Zymeworks Inc. (ZYME) Earnings Call Transcript & Summary

Thank you for standing by. This is the conference operator. Welcome to the Zymeworks ZW49 Clinical Update Conference Call. [Operator Instructions] And the conference is being recorded. [Operator Instructions] I would now like to turn the conference over to Ryan Dercho, Senior Director of Corporate Affairs. Please go ahead.

Good afternoon, everyone, and welcome. Today, we will provide an update on our novel antibody drug conjugate, ZW49. The call will be led by Dr. Ali Tehrani, Zymeworks' President and CEO; followed by comments from Zymeworks' Chief Scientific Officer, Dr. Tony Polverino; and Zymeworks' Chief Medical Officer, Dr. Diana Hausman. Final closing remarks will be provided by Dr. Tehrani, and the speakers will be available for Q&A after the prepared remarks. Before we begin, I would like to remind you that we will be making forward-looking statements during the call. Forward-looking statements can be identified by words such as will, continue, may, potential of, initiate, look forward to, expect, believe, plan, anticipate, enable and similar words. Forward-looking statements are based upon our current expectations and various assumptions and are subject to the usual risks and uncertainties associated with companies of our industry and of our stage of development. For a discussion of these risks and uncertainties, we refer you to our 10-Q for the quarter ended September 30, 2020, as well as our other filings with the SEC. As a reminder, the audio of today's event will be available on Zymeworks' website later today. I will now turn the call over to Ali.

Thank you, Ryan. Good afternoon, and welcome, everyone. My name is Ali Tehrani, and I'm the President and CEO of Zymeworks. We are pleased to have you here today to provide an overview of the most recent clinical development of our HER2 bispecific ADC, ZW49. On the call, you will learn that ZW49 is an active agent with anti-tumor activity in several tumor types, that ZW49 has a differentiated safety profile compared to other ADCs and that based on the data we have generated to date, we have advanced the ZW49 into the next stage of clinical development. Before we present the clinical data, we will start with a brief introduction to ZW49 from our Chief Scientific Officer, Dr. Tony Polverino. Tony?

Thanks, Ali. So for those of us today that are less familiar with ZW49, I just want to give a brief description of the design goals and highlight the differential attributes of this molecule. The ZW49 is a novel bispecific ADC, targeting 2 nonoverlapping epitopes of HER2. It combines the unique design of zanidatamab with our ZymeLink platform, comprised of our proprietary auristatin cytotoxin and cleavable linker conjugated at a drug-to-antibody ratio, or DAR, of 2. Now as a class, ADCs are designed to deliver potent toxins specifically to target tissues and to reduce effects on normal healthy cells. Now despite some early success, many ADCs are still limited by off-target toxicities and inefficient delivery of their toxins to target cells. ZW49 and the ZymeLink ADC platform were specifically designed to enhance the delivery of toxin to the tumor and minimize toxicity on normal tissues. We thought to accomplish this in 2 distinct ways. To increase toxin delivery, we exploited the unique binding geometries of our biparatopic antibody, zanidatamab, which promotes high order complex formation of HER2 receptors. This leads to increased cell binding, increased receptor internalization and increased release of toxin intracellularly compared to normal monospecific antibodies. These attributes result in potent anti-tumor activity in a variety of pharmacology models. ZW49 49 was tested in multiple tumor types, including breast, gastric, colon and esophageal cancers, and they encompass the range of HER2 expression. ZW49 demonstrated compelling efficacy across a range of tumor types and in HER2 high and HER2 low expressing channels. Now on the other hand, to minimize normal tissue toxicity, we sought to improve both the linker-toxin stability and the physiochemical properties of the ADC itself. The proprietary linker-toxin payload enhances the serum stability of the ADC, resulting in pharmacokinetic and biophysical properties that are similar to conventional antibodies. Studies in nonhuman primates and patients have confirmed the PK profile of ZW49 overlapped with that of total antibody, demonstrating the enhanced stability of our ADCs. The selection of ZW49 as the lead clinical candidate involved testing different toxin analogues in different DARs. ZW49 had the highest therapeutic index of the molecules tested. In our nonhuman primate studies, we dosed animals up to 18 mg per kg with no significant impact on hematological parameters. At this dose of 18 mg per kg, the level of free toxin in plasma was below 1 nanogram, [ too ]. Other ADCs with a less stable linker toxins suffer from plasma instability and consequently, hematological toxicity often masses as a key adverse effect, both in nonhuman primates and in patients. The totality of our preclinical data enabled us to initiate the first-in-human trial at a starting dose of 1 mg per kg. I would like to now turn the call over to my colleague and Zymeworks' Chief Medical Officer, Dr. Diana Hausman. Diana?

