Q1 2024 Zymeworks Inc Earnings Call
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Operator: 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 Inamdar, Director of Investor Relations. Shrinal, please go ahead.
Speaker Change: Thank you for standing by this is the conference operator.
Speaker Change: Welcome to Xyrem works first quarter 2024 results conference call and webcast.
Speaker Change: 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.
Speaker Change: To withdraw your question. Please press star one again.
Speaker Change: I would now like to turn the conference over to sure know and up.
Sure Know: And upped our director of Investor Relations. Please go ahead.
Shrinal Inamdar: 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. These forward-looking statements are based on 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.
Speaker Change: Thank you Felicia.
Speaker Change: Good afternoon, I'd like to welcome you to our first quarter <unk> results conference call.
Speaker Change: Before we begin I'd like to remind you that we'll be making a number forward looking statements. During this call, including without limitation. Those forward looking statements identified an outsized and the accompanying all commentary.
Speaker Change: 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 our stage of development.
Shrinal Inamdar: For a discussion of these risks and uncertainties, we refer you to our latest SEC filings, as found on our website and in the SEC. In a moment, I'll hand the call over to Ken Galbraith, our Chairman and Chief Executive Officer. We'll be discussing recent corporate updates along with our financial results for the first quarter of 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.
Speaker Change: For discussion of these risks and uncertainties, we'll refer you to our latest SEC filings I found on our website and I spoke with the SEC.
Shrinal Inamdar: At the end of the call, Ken, Paul, and Bijal Desai from 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 Zymeworks website later today. I'll now turn the call over to Ken.
Speaker Change: In a moment I'll hand, the call over to Ken Galbraith, Our chair and Chief Executive Officer will be discussing recent corporate updates along with our financial results for the first quarter switched to digital ordering.
Kenneth H. Galbraith: Let's jump to promo our chief Scientific Officer will talk about recent data showed that eat.
Kenneth H. Galbraith: The annual American Association for cancer research or ACR meeting and key takeaways.
Speaker Change: And it's a cool tent pole M P J Desai.
Speaker Change: Finally, the trustee will be available for Q&A.
Speaker Change: As a reminder, the audio and slides from this call will also be available.
Speaker Change: Today.
Speaker Change: I'll now turn the call over to Ken.
Kenneth H. Galbraith: Thank you, Shrinal, 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 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 the session.
Kenneth H. Galbraith: Thank you Shannon and thanks, everyone for joining us today on our first quarter.
Kenneth H. Galbraith: Earnings call with that I'll begin today's update with an overview of key achievements from our development program as well.
Kenneth H. Galbraith: Well as our financial results.
Kenneth H. Galbraith: I'm 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 with showcase the capabilities and internal expertise, we have in screening and optimizing our cabinet as presented at ACR, which Paul will speak to later in this call.
Kenneth H. Galbraith: Beyond that, we've also made progress on the clinical development readiness of our teams, including conducting steering committee meetings at various regulatory agency consultations to fine-tune our clinical strategy for our two upcoming Investigational 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.
Kenneth H. Galbraith: We've also made progress on the clinical development readiness of our teams, including conducting steering committee meetings with various regulatory agency consultation.
Kenneth H. Galbraith: Thank you and our clinical strategy for our two upcoming investigational, new drug applications or R&D and foreign equivalents coming up this year.
Kenneth H. Galbraith: We've also been expanding our presence in key locations to carry out a broad phase one clinical trial for a rabbit in North America, Europe and Asia Pacific.
Kenneth H. Galbraith: But the majority of our patients.
Kenneth H. Galbraith: Phase one studies expected to be recruited outside the United States.
Kenneth H. Galbraith: 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 I study. To support this continued growth, we've brought in Dr. Neal Gallagher to join our Experience Board. His experience and leadership in leading multiple development programs through 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 complementary guidance along with the new and longer-serving members of our board.
Kenneth H. Galbraith: Look forward to talking more about our plans in the near future. When we posted our respective study protocol publicly on the clinical trials website and are actively recruiting in the dose escalation stage of our phase one studies.
Kenneth H. Galbraith: To support this continued growth we brought in Dr. Neil Gallagher to joining our experienced board his experience and leadership in leading multiple development programs through the global regulatory approval will support our efforts to rapidly advance our pod by pod program into clinical studies and our continued pipeline expansion of novel antibody drug conjugate in Multistem.
Kenneth H. Galbraith: <unk> antibodies in the year that Dr.
Kenneth H. Galbraith: Dr. Gallagher is in very good company will provide complementary guidance, along with the new and longer serving members of our board.
Kenneth H. Galbraith: I'm very confident that these advances, coupled with R&D reprioritizations 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 asset, we're very pleased that Jazz has completed its BLA submission seeking accelerated approval for xenodatamab in second-line biliary tract cancers, or BTC, in the United States as monotherapy.
Kenneth H. Galbraith: I'm very confident that these advances coupled with R&D re prioritization and some difficult but necessary personnel decisions over the past two years will position us for success as we approach a pivotal milestone for <unk> this year.
Kenneth H. Galbraith: But focusing our resources and energy on our most advanced and highest potential clinical value drivers.
Kenneth H. Galbraith: On our later stage asset we're very pleased that jazz has completed its BLA submission seeking accelerated approval presented data map in second line biliary tract cancers or PTC.
Kenneth H. Galbraith: Yesterday, JAS also announced that their plans to submit a Marketing Authorization Application, or MMA, to the European Medicines Association presented in a map are proceeding. Similarly, Beijing is expecting to submit their BLA for Xanadata to the National Medical Products Administration in China during the second half of this year.
Kenneth H. Galbraith: On the face of monotherapy.
Kenneth H. Galbraith: Yesterday's jazz also guided that there they their plans to submit a marketing authorization application or MAA.
Kenneth H. Galbraith: To the European Medicines Association presented data map are proceeding.
Kenneth H. Galbraith: Similarly, Beijing is expecting to submit their BLA presented data map with the National Medical products administration in China during the second half of this year.
Kenneth H. Galbraith: JAS has also initiated a Phase III confirmatory trial for Zantdatumab as first-line treatment in VTC in combination with the current standard of care, and enrollment for this trial is ongoing. JAS has also noted that they expect to present updated data with longer follow-up, including overall survival findings, from the Phase 2b Horizon BPC-01 trial at the 2024 ASCO annual meeting. Additionally, Jazz is targeting the top-line PFS data readout from the pivotal phase 3 trial for that data map in first-line gastroesophageal adenocarcinoma, or GEA, in late 2024.
Kenneth H. Galbraith: <unk> also initiated a phase III confirmatory trial presented data map as first line treatment of BTC in combination with the current standard of care and enrollment for this trial is ongoing.
Kenneth H. Galbraith: Jeff has also noted that they expect to present updated data with longer follow up including overall survival findings from the phase <unk> horizon.
Kenneth H. Galbraith: One trial at the 2024 after the annual meeting.
Kenneth H. Galbraith: Additionally, jazz is targeting the top line PFS data readout from the pivotal phase III trial presented data map in first line gastroesophageal adenocarcinoma or gea in late 2024.
Kenneth H. Galbraith: Furthermore, JAS announced they expect to initiate a phase 3 trial anticipated for the second half of 2024, present a data map, and then HER2-experienced patients with HER2-positive breast cancer. We sincerely appreciate the progress achieved and commitment shown by our partners, JASC and Beijing, in leading XenodataMap towards commercialization, initially in BTC, and then with additional clinical development investment for potential label expansion, including in GEA and Zymeworks net loss for the three months ended March 31st, 2024, was $31.7 million, or $0.42 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.
