Zymeworks Inc . (NYSE: NASDAQ:ZYME) reported its financial results for the third quarter of 2024, revealing a net loss of $99.2 million, which is a slight improvement from the $104.2 million loss in the same period last year. The company, which specializes in the development of innovative cancer treatments, has made significant progress in its clinical programs, including the advancement of its bispecific T cell engagers and antibody-drug conjugates (ADCs). The IND applications for two of its promising ADCs, ZW220 and ZW251, are set to be filed in 2025. Zymeworks also announced a $30 million stock repurchase program and reported substantial cash reserves, ensuring company operations into the second half of 2027.
Key Takeaways
Zymeworks reported a Q3 2024 net loss of $99.2 million, a decrease from the previous year’s loss.
The company has $374.9 million in cash resources, providing a runway into the second half of 2027.
FDA cleared IND applications for bispecific T cell engagers ZW171 and ZW191, with ZW171 already in Phase 1 trials.
Preclinical data for ZW220 and ZW251 presented at the ENA conference showed strong potential for treating various cancers.
IND applications for ZW220 and ZW251 are planned for the first and second half of 2025, respectively.
Zymeworks is advancing its pipeline with a focus on innovative ADC design and safety, as well as a trispecific T-cell engager expected to file an IND in the first half of 2026.
Company Outlook
Zymeworks plans to file IND applications for ZW220 and ZW251 in 2025, aiming to have all three of its 519 payload ADCs in early clinical development by the end of that year.
The company is preparing for an R&D Day in December to share updates on their portfolio, including a new trispecific T-cell engager product candidate.
Bearish Highlights
Total revenue for the nine months ending September 30, 2024, was $45.3 million, down from $59.1 million in the same period in 2023.
The company reported a net loss, though it was a slight improvement from the previous year.
Bullish Highlights
Zymeworks completed a $30 million stock repurchase program, signaling confidence in the long-term value of the company.
The company’s cash reserves are substantial, providing a significant runway for future operations and development.
Misses
No immediate data expectations were set for the upcoming R&D Day regarding Phase 1 studies for programs 171 and 191.
Q&A Highlights
CEO Kenneth Galbraith expressed optimism about the progress and upcoming milestones in 2024.
The company is interested in pursuing autoimmune diseases and is focusing on balancing tumor expression versus normal expression in target selection.
Zymeworks is cautious about sharing initial clinical data until more robust datasets are available.
The company is open to future business development opportunities, including collaborations and licensing deals.
Zymeworks continues to make strides in its mission to develop transformative therapies for patients with cancer. Despite facing a net loss, the company’s management remains optimistic about the future, emphasizing the potential of its innovative ADCs and bispecific T cell engagers. With a robust cash position and strategic plans for future partnerships, Zymeworks is poised to continue its pursuit of advancing cancer treatment options. The upcoming R&D Day in December is expected to provide further insights into the company’s long-term strategies and development progress.
InvestingPro Insights
Zymeworks Inc. (NYSE: ZYME) has shown promising developments in its clinical programs, and this progress is reflected in some of its financial metrics. According to InvestingPro data, the company’s stock has demonstrated strong performance, with a 95.16% price total return over the past year and a 56.39% return over the last six months. This upward trend aligns with the company’s advancements in its cancer treatment pipeline and the positive outlook shared in their recent earnings report.
Despite the reported net loss, InvestingPro Tips highlight that Zymeworks holds more cash than debt on its balance sheet, which supports the company’s statement about having substantial cash reserves to fund operations into the second half of 2027. This financial stability is crucial for a biotechnology company in the development stage, allowing it to continue its research and clinical trials without immediate funding concerns.
Another relevant InvestingPro Tip indicates that four analysts have revised their earnings upwards for the upcoming period. This could be interpreted as a positive signal, possibly reflecting confidence in the company’s pipeline progress and potential future revenue streams from its developing cancer treatments.
It’s worth noting that InvestingPro offers 11 additional tips for Zymeworks, providing investors with a more comprehensive analysis of the company’s financial health and market position. These insights can be particularly valuable for those looking to understand the full picture of Zymeworks’ potential in the competitive biotechnology sector.
Full transcript – Zymeworks Inc (ZYME) Q3 2024:
Operator: Hello. 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 a listen-only mode and the conference is being recorded. After the presentation, there will be an opportunity to ask questions. [Operator Instructions] I would now like to turn the conference over to Shrinal Inamdar, Director of Investor Relations. You may begin.
Shrinal Inamdar: Thank you, operator. Good afternoon, everyone and thank you for joining our third 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 a discussion of these risks and uncertainties, we refer you to our latest SEC filings as found on our website and as part of the SEC. In a moment, I will hand over to Leone Patterson, our Executive Vice President and Chief Business and Financial Officer. Leone joined our leadership team in September 2024 and today Leone will be discussing recent corporate updates along with financial results for our third quarter 2024. Following this, Dr. Paul Moore, our Chief Scientific Officer, will talk about key highlights for our third quarter, including the initiation of a first patient dose in the Phase 1 trial of our first bispecific 2 plus 1 [ph] mesothelin T cell engager ZW171. At the end of the call, Leone, Paul and Ken Galbraith, our Chair and CEO, 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 will now turn the call over to Leone.
