Zymeworks Inc. (ZYME) Earnings Call Transcript & Summary

Thank you for standing by. This is the conference operator. Welcome to Zymeworks conference call to discuss initial results from the Phase I trial of ZW191. [Operator Instructions] The conference is being recorded. [Operator Instructions] I would now like to turn the conference over to Dr. Sabeen Mekan, Senior Vice President of Clinical Development of FarmWorks. Dr. Mekan. Please go ahead.

Good afternoon. Thank you for joining our call discussing the highlights from our presentation on preliminary Phase I trial results for ZW191 at the AACR-NCI-EORTC Conference on molecular targets and cancer therapeutics to date in Boston. Before we begin, I would like to remind you that this presentation contains forward-looking statements, and we encourage you to review our latest SEC filings for a full breakdown of risks and uncertainties related to any forward-looking statements we make during today's presentation. On today's call, Stuart Barnscher, Senior Director of ADC Development at Zymeworks will begin by providing a review of the design rationale and scientific principles that guided the development of ZW191. Following this, Dr. Patricia LoRusso, Professor of Medicine at Yale Cancer Center will then summarize highlights from the initial Phase I clinical data as presented at the conference. Lastly, I will outline next steps for ZW191, including our development path forward. At the end of the call, Dr. LoRusso and I 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 Stuart.

Thank you, Dr. Mekan, and thank you all for joining us today. Before we get to the exciting clinical data, I'd like to quickly review the design of ZW191. At Zymeworks, we think deeply about how we design our antibody drug conjugates. And over the past few years, we've shared many of our insights through publications, all of which can be found on our publications page of our website. Those learnings directly shaped the design of ZW191, including both the antibody features and the linker payload properties. The ZW191 has built on a novel IgG monoclonal antibody that specifically binds to folate receptor alpha and is conjugated through a peptide cleavable linker to our proprietary topoisomerase 1 inhibitor ZD06519 to a drug-to-antibody ratio of 8. The antibody binds a distinct epitope on folate receptor alpha and was selected for its ability to internalize efficiently deliver high levels of payload and penetrate tumors more effectively, allowing ZW191 to target tumors with low fully receptor alpha expression and achieve strong antitumor activity. The ZD06519 payload was selected for its moderate potency in the 1 to 10 nanomolar range, along with strong bystander activity and proven antibody linker stability all of which are intended to support better tolerability, enable higher protein dosing and maintain activity even in tumors with low or heterogeneous fully receptor alpha expression. Taken together, the antibody and linker payload features create a differentiated profile for ZW191 that we believe will translate into a compelling clinical performance and that's exactly what we're beginning to see in the data presented today. With that, it is now my pleasure to hand over to Dr. LoRusso, the lead author of the poster presented at the AACR-NCI-EORTC Conference today. Dr. LoRusso brings more than 25 years of expertise in medical oncology, drug development and early phase clinical trials. Dr. LoRusso, over to you.