Kenneth H. Galbraith: Furthermore, jazz announced they expect to initiate a phase III trial anticipated for the second half of 2024 presented data map in and hurt too experienced patients with her two positive breast cancer.
Kenneth H. Galbraith: We sincerely appreciate the progress achieved and commitment shown by our partners jazz and Beijing, and leaving US on data map towards commercialization initially in DTC and then with additional clinical development investment for potential label expansion, including <unk> and metastatic breast cancer.
Kenneth H. Galbraith: As reported, our revenue for the three months ended March 31, 2024 was $10 million compared to $35.6 million for the same period in 2023. Revenue for the three months ended March 31, 2024 included $9.9 million for development support and drug supply revenue from JASD 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 direct supply payments from Jazz, and $1.2 million from our partners for research support and other payments.
Kenneth H. Galbraith: Turning now for our financial position. This afternoon <unk> reported financial results for the first quarter of 2024 <unk> net loss for the three months ended March 31, 2024 was $31 7 million or.
Kenneth H. Galbraith: <unk> 42 loss per diluted share compared to a net loss of $24 4 million for the same period in 2023.
Kenneth H. Galbraith: 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.
Kenneth H. Galbraith: As reported our revenue for the three months ended March 31, 2024 was $10 million compared to $35 $6 million for the same period in 2023.
Kenneth H. Galbraith: Revenue for the three months ended March 31, 2024 included $9 $9 million for development supporting drug supply revenue from jazz and <unk> $2 million from our partners for research support and other payments.
Kenneth H. Galbraith: Revenue for the same period in 2023 included $34 $4 million in revenue for development support and drug supply to having some jobs and $1 2 million from our partners for research support and other payments.
Kenneth H. Galbraith: The decrease in revenue from JAS was the result of a transfer of responsibility for certain clinical trials regarding xenodatamab to JAS under our transfer agreement and amended collaboration agreement with JAS. Overall operating expenses were $47.8 million for the three months ended March 31, 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 expenses, as well as a decrease in general and administrative expenses.
Kenneth H. Galbraith: The decrease in revenue from jazz was the result of a transfer of responsibility for certain clinical trials regarding sending them out to jazz for our transfer agreement and amended collaboration agreement with jazz.
Kenneth H. Galbraith: Overall operating expenses were $47 8 million for the three months ended March 31, 2024 compared to $62 $9 million.
Kenneth H. Galbraith: Same period in 2023, representing a decrease of 24% year over year.
Kenneth H. Galbraith: 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.
Kenneth H. Galbraith: The decrease in R&D expenses was primarily due to a decrease in expenses for ZENI-DataMap as a result of a transfer responsibility for the program to JAZ under 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 expenses was primarily due to a decrease in expenses related to external legal spending and insurance expenses compared to the same period in 2022.
Kenneth H. Galbraith: The decrease in R&D expense was primarily due to a decrease in expenses presented data map as a result of a transfer responsibility for the program to jazz for our transfer agreement and amended collaboration agreement.
Kenneth H. Galbraith: 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 candidate GW 171, that'd be 191, and TWD 220.
Kenneth H. Galbraith: 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.
Kenneth H. Galbraith: The decrease in general administrative expense was primarily due to a decrease in expenses.
Kenneth H. Galbraith: External legal spending and insurance expenses.
Kenneth H. Galbraith: Compared to the same period in 2023.
Kenneth H. Galbraith: As of April 30, 2024, we have approximately 70.7 million shares of common stock outstanding and approximately 5.1 million shares of common stock issuable under pre-funded warranty. As of March 31, 2024, we had $420.5 million of cash resources, consisting of cash, cash equivalents, and marketable securities as compared to $456.3 million as of December 31, 2023. Based on our current operating plans, we expect our existing cash resources as of March 31st, 2024, when combined with receipt of certain anticipated regulatory milestone payments, will enable us to fund planned operations into the second half of 2026.
Kenneth H. Galbraith: As of April 32024, we had approximately 77 million shares of common stock outstanding and approximately five 1 million shares of common stock issuable under pre funded warrants.
Kenneth H. Galbraith: As of March 31, 2024, we had 425 million of cash resources, consisting of cash cash equivalence and marketable securities as compared to $456 3 million as of December 31, 2023.
Kenneth H. Galbraith: Based on current operating plans, we expect our existing cash resources as of March 31, 2024, when combined with the speed of certain anticipated regulatory milestone payments will enable us to fund planned operations into the second half of 2027.
Kenneth H. Galbraith: For additional details on our quarterly and year-end results, I encourage you to review our earnings release and other SEC filings, which are available on our website at www.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 filed an automatic shelf registration statement today to take advantage of our new, well-known seasonal issuer or
Kenneth H. Galbraith: For additional details on our quarterly and year end results I encourage you to review our earnings release and other SEC filings are available on our website at www Dot <unk> dot.
Kenneth H. Galbraith: Stock comp 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 seasoned issuer or whats the status there.
Kenneth H. Galbraith: 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 registry.
Kenneth H. Galbraith: <unk> shelf registration statement like our existing our ATM equity program and 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.
Kenneth H. Galbraith: Further financial housekeeping you may see some further upcoming filings with the SEC to bring our existing prospective supplement filings regarding our exchangeable shares on our ATM program under our new with the automatic shelf registration statement.
Kenneth H. Galbraith: Turning to slide 7, our strategy of refocusing the business and building a diverse clinical stage product pipeline of antibody drug conjugates and multi-specific antibody 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 31, 2024, together with certain anticipated regulatory milestone payments, gives us an expected runway into the second half of 2027.
Kenneth H. Galbraith: Turning to slide seven our strategy of refocusing the business and building a diverse clinical stage product pipeline of antibody drug conjugates and multi specific antibody 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.
Kenneth H. Galbraith: The development and commercialization.
Kenneth H. Galbraith: Our strong financial position of $420 million in cash resources as of March 31st 2024.
Kenneth H. Galbraith: Got them, a certain anticipated regulatory milestone payments gives us unexpected runway into the second half of 2027.
Kenneth H. Galbraith: 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, such as 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 as a data map and tiered royalties between 10% and 20% on Jazz's annual net sales and between 10% and 19.5% on Beijing's.
Kenneth H. Galbraith: 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 partnership with jazz in Beijing, or new partnerships and collaborations, which we may choose to form.
Kenneth H. Galbraith: In addition, pending regulatory approval, we are eligible to receive commercial milestone payments based on annual sales is going to do the math and tiered royalties between 10 and 20% on Jazzes annual net sales and between 10 and 19, 5% on beans.
Kenneth H. Galbraith: 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-civic antibody therapeutics.
Paul Moore: With that I'd like to hand over to our Chief Scientific Officer, Dr. Paul.
Paul Moore: We'll talk more about the really interesting work our team presented at ACR on our Adcs multi specific antibody therapeutics over to you Paul.
Paul Moore: Thanks, Ken. As you said, we were pleased 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. Posters presented on our multi-specific antibody therapeutics focused on our tri-TCE co-stim platform. Next Generation Tri-Specific T-Cell Engager with Integrated CD28 Co-Stimulator We presented data on the platform itself and in the context of two tumor targeting ads,highlighting enhanced mechanistic and anti-tumor activity compared to clinical benchmark CDC bi-specifics. Targeting the same anti-tumor activity.
