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spk03: Thank you for standing by. This is the conference operator. Welcome to Zyneworks' second quarter 2024 results conference call and webcast. As a reminder, all participants are in a 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 join the queue. I would now like to turn the conference over to Shurnal Inamdar, Director of Investor Relations. Shurnal, please go ahead.
spk01: Thank you, operator. Good afternoon and thank you for joining our second quarter 2024 results conference call. Before we begin, I would like to remind you that we'll be making a number of forward-looking statements during this call, including, without limitation, those forward-looking statements identified in our slides and the accompanying oral commentary. Forward-looking statements are based 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. For discussion of these risks and uncertainties, we refer you to our latest SUT filings as found on our website and as filed with the SUT. In a moment, I will hand over to Bijal Desai, our VP of Finance and Strategy, who will be discussing recent corporate updates along with our financial results for the second quarter 2024. Following this, Dr. Paul Moore, our Chief Scientific Officer, will talk about key highlights for our second quarter including the investigational new drug application clearances for ZW171 and ZW191 by the FDA. At the end of the call, Bijal, Paul, and Ken Galbraith, our chair and CEO, will be available for Q&A, as well as Pranshul Chauhan, Associate Medical Director for Early Stage Development for ZW171. As a reminder, the audio and slides from this call will also be available on the DesignWorks website later today. I will now turn the call over to Bijal.
spk06: Thanks, Chanel, and thank you, everyone, for joining us today for our second quarter 2024 earnings call. I will begin today's call with an overview of key achievements from our development program as well as our financial results. In the second quarter, we achieved key milestones regarding the global regulatory review of our late-stage asset Xanadatamab, including being granted priority review of the Biologics License Application, or BLA, for Xanadatamab as second-line treatment for biliary tract cancers, or BTC, in the United States, with a target action date of November 29, 2024. Similarly, the European Medicines Agency has validated the marketing authorization application for Xanadatamab in second-line BTC, and regulatory reviews for Xanadatamab in BTC remain underway in China. We are pleased to have received a milestone payment of $8 million USD in July under the terms of Zymer's Asia-Pacific License and Collaboration Agreement with Beijing in conjunction with Xanadatamab's BLA acceptance in China. Our partner, Jazz, has confirmed that the Pivotal Horizon GEA-01 trial evaluating Xanadatamab in first-line gastroesophageal adenocarcinoma, or GEA, is ongoing and enrollment remains on track. Based on a blinded assessment of progression events, JAWS estimates top-line progression-free survival, or PFS, data will be available in second quarter 2025. JAWS continues to track events in the trial relative to the initial protocol assumptions. Near term, we look forward to a potential approval for Xanadatamab in second-line BTC in the United States. And based on the expected timeline and subject to approval, Jazz is aiming to launch Xanadatamab in the United States for a second-line BTC in the fourth quarter of 2024. Together with our partners, we look forward to opportunities where we can continue presenting promising data that support deep and durable responses, further highlighting Xanadatamab's potential to provide meaningful benefits for patients. This includes the first-ever overall survival findings from the Phase 2B Horizon BTC-01 clinical trial for Xanadatamab presented at the American Society of Clinical Oncology annual meeting by our partner, JAS. Results from this long-term analysis of the trial indicate that Xanadatamab as monotherapy demonstrated sustained and durable antitumor responses in previously treated patients with HER2-positive BTC-01 and support the clinically meaningful benefit of continued treatment with Zanidatimab. The safety profile in all enrolled patients remained manageable with favorable tolerability compared with the initial analysis. In addition, we are pleased to report significant progress for our wholly owned pipeline, which transitions two of Zymerc's early stage programs into clinical candidates. We have successfully cleared IND applications by the FDA for ZW191 and ZW171 with first-in-human studies planned to initiate in the second half of 2024 in the United States, and we are actively progressing applications seeking regulatory permission to commence clinical studies for ZW191 and ZW171 in other non-U.S. jurisdictions in the second half of 2024. With these advancements in mind, following a strategic review of our emerging wholly-owned pipeline, we made the decision to formally discontinue the clinical development program of our HER2-targeted antibody drug conjugate zanidatamab zovodotin, also known as ZW49 or Zanizo. This decision aligns with our commitment to focus on the development of our early-stage programs which we believe have the potential to be best-in-class and or first-in-class therapeutics. By reallocating our resources, we can focus on accelerating the progression of ZW171 and ZW191 into the dose escalation stage of the respective Phase I clinical trials, as well as the planned IND filings for ZW220 and ZW251 in 2025. We believe Xanizzo remains a promising phase two ready asset, and we continue to explore partnering discussions