Thank you so very much. And I thank everybody on the link for watching this presentation today as I'm very excited about this drug. I've actually been doing clinical drug development for over 35 years and to have a drug as exciting as this one is true treasure, not only as an investigator and a physician treating patients. But as I think you will see and hopefully appreciate and understand as well a true pleasure and very exciting data for our patients. So if you could advance to the next slide, please. So first, I'm going to just show you briefly, this is the study schema of the Phase I trial that we've been -- that is currently ongoing, pursuant to ZW191. As you can see, the key eligibility included, obviously, patients greater than or equal to 18 years of age and focused in escalation on 3 primary tumor types. Platinum-resistant epithelial ovarian cancer, serous or endometrial cancer; and finally, adenocarcinoma non-small cell lung cancer. These patients, as you will see, had exhausted available systemic treatment options and we did not require a prerequisite of folate receptor alpha expression on that -- that was done looking at that retrospectively. And our patients were allowed to have a performance status of either 0 or 1. I'm going to be presenting to you today the dose escalation cohort as it exists prior to the data cutoff date. But this trial is currently ongoing. And as Sabeen will talk to you later, is going into -- or currently enrolling in dose optimization. As you can see, the many cohorts that we evaluated all the way from 1.6 up to 11.2 mgs/kg in this dose escalation cohort. Next, this drug, by the way, is given once every 3 weeks intravenously. This is a very busy slide, I know, but it looks at the baseline characteristics of the 41 patients that were treated up to the time of data cutoff, which was September 10, 2025. As you can see, there was a mix of Asians and Caucasians, roughly 70% to 75% of them are Asians, the remainder Caucasians. Next slide. as you can see, there was about a 50-50 split between patients who had an ECOG of 0 versus those that had an ECOG of 1. Next slide. Also, as you can see, 70% of the patients that were recruited in the escalation had metastatic platinum-resistant ovarian cancer, 20% endometrial cancer and the remaining 10% non-small cell lung cancer. Next slide. The median number of prior treatments was 3. But as you can see, the range of prior treatments in this population were anywhere between 1 to 9, but looking specifically at the number of prior treatments, what you see is that roughly a little over 1/3 had 3 to 4 prior treatments and about 1/3 also had 5 or more prior treatments. I would consider this a heavily pretreated patient population. Next slide. And as you can see, based on the prior treatments that these patients had, because the ovarians were the predominant patient population and because of the tumor types involved, all patients had seen prior platinum as well as prior taxing. The majority had seen also prior bevacizumab, there were only 2 patients recruited because of that -- there were only 2 patients that were treated on the study that it had prior mirvetuximab in part -- in large part because of the geography of where the patients had been treated as well as not requiring prior mirvetuximab for protocol entry. Next slide. So overall, based on the summary of baseline characteristics, enrollment continued at a dose of 11.2 milligram per kilogram and that was currently ongoing at the time of data cutoff. Only 6 participants had discontinued 191 treatment, and all of them had discontinued because of disease progression. Of the 41 patients enrolled, 35 were continuing on 191 treatment at the time of data cutoff. Next slide. This is just a slide looking at the summary of safety of this patient population. As you can see in those 41 patients, the Grade 3 or greater treatment-related adverse events was very minimal. Very minimal compared to what I see with many of the other antibody drug conjugates of similar payload. Only 7 patients had greater than or equal to grade 3 treatment-related adverse events. But importantly, there were no serious treatment-related adverse events. There were no discontinuations due to adverse events, and there were no deaths from drug. Next slide. This, again, is a busy slide, but basically, it shows treatment-related adverse events of any grade that occurred in at least 15% of patients. It looks quite busy, but the data is actually very similar, especially if we look at the last 2 columns, which are the total number of treatment-related adverse events of greater than or equal to 15% in the cohort of 41 patients that were recruited to this trial. As you can see, any treatment-related adverse event of greater than or equal to grade 3 occurring in at least 15% or more of patients only occurred in 7 patients for a total of 17%. Of those 7 patients that reported greater than or equal to grade 3 adverse events, treatment-related adverse events -- the most common was anemia, which was identified, as you can see, in 4 patients as well as neutropenia, which occurred in 2 patients and thrombocytopenia that occurred in 2 patients as well. Next slide. This is the waterfall plot as well as a preliminary efficacy table, demonstrating the antitumor activity in this patient population. As you can see on the left, the waterfall plot shows significant reduction in tumor size across various doses of drug administered and responses as seen in as low as the 3.2 milligram per kilogram dose. But I think what's also very interesting on this graphic on the left is that looking at the bar graph on the top or the bar on the top, what we see is, albeit there were responses in folate receptor alpha high patients we see quite amazingly significant antitumor activity in patients that were either folate receptor low or negative, which with other folate receptor alpha inhibitor targeted ADCs currently FDA approved. The requirement for efficacy based on significant data in those drugs -- in mirvetuximab as an example, those patients had to have folate receptor alpha high based on the data that had come out of the randomized Phase III trial. The initial data showing very little activity or no therapeutic advantage of that ADC in folate receptor low to medium patients. So this is, to me, quite astounding data to be able to not have to necessarily preselect for folate receptor alpha expression and yet get significant antitumor activity in this patient population. The chart on the right is looking at preliminary efficacy for response evaluable participants that had gynecologic cancers. There were 24 patients for which that we could look at response in this patient population. Of those, 50% of the patients had a partial response. And at the time of data cutoff, 29% had confirmed partial response. But if we look specifically at the 6.4 to 9.6 milligram per kilogram dose. 64% of patients with GYN malignancies had a partial response at the time of data cutoff with, as you can see, over 25% having confirmed partial response. Next slide. This is on the left, the swimmers plot and as you can see again, across the board, patients had response at low doses, and there were several patients that actually had dose escalation. But I think what is very impressive in this swimmers plot is that the majority of patients that were treated. In fact, there were very, very few patients at the time of data cutoff that had discontinued treatment. The majority of patients remained on study for a prolonged period of time while they were being followed on this trial up to the time of data cutoff. And the graph on the right shows the percent change from baseline in CA-125 over a week's duration, which again, is quite impressive in this patient population. Next slide. So in conclusion, I believe that 191 has been safely administered during dose escalation up to the 11.2 milligram per kilogram dose with the majority of participants still on treatment. I personally enjoy treating patients on this drug because of the lack of side effects and the prolongation of response. There have been low rates of dose modifications, dose delays and greater than or equal to grade 3 adverse events, and there were no discontinuations due to adverse events, again, quite impressive. Preliminary activity, I believe, is promising, starting at 3.2 mg per kg every 3 weeks. The overall response rates, especially at the doses between 6.4 to 9.6 mg per kg were overall 53%. But if you looked at GYN malignancies, 64% of patients up to the data cutoff that had GYN cancers had a minimum, a partial response. The antitumor activity was observed, as I said previously, across all folate receptor alpha expression levels. And finally, these data represent a broad therapeutic window for 191 and support further investigation in advanced solid tumors. As a practicing medical oncologist that does early phase clinical trials exclusively in my practice. This type of a trial, this very trial, which I am participating in is extremely exciting for us, and we welcome recruiting patients to this clinical trial. Thank you so very much for your time today.