Paul: Thanks, Ken.
Paul Moore: We were pleased to be able to showcase some of these capabilities at ACR.
Paul: <unk> insight since both of these technologies can be applied to the screening and optimization of our preclinical development candidates keeping a specific targets and patient populations in mind with the aim of Derisking clinical development efforts.
Paul: Posters presented at our multi specific antibody therapeutics focused on our <unk> platform and next generation try specific T cell engage with integrated CD 20 equally stimulation.
Paul: We presented data on the platform itself.
Paul: In the context of a true tumor targeting outages, highlighting enhance mechanistic and anti tumor activity compared to clinical benchmark CDP bi specifics targeting the same package.
Paul Moore: By providing balanced activation of both signal 1 through CD3 and signal 2 through CD28 in a single molecule, tri-TC co-stem molecules have the potential to induce more sustainable T-cell responses in the tumor microenvironment beyond that achievable with conventional biospecific 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 Slide 10 summarizes the first Tri-PC Ecostim presentation, which utilizes Clogin 18.2 as a model tumor target. And it focused on the various design features optimized through protein engineering and repeated functional screening to enable certain key functional properties desired in the platform.
Paul: Yes.
Paul: By providing balanced activation signal one through CD three <unk>.
Paul: As signaled to us through CD 28 in a single molecule <unk> Costa molecules have the potential to ingest more sustainable T cell responses in the tumor microenvironment.
Paul: And that achievable with conventional bi specific T cell engagements.
Paul: It only engage C D three for CD 28 alone.
Paul: Providing a potential therapeutic modality to treat solid tumors with <unk> T cell infiltration T. A pure T cell function.
Paul: Our underserved by existing immune based therapies.
Paul: On slide 10.
Paul: Summarizes the first tried PC ecosystem presentation, which utilizes clothing 18.2 of the model tumor target.
Paul: And it focused on the various design features optimized through protein engineering and reiterate a functional screening to enable certain key functional properties desired in the platform.
Paul Moore: This includes conditional binding of CD28 contingent on CDC 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 Clodin 18.2, the simultaneous engagement of Clodin 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.
Paul: This includes conditional banning of CD 28 contingent on C. D C binding.
Paul: It says T cell binding of CD 28, CD three with new T cell cross linking between CD three CD 28 on separate T cells.
Paul: And with T cell activation continued contingent upon tumor antigen engagement.
Paul: And the presence of tumor cells expressing coordinating point to the simultaneous engagement with coordinating two on tumor cells with fuel CD three CD 20, co engagement of T cells with <unk>.
Paul: Dissipated the yields higher functioning T cells capable capable of driving more durable T cell responses, culminating in sustained antitumor activity.
Paul Moore: As shown on 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-clawed 18.2-tri-TCE molecule relative to the clinical stage benchmark. From Cloth Prom, I'm James, and that's about it.
Paul: As shown in the last we tested this hypothesis and in in vitro cereal repeat challenge I see with results demonstrating superior T cell liability T cell proliferation and tube ourselves set of toxicity over time with the lead Claude and 18th to try TCE molecule relative to clinical stage bank benchmark.
Paul: Bi specifics.
Paul: From Amgen.
Paul Moore: 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, Clodin 18.2-tri-TCE-CoSTIM was well tolerated upon repeat dosing at 3 mg per kg, with mild changes in peripheral cytokines and no histopathological changes observed in the stomach where Clodin was expressed.
James: I'm James and Astellas.
James: On the right hand side of the slide you can see that this also translates into enhanced antitumor activity and establish gastric cancer models.
Paul: Building on data shared in prior presentations on the platform demonstrating lack of systemic cytokine beliefs. We also continue to characterize the safety profile of the platform.
Paul: Pilot and HP studies clothing, 18.25, TCE <unk> was well tolerated upon repeat dosing at three mix per kg.
Paul: Changes in peripheral cytokines and lowest pathological changes observed in the stomach record with express.
Paul Moore: Taken together, we view these results as very encouraging, further validating the potential of the Tri-PCE Co-STEM approach and supporting continued evaluation against additional tumor targets. This is the second Phi TCE co-STEM presentation describing the design and characterization of a DLL-3-targeted tri-TCE co-stimulus. 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 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 CLAUDIN18-2-based This slide shows a subset of data from the post.
Paul: Taken together, we view these results as very encouraging further validating the potential of the <unk> approach and are supporting continued evaluation against additional tumor targets.
Paul: The second criteria equally stem presentation.
Paul: Describe the design and characterization of I D O L. Three targeted try TCE coaster molecule again, incorporating balanced <unk> and CD 28 T cell activation.
Paul: The enhanced cytotoxic T cell responses against DLL, three expressing tumor cells beyond that achieved with benchmark DLL three CVT bi specifics.
Paul: As described in the presentation molecule selection was achieved through a rigorous evaluation and functional screening of various formats geometries and power tool affinities.
Paul: Also leveraging advances in that platform described into Claude <unk> two based poster.
Paul: This slide shows a subset of data from the poster.
Paul Moore: On the left, we show example in vitro cytotoxicity results performed at a low ET ratio, demonstrating favorable activity of DLL3 tri-TCEcostin relative to benchmark clinical stage. DLL3 CD3 bi-specifics such as AMG757 or Teladamab and HPN328 from Harpoon. In additional experiments reported in the poster, we further demonstrated that DLL3 tri-TCE, as by design, improves T-cell proliferation and survival, resulting in more sustained T-cell cytotoxicity in re-challenged experiments relative to benchmark TCE, while maintaining desired T cell engagement properties such as conditional binding to CD2080 that requires co-engagement of CEDs.
Paul: On the left we show example in vitro cytotoxicity results performed at low <unk> ratio demonstrating favorable activity.
Paul: L L III <unk> ecosystem relative to benchmark clinical stage.
Paul: DLL three CDP bi specifics such as AMG 757 or to a lot of them out at H P. M <unk> from Harpoon.
Paul: And additional experiments reported in the poster we further demonstrated the DLP DLL three TCE by.
Paul: By design improves T cell proliferation, and survival, resulting in a more sustained T cell cytotoxicity and re challenge experiments relative to benchmark Tcs.
Paul: While maintaining desire T cell engagement properties, such as conditional binding to <unk> 28.
Paul: It requires co engagement with CD three.
Paul Moore: Similar to our Claudin 18.2 tri-TCE, the novel geometry that prevents binding of the CD28 pyrotope 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 on the right-hand side of the slide, in vivo studies using a high-bar established small-cell lung cancer humanized x
Paul: Similar to our Claude and $18 two <unk> the novel geometry that prevent spending of the CD 28 power took in the absence of CDP binding reduces the potential of cytokine release syndrome is tested using a predictive in vitro model.
Paul: Monitoring cytokine release.
Paul: Finally, as shown on the right hand side of the slide in vivo studies using a high bar established small cell lung cancer Humanized geographic model.
Paul Moore: Comparing the DLL3-Tri-TCE to the AMG75 benchmark demonstrates tumor regression with the DLL3-Tri-TCE not observed with the AMG75 benchmark. 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 opportunities to expand and enhance therapeutic responses in solid tumor patients beyond that achieved thus far with T cell engagement.
Paul: Impairing the TLLP <unk> two to <unk> 75, benchmark demonstrated demonstrates tumor regression with the deal with <unk>, notably the benchmark control.