where Xanizzo may provide complimentary coverage to a pipeline for non-small cell lung cancer, breast cancer, and other indications. Our team extends heartfelt gratitude to the patients, families, and healthcare professionals involved in the Xanizzo development program. We remain committed to the highest degree of scientific rigor in our development processes with the goal of focusing on candidates with the potential to deliver the greatest benefit to patients. Our broader oncology development program continues to be a priority with two phase one trials anticipated to commence in 2024, including enrollment of patients with non-small cell lung cancer. Turning to our financial position, this afternoon, Zymerx reported financial results for the second quarter of year 2024. Zymerx's net loss for the six months ended June 30, 2024, with $69.3 million, or $0.91 loss per diluted share, compared to a net loss of $75.5 million for the same period in 2023. The decrease in net loss is primarily due to lower research and development and general and administrative expenses, which is partially offset by a decrease in revenue and an impairment charge recognized in 2024 related to Xanadadamab-zovidotin. As reported, our revenue for the six months ended June 30th, 2024 was $29.3 million compared to $42.6 million for the same period in 2023. Revenue for the six months ended June 30, 2024, included $20.7 million for development support and drug supply revenue from JAS, $8 million of milestone revenue from Beijing in relation to the acceptance by the CDE of the NMPA in China of the BLA for Xanadatamab for second-line treatment of HER2-positive DTC, $0.4 million from Beijing for research support payments and $0.2 million from our partners for research support and other payments. Revenue for the same period in 2023 included $61 million for development support and drug supply revenue from JAS, which was partially offset by a $20.1 million credit issued to JAS for contractual amendments to our partnership arrangement and $1.7 million from our partners for research support and other payments. Overall operating expenses were $110 million for the six months ended June 30th, 2024, compared to $124 million for the same period in 2023, representing a decrease of 11% year over year. The decrease in overall operating expenses resulted from a decrease in both research and development expense, as well as a decrease in general and administrative expense. The decrease in research and development expense was primarily due to a decrease in expenses for Xanadatamab as a result of transfer of responsibility for this program to JAS. This decrease, compared to the same period in 2023, was partially offset by an increase in expenses of other development programs, primarily with respect to product candidates ZW171 and ZW251, costs incurred for manufacturing activities to support the IND for ZW220, and other preclinical and research programs. Salaries and benefits expenses decreased compared to the same period in 2023 due to non-recurring severance expenses in 2023, which was partially offset by an increase in stock-based compensation expense in 2024. The decrease in general and administrative expense was primarily due to a decrease in external consulting expenses for information technology, legal fees, and other expenses for advisory services a reduction in insurance costs and a decrease in depreciation and amortization expenses compared to the same period in 2023. This was partially offset by costs due to the termination of our long-term facility lease in Seattle in 2024. During the six months ended June 30th, 2024, we recorded a non-cash impairment charge of $17.3 million as a result of the company's decision to discontinue the Xanadatamab-Zovodatin Clinical Development Program, which utilized the technology represented by acquired in-process research and development assets. As of July 31st, 2024, we had approximately 71 million shares of common stock outstanding and approximately 5.1 million shares of common stock issuable under pre-funded warrants. As of June 30th, 2024, we had $395.9 million of cash resources consisting of cash equivalents and marketable securities as compared to $456.3 million as of December 31, 2023. For additional details on our quarterly and year-end results, I encourage you to review our earnings release and other SEC filings as available on our website at www.zimerx.com. Our strategy of refocusing the business and building a diverse clinical stage product pipeline of antibody drug conjugates, or ADCs, and multi-specific antibody therapeutics continues to provide a solid foundation which we believe will help 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. Based on current operating plans, Our strong financial position of $395.9 million in cash resources as of June 30, 2024, together with certain anticipated regulatory milestone payments, gives us an expected runway into the second half of 2027. We may also be able to extend this runway or fund an expanded R&D scope through potential regulatory approval milestone payments in connection with our existing partnerships with Jazz in Beijing or new partnerships and collaborations which we may choose to form. In addition, pending regulatory approval, we are eligible to receive commercial milestone payments based on annual sales of Xanadatamab and tiered royalties between 10% and 20% on Jazz's annual net sales and between 10% and 19.5% on Beijing's net sales. With that, I'd like to hand over to our Chief Scientific Officer, Dr. Paul Moore, who will provide more details regarding our wholly owned pipeline, and specifically on ZW191 and ZW171 moving into the clinic. Over to you, Paul.