Thank you, Tony, and good afternoon, everyone. Today, I'm going to provide an overview of the ongoing Phase I study of ZW49. This study initially opened in the second quarter of 2019 and has been actively enrolling patients at 12 clinical sites across the United States and Canada with 35 patients enrolled to date. The data I'll be speaking to are from a database snapshot from earlier this month, and they are subject to change. The ongoing study is a first-in-human, 2-part Phase I study consisting of dose escalation and indication-specific expansion [ dose -- cohorts ] at doses and schedules that are under evaluation for future study. [ Dose escalation ] of the portion of the study is using a 3+3 design to evaluate different doses and dosing regimens, including a once-every-2-week and once-every-3-week schedule in order to best assess the therapeutic window of ZW49 and provide optionality for future studies. Enrolled patients include those with HER2-positive cancers based on local site assessment using IHC, FISH or next-generation sequencing. Retrospective central assessment of HER2 status by IHC and FISH is also being performed. Patients with a variety of cancer types have been enrolled, including breast cancer, gastroesophageal adenocarcinoma, gynecologic cancers, non-small cell lung cancer, anal cancer and colorectal cancer. Patients must have disease that has progressed after standard of care therapies. As is typical for a study at this phase of development, patients have been heavily pretreated, with approximately 80% of patients having received prior HER2-targeted agents, including trastuzumab, pertuzumab, T-DM1, trastuzumab deruxtecan and a variety of investigational agents. The initial regimen evaluated a once-every-2-week schedule, starting at a dose of 1 milligram per kilogram. This starting dose is higher than typical for an ADC, reflecting the good tolerability observed in the GLP toxicology study. As the study has progressed, we've amended the protocol to include additional dosing regimens. Next, I'm going to focus on the overall safety and anti-tumor activity. In the 35 patients who have been treated to date against -- across all dosing regimens, there have been no dose-limiting toxicities; no treatment-related hematologic toxicities, including neutropenia or thrombocytopenia; no treatment-related pulmonary toxicity, including interstitial lung disease or pneumonitis; and no treatment-related liver toxicity. There have been no treatment-related deaths. Over 90% of treatment-related adverse events have been grade 1 or 2 in severity and manageable in the outpatient setting. The most common treatment-related adverse events have been keratitis in approximately 40% of patients; and fatigue and diarrhea, each in approximately 30% of patients. These have all been, again, reversible and manageable in an outpatient setting. There have been no discontinuations due to treatment-related adverse events, and we have not yet established the maximum tolerated dose. Encouragingly, we've seen evidence of anti-tumor activity across all regimens and dose levels evaluated to date. Even at our lowest dose level of 1 milligram per kilogram once every 2 weeks, [ tumor shrinkage is observed ]. We have been evaluating the safety and anti-tumor activity of the every 2-week and every 3-week regimens over the past year with the objective of selecting a go-forward dosing regimen to advance into disease-specific expansion cohorts. From both a safety and anti-tumor perspective, the every 3-week schedule has demonstrated a more optimal profile for continued development. With respect to safety, while we saw [indiscernible] toxicity [indiscernible] dosing regimen, we did observe the only 2 grade-3, treatment-related adverse events that have occurred in the study to date, [ it ] consisted of 1 reversible grade-3 diarrhea and 1 event of reversible grade-3 keratitis, with the severity based primarily on changes in visual acuity. Conversely, as of today, we have not seen any treatment-related grade-3 events in the once-every-3-week regimen. With respect to anti-tumor activity, we have observed partial responses in stable disease per RECIST, in both the once-every-2-week and once-every-3-week dosing regimens. Focusing on the 3-week regimen, we have started to observe the emergence [ of dose-response relationship that ] dose is evaluated. At the initial dose of 2 milligrams per kilogram, we observed several patients with stable disease, including some patients with disease control greater than 4 months. At the highest doses tested in the once-every-3-week regimen at dose levels of 2.5 or 3 milligrams per kilogram, there have been 6 response-evaluable with centrally confirmed HER2-positive disease. The anti-tumor in these 6 patients with a variety of tumor types includes 2 patients with confirmed partial response and 2 with stable disease. Three of these patients are still active on study. We are currently enrolling in the 3 milligram per kilogram cohort and are encouraged with the activity thus far and plan to dose escalate with this regimen. In addition, we have opened a once-weekly dosing regimen to explore an alternative exposure profile. While we have not yet established a maximum tolerated dose for ZW49, we have seen encouraging anti-tumor activity and have decided to advance the program to the next stage of development. We have opened and patients have started dosing an indication-specific expansion cohort at 2.5 milligrams per kilogram in the every 3-week regimen in HER2-positive breast cancer, HER2-positive gastroesophageal adenocarcinoma and a basket cohort of other HER2-positive cancers. These cohorts will help us better define the activity of ZW49 in these different indications. The decision to open these cohorts was also driven by the high level of clinician and patient interest in the study. We have lots of flexibility in the study designed to either increase the dose in the current expansion cohorts or to add additional cohorts to the study depending on the outcomes from these efforts. The expansion cohorts are now enrolling at our active sites in the U.S. and Canada and are expected to open soon at additional sites in South Korea and Australia in collaboration with BeiGene. Going forward, we plan on adding cohorts in lower HER2-expressing cancers. In addition, as auristatin-based ADCs have the potential to augment immune response, we're looking at possible combination studies with PD-1 inhibitors. In summary, we've made good progress from a clinical perspective with ZW49, enrolling over 30 patients despite the challenges of COVID, which interrupted and slowed enrollment the first half of last year. We have demonstrated a differentiated safety profile manageable in the outpatient setting, with no treatment-related hematologic pulmonary or liver toxicity and no treatment-related discontinuations. We've seen encouraging evidence of anti-tumor activity in a heterogeneous group of tumor types across the range of dose levels and schedules and have opened up expansion cohorts to allow us to advance the program while continuing to explore additional treatment regimens. We are doing this with the strong support of our clinical investigators and our patients to continue to be excited about the program. I'd now like to ask Ali for his closing comments.