Paul: Taken together, we feel both ACR posters, describing the tri specific T cell engaging platform.
Paul: Illustrates our ability to engineer T cell engages the supplement CD three activation with CD 20, co stimulation to enhance T cell responses and anti tumor activity, while maintaining a desire tolerability profile, leaving potential opportunity to expand in the therapeutic responses in solid tumors.
Paul: Patients beyond that achieved thus far with T cell engagements.
Paul Moore: 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 grey on this slide, highlighting the exciting potential of CD28 co-stimulation to augment T-cell-based therapeutic strategies. The Zymeworks approach, highlighted in green, however, differentiates from these competitor 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 CD28 activation to enable an optimal level of T-cell activation through signal 1 and signal 2. This differs from companies developing CD28.
Paul: Slide 12.
Paul: You are no doubt aware the appeal of incorporating CD <unk> equal stimulation enter T cell engage your strategies is also being pursued by others in the industry.
Paul: In Green on this slide highlighting the exciting potential of CD 20, Ecu stimulation to augment T cell based therapeutic strategies.
Paul: Design works approach highlighted in green ever differentiates from these competitive approaches in several key features.
Paul: First and foremost we are designing tumor targeted T cell engaging corporate booth CD three on CD 28 co engagement in a single molecule engineering balance CDP and CD 20 activation to enable an optimal level of T cell activation through signal, one and signal two.
Paul: This differs from companies developing CD 28.
Paul Moore: Bi-specifics alone or in combination with either anti-PD-1 or with CDC bi-specifics. 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 ZanaDataMap's advancement to regulatory review marks a significant milestone and validates our protein engineering expertise, including the azimetric platform, also a core component of our multi-specifics used in the next generation T cell engager.
Paul: Specifics alloy orange.
Paul: Or in combination with either anti PD, one or with CDC bi specifics.
Paul: But all the others have developed <unk> III CD 20 based Tri specifics in contrast to their approach we have been very careful to engineered conditional CD 28 binding and activation contingent with CDC Bailey to offset the potential for T cell T cell engagement and peripheral T cell activation.
Paul: Is that a deed of mobs that science into regulatory review marks a significant milestone and validates our protein engineering expertise, including the metric platform also a core component of our multi specifics user.
Paul: And the next generation T cell engagement.
Paul Moore: W171, alongside our latest Tri-PCE Kostom candidates. Much like our design and optimization of ZANI 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 and therapeutic benefits beyond the limits of first-generation T-cell engagement. And we look forward to nominating a Tri-TCE molecule at the end of this year as the final molecule of our 5x5 strategy. On our ADC team, we had three posters.
Paul: W 171, alongside our latest <unk> candidates.
Paul: Much like our design and optimization of Zandi as a next generation anti <unk>, we anticipate our protein engineering expertise and attention design features of next generation T cell engages.
Paul: Likewise provide enhancements and therapeutic.
Paul: Benefits beyond the limits of first generation T cell engages.
Paul: And we look forward to nominating <unk> molecule at the end of this year with the final molecule over 505 strategy.
Paul: From a <unk> ADC team, we had three posters.
Paul Moore: For ZW191, our folate receptor alpha-targeting antibody drug conjugate, we shared additional preclinical data demonstrating strong anti-tumor activity across an expanded set of folate receptor alpha tumor indications and its favorable tolerability in repeat-dose NH 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 Foliar Receptor Alpha MAV compared to Foliar Receptor Alpha-Targeting Antibodies Incorporated for other ADC programs. As you can see, ZW191 is marked in blue.
Paul: For CDW 191 are fully receptor alpha targeting antibody drug conjugate.
Paul: Shared additional preclinical data demonstrating.
Paul: Its differentiated profile relative to other fully receptor targeting adcs.
Paul: With strong anti tumor activity across an expanded set of fully receptor alpha tumor indications.
Paul: And its favorable tolerability and repeat dose.
Paul: Non human Primate studies.
Paul: On this slide but highlight a few of these results.
Paul: On the left we demonstrate the relative internalization payload deliberate in tumor spheroid penetration supported by <unk>.
Paul: <unk> <unk> hundred 90, folate receptor alpha mob compared to fully receptor alpha targeting antibodies incorporating for other ADC programs.
Paul: As you can see.
Paul: GW 191 mob in Blue.
Paul Moore: Demonstrated higher levels of internalization, spheric penetration, and paleodural delivery compared to the MABS from ELA-HEAR, MORAB-202, STRO-002, and PRO-1184. This observation is consistent with our decision to select ZW191 from a larger pool of polar receptor alpha antibodies based on its optimal ability to deliver payload through enhanced internalization. I'm consistent with our care and factoring in all components of the ADC when designing our candidates.
Paul: In dark blue.
Paul: <unk> demonstrated higher levels of internalization Sperry penetration appeal of deliberate compared to the mobs from Ella here, we're up to a two <unk> improved 11 84.
Paul: This observation is consistent consistent with our decision to select <unk>.
Paul: The GW one named one mile from a larger pool of fully receptor alpha antibodies.
Paul: As soon as the optimal ability to deliver payloads enhancement capitalization.
Paul: Consistent with our care and factoring in all components of the ADC when designing our candidates.
Paul Moore: 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 MIRV with ZW191. 191 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.
Paul: On the right hand side of the slate, which demonstrate.
Paul: GW wondering one antitumor activity in a range of pdx models.
Paul: Consistent with prior data, we saw greater total activity of 191 compared to <unk>.
Paul: With Z W.
Paul: One demonstrating activity in folate receptor alpha high medium and more models of ovarian cancer.
Paul: We also reported promising results in fully receptor alpha expressing non small cell lung cancer, endometrial and triple negative breast cancer models with representative examples what responses Shirley.
Paul Moore: 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 pregnant animals was 60 mg per kg, presenting a compelling profile for potentially efficacious dosing. Beyond the ZW191 poster, our ADC team also presented the development of a novel tumor spheroid model system applicable to multiple cancer types to aid in the screening characterization of our ADC molecules, including topo-based ADCs, that are more predictive of anti-tumor activity in vivo than traditional 2D cell-like models.
Paul: Further for GW, one day, one we disclosed up.
Paul: Data from our GOP Tox studies toxicology studies supporting the <unk> filing.
Paul: We reported the highest non severely toxic dose in non human premise was 60 megs per keg, presenting a compelling profile for potentially efficacious dosing.
Paul: Beyond the GW 191 poster or ADC team also presented development of a novel tumor spheroid model system applicable to multiple cancer types to aid in the screening characterization of our ADC molecules, including <unk> based adcs that is more predictive of antitumor activity.
Paul: Vivo than traditional <unk> selling models and also aid in the detection of ADC mechanism of action such as a tumor spirit penetration data as shown in the CW <unk> presentation.
Paul Moore: It also aids in the detection of ADC mechanisms of action, such as the tumor spheroid penetration data shown in the ZW191 presentation. Finally, we also share progress made on the design and functional screening of high-specific ADCs to identify those optimally formatted in affinity valency design to overcome challenges associated with tumor target 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.
Paul: Finally, we also shared progress made on the design and functional screening apply specific adcs to identify those optimally formatted and affinity balancing designed to overcome challenges associated with tumor target heterogeneity associated with targeting a single tumor antigen and we look forward to presenting more data from that novel technology in the future.
Paul: Including applications to additional tumor target peers.
Paul Moore: 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 5x5 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 action 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 therapy. Ken, I'll give it back to you.