spk10: Thank you, Bijal. So today I'm delighted to be talking about our growing oncology pipeline, which is currently built on two fundamental pillars, modality focus and therapeutic area focus. Today, we have targeted three areas of high unmet medical need, gynecological cancers, lung cancer, and cancers of the digestive system, while balancing ADC and T-cell engagers across these various therapeutic areas. We believe this approach ensures both a broad and comprehensive coverage of these challenging diseases. Moving forward, as we continue to progress with the development of our early stage assets, We believe that expanding on both our modality and therapeutic areas of focus will be key in driving the growth of our pipeline in the coming months and years. This includes leveraging our deep technical expertise to combine and adapt various modalities with the aim to improve patient outcome. You will hear more about that on our plans for growth and expansion later in the year, including the nomination of our fifth product candidate, a tri-specific T-cell engager or tri-TCE. A strategic balance of wholly owned ADCs and T-cell engagers targeting clinically validated antigens like folate receptor alpha, NAPI2B, and mesothelin underscores our commitment to delivery innovative treatments that meet the highest standards of care, not only as monotherapy, but also in combination with agents that have already shown previous activity and benefits. ZW171 and ZW191 are both designed to optimize efficacy, starting with the selection of targets with the highest level of expression. As you can see here, across ovarian cancer, mesothelin, folate receptor, and NAPI2B are expressed at relatively higher levels compared to other targets, such as Caterin 6, providing a broad and comprehensive coverage of ovarian cancer, something which also holds in non-small cell ones. We believe that the relatively high tumor expression levels are crucial for maximizing the efficacy of our therapeutic agents, helping the ADCs and T cell engagers to effectively bind to and eliminate cancer cells, regardless of modality. By leveraging T cell killing through an enhanced 2 plus 1 format and unique geometry, our ZW171 candidate offers a potentially robust and precise immune response against mesothelin-expressing tumors and helps her enhance her position in the competitive landscape. Similarly, leveraging a unique antibody and payload linker for ZW191 offers a potentially robust and effective therapeutic against folate receptor alpha-expressing tumors. This quarter, we have achieved significant milestones in progressing our pipeline by advancing both ZW171 and ZW191 into clinical stage development. With the FDA clearance of these IDs, we are one step closer to our goal of providing patients with potentially best-in-class therapeutics that could improve the standard of care for these treatment landscapes. T-cell engagers offer great opportunity for more effective therapies, and in particular, ZW171 has the potential to treat patients with the right range of tumors with moderate to strong mesothelin expression, observed in ovarian cancer, pancreatic cancer, non-small cell lung cancer, and endometrial cancer. However, the opportunity for developing T-cell engager targeting mesothelin-expressing cancers doesn't come without its challenges. For 171, we have taken a thoughtful approach to what a target profile would look like for this patient population, and we believe in our design approach, which uses an ability-dependent mesothelin binding of two mesothelin paratopes to enable selective such toxicity tumor cells with high mesothelial expression relative to normal tissues and reduces the impact of soluble mesothelial impotency, potentially minimizes off-tumor, on-target toxicity. On slide 13, the preclinical data shown here demonstrates 171's ability to exhibit mesothelial-dependent cytotoxicity across various cancer cell lines, including lung, ovarian, colorectal, and mesothelioma. In cancer cell lines with relatively high or moderate mesothelial expression, including representative lung and ovarian cancer, CRC, and mesothelial cancer cell lines, 171 demonstrated potent cytotoxic effects, significantly reducing tumor cell survival at low concentrations. Importantly, in cell lines with relatively low mesothelial expression, relative Reflective of mesothelin expression on normal healthy tissue, 171 showed minimal cytotoxic effects, similar to the negative control. We believe that this selective activity helps to ensure that 171 specifically targets mesothelin-expressing tumor cells, minimizing potential off-target effects and improving safety profiles. The demonstrated efficacy across high and moderate mesothelin-expressing tumors suggests a broad therapeutic potential for 171 in treating various cancers, as shown in the previous slide. Based on these promising preclinical results, we are