Leone Patterson: Thank you for the introduction, Shrinal, and thank you all for joining us today. I’m very pleased to have joined the Zymeworks team at such a pivotal time of growth and at a time when we are on the cusp of many exciting developments still to come as you close out the rest of 2024 and a series of new developments anticipated in 2025 which underpin our long-term growth strategy. I look forward to talking more about these milestones as we continue to execute on our R&D pipeline and corporate objectives. If you could now turn your attention to slide five where I will touch on recent key achievements across our development program. Starting first with our wholly owned pipeline, we received FDA clearance for our IND applications for both ZW171 and ZW191 in August this year. Since then, over the past few months, our global clinical development team has been working very quickly and efficiently to enable dosing of the first patient with ZW171 as part of our global Phase 1 clinical trials. Later, during today’s call, Paul will provide more details on the clinical trial design for ZW191, as well as providing an update on the progress we have made in the clinical development of ZW171 across North America, Europe, and the Asia-Pacific region. We also had the opportunity to present more promising preclinical data on our wholly owned pipeline at the ENA conference earlier this month in Barcelona for both ZW220 and ZW251, which Paul will go through in more detail later in the call. These preclinical data highlight the transformative potential of our novel approach to designing ADCs utilizing our proprietary payload 519 and highly differentiated antibodies, and we look forward to updating on the anticipated IND filings for both ADCs in 2025. Moving on to our partner programs, Jazz Pharmaceuticals (NASDAQ:JAZZ) provided updates for our internally developed HER2-positive targeting bispecific antibody Zani. Recent presentations at the ESMO Annual Congress in Barcelona continue to highlight Zani’s potential for the treatment of multiple HER2-positive indications, including long term follow up data in metastatic DEA patients for which a Kaplan Meier estimated 30-month overall survival of 59% was reported from an ongoing Phase 2 clinical study of Zani in combination with chemotherapy. We’re also pleased to recognize in our Q3 revenues a $2.5 million research milestone from our longstanding partner GSK. This milestone provides continued validation of the strength and versatility of our internal platforms and technologies, including asymmetric, where we continue to have a range of legacy licensing arrangements in place. As a reminder, under the terms of this agreement with GSK, we received an upfront technology access fee and we remain eligible for future research, development and commercial milestone payments of just over $1 billion. In addition, we are also eligible for 10 royalties on any worldwide sales of the licensed products. While we’ve had a busy few months on the development of our R&D pipeline, we have also been executing on our corporate goals. This includes completing the first $30 million of our share repurchase program, which I will touch on next. On August 1, 2024, we adopted a stock repurchase program to repurchase up to $60 million of the company’s outstanding common stock, with an initial authorized price of $30 million. As of October 31, 2024, we have completed the initial $30 million of the repurchase program through the purchase of approximately 2.5 million shares of common stock at an average price per share of $11.79. Now turning to our financial position. This afternoon Zymeworks reported financial results for the third quarter of 2024. Zymeworks net loss for the nine months ended September 30, 2024 was $99.2 million or $1.30 per diluted share compared to a net loss of $104.2 million for the same period in 2023. The decrease in net loss was primarily due to lower research and development, and general and administrative expenses, as well as a decrease in income tax expense, which was partially offset by the decrease in revenue and an impairment charge recognized in 2024 related zanidatamab zovodotin. As reported, our revenue for the nine months ended September 30, 2024 was $45.3 million compared to $59.1 million for the same period in 2023. Revenue for the nine months ended September 30th, 2024 included $32.8 million for development support and drug supply revenue from Jazz, $8 million of milestone revenue from BeiGene (NASDAQ:BGNE) in relation to the acceptance by the CDE of the NMPA in China of the BLA for Zani for second line treatment of HER2-positive BTC, $2.5 million of milestone revenue from GSK in relation to the sequence peer nomination by GSK under the 2016 licensing agreement with them, and $2 million from BeiGene and other partners for research support payments. Revenues for the same period in 2023 included $56.3 million for development support and drug supply revenue from Jazz and $2.8 million from BeiGene and other partners for research support and other payments. Overall, operating expenses were $160.2 million for the nine months ended September 30, 2024, compared to $173.7 million for the same period in 2023, representing a decrease of 8% year-over-year. The decreases in overall operating expenses resulted from a decrease in both research and development expenses, as well as general and administrative expenses. The decrease in research and development expense was primarily due to a decrease in expenses for Zani as a result of transfer of responsibility for this program to Jazz and a decrease in expenses for ZW171 and ZW191. This decrease compared to the same period in 2023 was partially offset by an increase in expenses for ZW220 and ZW251 and other preclinical and research activity. Stock based compensation expense increased primarily due to a lower expense in 2023 as a result of the cancellation and modification of awards in respect of employees transferred to Jazz. Now turning to G&A. The decrease in G&A expense was primarily due to a decrease in external consulting expenses for information technology, legal fees and other expenses for advisory services, insurance and depreciation and amortization expense compared to the same period of 2023. This was partially offset by costs incurred due to the termination of our long-term facility lease in Seattle in 2024 and an increase in stock based compensation over 2023 primarily due to reversal of compensation expense for option cancellations and modifications in 2023. During the nine months ended September 30, 2024, we recorded a non-cash impairment charge of $17.3 million as a result of the company’s decision to discontinue the zanidatamab zovodotin clinical development program which utilized the technology represented by acquired in process research and development assets. Other income net was $16.1 million for the nine months ended September 30, 2024 compared to $14.6 million for the same period in 2023. The increase was primarily driven by an increase in the average interest yield of our cash balances and investments during the period. As of October 31, 2024, we had approximately 68.9 million shares of common stock outstanding and approximately 5.1 million shares of common stock issuable under prefunded warrants. As of September 30, 2024, we had $374.9 million of cash resources consisting of cash, 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.zymeworks.com. Now I want to turn to the cash runway. Based on current operating plans, our strong financial position of $374.9 million in cash resources as of September 30, 2024 together with certain anticipated regulatory milestone payments continues to provide an expected cash runway into the second half of 2027. And just as a reminder that we may also be able to extend this runway or fund an expanded R&D scope through potential additional regulatory approval milestone payments in connection with our existing partnerships with Jazz and BeiGene, 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 Zani and tiered royalties between 10% and 20% on Jazz’s annual net sales and between 10% and 19.5% on BeiGene sales. With that, I’d like to hand over to our Chief Scientific Officer, Dr. Paul Moore, who will provide more details regarding the development of our wholly owned pipeline and our highly anticipated R&D Day later this year.