Paul: In addition to today's updates we anticipate further opportunities to showcase our progress from for both our preclinical and clinical milestones at upcoming Congresses.
Paul: 2024, including the nomination of our final product candidate within a five by five portfolio.
Paul: Our commitment to innovation and mission to provide effective treatment options for patients remains at the heart of what we do at <unk>.
Paul: Actively exploring alternative mechanisms of actions and harnessing new modalities to optimize efficacy while minimizing toxicity.
Paul: Limited with the aim of raising the bar for the standard of care, particularly in challenging to treat diseases.
Paul: We're excited about the journey ahead and remain dedicated to advancing transformative therapies.
Kenneth H. Galbraith: That's great. Thank you, Paul.
Paul: Ken back over to you.
Kenneth H. Galbraith: That's great. Thank you Paul.
Kenneth H. Galbraith: In summary, as mentioned earlier, we're very pleased with the BLA submission seeking accelerated approval for <unk> data map in second line DTC in the nine states, having been completed and we continue to work very closely with our partner CASM Beijing to achieve key near term milestones.
Kenneth H. Galbraith: In summary, as mentioned earlier, we're very pleased with the BLA submission seeking accelerated approval for SendDataMap in second-line B2C in the United States having been completed, and we continue to work very closely with our partners, Jazz and Beijing, to achieve key NERC 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 I 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.
Kenneth H. Galbraith: First by our progress to date in 2024 and as excited as ever about the future as <unk> as we prepare to enter multiple phase one trials next coming 24 months, our commitment to advancing innovative solutions remains evident with more preclinical data for our early stage pipeline that presented throughout 2024 beyond that we wish to further build upon and leverage that.
Kenneth H. Galbraith: Beyond that, we wish to further build upon and leverage the differentiated platform of 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 R&Ds annually from 2027 onwards. Our cash runway remains on track to support the development of our 555 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 apps. We look forward to reporting our continued progress against our key priorities during the remainder of 2024.
Kenneth H. Galbraith: <unk> platform, it's IMAX to generate continued long term R&D productivity with the ability to expand our therapeutic focused research go beyond the current pipeline with the potential for two new <unk> annually from 2027 onward.
Kenneth H. Galbraith: Our cash runway remains on track to support the development of our 505 product pipeline and invest in our long term R&D strategy called advance.
Kenneth H. Galbraith: We approach milestones that May result in a further extension of this runway or allow us to expand our R&D scale, we remain diligent in efficiently managing our operating expenses as we continued 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.
Kenneth H. Galbraith: 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? Thank you. At this time, we will
Speaker Change: 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.
Operator: 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 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Please stand by while we compile the Q&A list. Our first question comes from the line of Stephen Willey of Stifle. Your line is now open.
Speaker Change: Thank you at this time, we will conduct a question and answer session and as a reminder to ask a question you will need to press star one on your telephone and wait for your name to be announced.
Speaker Change: To withdraw your question. Please press star one again.
Operator: Standby, while we compile the Q&A roster.
Speaker Change: Okay.
Paul: Our first question comes from the line of Stephen Willey of Stifel. Your line is now open.
Stephen Douglas Willey: Yeah, good afternoon. Thanks for taking the questions. Maybe they're just a couple of zany questions for me.
Stephen Douglas Willey: Yeah. Good afternoon, thanks for taking the questions.
Stephen Douglas Willey: 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, you know, some suggestion that this could be the case per the interim analysis that we saw at ESMO back in October. But just wondering if this changes the longer term competitive dynamic at all in frontline GEA. That now kind of raises the bar for perhaps what the triplet arm needs to show on the horizon.
Stephen Douglas Willey: Maybe just a couple of has any questions for me so.
Stephen Douglas Willey: Ken and perhaps Paul just curious as to your thoughts regarding merck's disclosure.
Stephen Douglas Willey: Benefit that was seen in keynote 811.
Stephen Douglas Willey: I know that there was some.
Speaker Change: Some suggestion that this could be the case for the interim analysis that we saw at ESMO back in October, but just wondering if you think that if if this changes the longer term competitive dynamic at all in frontline gea and if.
Speaker Change: That now kind of raises the bar for perhaps what the triplet arm needs to show in the Horizon trial.
Kenneth H. Galbraith: 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.
Speaker Change: Yes. Thanks for the question, Steve I mean, obviously, we don't know much more than what was put.
Speaker Change: In the press release about.
Speaker Change: Pos outcome.
Speaker Change: There is no actual data there so it's hard for us to comment.
Speaker Change: About the strength of that data the consistency across the patient population.
Speaker Change: Obviously, the OS was determinant ITT as it needs to be across the population obviously the previous.
Kenneth H. Galbraith: 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 at JAS and Beijing, we're focused on completing the Verizon GA-01 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.
Speaker Change: PFS result was not across the entire patient population, but but only in the PD lone positive stratified part of that that study.
Speaker Change: So until we see the actual data presented until we understand.
Speaker Change: What's on the label is pivotal for up to.
Speaker Change: To your question about.
Speaker Change: The attractiveness of that regimen.
Speaker Change: Our own and I think for US then jazz imaging, where we're focused on completing the horizon <unk>.
Speaker Change: Study.
Speaker Change: And we're more focused on seeing the results.
Speaker Change: Of our own combinations <unk> plus chemotherapy in banning plus chemotherapy.
Speaker Change: With Tesla and how that compares to our own active control arm traveling chemo and the patient population, we're studying which you remember it is different than the 211 patient population just because of the inclusion of the esophageal adenocarcinoma patients.
Kenneth H. Galbraith: So I think we're more interested in 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, it'll probably be a little bit easier to understand the competitive environment for everyone.
Speaker Change: So I think we're more interested in the patient recruitment in our study understanding.
Speaker Change: The PFS result in continuing to follow the patients.
Speaker Change: Once we have more data available on our study and the other study then it'll be probably a little bit easier to understand.
Speaker Change: The competitive environment for everyone.
Stephen Douglas Willey: Okay, I guess that's fair. And then, I know Jazz obviously has outlined plans to pursue registration in post-inherit metastatic breast cancer, and I think there was, you know, some KOL discussion on their call regarding the need for prospectively generated data in this patient population. Just curious, you know, given that most KOLs think HER2 is going to become a frontline standard of care, I'm just kind of interested in your thoughts regarding the relevance of this trial.
Speaker Change: Okay. That's.
Speaker Change: That's fair and then.
Speaker Change: Hello Jazz.
Speaker Change: Obviously, youre has outlined plans to pursue registration and posts and hurt too bad.
Speaker Change: Metastatic breast and.
Speaker Change: I think there was.
Speaker Change: Some kols discussion on their call regarding the need for prospectively generated data in this patient population, but.
Speaker Change: Just curious you know.
Speaker Change: Given that most kols thinking of her who's going to become frontline standard of care.
Speaker Change: Kind of interested in your thoughts regarding the relevancy of this trial.
Stephen Douglas Willey: With respect to gaining utilization in the second line setting, if indeed that inheritance to upstream move into the front line 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 Katsyla are, you know, kind of completely displaced and not repositioned as later line treatment options following HER2. So just kind of curious as to your Yeah,
Speaker Change: With respect to gaining utilization in the second line setting if indeed that in her two upstream move into frontline occurs.
Speaker Change: And I guess from a relevancy perspective I'm just.
Speaker Change: Questioning the THAAD right that one would need to assume that the Cleopatra regimen in <unk>.