preparing to further validate these findings in a clinical setting. We expect to dose the first patient this year in our Phase 1 open-label multicenter study of 171 and participants with advanced or metastatic ovarian cancer, non-small cell 1 cancer, and other mesothelin-expressing cancers. The Phase 1 study design is now available on clinicaltrials.gov website under the MCT number The global study is expected to enroll 160 participants across North America, Europe, and Asia Pacific regions. Part one of the study will evaluate the safety and tolerability of 171, and part two of the study will evaluate the anti-tumor activity of 171, according to the RESIST evaluation criteria, while continuing to evaluate the safety and tolerability. Inclusion criteria includes pathologically confirmed diagnosis of cancers with evidence of locally advanced, unresectable, and or metastatic disease, cancers that are refractory to all available standard of care treatment, cancers for which no standard of care treatment is available, or the participant cannot tolerate or refuses standard of care therapy. We look forward to reporting first patient dose in the near future and discussing progress in the coming hearing calls. Now moving to ZW191, which highlights our continued focus on targeting antigens with high levels of expression, as I described earlier. As illustrated in the attached slide, folate receptor alpha is frequently overexpressed in a substantial portion of non-small cell lung cancer, ovarian cancer, and angiometrial cancer. In non-small cell lung cancer adenocarcinoma, For example, over 70% of patients have been reported to exhibit folate receptor alpha positivity, with significant portions demonstrating high expression levels, as defined by a TPS over 50% and an IHC score of greater than or equal to 2+. Similarly, in ovarian cancer, around 80% of platinum-resistant ovarian cancer tumors express some level of folate receptor alpha, with 35% scoring as folate receptor alpha high. Endometrial cancer also presents a notable opportunity with 33% of tumor scoring as folate receptor alpha positive and 15% as folate receptor alpha high. By focusing on antigen such as folate receptor alpha, which are commonly expressed in these cancers, we aim to develop treatments that not only demonstrate strong therapeutic efficacy, but also minimize off-target effects, potentially improving patient outcomes. We are pleased to report that the FDA has cleared the IND submission for 191. We're looking forward to seeing how our unique design and novel payload for this ADC translates in a clinical setting. As we have discussed previously on these calls, our efforts on developing a novel topoisomerase I inhibitor, or topo I payload, known as ZD06519, has focused on selecting properties that we expect would drive strong efficacy while maximizing tolerability, specifically moderate potency with high bystander activity. 6519 was designed and selected to potentially allow high antibody dose in humans compared to ADCs with more potent TOPO1 inhibitor payloads, as evidenced by the DXD ADCs. In non-human primate studies, we observed superior tolerability of the 519 ADCs as exemplified at the 120 mcg per kg dose of EDCs with a drug antibody ratio of four. We then implemented well-established and clinically validated linker and antibody attachment chemistry with a balanced approach of designed instability. As you can see here in the bottom section of the table, EDCs of higher stability show an expected or higher toxicity compared to the DXB platform. In slide 17, as we highlight In our AACR poster presentations earlier this year, we demonstrate the relative internalization by 191's folate receptor alpha monoclonal antibody compared to folate receptor alpha targeting antibodies incorporating for other ADC programs. As you can see, 191's monoclonal antibody in dark blue demonstrated higher levels of internalization compared to the monoclonal antibodies from Elihir, Morab 202, Stro002, and Pro1184. This observation is consistent with our decision to select the 191 monoclonal antibody from a larger pool of antibodies for its ability to deliver payload through enhanced internalization, and our care in factoring in all components of the ADC in designing our candidates. This tecloxiferid model is more predictive of anti-tumor activity in in vivo models than traditional 2D cell-led models, and also aids in the dissection of ADC mechanism of action, which gives us confidence in being able to replicate these results in humans. Further, for 191, we are pleased to have achieved the highest non-severely toxic dose in non-human primates of 60 mg per kg, presenting a compelling profile for potential efficacious dosing in our Phase I clinical trial expected to initiate later this year. I will now hand over to Ken, our CEO and Chair, for closing remarks before we begin the Q&A portion of the call.