Thank you, Diana. I would like to conclude the session by focusing on our vision for ZW49. The [ focus ] of ADCs was that they were going to target cytotoxic chemotherapy specifically to the tumor and eliminate the systemic side effects that have plagued and limited chemotherapy for decades. And while there are now several approved ADC-based therapeutics that have demonstrated meaningful efficacy, serious side effects continue to be the Achilles' heel. Common occurrences of severe myelosuppression, neuropathy, hepatotoxicity and lung toxicities leading to high discontinuation rates remain a signature of cytotoxin-based treatments. From the beginning, our aim has been to develop an efficacious treatment for patients without asking them to compromise on safety. The emerging clinical profile of ZW49 that you learned about today is consistent with what we envisioned from this program from the outset. Our preclinical data supported our thesis. And our clinical data suggests we are on track to accomplish our goal. I believe we have just scratched the surface of what is possible with ZW49. The activity and the differentiated safety profile enabled us to continue to develop ZW49 as a single agent and to explore a number of combinations with other therapeutics such as IO agents to maximize the value to patients and address their need while reducing the potential risk of irreversible treatment-related adverse events. I look forward to our next update on this program at a future medical conference and perhaps, before that, informing you of potential partnerships involving the ZymeLink platform, which consists of the linker and the payload that is used with ZW49. Operator, we're now happy to take questions.

[Operator Instructions] Our first question comes from Jim Birchenough of Wells Fargo. Is it possible your line is muted? Our next question comes from Stephen Willey of Stifel.

I guess maybe just with respect to the keratitis that was observed, can you maybe just speak as to whether or not there were any adverse events that were also coded in the context of visual acuity, stuff like photophobia, blurred vision? And then -- and it sounded like you're also initiating a once-weekly dosing regimen. And I think you had also kind of made the point to suggest that none of the grade-3 adverse events were observed in the once-every-3-week dosing regimen. So just kind of curious as to what you think you might be able to achieve with once-weekly given the differentiation on the safety side that you've seen thus far.

Sorry, this is Diana. And I'll certainly start with the first part of that question. So just to make sure I heard you correctly and just to clarify, what -- we saw the 2 treatment-related grade-3 events in the once-every-2-week dosing regimen. I wasn't sure if I heard you say that, that was with the once-every-3-week regimen. So just to clarify that. We did have a few patients where there were adverse events that were reported as blurred vision or dry eye. I think I'd have to go back and look on a per patient basis to see whether some of those same patients were also evaluated as keratitis. We are looking at every event with an external expert in ophthalmology, who basically is advising us and performing adjudication on each of the events. So I think we're being very cautious and very careful in how we're reporting these events. And when we do have our data presentation later this year, we'll be able to present a much more detailed picture of the safety profile. I think, Tony, maybe I'll ask you to address the week -- the rationale for the weekly dosing.