Speaker Change: Kind of completely displaced and not repositioned as a later line treatment options person her too so just kind of curious as to your thoughts there.
Kenneth H. Galbraith: Yeah, I mean, I think Jazz indicated in their call yesterday that 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.
Speaker Change: Yes, I mean, I think John indicated their clients, so they're going to talk more about that study design.
Speaker Change: In the second half of this year when it when it's initiated so don't want to get ahead of.
Speaker Change: That.
Speaker Change: I will say from our own perspective, we obviously did.
Speaker Change: A number of studies in different combinations in the metastatic breast.
Speaker Change: Cancer setting.
Speaker Change: And you can certainly see the potential for <unk> in combination with other agents just because of its tolerability nature makes it a great combination with other agents as we're doing in <unk> and we'll seek to do in biliary tract cancer. So you can certainly see the potential presenting to find a place.
Kenneth H. Galbraith: From our own perspective, you know, 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.
Speaker Change: In the treatment paradigm for for metastatic breast cancer and I know from the Kols work that we did when I got here before the Giles transaction.
Speaker Change: There was certainly a need.
Speaker Change: For something in a post <unk> environment, where patients may have about our response, but then progressed.
Kenneth H. Galbraith: 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-inheritu 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 Dany being, you know, 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.
Speaker Change: And I think there was some sense that maybe having a different mechanism done another ADC at that timeframe.
Speaker Change: Might be something that might be attractive.
Speaker Change: Obviously looking at any being a unique bi specific antibody and the her two space surrounded by a wave of different ADP formats, including to DXP.
Speaker Change: Might be a really attractive proposition provide 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 we initiated the second half of this year too. So you can understand more of the clinical and regulatory pathway that they intend to.
Kenneth H. Galbraith: And I think, you know, we'll let Jazz describe their study in more detail when they initiate it in the second half of this year so you can understand more of the clinical and regulatory pathway that they intend to... pursue, but as 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 capital that they could put to work beyond what we could do on our own in attractive opportunities beyond the ability to track cancer and GA. And that's what they've announced they intend to do in that. Now that
Speaker Change: Pursue but from a commercial opportunity it was evident to us that that was something that was very attractive.
Speaker Change: Obviously, we just didn't have the capital to pursue that on our on our own and one of the benefits of the <unk> transaction for US is that they do have capital that they can put to.
Speaker Change: To work beyond which we could do on her own in attractive opportunities beyond biliary tract cancer, and GE and that's what they've announced we intend to do that.
Stephen Douglas Willey: Alright, thanks for taking the questions.
Speaker Change: That's fantastic.
Speaker Change: Alright, thanks for taking the questions.
Operator: Thank you. One moment for our next question. The next question comes from the line of Yigal Nochomovitz of Citi. Your line is now open.
Speaker Change: Alright. Thank you one moment for our next question.
Speaker Change: Next question comes from the line of Yigal <unk> of Citi. Your line is now open.
Yigal Dov Nochomovitz: Hi guys, this is Ashiq Mubarack on Vigo. 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, you know, a cash runway, I think, 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 part of that runway or how much of that runway is being contributed to from potential milestone payments. Are you able to break those up in more detail?
Yigal: Hi, guys. This is logical Mubarak until you go off thanks for taking my questions.
Yigal: One operational question and then one scientific question.
Yigal: Just first one on the sort of financing I mean, you're guiding to cash.
Yigal: Cash runway and I think in the second half of 2027.
Yigal: Clothing, some some regulatory milestones I'm just kind of wondering if you could give us a little color on what of that in one way or how much of that runway as being contributed to from potential milestone payments are you able to break those out in more detail.
Kenneth H. Galbraith: Yeah, and not beyond the guidance that we've previously given, and again, you know, not all of the milestones that we may be entitled to for approval from our current deals with Jazz in Beijing are included in that. So there are some elements, but not all, but 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 under a number of different scenarios.
Speaker Change: Yes, not beyond the guidance that we've previously given and again.
Yigal: Not all of the milestones that we may be entitled to for an approval from our current deals with jazz imaging are included in that.
Yigal: So there is some element, but not all of it I think we feel comfortable with our with our current financial position and current financial outlook.
Yigal: We can fund the R&D strategy that we have right now through the second half of 2027 and in a number of different scenarios.
Kenneth H. Galbraith: So I think, you know, we feel we have a very strong financial position and a good outlook for the business. Obviously, a number of other technology companies in our sector went and accessed additional equity capital through offerings or ATMs 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, 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 them.
Yigal: So I think we feel we have a very strong financial position.
Yigal: Good outlook for the business, obviously, a number of other biotechnology companies in our sector.
Yigal: Went to access additional equity capital through offerings right.
Yigal: In the first quarter of this year, we were not one of those.
Yigal: 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 have previously provided until all of the milestones starting to be received and there's.
Yigal: Obviously be in a position to announce those.
Yigal Dov Nochomovitz: Okay, that's understandable. Maybe one more.
Speaker Change: Okay, that's understandable maybe one more.
Yigal: On the on the <unk> platform.
Speaker Change: Sure to ACI, but that was pretty interesting.
Yigal Dov Nochomovitz: On the Tri-TCE platform, which you shared at 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 the improvement could be meaningful enough in something like CRS that there may be practical differences in terms of, you know, maybe less steroids or less step doses, maybe potential to be in the outpatient setting versus, you know, continuous IV, et cetera. I'm just curious what you can comment from a maybe a practical potential standpoint.
Yigal: I'm just curious if you could talk a little more but how do you expect in the clinic, the Crs profile might be might be differentiate the comparator or more traditional CD three bispecific.
Yigal: You alluded to the idea of the peripheral cytokines might be less.
Yigal: But I'm just curious if you think the improvement can be.
Yigal: Meaningful enough something like Crs that there may be practical differences in terms of maybe less store on steroids or less step dosing or maybe potential to be in the outpatient setting versus continuous IV et cetera, I'm just curious whether you could comment maybe a practical potential standpoint.
Paul Moore: Yeah, sure. Good.
Speaker Change: Yeah sure good question.
Speaker Change: Yes, let me clarify that a little bit so for.
Paul Moore: Good question. Just, you know, let me clarify that a little bit. So for the TRI-TCE, something that we were very careful of was actually the level of interaction with T cells that could, you know, 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 CD-CD28, we get T cell engagement when we co-engage with a tumor target, okay? So the amount of binding, say, in the periphery is very low.
Speaker Change: For the Tri TCE something that we were very careful of what is actually the level of interaction with.
Speaker Change: With T cells.
Speaker Change: Could trigger.
Speaker Change: T cell activation so.
Speaker Change: So we actually we are using a lower affinity CD three and the CD 28, <unk> is actually quite.
Speaker Change: Sure.
Yigal: Weak.
Yigal: But upon a bit anybody in <unk> 'twenty, we get we get engagement of T cells, when we could engage with a tumor target. Okay. So the amount of binding C. In the periphery as Barry rule only when we engage the target and then engage the T cells could we see this nice ability powered CD 20, ACDC activation sooner.
Paul Moore: Only when we engage the target and then engage the T-cells do we see this nice ability-powered CD28-CD3 activation. And so that, we feel, is important. It's 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 in non-human primates, does not support the level of T cell activation we see with other CD3. So that's kind of how far we can take it.