Thank you, Dr. LoRusso. The data that we've shared today will provide important clinical validation for our ADC design philosophy. We're encouraged by these initial results and look forward to continue following the data as it matures further over the coming months. Beyond the data presented here, we have determined 11.2 milligram per kilogram as the maximum tolerated dose and are proceeding with Part 2a of the study focused on dose optimization in patients with platinum-resistant ovarian cancer. Based on the integrated assessment of safety, efficacy and pharmacokinetic data, we have selected 2 doses, 6.4 milligram per kilogram and 9.6 milligram per kilogram for randomized dose optimization with approximately 30 patients planned in each cohort. We are planning to begin enrollment this quarter. This will allow us to further refine the balance between efficacy and safety and justify the optimal dose for registrational studies. We expect to share additional data at a future medical conference with a larger and more mature data set. Overall, Early results continue to support ZW191 as a potential best-in-class asset with promising early activity and a manageable safety profile. As previously, we would continue to be data-driven and planning our further development plans for registration and expand into earlier lines of monotherapy and combinations. As we move forward, our focus remains on disciplined clinical execution by exploring strategic partnerships that could accelerate development and expand global reach. That said, the ZW191 is also giving us important translational insights that could help accelerate and derisk the future development of ZW251 and other pipeline ADCs using our ZD06519 payload. Based on our data thus far, informing our growing understanding of tolerability and efficacy for our novel payload, we're confident in moving ZW251 into Phase I clinical development this year. As you can see on this slide, we also have other preclinical candidates beyond ZW151 targeting more novel antigens such as [indiscernible] and PTK7. Our NaPi2b program remains IND ready and we continue to explore next-generation ADCs. 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?

[Operator Instructions] Our first question coming from the line of Mayank Mamtani with B. Riley Securities.

Great to see some exciting data here. So on the 2 patients who had prior mirvetuximab, could you maybe talk about what experience there was? And then also, I was curious, as you think about dose expansion and optimization, do you expect to enroll more with prior mirv exposure? And -- and I was also obviously curious to hear the data that you presented on FR alpha positive versus negative. And I guess, a derivative question there is, are you thinking of the development plan being different for positive versus negative patients?

I think i'll let Sabeen start, Sabeen?

Sure. Thank you for this question. I think from our clinical trial eligibility, we allow patients with prior mirvetuximab treatment. However, this is a global trial, and we enrolled a large number of patients from Asia where mirvetuximab is not approved and available. That is one of the reasons we had a few patients with mirvetuximab. The other reason also is we're enrolling all levels of folate alpha expression levels. And as you know, about 2/3 of patients even in the U.S. where mirvetuximab is available are not candidates for this treatment. That's I think part of the reason -- main reason why we have fewer patients. But I think as mirvetuximab gets approved globally, and gets more views. So as we go into expansion part of our studies, we probably would get more patients. And then over to efficacy with regards to folate receptor expression levels, we are pretty pleased with efficacy across, hopefully, a receptor expression. I'll turn over to Dr. Patricia LoRusso. She talked a fair amount about it. in terms of the fact that we're seeing efficacy in patients, both folate receptor high as well as medium low. Dr. LoRusso?

Yes. But first, I'd like to answer or have you, Sabeen, help me answer the 1 question that he had. Do you know what the responses were in the 2 patients that had prior mirvetuximab.

We are seeing activity regardless of prior mirvetuximab.