spk09: That's great. Thank you, Paul. We're excited to see how our data-driven approach for designing and developing most DW171s and ZW191 translates into our respective phase one studies. And we remain dedicated to advancing transformative therapies with IND submissions for ZW220 and ZW251 in 2025, as well as nominating our tri-TCE product candidate later this year. On another business update, we're pleased to announce the appointment of Leonie Patterson as Executive Vice President, Chief Business Officer, and Chief Financial Officer, effective September 1st. Ms. Patterson brings more than 20 years of public company biotech experience, with a proven track record of guiding strategy, finance, operations, and government through multiple phases of growth. The owner's expertise in planning and executing successful financial strategies will be key as we continue to plan for the next period of growth and expansion for the company. We're pleased to announce that our partner, Jazz, has initiated the Phase 3 EMPOWER trial, which is designed to evaluate Xanadatamab in combination with chemotherapy after progression on Inher2. where there's an opportunity for Zenedatamab to be the first HER2-targeted therapy to demonstrate efficacy and safety in breast cancer patients after an HER2 treatment. Together with our partners, GAS and Beijing, we look forward to sharing more data on Zenedatamab's efficacy this year during peer-reviewed medical meetings where we can further validate Zenedatamab's potential to improve the standard of care for these patients. We're also looking forward to the pivotal Phase III top-line data readout in our first-line GEA study by our partner, GAS, who estimate top-line CFS data will be available in the second quarter of 2025. In the near term, we also look forward to an important catalyst, our upcoming PDUFA date of November 29, 2024, for our ZenaDataMap filing and second-line BPC in the United States. Before we turn the call over to Q&A, I'd like to talk about the Share Repurchase Program, which was announced via a press release concurrent with our second quarter 2024 financial report. As disclosed in the press release, our board has authorized a $60 million share repurchase program with $30 million of the program repurchases expected to begin promptly and continue during the second half of 2024. This decision reflects our confidence in the future outlook for our business, the potential of our product candidate portfolio, and the long-term value of our preclinical and clinical development pipeline. We believe our strong capital position bolstered our strategic partnerships, enables us to execute on the share purchase program while maintaining ample cash resources to continue advancing our product candidate portfolio and providing optionality around strategic capital allocation. The share purchase program is further supported by our decision to de-prioritize the development of Zanizo, which allows us to reallocate that associated R&D spending. We also expect to maintain our projected cash runway into second half 2027 assuming completion of the full $60 million share purchase program based on existing cash resources and assuming the receipt of certain anticipated regulatory milestone payments. We believe our stock is currently undervalued and see this buyback as a strategic way to invest in ourselves through thoughtful capital allocation ahead of upcoming expected catalysts in 2024 and 2025. Our plan to execute the share repurchase in two phases gives us the flexibility to manage repurchases over time, allowing us to adapt to market conditions and pursue additional growth opportunities as they may arise. By reserving the remaining $30 million for future repurchases, we maintain flexibility that can enable us to capitalize on strategic opportunities without compromising our cash resources. This balanced approach and thoughtful capital allocation enables us to make prudent decisions that we believe will benefit our shareholders both now and in the future. With that, I'd like to thank everyone for listening, and I'll turn the call over to the operator to begin the question and answer session. Operator?
spk03: We will now begin the question and answer session. To join the question queue, you may press star 11 on your telephone keypad. You will hear a tone acknowledging your request. If you're using a speakerphone, please pick up your handset before pressing any keys. To withdraw your question, please press star 11 again. We will pause for a moment as callers join the queue. Our first question comes from the line of Stephen Wally at Stifle. Stephen, your line is now open.
spk11: Yeah, good afternoon. Thanks for taking the questions and thanks for getting 171191 on the clinic. Just wondering if you can speak to the levels of mesothelium and fully receptor alpha expression that you're requiring at baseline for the phase one. What are the IHC cutoff values that you're requiring for both? And then is there anything that you might be able to say about the starting ZW171 dose, the cadence of any step-up dosing you'll be using, and any requirements for inpatient administration? Thanks.
spk09: Sure, thank you, Stephen. Maybe I'll ask Pranchal, who's the global clinical lead for ZW171. He wants to answer some, but maybe not all of those questions, Stephen.
spk07: Hi, Stephen. Thank you for your question. I can share with you what's publicly available on clinicaltrials.gov. To start off, I think you asked about the expression levels of mesothelium and folate receptor alpha in our studies. Initially, in our dose escalation phases, we'll be analyzing expression levels retrospectively, so there's no cutoff as such, as some of these are yet to be validated for mesothelin, for example. Your second question regarding dosing strategy, this is something that we haven't made available publicly yet. However, we do intend to explore various dosing formats of CW171 in clinic. And your, what was your next and last question, Stephen? Sorry.