Sure. So with respect to the weekly dosing, I think we've -- collecting the information about the exposure response relationships now that we have started on both Q2W and Q3W. And both from a profiling perspective and from the clinical perspective, we understand that a QW schedule enables us to have a lower Cmax, a high Cmin and overall a higher AUC. And so as we're trying to build the data set to establish the dose exposure response relationships, the more information that we have, the better. Plus there is preexisting information that going to a weekly schedule can mitigate some of the activities and some of the effects that are seen with other agencies. And with what we're seeing with ZW49, I think we are just trying to ensure that we have as full a data set as possible.

Great. And then just lastly, can you maybe just speak a little bit to the kinetics of response? I think you had said that within the 6 response-evaluable patients at 2.5 to 3 mg per kg, you had 2 confirmed PRs, 2 stable disease patients and, I think, 3 that are still on therapy. So I guess any color you might be able to provide around response kinetics that you've seen thus far across all doses would be of interest.

No, I think this study is still evolving, and this is really a snapshot of living data. So we will be planning on presenting the data at -- as I said, in much more detail with response kinetics when we have a better sense of exactly what they are with a more firm database snapshot, so that will be later this year. But we've been -- I do want to emphasize that we have been encouraged by the level of activity that we've seen at the doses that we've been evaluating.

Our next question comes from Etzer Darout of Guggenheim Securities.

I guess, firstly, just if you can remind us on how long the nonhuman primates were studied with 49 preclinically and how, what you're seeing so far, correlate with what you've seen in the Phase I dose escalation with respect to both efficacy and safety given the lower doses at which you're seeing the clinical activity for ZW49.

I'll take that one. It's...

Tony, do you want to...

Yes. Not a problem. So thanks for the question. So the nonhuman primates, it was a Q2W schedule for 4 doses, and then there was also a cohort with the recovery phase of 6 weeks. So we ran out quite extensively there. With respect to the activities that we're seeing, I would say that we're right in the ballpark. I think one of the advantages for ZW49, as I mentioned in my section, is because of the great safety profile and therapeutic index we established in the nonhuman primates. We went into that first-in-human studies at a very high dose, relatively speaking, which is 1 milligram per kilogram. And so the exposures that we are seeing now are very much in line with what we would expect to observe activity in the pharmacology models, so not unexpected at all. Did that address all of your questions?

Great. Yes. And then just a quick follow-up, I just wondered if you can talk a little bit about how experience, in terms of the therapies, those 6 patients were -- what treatments they had received prior if you're able to answer that question.

Yes. I have -- that will be the type of detail that we'll be providing at -- in our presentation, hopefully, later this year. Again, as I said, this is a snapshot, we're still collecting all of that data. But all of the patients have been, as I said, heavily pretreated and have progressed after standard of care treatment.

Our next question comes from Jim Birchenough of Wells Fargo.

I guess just first, and I hope it wasn't already asked, but anything you've seen in terms of pattern across those groups in terms of patients that respond versus those that progress? Are there certain cancer types or any patient attributes that help select the responders versus the nonresponders?

So at this point in time, I think it's too early for us to say that we've seen any patterns of response. I think we have seen activity across multiple tumor types. As I mentioned, we have enrolled a number of different types of cancer, and that's part of our rationale for wanting to move forward with the expansion cohort so that we can start to look in more homogeneous patient populations and begin to look at what patterns we might see there.

And then just in terms of where dosing could go, is there anything based on the preclinical data that might suggest where the sweet spot in dosing might be above the go-forward dosing you've already selected? And is there a way to manage the keratitis conservatively so you could push through it?

So I think this is probably a 2-part answer. I'm going to let Tony speak a little bit more about the sweet spot. With regard to the keratitis, we do feel that it's manageable. We have been using really standard methods to manage patients and again, these events have been reversible, and we've had patients remain on study despite having keratitis at times. Tony, did you want to talk about the sweet spot?

Yes. So again, I think that when we think about the mechanism of that kind of ZW49, it is unique, and the biparatopic nature of the molecule really enhances that binding internalization. And so I think we are able to deliver toxin to tumor cells much more efficiently than monospecifics. And as I mentioned, I think we're right in that ballpark now where anticipation of activity is matching out with the exposures that we're seeing. But we're also very encouraged with the fact that we're continuing to dose escalate, and we're continuing to go into expansion cohorts so that we can fill out those exposure response relationships and really understand what that, as you call it, sweet spot, may end up being in patients themselves.

And just finally, are there some key expansion cohorts we should be thinking about that -- how you're categorizing the different expansion cohorts if you're grouping them by tumor type?

We can't hear you, Diana.

