonne for Derek. Thanks for taking our questions. A quick one from us. Can you share how the IND filing activities are progressing for 191 and 171? And when are we expecting, are you expecting to initiate the phase one studies? I'm just trying to understand, is this like a 2024 event for any of these molecules?
spk08: Thanks. Yeah, we previously got it. It was our intention to file INDs and commence first in human studies for both 171 and 191 this year. We haven't given any more guidance specifically to that. And I won't on the call today. I think once both of those studies are up on twin trials, which means we've initiated our first site, then we'd be happy then to talk more about the details of the study design and timing that's available on twin trials. I think once you see them up there, we'll be happy to publicly comment on them. But until then, we're on track. We're a little bit ahead of schedule where we might've been. And hopefully we can keep that a little bit ahead of our schedule and be discussing those in the near future. But until we have those publicly disclosed and initiated, we won't be talking about them further.
spk12: Okay,
spk04: thanks. All right, thank you. As a reminder,
spk02: to ask a question, you will need to press star one one on your telephone and wait for your name to be announced. Please stand by while we
spk04: wait for additional questions. Okay, one moment for our next question. Our next question comes from the line of John Miller of Evercore, please
spk06: go ahead. Hi, thanks for letting me hop in the queue again. One thing that you mentioned that, prepared remarks, I just wanted to get a little bit more color on. You mentioned that you expected that your phase ones would have mostly XUS, it'd be global studies, but mostly XUS patients. Obviously you're not commenting on the specifics of trial design, but you're talking about at this point, but I would love to hear you talk a little bit more about strategy on where you're running, where you anticipate running the studies and what the pushes and pulls are in terms of where you're getting your patients from.
spk08: Yeah, absolutely, I think we took a decision a while ago that we could go faster and potentially get a higher quality and more diverse set of patients, even from the very first dose escalation cohort, if we structure ourselves to be able to globally recruit patients. So you should see in our phase one studies, not just IMD filings, but foreign equivalents very quickly thereafter, so that we can get up a pretty global program, which encompasses sites in Europe, North America, and Asia pretty concurrently, so that we can recruit in all those jurisdictions, even from the early dose escalation cohorts. And I think that just allows us to go quickly, get high quality and diverse patients from the start. And more importantly, if we see data that looks pretty interesting and compelling, we can go further, faster, to follow those data signals in a broader phase one program, as we move from dose escalation to expansion cohorts, and eventually to combination cohorts, and eventually beyond phase one. So I think we've thought a lot about how we would execute this. I think we structured our groups internally and externally to be able to do this, and the hope is that we can go fast with high quality, diverse patients, so the data that comes out of that will come to us faster, and also in a way that allows us to interpret it in a more significant way. So we will have U.S. sites, but I would expect the majority of patients in both those studies in phase one, the vast majority, will be recruited outside the United States. And hopefully we structure ourselves and made those decisions to accomplish what we want, which is a faster phase one study and clearer data, and a more diverse data set by recruiting patients globally. So we'll have to see if we can do that, but that is the goal, and hopefully you'll see evidence of that pretty soon.
spk06: Thanks
spk02: so much. All right, thank you. There appear to be no further questions. I'd like to turn the conference back over to Ken for closing remarks.
spk08: No, thank you very much. And I really appreciate everyone taking time today to listen to our call and ask the questions. Hopefully we're able to answer them fully. If there's any follow-up questions, please don't hesitate to reach out to us. We're happy to address any questions or clarify. And even the call, hopefully you can see we're very excited about 2024. This is getting very interesting for us this year and next year, and we are all in on executing the plan in front of us in the best way possible, and look forward to reporting the results of that execution to you as we move forward through 2024. So thank you for everyone for listening today.
spk02: This concludes today's conference call. You may disconnect your lines. Thank you for participating, and have a pleasant day.
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