Paul Moore: Thank you, Leone. So I’d like to start off by talking about some of the preclinical work Leone mentioned earlier in the call, which we presented last week at the ENA conference in Barcelona. For ZW220, we were pleased to share data which demonstrates that 220 exhibits robust activity across a wide range of NaPi2b expression levels in vitro and then showing also significant antitumor efficacy in patient derived xenograft models of ovarian, endometrial and non-small cell lung cancer. In these preclinical models, 220 was highly active at a single dose of 6 mg per kg across the models tested. In these studies, we evaluated between four and eight models per indication and based on tolerability data, the 6 mg per kg is actually considered a conservative dose for 220, suggesting room for dose optimization in future preclinical studies. Importantly, 220 also displays bystander mediated killing activity as shown in this slide in two different in vitro models. First, on the bottom left of the slide we observe bystander activity against the NaPi2b negative cell line in a classic 2D culture model system with 220 which incorporates our proprietary Topo1 payload at DAR4, demonstrating bystander activity comparable to that observed with version of 220 incorporating DXd at DAR8. Furthermore, 220 also effectively inhibits the growth of heterogeneous NaPi2b expressing 3D spheroid models comprising a mix of NaPi2b positive and NaPi2b negative tumor cells. This demonstration of strong bystander killing in vitro we believe is a critical attribute of 220 when targeting tumors with potentially non-uniform expression of NaPi2b. Our ADC also demonstrates a well differentiated safety profile. Compared to higher potency Topo1 inhibitor ADCs such as dosing incorporating Exatecan, 220 has shown a more favorable safety profile in preclinical toxicology studies with a maximum tolerated dose of greater than 90 mg per kg in non-human primates and greater than or equal to 200 mg per kg in rats. This indicates the potential for high dosing in humans which could further enhance its therapeutic impact. Taken together, we’ve incorporated several key features to optimize the efficacy and safety of 220. The low drug to antibody ratio and moderate stability of the antibody linker provide a good balance between tolerability and antitumor activity, minimizing potential on target or off tumor toxicities. The strong internalizing antibody we’ve developed ensures efficient tissue penetration and cellular trafficking, improving our antibody tumor activity especially in tumors with lower NaPi expression. Lastly, the Fc gamma receptor silenced antibody design minimizes the risk of off target toxicities, particularly from uptake by normal macrophages. This design contributes to the overall safety profile of 220 which as I showed has been well tolerated in both non-human primates and rats. All of the features discussed above related to the design of 220 provide a clear differentiation from other NaPi2b ADCs in early development and gives us confidence in the potential of 220 to be best-in-class as we transition 220 from preclinical development into early stage clinical studies next year. We remain on schedule with our preclinical development of 220 to support an IND filing and form applications in the first half of 2025. Moving onto other data presented at the Triple meeting or the ENA on ZW251, another ADC incorporating our 519 payload. That data continues to demonstrate significant potential for 251 addressing unmet needs in hepatocellular carcinoma and other GPC3 expressing tumors. 251 is designed to selectively bind, internalize and kill GPC3 expressing tumor cells or glypican-3 expressing tumor cells. This precise mechanism of action coupled with the antitumor efficacy we’ve observed reinforces its potential as a targeted therapy for glypican-3 expressing cancers. One of the most promising aspects of 251 is its robust antitumor activity observed across a broad panel of hepatocellular carcinoma xenograft models, including both cell line derived xenografts and patient derived xenograft models. Importantly, 251 demonstrates a dose responsive antitumor effect with a single 8 mg per kg dose showing activity in 5 out of 6 cell line derived models and 9 out of 12 PDX hepatocellular cancer models. This includes models with lower or heterogeneous glypican-3 expression, underscoring the breadth of its therapeutic potential in targeting tumors with variable antigen presentation. Our team selected the drug to antibody ratio or DAR4, but this ratio provides an optimal balance between safety and therapeutic impact. In fact, the DAR4 molecule has demonstrated a compelling breadth of antitumor activity in vivo which is crucial for maximizing its efficacy across diverse tumor types. This broad target mediated activity across this range of hepatocellular cancer models continues to validate the strength of our ADC platform. In terms of safety, 251 has been well tolerated in repeat dose toxicology studies in non-human primates exhibiting dose proportional pk. This positive safety profile along with its robust preclinical efficacy positions 251 well for clinical advancement. Looking ahead, we expect our preclinical development to support an IND submission in the second half of 2025 and we believe 251 has the potential to provide a much needed therapeutic option for patients with hepatocellular carcinoma and other GPC3 expressing tumors. We’re excited to continue developing this promising candidate and help make a meaningful impact in oncology. By the end of 2025, we expect to have all three of our 519 payload ADCs in early clinical development. We look forward to understanding how the design of our optimized antibody and proprietary payload might translate these promising preclinical findings into clinical efficacy for our ADC candidates. At Zymeworks, the time and care to ensure we have a deep understanding of target biology allows us to innovate on elements of our ADC which we think could make a meaningful difference for efficacy but importantly also for tolerability. Together, we believe that these design features could allow us to optimize at higher protein doses than other ADCs, ultimately maximizing the potential of these therapies to improve the standard-of-care for patients. Increased tolerability would also allow us to explore combination regimens for our candidates with the hope that we can reach first line patients to really make a difference and extend progression free survival and overall survival for these patients. Notably, we made a conscious decision not to repurpose existing molecules like Exatecan for our ADCs. Instead, we aim to create a proprietary Topo1 payload with characteristics ideally suited for an ADC, potentially allowing our candidates to outperform efficacy seen today with drugs that utilize a repurposed payload. These characteristics include moderate potency which we believe could have a two-pronged effect of one, enabling protein dose and bystander activity to enhance potential efficacy, while two, also limiting damage where conjugated drug accumulates in some normal tissues and therefore, increasing also tolerability. By reviewing ADCs that have been explored in the past, we believe our design philosophy is consistent with learnings from prior clinical data. We have observed that increased potency of other repurposed payloads such as Exatecan seems to limit its maximum tolerated dose relative to moderate potency Topo1 inhibitor payloads, which may limit the potential of the higher potency