Sorry. [ Just -- it's ] teleconference stuff. Anyway, we are enrolling, as we mentioned, HER2-positive breast cancer. And in this type of study, these are going to be very heavily pretreated patients who will have progressed after all standard of care therapies that have been shown to provide clinical benefit. And similarly, we'll be looking in a similar patient population in gastroesophageal cancer and then in basket cancers. We do have plans in the future to be adding in additional cohorts that will include lower HER2-expressing cancers that do not have HER2 gene amplification.

Our next question comes from David Novak of Raymond James.

Folks, can you hear me now?

Yes, we can hear you.

Yes, we can.

Fantastic. Thanks for taking my questions here and for the program review today. A few quick questions from me. Just looking back to JPM 2020, perhaps my memory is inaccurate here, but I remember thinking at the time, we were in the third dose cohort, and we weren't stepping up in fractional mg at the time, which I remember thinking might have put us at 3 mg per kg back in Jan 2020. Is that true? And if so, does that mean that you went back to fine-tune between dose cohorts? And if you did do that, why? What was the rationale behind that if we haven't hit MTD or pushed the upper end of the therapeutic window yet?

David, this is Ali. I'll take that question. So if you go back to January of 2020, we mentioned that we had dosed approximately 10 patients. And to specifically answer your question, we did not go back in a dose or we did not sort of backtrack. What you heard us say through the presentation today is that we started to see anti-tumor activity pretty much from our very first dose of 1 mg per kg Q2W. And based on that, we followed that signal and we made sure that our plans reflect that signal that early on. And our activity to date and our safety profile to date is the driving force of where we're headed. So that initial signal that, as we said, the emergence of a dose response enabled us to chase the signal and chase the opportunity that is in front of us.

Got you. Great. That's very helpful, Ali. And just following that, in the prepared remarks, I think I heard that a number of patients had progressed through -- in HER2. Is that true? And have these patients also previously seen Kadcyla?

So this is Diana. So we have had patients who've had prior in HER2. We have not disclosed today which patients those are. And again, that will be the level of detail that we hope to be presenting later this year, particularly as we get more experience in a more homogeneous patient population, specifically breast cancer or gastric cancer.

And what about Kadcyla? And the reason I ask that is I'd be curious of your thoughts around whether or not a patient seeing Kadcyla would handicap potential activity that you would see with 49. But is there any data out there in the literature that suggests resistance to antimitotic agents or tubulin inhibitors that would be a concern if you're dosing a patient that had previously progressed through Kadcyla?

I'll let Tony speak to the literature data. In terms of the clinical data, as you can imagine, pretty much all of the breast cancer patients would have received prior Kadcyla, since it is approved and in HER2 just was recently approved. Tony, I don't know if you have any comments to add.

Yes. With respect to potential resistance mechanisms, we've started to explore that, and we believe that ZW49 will not be subject to the same level of some of the resistance mechanisms that Kadcyla [ suffers ], that we wouldn't be subject to that. So that's a very encouraging sign for us. And obviously, as we continue our enrollment, we would like to establish that within the clinical setting.

Our next question from -- comes from Akash Tewari of Wolfe Research.

So if I can start off with just kind of a basic question because the audio cut off, I just want to be clear. Can you give us a very clear breakdown of at what doses the 6 PR responses occurred and in what tumor types, just so we can have a clarity on where we are seeing activity and if there's a dose response? I'll just start with that one, and then I'll follow-up, if I may.

Okay. So at this time, we are not presenting that level of detail since the numbers are just too small. We said this is -- what we're seeing is activity in a heterogenous group of different cancers with patients with different prior treatment profiles, and what we're really looking to is moving into our expansion cohorts where we do have the more homogeneous patient populations and can provide more meaningful information to allow us to estimate rates. I think that Tony will add something.

I'll jump in. Yes, you're right. The phone was cutting in and out. Again, just for clarity, what we mentioned is that the 6 patients that are response-evaluable are at our 2.5 Q3W and 3 mpk Q3W. We did not specify how -- what -- where the numbers are between these 2 doses. And we did say that we have 2 confirmed PRs and 2 SDs, 3 of the patients of the 6 are active on the study as of the data cutoff for this presentation. Does that provide what you are looking for, at least in terms of [ what the phone had cut off ]?