Yigal: That we feel is important it's something we've also embedded in the <unk> 71 program, where we're using a lower affinity novel <unk> epitope that so far but we've modeled that in preclinical studies, both in vitro and in nonhuman primates does not support the level of T cell activation, we see with other <unk>.
Yigal: So that's.
Paul Moore: 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 think we have engineered peripheral cytokine activation that's independent of tumor engagement.
Yigal: That's kind of how far we can take it obviously, we will need to see a lot of it a lot of the T cell activation that you see in the clinic, we will also be driven by the target.
Yigal: Compare with the with the T cell engagement.
Yigal: So that that's also a factor that we consider but overall we've done what we think to engineer.
Yigal: Real cytokine activation.
Yigal: Independent of tumor engagement.
Yigal Dov Nochomovitz: OK, OK, maybe the last question for me. I'm just curious, I mean, I think you said that the final program of the 5x5 will be one of these tri-TCEs. I'm just wondering if it potentially might be DLL3 or CLAWD in the 18.2 programs you kind of outlined, or could it be something else entirely?
Speaker Change: Okay. Okay, maybe the last question for me.
Speaker Change: I'm just curious I mean, I think you said that the the final program and applied by five.
Speaker Change: We will be one of these trials Tce's I'm just wondering if it if it potentially it might be the DLL three or the cloud native <unk> two programs, you've kind of outlined or could it be something else entirely.
Paul Moore: Yeah, I mean, we obviously have a pretty broad program in both the Tri-TC with CoSTEM, but also other Tri-specific formats that we've been working on in research, so we haven't disclosed that. Yes, I think, you know, we have published data preclinically around CLAUDIN 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 co-STEM might give you that you don't see in another bi-civic antibody or an ADC or just a simple antibody approach.
Speaker Change: Yes, I mean, we obviously have a pretty broad program.
Speaker Change: In both the <unk> with the coast down, but also other try specific formats that we've been more kind of research that we havent disclosed.
Speaker Change: Yes.
Speaker Change: I think we have published data pre clinically around the quad and $18 two and DLL three because those were good programs to work on to benchmark ourselves against other product formats and understand what that that trial TCE coast, Tim might give you that you don't see and another by civic antibody, you arent ADC or our interest in simple and.
Speaker Change: Peabody approach.
Paul Moore: I think we will make a nomination of the candidate we want to move forward with as our first bid later this year, but I don't want to speculate as to whether it's one of the two that we publish data on or something else that we still continue to work on as a part of a 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 the change.
Speaker Change: I think we will make a nomination of the accounting we want to move forward.
Speaker Change: With us are fit later this year.
Speaker Change: But I don't want to speculate as to whether it's one of the two that we've published data on or something else that that we're still continuing to work on as a part of our broad portfolio of products there.
Speaker Change: Beyond those two and you just have to wait until we nominated two to see that and that will be this year.
Speaker Change: Got it thanks very much.
Operator: Thank you. One moment for our next question. Our next question comes from the line of Akash Tiwari of Jeffries. Your line is now open. Hi, this is Phoebe on behalf of
Speaker Change: Thank you one moment for our next question.
Speaker Change: Okay.
Speaker Change: Our next question comes from the line of <unk> <unk> of Jefferies. Your line is now open.
Speaker Change: Hi, This is Steven on for Kash. Thank you for taking our question. So profound bio with recently acquired by Jim which is the lead molecule arena as switches a folate receptor alpha targeting ADC.
Speaker Change: <unk> ADC.
Steven: It is ahead of time with encouraging initial human data I guess, where do you think you can differentiate with GW and laser approach here.
Speaker Change: Thank you.
Unknown Attendee: Yeah, again, we don't, like, 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 GenMed may have had available to it. And so we're really interested in putting 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.
Speaker Change: Okay.
Speaker Change: Yes, again, we don't like 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 the public data that genmab may have had available to it.
Speaker Change: So I can really only comment on our own programming approach with that'd be 191, and I think thats reflected in data. We've previously published and also at ACR, where I think we think theres a lot of differentiation of what we're doing.
Speaker Change: The payload so we disclosed earlier this year, our proprietary payload by one nine.
Speaker Change: Which was through a significant medicinal chemistry effort defined.
Speaker Change: A payload that was a camptothecin analog are proprietary to us and with properties that we believe are ideal to be used in an ADC.
Speaker Change: <unk> in the indications of interest and five receptor alpha.
Speaker Change: 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.
Speaker Change: One of our publications at ACR was to focus on on not just binding, but internalization and tumor penetration as a way to get efficiency out of our payload with maybe less tolerability given up to get that activity and so we're really enthused about that.
Speaker Change: Put that to the test in clinical studies that won't be too long from now.
Speaker Change: And I think then we'll understand the characteristics of our own molecule. We do 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.
Unknown Attendee: We definitely have some differentiated features in there from any of the other foliar 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 different agents. And it's just too difficult for us to try and make a comparison at this point between any of the other agencies.
Speaker Change: Find the dose understand the tolerability of of that agent and then be able to understand where we can create clinical differentiation against a host of.
Speaker Change: Our competitors.
Steven: It's difficult for us to try and make a comparison at this point, but good opportunity ahead of the other agents.
Speaker Change: Okay understood. Thank you.
Operator: Thank you. One moment for our next question. The next question comes from the line of Brian Chang of J.P. Morgan. Your line is now open. I can.
Speaker Change: Thank you one moment for our next question.
Speaker Change: Next question comes from the line of Brian Cheng of J P. Morgan. Your line is now open.
Brian Chang: 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 scleroderma and myasthenia gravis, just these recent weeks. Just curious if you have any interest or whether you have any potential ability to disrupt that space with your Tri-TCE platform.
Lut Ming Cheng: Hi, Kevin and team thanks for taking my questions today.
Lut Ming Cheng: We're seeing some excitement around the application of T cell engaged Ernst any autoimmune space like Scott Derm on myasthenia Gravis just hit these recent weeks Jim.
Lut Ming Cheng: Just curious if you have any interests or whether you have any potential ability to whether you see any potential ability to disrupt that space. So if you are a <unk> platform.
Speaker Change: Yes, yes.
Kenneth H. Galbraith: No, thanks, Brett. No, it, you know, it's obviously, you know, we Zymeworks has never been exclusively an oncology company. We have been working in autoimmune and inflammatory, and dermatology indications for some time now. But 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 have worked on preclinically.
Speaker Change: Thanks, Brian.
Speaker Change: It's obviously now we have.
Speaker Change: We've 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 five by five.
Speaker Change: But we definitely have some platforms and capabilities and experience in that area given things we work on pre clinically.
Kenneth H. Galbraith: 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 555, we definitely have an interesting understanding of some of our platforms and apps that can be really differentiated from what we see from others and be applicable to a patient population beyond oncology.
Speaker Change: And if you look at the folks who have added since I got here, including Paul We do have a number of folks who have some great experience in commercializing in.
Speaker Change: 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.
Speaker Change: And be applicable to a patient population beyond oncology.
Speaker Change: 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 will outline some of our thoughts around assets and approach and differentiation against others, who are in that space.
Kenneth H. Galbraith: 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.
Brian Chang: Okay, great. And then maybe just a follow up. In your prepared remarks, you talk about, you know, you mentioned partnership, and I think, you know, your past partnership has always been a core part of your approach. We're about halfway through the year. So just curious if there's also, you know, a particular direction that you're looking at from a partnership standpoint. And then, you know, on top of that, if, you know, are you looking for a partnership to kind of accelerate your development on the auto union side? Just, you know, any color they can provide will be super helpful.