payloads to get into the efficacious dose range. Another feature we have factored into our design to potentially maximize tolerability and efficacy of ADCs is linker stability. Historically, increased antibody linker stability has demonstrated improvements in preclinical therapeutic index, but these findings have not translated into the clinic. We believe that moderate linker stability as employed in most clinically approved ADCs will limit normal tissue exposure to conjugated drug, also contributing to improved tolerability. Regarding DAR and drug antibody ratio, we studied both DAR4 and DAR8 versions of all three of our 519 payloads before carefully selecting the most appropriate DAR for each base — each molecule based on our understanding of target biology, the targeted patient population and the results of our preclinical studies. Lastly, and importantly, our efforts have been concentrated on optimizing the antibody properties, particularly internalization and tumor penetration. We firmly believe that the key to ADCs being effective and tolerable and ultimately reaching those early lines of therapy is ensuring an appropriate protein dose. We have also carefully considered the potential benefit of incorporating HepC mutations on our antibodies based on the target population and that data supported — and data supported by preclinical studies. From our preclinical work and empirical review of clinical data over the past 40 years, we believe that our approach is differentiated from other ADCs currently under development. We believe the primary factor is ensuring an appropriate protein dose within the optimal range. Together, we believe that these design features could allow us to optimize at higher protein doses than other ADCs, ultimately maximizing the potential of these therapies to improve the standard-of-care for patients in both monotherapy settings and for combination therapy as well as in earlier lines of treatment. We are very much looking forward to evaluating these novel design features and their effect on tolerability and efficacy using against relative to clear benchmarks from peers and highly validated targets. The first of which will be our Phase 1 clinical trial of our ADCs ZW191. Based on the encouraging preclinical findings, we are moving forward to validate these results in the clinical setting. We anticipate dosing the first patient this year in our Phase 1 open label multicenter study of 191 registered under NCT06555744 on clinicaltrials.gov. The study is actively recruiting and aims to enroll 145 participants with advanced solid tumors including ovarian, endometrial and non-small cell lung cancers across North America, Europe and the Asia-Pacific region. The study is designed to evaluate the safety, tolerability, pharmacokinetics and preliminary antitumor activity of ascending doses of 191. Part 1 of the study will evaluate the safety and tolerability of 191. Part 2 of the study will evaluate safety and explore the potential of antitumor activity of ZW191 according to the RECIST evaluation criteria while continuing to evaluate the safety and tolerability. Criteria includes pathologically confirmed ovarian cancer, endometrial cancer, non-small cell lung cancer and or progressive disease refractory to all standard-of-care that confer clinical benefit measurable disease per resist. We look forward to reporting first patient dose in the near future and discussing progress in the coming earnings calls. Regards to 171 or ZW171. As Leone mentioned earlier in the call, it was only in August that we were announcing the FDA clearance to move forward with Phase 1 clinical trials for 171. The speed of efficacy in our team’s ability to move 171 forward to first patient being dosed in such a short time as a credit to the dedication and collaboration of our global hubs. Since we last presented our earnings, we have been working towards activating sites in North America, Europe and the Asia-Pacific region in our Phase 1 trial for 171. In this slide you will see that we have made progress here with clinical sites activated in North America. As a reminder for our clinical trials for 171, we expect to recruit 160 patients globally which we anticipate will present us with a high level of diversity in patient characteristics including expression levels across tumor types. We believe this diversity should result in higher quality data sets and hopefully more conclusive results will retrospectively determine expression cutoffs. We look forward to talking more about the work our team conducted to support selection of the starting dose for 171 at SITC next week. As we have previously communicated, internally we have a very clear target product profile for our candidates, and so the ability to initiate dosing closer to the expected efficacious dose means that it provides the potential to understand signs of efficacy as well as tolerability more clearly early on in the study. This is especially important as we continue to keep financial and scientific discipline within the organization in order to focus on the candidates that have the best chance of success in being meaningful treatment options for patients. Our R&D engine is continuing to work in the background on the next wave of innovative modalities in therapeutic areas where patients with significant unmet needs are lacking effective treatment options. With this in mind, we will continue to advance assets that have the highest potential to change the standard-of-care or to move on to other promising candidates where we can innovate further with the hope for better patients — for better therapies for patients. Finally, I’m also pleased to share an update about our upcoming R&D Day where we will provide in-depth updates on our growing portfolio of solid tumor targeting antibody drug conjugates and T-cell engager molecules. This will be a unique opportunity for us to showcase the progress we’ve made in advancing our innovative pipeline, and we are thrilled to be joined there with several key opinion leaders from the oncology field. Together with our management team, these experts will discuss the latest developments in our ongoing R&D and clinical activities, underscoring our commitment to delivering transformative therapies for patients. One of the highlights of the day will be the formal nomination of the latest product candidate from our 5 by 5 portfolio, a tri T-cell engager — Trispecific T-cell engager. This will mark the final nomination in our ambitious 5 by 5 R&D strategy with a projected IND filing in the first half of 2026. This nomination is a major milestone for us, reinforcing the strength of our T-cell engager platform. We’ll also discuss our strategy for our continued focus in solid tumors, while also expanding into new therapeutic areas, particularly in hematological cancers and autoimmune inflammatory diseases. These areas represent a natural extension of our core strengths and we see tremendous potential to apply our technology platforms to these new indications. Lastly, we’ll provide updates on our preclinical development progress, which includes potential IND filings for new product candidates in 2026 and beyond. This progress is a testament to the innovation happening within our labs and positioned us well for continued growth of an exciting R&D portfolio in the years ahead. We were excited to share these developments at our R&D Day and look forward to highlighting the advancements that will drive the next chapter of our company’s growth. And with that, I’ll hand it to Ken for closing remarks.