spk11: Just a question of any starting dose, step-up dosing, and then any inpatient administration requirements.
spk07: The starting dose is something we haven't shared publicly yet. There will be requirements for inpatient in a small subset of patients during the dose escalation phase. This is mandated by regulatory requirements in our discussion with the regulatory bodies. However, we do intend to work at different strategies for dosing where we will explore dosing without hospitalization requirements later on in the study.
spk11: Okay. Can I just ask a clarification question? so that I'm clear, on the mesothelian side, and I guess maybe even on the foliar receptor alpha side, you will be enrolling tumor types that you know to be enriched for expression of each of these target antigens, and then you'll be retrospectively looking at expression levels via IHC?
spk07: Exactly. Exactly.
spk11: Okay. Okay. Thank you for taking the questions.
spk03: Thank you. Thank you. Thank you. Our next question comes from from Citi. Yigal, your line is now open.
spk00: Hi, this is Amin for Yigal. Thank you for taking our questions. We had a couple. First, on the ZW220, given the prior failures in NAPI2VA disease, what do you think differentiates 220 from the previously investigated molecules by Marsana and Genentech? And then the second one, on the general ADC strategy, do you see any risk in using the same payload for your three ADC programs? What gives you confidence about this payload?
spk09: No, two great questions. Paul, would you like to answer both of those questions?
spk10: Sure, sure. So, first of all, on our confidence level in 220 being successful for others, ADCs against NAFI have failed, I think. That really comes down to, you know, the design of our ADC, you know, from the antibody selected to the payload. So your second question regards the payload, but as you may be aware, we spent a lot of time really carefully picking what we believe was the right balance of potency, bystander activity for the total payload. So we feel comfortable. in what we've selected from a larger options of payloads to select from there. And that we feel is very important, that level of potency overall across all our ADCs. And particularly for NAAPI, there we think, again, the safety profile and the efficacy profile and the use of a topo payload, which is not what others have tried before, differentiates our program from previous efforts to target through an ADC approach. And then regarding your question about you know, using that across three different targets. We feel all of those three targets could benefit within our disease indication from ADCs with this type of payload, and so our preclinical data supports that when we benchmark it against, you know, competitor programs or prior programs, both the efficacy profile and the breadth of patients that we can tackle with this payload balance. with the antibody really looked very favorable. So that supports our moving forward in the clinic with all three programs.
spk00: Thanks. That's helpful.
spk03: Thank you. Our next question comes from the line of Akash Tiwari from Jefferies. Akash, your line is now open.
spk05: Hi. This is Stevie. I'm for Akash. Jaz announced yesterday that data from Horizon GEA 01 was pushed back from late 2024 to Q2 2025. Does that mean that enrollment is progressing slower than originally anticipated, or is it just related to not enough PFS events getting accumulated as pre-specified by the interim analysis protocol? And have you disclosed any of the number of events for PFS to be accumulated for the pre-planned interim analysis? Thank you.
spk09: Yeah, and that's your first question. I think Jazz was very clear on the guidance that's in their earnings call, because I did listen to it. And they were very clear that enrollment's on track. And the delay in unblindness study was related to getting to the required number of events to unblindness study, which is currently targeted and now estimated to be in Q2 2025. And the answer to your second question is no, there's no disclosure of the actual number of events.
spk05: Okay, understood. Thank you.
spk03: Yep, no worries. Thank you. Our next question comes from the line of Brian Chang at JPMorgan. Brian, your line is now open.
spk12: Thanks for taking our questions. This is Sean on for Brian. So firstly, on 171, we saw that the phase one was posted on clinicaltrials.gov. How should we think of the side effect profile based on the target you selected? Just curious if there's any additional preclinical insights that you can share. And how many doses are you evaluating? And I have a quick follow-up.
spk09: Paul, do you want to take the first question about preclinical characterization, the tolerability of mesothelin, what medicine?