Yes. They both responded. And just to let you know, I mean, that is the one huge advantage of this drug over mirvetuximab as an example because mirvetuximab, I mean, if you know the randomized Phase III data that the first Phase III that they did, they didn't get a therapeutic advantage in the medium, low or negatives. They were only in the high folate receptor alpha. This has a huge advantage there. And I don't even believe yet in the data in the patients that we're treating that the degree of expression has anything to do with the efficacy. This is pretty amazing for me as a clinician and clinical investigator. I've done a lot with antibody drug conjugates, especially with TOPO1 payloads. And to see this lack of efficacy as early as in the Phase I trial, not efficacy of toxicity, excuse me, this little toxicity with this degree of efficacy, I'm very impressed. I'm very impressed. I don't have the fortune of having that opportunity often even after working with some of the ADCs that have since been FDA approved for this patient population, mirvetuximab as well as others. I hope that answers your question.

Yes. And Dr. LoRusso, maybe just a quick follow-up for you. We saw at ESMO a lot of data also from the FR alpha ADC, some of them next generation. If I had to ask -- I know the data is very early in this case, but was just is, as we think about a lot of these therapies moving earlier lines and they will be all TOPO1 based, you're thinking of the next generation. How would you maybe think about the different data sets that?

Yes, I'm familiar with about 3 of them that were presented, Ryan, I know the AZ one and a few of the other ones. In fact, I believe one of them may have been presented in one of the sessions that I also presented a different drug on. One of the unique characteristics -- and remember, that data was Phase I, primarily Phase I. Some of it included some expansion. But for the most part, what we saw was the Phase I data. And if you dissect out just toxicity initially, let's just look at toxicity and look at the toxicity profiles of at least 3 of them that we saw versus what we see with this drug, this drug is much safer. Some of the Phase 1s required folate receptor expression. We don't require folate receptor expression within the context of our Phase I trial to demonstrate efficacy. But when we're treating patients, efficacy is very important. But for quality of life, toxicity is extremely important as well. And I don't work for Zymeworks. I have no stack in Zymeworks. I have no reason other than benefit for my patients to talk about this drug. The toxicity profile that I'm seeing at this stage is extremely encouraging relative to what some of the toxicity profiles of some of the other drugs that were presented demonstrated. Does that help?

Super helpful. Thank you. Yes, very helpful.

I mean some of them had like grade 2, 3 nausea like 80%. One of them -- anyway, I don't have to go on. I think I've brought my point home. I apologize.

Our next question coming from the line of Yigal Nochomovitz with Citigroup.

Yes. So I had a question. So in the folate receptor alpha low negative. So for the -- there are 2 ones in blue there that are low negative at the very right side of the waterfall, I guess, how do you get responses in the negatives meaning, I guess, it's just negative on the biopsy, but it was a false negative. There must be some folate receptor alpha present, obviously, right? Or can you just explain how you get the strong responses in the negatives, not the lows, but the negatives.

I think that relates to our construct of our ADCs and our ADC design, as Stuart had pointed out earlier, during our presentation, we -- for our ADCs, particularly for this one as well, we utilize a very highly internalizing antibody and go in tumors that have high levels of expression for the targets. So ovarian cancer, endometrial and non small cell lung cancer that we are evaluating have all very high levels of expression of folate. We are moving with high-expressing antibody, internalizing antibodies, and our linker payload system. It's moderately tight linker, moderately toxic payload that allows us to deliver a lot more payload to the tumor compared to some of our competitors. And that we believe brings us to the edge in terms of having patients respond at very little levels of expression for the target. I think one of the examples that I can provide with ADC construct in this design is the fact that certain gynecological tumors, for example, are pretty sensitive to topoisomerase. So you have very, very -- they require very, very little expression of folate receptor with this highly internalizing antibody and payload construct to work.

Okay. And then my second question for the principal investigator, please. So you mentioned that 11.2%, I think is the maximum tolerated dose, but you also mentioned that you're going to take forward 2 of the lower doses in the dose optimization. And Dr. Given that you said that it's so well tolerated. I'm just wondering if you would be curious or are you curious to see how this drug could perform in more patients at that higher 11.2% or are you sort of happy with the way the company is going with these 2 other doses?