Kenneth Galbraith: That’s great. Thank you, Paul. I’m very pleased with all the progress we’ve made so far this year, and we’re only just getting started on the clinical development for some very interesting targets in patient populations with significant unmet need. With that being said, there’s still plenty more time left in 2024 and we plan to make full use of this time to continue building on our momentum so far this year and complete a few more significant pipeline events before the end of the year. First, I also share in Paul’s enthusiasm for updates we plan to make during our upcoming R&D Day in December, where we’ll officially nominate our new Trispecific T-cell engager product candidate. This nomination is a significant milestone for us to complete the 5 by 5 portfolio almost two years ahead of the initial schedule and certainly highlights the continued growth and diversification of our pipeline as we expand our new modalities and novel treatment approaches. In addition to some of these updates, I also want to highlight that our partner Jazz has initiated a pivotal Phase 3 trial named EmpowHER, evaluating zanidatamab patients with HER2-positive breast cancer whose diseases progressed on previous T-DXd treatment. This is a major step forward in potentially bringing new potential treatment options to patients with metastatic breast cancer. Internally, we’re extremely proud of the potential impact zanidatamab could have for patients across multiple tumor types in oncology based on the breadth of clinical activity seen today, which really showcases how this targeted therapy is able to bind to HER2 and kill tumors with a very unique mechanism of action. Having discovered and developed zanidatamab at our labs in Zymeworks, our teams have been taking some learnings from the screening, optimization and clinical development of this unique bispecific antibody and we look forward to continue reporting on progress of how we hope to replicate this level of optimization efficacy with our wholly owned pipeline. The success of Zani as a target HER2 agent also gives us reassurance that highly expressed targets are where we want to focus on developing future therapeutics. We believe that high and clear levels of expression are important when developing highly targeted candidates and moving away from previously used chemo like treatments. The decision to develop candidates for these highly expressed and validated targets such as folate receptor alpha, NaPi2b and GPC3 mean that we can quickly and effectively understand if there’s a correlation between efficacy and expression levels across tumor types, as well as benchmark our data against previously developed candidates. Looking ahead, Jazz has estimated that top line progression free survival data for the ongoing Phase 3 HERIZON-GEA-01 study will be available in the second quarter of 2025. Finally, we’re eagerly anticipating the PDUFA date of November 29, 2024 for zanidatamab in second line HER2-positive biliary tract cancer in the U.S. This potential approval in the United States would be one of the most substantial achievements for Zymeworks history and in collaboration with our partners Jazz Pharmaceuticals and BeiGene, a critical step forward for biliary tract cancer patients who currently have limited treatment options. Jazz is scheduled to hold their Q3 earnings call within the next week and we encourage you to follow that for any further developments or guidance related to zanidatamab. Before we move on to Q&A, I’d like to acknowledge this is the first earnings call since Leone has joined us at Zymeworks in September. She’s a very experienced executive leader in biotech and has already had a positive impact in many aspects of our operations, working in collaboration with our management team. We’re very fortunate to have tracked her design and I look forward to working closely with her alongside the wider leadership team on building Zymeworks further. I’d also like to take a moment to thank Mr. Hollings Renton, who will be stepping down from the Board in December, for his significant contributions to our company over the past eight years and also being a great advisor for me during my tenure as CEO. Hollings guidance has been invaluable in shaping the direction and growth of our business. He’s had an amazing and successful career in our sector and we’re very grateful for his dedication to our mission at Zani. As we continue to evolve as a company, I’d like to highlight that over the past 18 months we have welcomed six new members for our Board of Directors as part of a strategic forward refresh process. This initiative is a reflection of our commitment to ensuring we have the right mix of experience and expertise to guide our next phase of development and growth. The Board remains diverse, strong and well-positioned to support our long-term objectives as we continue building on our momentum. With those closing remarks, I’d like to thank everyone for listening and I’ll turn the call over to the operator to begin the question-and-answer period.
Operator: Thank you. [Operator Instructions] Our first question comes from the line of Stephen Willey with Stifel. Your line is open.
Stephen Willey: Yeah. Good afternoon. Thanks for taking the questions. Maybe a couple for Paul and/or Ken. With respect to the ongoing Phase 1 trials for 171 and 191, just curious how you’re thinking about dose optimization? Are you going to be backfilling specific dose levels in the escalation phase to generate the exposure data, you need to select a Phase 2 dose for expansion, or do you think it’s more likely you’ll be carrying two doses forward into the expansion phase? And then I just have a follow-up.
Kenneth Galbraith: Yeah. Good question, Steve. I think the way we think about it is in the dose escalation phase, we hope to really have a chance to have a good high-quality set of patients with diversity around tumor types, diversity around expression levels that really let us understand the tolerability profile. And that’s both for 171 and 191. I think our expectation is that in addition to backfilling and having a chance to explore some alternative doses in dose escalation, we’re likely going to have to move forward into the expansion cohorts and optimize more than one dose in specific cohorts, maybe one or maybe two of those cohorts. But I think it’s really necessary to do that so that by the time we leave a Phase 1 study, we have a very clear understanding of the tolerability profile and a very clear understanding of the optimum dose to take forward. I think we’ve seen examples of other companies who have tried to accelerate or maybe go a little too fast in that process. And then again, that doesn’t help you accelerate to a registration study or accelerate to a potential filing or approval pathways. I think we’ve given ourselves a pretty big clinical footprint in Phase 1, as you’ve seen from 171, 191 geographically, a number of sites that should allow us to quickly recruit and study a pretty broad range of patients. If you look at the target patient populations we have for both 191 and 171 on Phase 1. So, I think we can move very quickly at the same time, make sure we collect enough patient data to be very clear about the tolerability profile, very clear about signs of activity, and very clear about the optimum dose that we want to take forward and not leave Phase 1 with any of those questions unanswered.
Stephen Willey: Okay. That’s helpful. And then I know Paul touched on this a bit in the prepared remarks, but obviously the preclinical data you have for all the ADCs and in your preclinical tox models would suggest that you’ve got a much wider TI versus some of the other ADCs that we’ve seen with Topo payloads using equivalent DARs. So, just wondering how that informs your development strategy specifically in terms of how you’re prioritizing combinations for each of these three assets. And I guess, is there any one of these ADCs in particular that you think might warrant a more accelerated path to a combination based development strategy? Thanks.
Paul Moore: Yeah. No, thanks, Stephen. And thanks for pointing that out — about the careful design that we’ve incorporated in the preclinical data that supports that we have this flexibility to hopefully have a little bit more therapeutic index than potentially others with different design. I think regarding combination strategies, we’re pretty much thinking about that for all three programs, because we do hope that we will be able to move up in earlier lines. So, I think we’re thinking quite broadly there. We don’t particularly specify one over the other. I think for all three we’re thinking that way. Obviously, in the treatment paradigm of the disease indication that you’re going against that that will drive the specific combination partner molecules. So, whether that’s VEGF inhibitors or PARP inhibitors in the context of ovarian cancer or PD1 inhibitors in the context of non-small cell lung cancer, those are the types of combinations that we’re thinking about and we think are compatible with the design strategy that we have.