Yes. No, that is helpful. So now maybe on the second issue, so it sounds like you don't have a lot of grade-3 AEs. You don't have any lung tox. You have somewhat of an eye toxicity, which is not surprising given the class. Where -- so I think -- and this is where I think there's some confusion. What is [ the -- shown on ] where you are on your therapeutic index right now, right? Like that's what we're trying to understand. Are you [ talking that ] we can go to 4, we can go to 5, we're not seeing any dose-limiting AEs, we're not seeing an MTD, we're going to continue to expand? Or are we saying we've identified a therapeutic index and we're going to explore these doses as it's something we're seeing on safety? I just want to understand from a dosing perspective, where are we on that spectrum? And then I think also, given really just frankly how confusing kind of the update has been today, if you were to say like -- okay, why investors should be interested in this program, why should we not give up or why should we be interested? What do you think is the most important disclosure today that gives us confidence that you could have something that has similar response rates to -- in HER2 while having a differentiated safety profile, like going back to that original story? So...

Fantastic. Thank you. There's a multi-part there. So I'm going to try to address everything you brought up there, Akash. Let's go first to the investors. What we've discussed today is we have an active agent. We have an agent that has no death, no discontinuation. Just think about the other ADCs, whether they're HER2 or otherwise that have been discussed over the course of the last quarter, no discontinuation. No grade 3s on our Q3W going forward. Grade 1, grade 2, reversible, manageable on an outpatient basis. No treatment-related liver tox. No heme-related, treatment-related tox there. And as you even brought up the notion of an eye tox, I think we need to be a little bit clear on where we're talking about eye tox. We have no treatment-related corneal damage or any nerve damage to the eye where normally, this is associated with an eye tox. So let's be really careful of the difference between a change in visual acuity that is reversible or dry eye or blurry eye or an itchy eye versus eye tox. That's something that we need to be crystal clear on. And in terms of who we are in going forward with this asset, we need to really look at what we mentioned here. We have an asset that has a differentiated safety profile while we are escalating. We have not reached DLT. We have not reached MTD. We are moving forward. We started expansion cohorts so we can enroll and we can move towards a defined rate. In terms of our friends at Daiichi, they have a great rate in breast cancer. That rate is very different in gastric cancer. Along with those rates come a lot of concerns with regards to safety that do not exist with ZW49. ZW49 is an active agent. We presented the data so far, but we have a lot more to explore. We have higher doses to go to. As I said, we're continuing to escalate. We have combinations to explore. We have a lot of room to grow. This is an interim look, not a finality. And we have the support and the enthusiasm of our investigators and patients. As we've mentioned in several calls, we have a waiting list for our study. I think in totality, we have the opportunity of a very differentiated asset going forward based on safety and having an active agent. And my final comment, Akash, is that at the end of the day, approvals look at total efficacy, overall survival and PFS. And safety is a big component of it, and activity is a big component of it. We mentioned we have an active agent, and our data speaks for that. I hope I answered all of your questions. Was there a part that I'm missing?

No. I mean that -- it's just -- maybe just on the dose escalation, like would it be crazy if we looked at your data today and said Zyme would be comfortable dosing up to, let's say, 4 to 6 mg per kg, given the profile that you've given today? Like that's really the question. Is that a crazy assumption if you're not having grade-3 AEs at this point?

Well, as I said, the escalation is continuing, Akash, and the doses that we get to is the doses that we get to. Would I say it's a crazy assumption? No because the escalation is continuing. We're not at DLT. We're not at MTD. But let's also, for a second, review the requirements for getting to 4 to 6 mg per kg, which is driven by Daiichi. As Tony mentioned, we have a different asset. We have the linker payload. We have a different DAR. So we need to compare apples to apples here. And we need to remember that their requirement of getting to 5 or 6 mg per kg is very different than our requirement and the doses that are required to generate a highly efficacious asset that is also very safe. We have a differentiated antibody backbone. We have a differentiated mechanism of action. So we've never looked at Daiichi was at 5 or 6, therefore, we must be at 5 or 6. Our confirmed partial responses, our duration of response, our safety speaks for itself without necessarily having to look at a minimum 5 or 6 mg per kg [ dose ]. We're also looking at multiple avenues for this asset in the future in terms of single agent and combination, which is not readily possible [indiscernible].

Our next question comes from Jessica Fye of JPMorgan.

First one, can you tell us what the tumor types were of the patients who had the 2 confirmed PRs at your 2.5 and 3 mg per kg dose levels?

So as we said, at this point, we're not releasing those details because it's really too soon to say if there is a pattern. And that, again, is why we will be enrolling patients at -- in the expansion cohorts, but we will be planning on presenting those data at a conference later this year. And as was required for this study, the patients had to be HER2 gene-amplified and had to have progressed after prior standard of care treatment.