spk10: Yeah, that's a good question because, you know, others, it is a target that, although it's very highly expressed on cancer types, there is some level of normal expression of mesothelin. And so you have to think carefully about how you differentially target the tumor without avoiding the normal. And so that's why we spent so much time preclinically trying different formats to get a format that gave us that better window where we wouldn't have activity on low-expressing models that represent normal tissue levels of mesothelin, but has very potent and doesn't compromise the anti-tumor activity on the mesothelin-positive tumors, the high-expressing. And that we've seen in our preclinical profile, we've taken the molecules into non-human primates, we've done a lot of other evaluation of the molecules regarding safety, and there we haven't seen evidence of toxicity. Of course, we have to, going into the clinic, we'll have to monitor that, pay attention there, that's part of the dosing strategies that that Pranchal alluded to that we'll be evaluating. But so far, we really tried to come up with a design model to address exactly what you're asking.
spk09: And I'll let Pranchal answer the second question about the number of dose levels planned for the Phase I study.
spk07: Yeah, so we've tried to evaluate six different dose levels. This may increase or decrease based on the safety and tolerability profiles The DLT evaluation period is 21 days for the study, but we will continue to gather safety and tolerability data as long as the participant remains on trial and to remain on trial until the toxicity or progression. I hope that answers your question.
spk09: I think you had another question.
spk12: Yeah, thank you for the clarification. I just have a quick modeling question. So we saw that the cash-run rate hasn't changed, but with ZANiZO now discontinued, is there any near-term impact that we should model for the R&D expenses? Thank you.
spk09: Yeah, there will obviously be a subsequent decline in some of the expenses that would have been related to continued spending on ZANiZO to complete the Plan Phase 2 study and prepare for a registration study, so that will that will decline over the next period of time. And again, that's approximately $30 million that was allocated, which coincidentally matches the initial repurchase program from our share repurchase program. So we would expect that that will be released from future R&D expense, and we'll be using that capital to reallocate to the share repurchase program over time. Thanks for taking our questions.
spk03: You're welcome. Thank you. Our next question comes from the line of John Miller at Evercore. John, your line is now open.
spk02: Thank you very much for taking the questions. I'll start on the mesothelin program. I know you mentioned you'll be looking at mesothelin expression retrospectively in some of these patients. I guess, what are your expectations for those mesothelin negative patients? Presumably, there would be an absence of expected activity there, but Does the absence of sufficient antigen, you know, I know you don't see tox from a cytotoxicity perspective in normal expressing tissues, but can you drive CRS or T cell exhaustion by circulating T cells if you don't have a good antigen sink to sop up the bispecific to the tumor itself? And sort of separately, maybe relatedly, you note in the slides that you have potency even in the presence of soluble mesothelin, and I'd love to get a little bit more color on that. Is that driven by the binding mode? Do you not bind soluble mesothelin, or is there something else going on that's helping you maintain activity?
spk09: No, thanks, John. Paul, do you want to address both of those questions for mesothelin?
spk10: Yep, sure. So maybe on the first question about patients that, you know, you wouldn't have a mesothelin target or it would be limited, that is possible. I mean, most of the tumor types that we're going into have some level of mesothelin, so we would probably not think it's possible, you know, unlikely, but you're right, it theoretically could happen. And I think then, but your question about then, that then leading to potential, you know, deleterious effects through T cell exhaustion or having a negative effect, part of the design, you know, consistent with other T cell engagers as well, but we also made sure on 171, you don't get T cell activation. The interaction that we've got with the CD3 is very low affinity, and it's not, you know, it requires first that you co-engage two binding sites on mesothelin to really sit the molecule down on a mesothelin target population, and then you engage the CD3, and then that gives you the activation. And that's pretty comprehensively looked at. So I'm not so worried about that being a negative effect. The other part about the soluble mesothelin there, we tested that. in vitro, and you basically just combine with mesothelin, and there's a very limited impact on the killing, and you can still get to maximal levels of killing. And I think, again, that there is partly this avidity-driven effect that we have, and the fact that to get any impact on activity, you really need to be launched or binding to a cellular surface as opposed to a soluble protein. That, you know, happy to share more data on that with you and discuss it further, John. But the data, you know, speaks to that and supports that mechanism.
spk02: Makes sense. I would love to talk more about the detail there, but maybe not on the Q&A section here. Can I ask a follow-up on the bullet receptor alpha program? One of the things you said in the prepared remarks was that you were specifically looking at for a payload that would support a higher antibody dose. And I guess I'm curious why that's intrinsically valuable, given that blocking FR-alpha isn't in itself effective. So what's the benefit to giving a higher dose versus a lower dose if aggregate payload toxicity is similar?