Stephen Willey: All right. Thanks for taking the questions.
Operator: Thank you. Please stand by for our next question. Our next question comes from the line of Akash Tewari with Jefferies. Your line is open.
Unidentified Analyst: Hi, thank you for taking my question. This is Phoebe on for Akash. Just one on Xani. The DESTINY-Gastric03 study in HER2-positive gastric cancer is reading out in July of 2026, but it’s being studied with chemo and/or immunotherapy and just wondering how you view this regimen and if it’s a threat to Xani at all. Thank you.
Kenneth Galbraith: Yeah. Thank you for the question. I think we’ve been obviously carefully following potential competitive programs to Zani and all the indications of interest for us from some time period now. And I know our partners Jazz and BeiGene are doing the same thing. I think, with respect to any view ourselves we feel very strongly about the clinical data that we’ve generated to date on zanidatamab and its potential as monotherapy as we have in our PTC (NASDAQ:PTC) filing and also sort of in gastric cancer. But it’s our ability to combine with other product modalities and really seem to generate much higher levels of response in that patient population and generate much more durable responses than have been seen by either approved therapies or some of those under development like you mentioned with a tolerability profile, which is very good compared to some of those other agents which might be under development. So, we feel very confident in the data center around zanidatamab with respect to where we are and obviously our upcoming clinical data readouts will hopefully confirm some of that confidence we feel behind zanidatamab and beyond that, don’t really feel in a position to comment about other companies datasets where we may not have access to all the data. But with respect to the data we have on Xani, we feel very comfortable and confident with zanidatamab’s ability based on the clinical dataset to date to really make a difference in this patient population in a significant way. And we’re looking forward to having that readout next year obviously.
Unidentified Analyst: Thank you.
Operator: Thank you. Please stand by for our next question. Our next question comes from the line of Yigal Nochomovitz with the Citi. Your line is open.
Ashiq Mubarack: Hi, guys. This is Ashiq Mubarack on Yigal. Thanks for taking my questions and appreciate the update today. I had one on how we should be thinking about timelines to data or maybe more generally your philosophy about data sharing related to the holly owned pipeline, especially the lead mesothelin and FR alpha programs. I’m just wondering if we should be expecting maybe an early look at the dose escalation cohorts or if your philosophies more are going to be along the lines of generating a robust dose escalation package or maybe even expansion package before sharing that data with us.
Kenneth Galbraith: Yeah. Thanks for the question. I think we do have a very specific philosophy obviously — undertaking these first two Phase 1 studies for 171 and 191, you can see that we do have the advantage of very tolerable molecules based on preclinical data which allows us to have what you might think is a higher starting dose than you might have seen with other agents in similar classes. And that’s obviously an advantage to try to go more quickly to an active range while studying the tolerability profile. We also have very broad global footprint with many active sites that we’re bringing online now, which again allows us to hopefully not only collect a quality and diverse dataset of patients across the population we want to study, but also do that on a very timely basis. That being said, we’ve not given any guidance to where early data will be given, and I don’t think we’ll do that until we’re comfortable that we have a large enough dataset to make some conclusions about the dataset and the product that we’d like to share in a peer reviewed scientific or medical meeting, which is where you’ll see it all, not by a former press release or investor call. So, once we feel comfortable, we’ve got a data set that we’d like to share and likely that we’ve had an abstract accepted, then I think we’re quite comfortable sharing publicly that we’re going to share that in a scientific medical meeting. Obviously, seen recent examples of companies who can do that quite quickly. And again, it depends on how quickly we can recruit patients, what that data tells us and what conclusions we’d like to share with the scientific and medical community in a peer reviewed manner. And so, I think we won’t provide guidance until we’re a little more certain about the timeframe to do that. But please be assured we’re trying to collect a quality, diverse, substantial dataset in Phase 1, including dose escalation. And if we do that well and timely, there might be a lot that we can understand from the drug at a very early stage. And then we’re happy to share that with the scientific medical community that understanding as quickly as we can.
Ashiq Mubarack: Got it. That’s very helpful. And if I could ask one more, apologies if I missed this. But as I recall, the stock repurchase program allows for up to $60 million, unless I’m mistaken. And with the sort of $30 million — first $30 million tranche already done, I’m just wondering how you’re thinking about deploying the second $30 million, if that should be expected maybe over the near term, or if that’ll be more over a multiyear horizon, depending on market conditions and so on.
Kenneth Galbraith: Yeah. There was an authorized $60 million share purchase program. We did activate $30 million of that, which again gave us a little bit of optionality and flexibility to complete that first and then decide what to do with the rest. There’s no strict deadline or necessity for completing the second phase. So, I think we will continue to evaluate market conditions and our financial position and other factors and working with the Board, decide when it may be the right time to Initiate the second part of that. It’s a very carefully evaluated decision. Obviously, we did this in early August and we felt very strongly that there was a strong rationale for doing it, including the fact that we felt that our share price was undervalued compared to what we saw in the company as important factors in enterprise value. We still feel that way today, even though the shares have appreciated substantially since August. We do have the ability to complete the entire full 60 million share purchase program and maintain our projected cash run rate into second half 2027. But I think now we’ll do what we did last time, which is just carefully assess our financial position, look at a number of factors before we make that decision. And as we did last time, we’ll be very definitive when we start. And again, you won’t hear much about it until we complete that. So, if there’s an update, you’ll obviously hear about that publicly as required. But as of right now, we feel comfortable with what we did. We think it was an appropriate thing to do with the cash we had available, and we think there is a strong rationale for improving total shareholder returns with the action we took. Still feel we’re in a very undervalued position compared to what we see inside the company. But we’ll just take a moment to reflect before we think about initiating the second tranche. Again, there’s no timeline or requirement or necessity for us to continue on that. We will always have the ability to initiate that whenever we and working with our Board decide that it’s an appropriate thing to do for shareholders.
Ashiq Mubarack: Got it. Thanks very much.
Operator: Thank you. Please stand by for our next question. Our next question comes from the line of Brian Cheng with JPMorgan. Your line is open.