Understood. Okay. And I think at the beginning of the call, you opened it up saying you've observed anti-tumor activity with this drug across several tumor types. Does that mean that you have confirmed PRs somewhere in this data set in at least 4 tumor types across like the overall dose escalation? Or when you say anti-tumor activity in several tumor types, does that sometimes mean kind of like directional tumor shrinkage?

It would include directional tumor shrinkage as well as confirmed PRs.

Okay. And can you also tell us how many dose levels you've studied now? I know you said you started at 1 mg per kg and clearly, you've gotten up to 2.5 and 3 mg per kg, but how many total dose levels does that make?

Jessica, I'll take that. Again, the level of information that you're asking for is very justified, and we totally appreciate that. We will present that level of information in totality and more comprehensively at an upcoming medical conference because we believe that's where we want to talk about everything in its totality. At this point, we wanted to put the focal point on the start of the expansion trials and the dose and the activity and the profile, which we believe we've provided.

Okay. Got it. Maybe just the last one. You're talking about kind of the various ways in which the product is differentiated, so I just want to make sure I don't make any assumptions. What do you think could be driving the keratitis here?

Well, again, I'll bring in Tony into the equation. But what we've seen in sort of the blurred vision, the itchy eye, the change of visual acuity is common in our class of a payload. This has been reported by other MMAEs, MMAFs, auristatins. And in our case, as we described before, there are grade 1, grade 2, reversible and manageable, which is quite common with this class and as reported by others. This itchy eye, blurry eye, change in visual acuity is not unique to us. Tony, why don't I let you jump in with more specifics.

Thanks, Ali. And I think this is somewhat of a nascent field. We have a lot of studies ongoing to try and understand this in more detail, but it is very clear that there are attributes of the antibody drug conjugate, some of which do not pertain to the target. So we're exploring what those attributes are, but we don't have enough information at this point, unfortunately, to provide you with any concise and precise data point.

Our next question comes from Gena Wang of Barclays.

So the first one, just wanted to make sure I understand correctly, so the next step will be expansion cohort at a 2.5 milligram per kg for Q3W dosing, is that right?

So yes, that's correct. We are opening up in parallel the expansion cohorts at the 2.5 milligrams once-every-3-week dose. And concurrently, we are continuing dose escalation in the once-every-3-week dosing regimen as well as dose escalation using another alternate dosing regimen of once-weekly.

Okay. And then for the once-weekly dosing, what will be the first dose you will start?

Gena, this is Ali. We haven't disclosed that, but suffice it to say, it would be at a dose that relates to our activity that we've seen with the other regimens. And just for complete clarity, our expansion phase has already started, and we have enrolled and dosed patients.

Okay. And since you mentioned that 1 milligram per kg, you already saw activity, so is it fair to assume for once-every-week dosing that would -- likely would be the starting dose?

That would be a fair assumption, although we're not confirming it at this point, but that's a fair assumption.

Okay. Okay. That's fair. And then regarding the keratitis, the grade-3 cases, just wondering, at what dose did you see that event at the once-every-2-weeks dosing? And then also after how many doses did you start to see that? And how long that lasts? And how will it resolve?

Right. I will start, and then I'll hand it over to Diana. Just again for clarity, there was a single grade-3 keratitis case, not multiple, just so we're clear. And that single grade-3 keratitis was resolved. Diana?

To -- and again, I think at this point, we're not disclosing the exact doses where we saw -- that we have looked at in the Q2W dosing regimen. We will be providing that, though, in the context of the full data presentation later this year.

Diana, can you give some color? Like did that happen very quickly, the first dose? Or did that happen after a few months?

So we've had keratitis come on at -- generally at different time points, and there's a lot of confounding factors for patients. Sometimes it depends on their underlying medical history, including underlying ophthalmologic history. So again, we'll have all of that information at our presentation later this year.

Okay. Any additional color you can give also for the other grade-3 diarrhea?

So I think the main color I have is that it was a single patient, and it was easily managed and reversible and was not associated with hospitalization. It was all managed as an outpatient.

Okay. Sorry, just one last question for the grade-3 keratitis. Did the patient stop? Like how patient was resolved, did that patient stop taking drug? Or the reduction, like how was that resolve?

So in general, we're using very standard methods to address keratitis, similar to what's been utilized by other ADCs. And what we've done is use topical agents as well as occasionally dose interruption as needed, so patients would pause treatment for a period of time.

Our next question comes from Yigal Nochomovitz of Citigroup.

I just want to make sure I understand correctly. You said that there were 6 response-evaluable at the 2.5 and 3 mg per kg dose cohort. So do those 6 response-evaluable, that's the totality of all the evaluable patients in the dose escalation? Or were there other response-evaluable patients at other doses that you're not discussing at this point?