Speaker Change: The answer yet.
Speaker Change: Okay, Great and then maybe just a follow up.
Speaker Change: On your prepared remarks, you talk about you mentioned partnership I think Pat.
Speaker Change: The partnership had always been a core part of our approach.
Speaker Change: We're about halfway through the year. So just curious if there is also in a particular direction that.
Speaker Change: Youre looking at from a partnership standpoint.
Speaker Change: And on top of that.
Speaker Change: Are you looking for partnership to kind of accelerate your development on auto Union side.
Speaker Change: Any color they can provide would be super helpful.
Kenneth H. Galbraith: Yeah, I think, you know, 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 stage in development.
Speaker Change: Yes, I think.
Speaker Change: Nearly partnership as a part of our strategy for a number of reasons. One one is obviously access to capital and it's no surprise that transactions in both adcs and <unk> have gotten a much higher valuation at an earlier time point in development.
Kenneth H. Galbraith: 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, you know, larger and more formidable competitors. And with the potential for broad applications, especially in 1.9, 1.1, and 1.7.1, going to the clinic first in both mesothelium and foliar receptor alpha, those targets are of interest to a pretty broad patient population.
Speaker Change: We also look at partnerships and ability for us to accelerating compete and obviously with the acquisitions, which have occurred over the past period of time in both Adcs and T cell engagement, we find ourselves against larger and more formidable competitors and with the potential for broad applications, especially in <unk> and 191 171 go into there.
Speaker Change: First in bulk mesothelium folate receptor alpha those those targets are of interest and a pretty broad patient population.
Kenneth H. Galbraith: I think we learned from Zannie that there was a certain breadth of opportunity for Zannie which was probably beyond the reach of ourselves on our own, and completing the Jazz partnership, as you see with their subsequent developments, may have allowed 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 the success of that. So that's a good lesson for us to look at.
Speaker Change: I think we learned from Danny that.
Speaker Change: There was a certain breath of opportunity because any which was probably beyond the reach of ourselves on our own and completing the jazz partnership as you see with their subsequent developments.
Speaker Change: May allow them to pursue that where we couldnt do that on our own.
Speaker Change: And hopefully we structured that in a way that allows us to continue to share and a good portion of the success.
Kenneth H. Galbraith: But we've also been very clear with Zannie being partnered exclusively with Jazz in Beijing that for our follow-on agents in 5x5, 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 U.S.-ex-U.S. potential partnering strategy. There's other forms we could do, but we'd obviously like to, if we're fortunate to find another agent in our 5x5, which has the potential that Zannie seems to have in a peak sales potential, which Jazz guided us on, we'd like to be able to keep some of that for ourselves and not look at a fully licensed strategy going forward.
Speaker Change: For that so that's a good learning for us to look at.
Kenneth H. Galbraith: 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 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.
Kenneth H. Galbraith: I think there is considerable interest in both of these areas, as well as in 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 to help us accelerate and compete against larger competitors, as well as retain 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 that are really interesting to us and are just going into clinical studies over the next 24 months for all five.
Operator: 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.
Jonathan Miller: Hey guys, thanks for taking the question. I wanted to ask a question on the trispecific stuff that you presented at AACR.
Jonathan Miller: In particular, in addition to the reduced CRS or cytokine release, the purple cytokine release that you already touched on, I was also interested in improved T cell survival or what looked like improved characteristics of the stimulated T cells that are coming from those reduced affinity CD3C28 binders. You know, obviously, you have the spider plots in the day-to-day and those were, you know, up there at AACR, but do you have evidence that improving T cell health means that you get continued stimulation?
Jonathan Miller: I mean, that is to say, as you get in longer and longer in the timeline, do you see less 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? [inaudible]
Paul Moore: 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 they then provide enhanced anti-tumor activity. So it's a little bit, 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, we can maintain the response for much longer if we challenge them with the trispecific with the CD28 compared to the CD3.
Paul Moore: So that's consistent with what you would expect by having fitter 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 infiltration, 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 tri-TCE platform that you don't see with the bispecific CD3.
Paul Moore: So that suggests to us that in the tumor microenvironment, not only this enhanced durability and sustainability, but we're seeing better activity in responses where you don't see responses without CD3 bispecifics with CD3 bispecific load, so that tells us that we are indeed doing something in the tumor microenvironment in an animal model, albeit that it's supportive of our hypothesis, and we then, of course, anticipate that that hopefully will translate in the clinic to better responses.
Jonathan Miller: Now, that makes sense. I guess one more on a related topic. Obviously, CD3 bispecifics are active drugs; they're used to great effect in many indications. Do you expect this 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 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? Yeah, that's another great question.
Paul Moore: Yes, that's another great question. I think we do anticipate that overall, this should yield better responses, you know, even where CDC biospecifics work. I don't want to be too hypothetical, but I think when you think about CAR-T space without co-stimulation on those T-cells, the responses were not generally as good without it. So you needed that co-stimulation.
Paul Moore: So there's a potential that we could have a 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 that are already anergic need a little bit more than just CD3. 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.
Operator: Thank you. One moment for our next question. The next question comes from the line of Derek Archila of Wells Fargo. The line is now open. Hi, this is Sevalin for Derek. Thanks for taking our question.
Unknown Attendee: Yeah, we previously got 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 ClinTrials, which means we've initiated our first site, and we'd be happy then to talk more about the details of the study design and timing that's available on ClinTrials.
Unknown Attendee: So 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 we hope we can keep that a little bit ahead of our schedule and be discussing those things in the near future. Okay, thanks.
Kenneth H. Galbraith: Thank you. As a reminder, to ask a question, you will need to press star 11 on your telephone and wait for your name to be announced. Please stand by while we wait for additional questions. Okay, one moment for our next question. Our next question comes from the line of John Miller of Evercore. Please go ahead.
Operator: Hi, thanks for letting me hop in the queue again. One thing that you mentioned in the prepared remarks, I just want to get a little bit more color on. You mentioned that you expected that your Phase I's would have mostly ex-U.S. patients, the global studies, but mostly ex-U.S. 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 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.
Kenneth H. Galbraith: Yeah, absolutely. I think we made 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 structured ourselves to be able to recruit patients globally. So, you should see, in our Phase 1 studies, not just ID 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.
Jonathan Miller: Yeah, food, I
Kenneth H. Galbraith: 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 I program as we move from dose escalation to expansion cohorts and eventually to combination cohorts and eventually beyond Phase I. So I think we've thought a lot about how we would do this.
Kenneth H. Galbraith: I think we've 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 US sites, but I would expect the majority of patients in both those studies in Phase 1, the vast majority will be recruited outside the United States.
Kenneth H. Galbraith: And hopefully, we'll structure ourselves and make those decisions to accomplish what we want, which is a faster Phase 1 study and clearer data and a more diverse data set by recruiting patients. So we'll love to see if we can do that, but that is the goal, and hopefully, you'll see evidence of that pretty soon.
Kenneth H. Galbraith: 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.
Kenneth H. Galbraith: No, thank you very much. And I really appreciate everyone taking the time today to listen to our call and ask questions. Hopefully, we were 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 during the call. Hopefully, you can see we're very excited about 2024. This is getting to be very interesting for us this year and next year.
Kenneth H. Galbraith: 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, everyone, for listening today.
Operator: This concludes today's conference call. You may disconnect your lines. Thank you for participating, and have a pleasant day.