Yes. So I mean, I can first comment on that, Sabeen, if you want me to, and then you can add to my comments. So I'm a big proponent, first of all, of dose optimization. And there was one DLT that was identified at the maximum tolerated dose of 11.2. We saw what makes one help identify what doses one is going to advance forward in Project Optimus dose optimization that would lend you some level of comfort to advance that dose into a randomized Phase III trial. We think that -- I believe that at 6.4, 9.2, we've really achieved many of the pillars that we would look at to assist us with a significant level of confidence that we have the right dose to advance forward. Number one, patients are extremely tolerable. There's very little toxicity, and I'm talking specifically at 6.4 and 9.2. There's very little toxicity. We've achieved with pharmacokinetics. We've overachieved with pharmacokinetics, the exposure levels that we were hoping to obtain in order to elicit significant efficacy based on preclinical models. The duration is significant, virtually minimal toxicity. Why would I want to potentially enhance with what I have now in my portfolio, which I'm looking as a clinician who's guiding in identification of the optimal dose, the main 5 pillars that would help me determine what dose I feel comfortable with moving forward. I've achieved all of those pillars with both 6.4 and 9.2. I've got -- and it's very tolerable. And let me just tell you something. I see a lot of patients that are treated with ADCs either on our investigational studies, but more importantly, have come to me on and have progressed on ADCs. This drug is so tolerable at those doses that I really feel we're there. I don't know if that helps, but I can go on and Sabeen, maybe you can add to that.

Thank you, Dr. LoRusso. I think you've been pretty comprehensive. So I don't have much to add beyond there.

Our next question coming from the line of Yaron Werber with TD Cowen.

This is [indiscernible] on for Yaron. Congrats on the data. A couple of quick ones from us. Yes, your overall response rate was really impressive at 6 mg per kg at 64%, but obviously, the confirmed response rate is a little lower. Have any of the 5 pending response unconfirmed responses been confirmed since your September data cut? And then to dig a little deeper into the mechanism. Obviously, safety is very, very [indiscrnible] all the other ADCs in the field. What aspect specifically of your ADC design do you think accounts for this very low rate of kind of grade 3 toxins, especially neutropenia versus other ADCs?

Sabeen, you want to start with both of those questions?

Sure. So I think from our safety profile, I think this is, again, coming back to rule that is also given the fact that we have very little free payload in the circulation because that's often what's associated with toxicity. And given the fact that our payload is a linker payload system where we have a moderately tight linker with a moderately toxic payload. We're different from a number of our direct competitors who have much more toxic payloads compared to us. And I think that's what is driving the safety profile that we're seeing.

And then they wanted to know about the efficacy of those 5 patients that had unconfirmed PRs at the time of data cut off. Can you expound on any of the efficacy that we've been seeing since then?

So as the efficacy, we -- a part of the reason that the unconfirmed responses was that those patients did not have enough follow-up at the time of the data cut for our confirmation of the responses. All of those patients are ongoing on study treatment. So they were all awaiting confirmation that when we reported them. And since then some of those responses have been confirmed. Others are still abating confirmation and all of those patients remain on treatment.

I just want to add one thing. I got cut off because I think Zoom froze, so I apologize if Sabeen had said this. But working with ADCs for as long as I have, the linker chemistry is pivotal for efficacy and toxicity and their linker chemistry is different.

Our next question coming from the line of Jonathan Miller with Evercore ISI.

Thanks for the great results and congrats on the progress. I would love to ask about time to response. And I ask that partially because of the questions you just had about confirmatory scans on patient who have uncontrolled responsed, but among the patients who have had responses, how late have you seen patients go before they tripped over into response? And is it possible we could see some of the stable disease patients still on therapy transition over? Is it reasonable to expect that ORR might even go up from here? And then I have a follow-up on that.

Yes, it depends -- this is a dose escalation. So we have started escalating from a pretty low dose of 1.6 milligram per kilogram. As we mentioned, we started seeing confirmed responses at 3.2 milligram per kilogram. That's a relatively low dose. So it does -- in seeing those responses that did take a little while more than the first couple of scans to see the confirmed responses. But as we've gone up higher on the doses, we started to see responses much faster, particularly at the higher doses going from 6.4 to 9.6. Many of the responses that we've observed have occurred on the first imaging scan.

The other thing you have to keep in mind is not only is it -- do you mind if I add to this? the other thing to keep in mind is not only are we starting low and going high, these are heavily pretreated patients. Many of the ADCs that are currently in development in Phase I are limiting the number of prior treatments in the metastatic setting. So that is something else to take into consideration where you're seeing patients that have had 5 prior, 6 prior up to 9 prior treatments responding. It's, first of all, amazing that they're responding. Secondly, it's not uncommon, at least with other drugs that we see that if we're going to get a response, it may be later. But these responses are actually happening earlier than what we would anticipate given the heavy pretreatment of this patient population.