spk10: Yeah, yeah, that's a good question. I think, you know, there's, you know, they are partly thinking is that the higher the dose that you can get into a patient, the more chance you've actually got of getting the drug to target. So you may be aware that lower doses, you've got, you know, just the penetrance through into the tumor, only one to 2% of the antibody actually gets to site. So the higher dose you've got in a patient, the more chance you've got of getting a threshold level of antibody ADC into that tumor. And that also, gives me the opportunity to also promote as well. That's why it's so important on the front end of the antibody as well. That's why we bring up this point about us having better internalization because you also want what does get to the tumor to also internalize very efficiently. So that's where our thinking on the design there is. And by having a more moderate payload or potency similar to DXD, that allows you to get that higher dose into a patient so that you've got that better amount of drug that can then get to tumor.
spk02: Makes sense. And then I guess one final one on the share repo. I guess I'm just curious about this is a use of capital given expectations for five plus programs in the clinic and obviously a very active drug discovery effort. Is there really excess capital at this point to return cash to shareholders versus driving value through clinical development?
spk09: No, good question. I think if you look at our current operations now, obviously, ZW171 and 191 are going very fast and are well-funded. ZW220 and 251 are on schedule to go into the clinic next year. They're well-funded. Beyond that, the fifth indication and what's in Paul's portfolio behind that, which we call advanced right now, is well-funded and moving forward. So we think we're adequately funding all the opportunities we have in front of ourselves and are quite happy with the level of R&D investments. Strategically, we've made the decision to claw back the capital allocation we had for Zanizo to complete the phase two and prepare for a registration study for the reasons we outlined. And that happens to provide about $30 million of cash, which doesn't need to be allocated to the remaining portfolio five by five or Paul's advanced portfolio. We've looked for a little while about opportunities that might be outside to use for that capital. But I think right now the most thoughtful capital allocation we can make with our current valuation, the catalyst in front of us, the strength of our cash runway, the optimism we have about the outlook being positive going forward is to, again, invest in ourselves, which we think will boost total shareholder return. And we certainly convinced that a thoughtful capital allocation process as with periodic buybacks and a smart R&D strategy can coexist in a biotech company. And hopefully that's the way to optimize total shareholder return over the long term. And that's what we're committed to. And we've seen the opportunity now uniquely to do it in front of some catalysts in 2024 and 2025 with some cash that we surely think is excess for now. And therefore, we're going to utilize that in a shareholder program to invest in ourselves. And we think that's of a benefit to all of our shareholders.
spk04: And so that's what we've chosen to do. Thanks very much. You're welcome. Thank you.
spk03: As a reminder, to join the question queue, you may press star 1-1 on your telephone keypad. You'll hear a tone acknowledging your request. If you're using a speakerphone, please pick up your handset before pressing any keys. Our next question comes from the line of Robert Burns at HC Wainwright.
spk08: Robert, your line is open. Thanks. Congrats on the question. From me, if I may. With regard to 171, you know, from a go-slash-no-go signal perspective in a dose escalation, What are you looking to achieve in particular with regards to ovarian cancer and MS-CLC? And would what Gavisal demonstrated in ovarian cancer be a good reference point for us?
spk04: Good question.
spk09: I'll let Pranchal decide how he wants to answer that question, what we're looking for.
spk07: Yeah, very good question. I think initially we want to assess the safety and tolerability of our assets. Paul's group has spent a lot of time and thought into the design of the structure. We feel we have a strong candidate that we're bringing to clinic. So the focus would be on a mesothelin targeting agent that shows safety and tolerability. So that's the core of the phase one study. We will gather data on efficacy in these tumor types and these will be measured using reasons criteria to measure our objective response rate. We'll be gathering other data such as PFS data and OS data, but the fundamental of the phase one study is to focus on safety and tolerability.
spk08: All right, thank you.
spk03: Thank you. I'm showing no further questions in the queue at this time. I would now like to turn it back to Chanel for closing remarks.
spk01: Pauline, that's being handed over to Ken for closing remarks.
spk09: Yeah, that's great. Well, thank you very much for your time and attention today and listening to questions, and we very much look forward to reporting on progress against our milestones for the remainder of 2024. And please stay tuned, and we'll provide some updates on progress throughout the course of the year. Thank you very much.
spk03: Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.
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