Brian Cheng: Hi, team. Thanks for taking our question this afternoon. And Leone, congrats on joining the team. Maybe just one related to the ongoing Phase 1 for 171 and 191. Can you talk about some of the criteria that you’ll be looking for in terms of efficacy before moving into larger expansion stage? And I might be asking this question a little bit earlier, but could we be expecting some clinical data at your R&D Day in December? And I have a follow up. Thank you.
Kenneth Galbraith: Yeah. Thanks for the question. Again, we haven’t given any guidance as to whether — when to expect clinical data for 171 and 191. We are interested because these are Phase 1 studies in understanding the tolerability and adverse event profile and that obviously takes some work in moving up in doses to understand adverse events as relate to the dose response. I doubt that’s going to be in place by the time we get to our R&D Day. And it was not the intention of the R&D Day to share initial data 171, 191 we — these are adverse — tolerability studies. So that’s the most important factor for us to understand that. Obviously, we look for signs of clinical activity, especially at doses that we think are more optimal for activity. We think a very important factor, especially with T-cell engagers, is the ability to drive a much more durable response than maybe you see with chemo and also with some ADC. So, understanding not only the ORR, but also DOR is extremely an important factor. And we have seen instances of where a very high initial response doesn’t end up being durable for the patient population. So having an understanding of that takes a little bit more time potentially. So, I doubt you’ll see anything at our R&D Day. But I think once we have enough data to tell us something and inform us about tolerability, adverse event profile, initial activity, and at least some idea of durability, which requires a little bit more follow up than maybe you see from some early dose escalation interim disclosures, then we’re happy to share that in a peer reviewed meeting. And when that happens, we’ll follow our data and obviously, make it public when we think we’re in a position to share that data. But I don’t think as you come to R&D Day in December 12th expecting to see initial clinical data in 171 and 191.
Brian Cheng: Okay. And then maybe just one more heading into the BTC’s PDUFA date next month and GEA’s top line next year. Just from a modeling perspective, how should we think of your partnership revenue near term?
Kenneth Galbraith: Yeah. I think, Brian, we’ve already publicly disclosed as much as we’re able in our agreements with Jazz. I can’t really say much more about that until we start to get paid milestones and receive them or get paid and receive royalties. We can’t really say much more about that. I think on timelines and guidance, with respect to top line on Zani, I will refer you back to Jazz and again also BeiGene, but especially Jazz for next week. They’ve already made some guidance around potential peak sales, but I would look for updates from them on development timelines, approval timelines, future filing timelines, and any revenue guidance they want to provide. That’s really up to Jazz. And they have their call next week. So, I would just pay attention to that.
Brian Cheng: Great. Thank you.
Kenneth Galbraith: Yeah. Thank you.
Operator: Please stand by for our next question. Our next question comes from the line of Jon Miller with Evercore ISI. Your line is open.
Jon Miller: Hi, guys. Thanks so much for taking the question. I guess, I’ll just first build on the earlier question. Maybe it was you guys on share repo. I know it seems like you’re not in any rush to get started with the second half, but did the first half of share repo achieve the goals that you hope to achieve with those purchases? And then beyond that, it seems like you’re suggesting a strong potential for more BD or other sources of funds in the upcoming years. And I’d love to get a little bit more color on that. What kinds of deals are you interested in? Discovery (NASDAQ:WBD) collabs, licenses on the 5 by 5 or collaborations and development there on the legacy tech? What are the things that you’re looking at when you talk about the potential for future deals? And I do have a follow up.
Kenneth Galbraith: No. Thanks for the questions. I’ll pick them both. So, I think respect to the share repurchase program, I think we carefully consider this before we initiate the first $30 million in August. I think we’ve been able to retire a little more than 2.5 million shares out of the cap table, which I think can provide a total shareholder return not just immediately, but over time. So, I think we still feel very strongly that we were able to achieve that objective despite the — obviously the increase in our price during that timeframe. I think we still feel that some of the elements related to our decision to do that still exist. We still believe that although we’ve had some appreciation since August in the share price, that we still feel very undervalued compared to what we believe the long-term value for the company is. And what we see inside it reflects our confidence in the future outlook of our business, potential of not just Zani, but our wholly owned product candidate portfolio. And I think the long-term value of even our further preclinical development pipeline, which you hear more about at R&D Day. I think the repurchase program is obviously one component of the overall capital allocation strategy we need to think about. I mean ideally first we need to make sure that we sufficiently fund the core business that we have, of all the exciting R&D opportunities we have inside the company. That’s always our first priority. I think if we do see opportunities to also provide some upside of total shareholder return, we are required to look at that and consider it. But I think we’ve accomplished the objectives we had. I think we, obviously, have the ability at any time to go ahead with a further shared purchaser program when we consult with our Board and make that known. Right now, we’re just taking a little pause to consider that with a number of other factors in consideration. I think with respect to partnership, collaboration strategy, I think we tried to be very clear. I think with the 5 by 5 program. And you’ll hear the last nomination at R&D Day. We’ve obviously got a really exciting portfolio of agents that we that we like a lot. And we’re moving into clinical data. We’re almost two years early in formulating that portfolio into clinical studies. It’s our nomination in clinical studies, which is great. I think you’ll hear at R&D Day. We have a whole host of other opportunities in the preclinical pipeline that we’ve also been working on advancing much closer to IND, so we can see a very broad and exciting portfolio in front of this. We realize that not all of those are going to work out the way that we might have expected. So, there will be some attrition rate in that portfolio. That’s the natural part of our business. You can’t be 100%. I think the other thing we realize is that the more exciting that portfolio looks, we can’t possibly do all of that ourselves. So, though, it’s wholly owned today, we do expect that we will have to bring in partners and collaborators to help us move that forward. Either accelerate some of the timeframes, use some of their capital or clinical resources to move this along. And we’re carefully considering how we overlay the continued growth of the R&D portfolio, not just the 5 by 5, but beyond that with potential partnerships and collaborations to get the right mix of capital we can allocate to the program of our own capital versus sharing risk and capital with others versus retaining commercial rights for ourselves. I think very clearly with zanidatamab, we decided to out license that program outright to BeiGene and Jazz and not have a commercial role. I think in the future we’re looking to retain some additional rights longer in development and potentially give us a commercialization option later. And so doing that on a portfolio basis is something that we’re really thinking about very carefully. And so, I expect as you learn more about the portfolio and look at how it might even grow beyond the 5 by 5, there are some natural points in time for us to think about adding some partners to help us move that portfolio forward. And those are things we’ve been thinking about all year, things we’ll continue to think about. I think once we find the right partner who’s interested in moving those assets forward with us in the way that we think they should be moved forward, and we can get paid appropriately for our efforts to date and continue to have upside as we work with partners to move those forward, then I think we’re quite happy to look at partnership possibilities at that time. The nice thing about having a strong financial position is that we can do that within a timeframe that generally we can set ourselves. And I think there’s some advantage in making sure you can find the right partner for the right set of products at the right time in the right deal structure that works for our shareholders. That’s one of the reasons that we try to put ourselves in a strong financial position and continue to be in a strong financial position going forward into those discussions.
Jon Miller: Great. Thank you. Makes sense. And then maybe more on the science side, in the prepared remarks, you spoke both about your interest in focusing on targets where there’s strong antigen expression on the tumor cells, good sensitivity there, where there’s previous validation of the target. But then you also talked a little bit about your ability to be tolerable enough, reflective enough to get good effect even in targets where there’s maybe more modest antigen expression. I know some of the ADC targets you’re looking at do have some variable antigen expression between — certainly between indications, but even between patients within indications that do express those targets. So, can you talk a little bit more about the pushes and pulls there, how you expect to be able to identify patients? Do you expect to have to be stratifying by expression? How do you expect your advances in the ADC field to enable those broader populations compared to focusing on those patients where there’s really strong expression?
Paul Moore: Yeah. Thanks, Jonathan. Yeah. No, thanks for the opportunity to clarify. So, I think in our design and our thinking, we really do value the importance of the front end of the antibody and its ability to recognize target and internalize. So, we do take quite a lot of care and we really value that aspect of the ADC. But we also appreciate that within the tumor microenvironment, not all the tumor cells are going to necessarily have high expression. And so that’s where things such as bystander activity are also a very important contribution to the mechanism. And then beyond that, within the ADC field, there’s also the chemo effect that you can also get from the design of your ADC and getting that balance between the potency of that ADC, that payload, as well as the release of that payload at a tolerable pace is very much also baked into the design of our features. So, we can get the on-target effect, we can get bystander effect, and then we can potentially get some chemo effect as well. And that’s how we try and factor that all into the design. And then it’s also balanced by the DAR and then the tolerability profile where you’re getting. You don’t want to run into issues of intolerability that others have seen with the higher potency payloads.
Operator: Thank you. Please stand by for our next question. [Operator Instructions] Our next question comes from the line of Derek Achila with Wells Fargo. Your line is open.
Derek Achila: Hey, guys. Thanks for taking the questions and congrats on the progress. Just two quick ones from us. I guess, first, what do you plan to cover at the R&D Day in terms of potential expansion into autoimmune disease? I guess, is there going to be a discussion around certain targets of interest? And then second question, just in terms of your target selection process for the Tri T-cell engager, I guess maybe just run us through that. And what type of preclinical data might you highlight at the R&D Day for the development candidate you plan to nominate next? Thanks.
Kenneth Galbraith: Yeah. Maybe I’ll let Paul answer both of those if he wants. Whatever order you want.
Paul Moore: Yeah. Yeah. Sure. Yeah. So, I think, Derek, the first question was the scope of what will present on the autoimmune programs. And as we mentioned before, we see great opportunity for bispecifics, our technology in the autoimmune space. And we do have certain specific programs that we’re pursuing. So, we will be talking — our plan, our anticipation is that we will talk about specific programs in addition to where we can take the technology and moving forward even beyond that. So that will cover the autoimmune space. And then on the Trispecific T-cell engagers, they are — we have different toggles that we can pull on the design sort of the most in the Trispecific space. I think the one that we’ve been talking about most and you’re most familiar with is the CD28 CD3 Trispecific platform or TriTCE Co-Stim. And there — when we’re thinking about the target there, we do appreciate that we want targets that have a profile that is more biased towards tumor expression and less normal expression. So we do appreciate there you have to take care. But the way that we’ve designed that molecule differently that others have thought about with deploying CD28 is that our CD28 engagement only occurs when you have the CD3 engagement and you have engagement of the tumor target. So, in some ways we’re not really that different. Even though we’ve got that extra punch on the CD28, we’re not really any different than how others think about target pairing with T-cell engagers. Of course, we have advances and we have things we think we can improve the therapeutic window moving forward. But for initial targets, we like very much the targets that we’ve already shared, the DLL3 and the CLDN18.2. We think the tolerability profile has been very encouraged to us as we’ve progressed those through preclinical development. So hopefully that answers it. We certainly are thinking about targets beyond those applications, beyond those as well. But again, it really depends on the platform that we’re leveraging and somewhat the profile of the target antigen as it fits into that platform.
Derek Achila: Got it. Thank you so much.
Operator: Thank you. Ladies and gentlemen, I’m showing no further questions in the queue. I would now like to turn the call back over to Ken for closing remarks.
End of Q&A:
Kenneth Galbraith: That’s great. Thank you, operator. So, thank you everyone for listening to our call today. As always, we’re extremely excited about the feature for Zymeworks. We still think there’s a lot of time left in 2024 for us to get some additional milestones and events behind us, so look forward to doing that. And again, we look very much forward to seeing all of you either in person or virtually for December 12th R&D Day, where we’ll be able to give a really great update of the 5 by 5 programs with some KOLs, providing some landscape analysis and also a good overview of where our long-term R&D strategy is beyond the 5 by 5. And we really need to accelerate that view just because we’re almost two years ahead of schedule in constructing the 5 by 5. So, we’ve been thinking about this for some timeframe and happy to share our vision for Zymeworks on a longer term basis from an R&D perspective and look forward to seeing all of you there in December 12th again in person or virtually. So, thank you very much.
Operator: Ladies and gentlemen, this concludes today’s conference call. Thank you for your participation. You may now disconnect. Everyone have a wonderful day.
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