Yigal, thank you. Good to speak with you. As we mentioned, these are 6 responsible -- response-evaluable, HER2-high patients.

Okay. So I guess what I'm getting at is you have -- you've enrolled 35 -- if I heard correctly, you've enrolled 35 patients across the dose escalation starting in the second quarter of 2019, so I'm just trying to square that with only 6 response-evaluable a year and 3/4 later.

Well -- and thank you for bringing that up. I'm really glad you put the highlight on the time. So January of 2020, we were at 10 patients. We presented that at a medical conference. And then, of course, we are at COVID. And at -- even at that time, with the 10 patients, we were across 2 different doses at Q2 and Q3W. And from a period of approximately January when COVID became a part of all of our lives, so about April, May, June, our enrollment essentially came down to a halt. So in reality, are we talking about the length of time that you're referring to? Are we talking about second half of 2019 and essentially second half of 2020? That's just one thing to consider, and that's in reference to your comment of a year and 3/4 or whatever it is that you mentioned. And the second thing here is the 35 patients are across 3 different regimens between the Q2 between the Q3W and the QW. And this is...

And just to also...

Go ahead, Diana.

Sorry, Ali. Yes. I was just going to say -- and just to clarify, we have had maybe more patients who are response-evaluable. We have seen activity in some of those other response-evaluable patients, including confirmed PR, including really notable, stable disease patients who've had tumor shrinkage. One patient has an anecdote, felt so much better, he gained 15 pounds. So this is just a snapshot of what we've been seeing and part of the rationale for why we're opening up our expansion cohorts, and we're looking forward to presenting the full data set at a medical conference. We have a lot of patients who are still active, who are still enrolling, so it's really hard to give a complete picture at this time until the -- we have a full data set for all of the different patients.

Sorry, Diana, I just want to make sure I understood. You're saying that there are other response-evaluable patients beyond those 6? And you've seen a confirmed response in some of those? I just want to make sure I'm clear on that.

That's correct. At different dose levels and regimens, that's correct.

Okay. Are you able to say at which doses?

We're going to talk about that, again, when we -- go ahead, Ali.

No, go ahead. You're finishing. Sorry. Go ahead.

I think that's the level of detail that we will be presenting later this year at the conference. We'll be having -- we'll have much more data on duration of response, many more patients who have been treated, and so we'll be able to -- we'll look forward to sharing all of that data with you. We're not disclosing that other dose level at this time.

So Yigal, I'll jump in. I know there is a big desire to determine the rate. But as we've mentioned before, our emphasis today is on the go-forward dose, and the ends are too small, including a very diverse patient population to try to extrapolate a rate. What we have said is we had anti-tumor activity across all of our doses and regimens. What we've said is that we started seeing it very early on. And we've said at our go-forward dose, we have confirmed PRs with 3 patients still active on study and going forward. So this is an ongoing study, there is a lot more to be reported and to be seen. And in terms of determining a rate at this stage, we just don't believe that's appropriate. We believe a rate can be determined from the expansion phase.

Okay. Fair enough. And I'm not sure if you can answer this, but are you able to say for those 2 confirmed PRs what the tumor shrinkage percentage was?

Well, they are confirmed PRs. And I think from what I know and what I've learned is that, first, you want to see that deep response and then you want to make sure that the response is -- has durability associated with it. It's both what we're reporting right now.

Our next question comes from Andrew Berens of SVB Leerink.

I was really hoping to get a better sense of where you guys are seeing activity as well as the competitive profile of the drug. I know you're saying the asset's differentiated, but I'm just not convinced from this update. What is it that makes you think this drug is differentiated versus [ in ] HER2? Is it the safety tolerability? Because it's obviously not the efficacy based on what you've presented today. Is there any waterfall plot? Or can you tell us if all the tumors at the higher doses were seeing some shrinkage? I mean just something to give us conviction in what you're telling us that this drug is a competitive drug, a real drug.

I totally appreciate where you're coming from, Andrew. This is Ali. All right. So if we take a step back, let's just review just the safety for a second. No death, no grade 5, no grade 4. What you've heard from us is, in the world of ADCs, in my humble opinion, that is actually quite a standout, no discontinuation -- no treatment-related discontinuations, I should say. So -- but if you kind of look at the landscape of ADCs and especially in HER2, I think that stands for itself.

Well, wait, let me just -- but you're not at a dose that you're competitive in terms of efficacy, so you don't know that you're not going to see a grade 5 or death when you go higher.

I completely respect your opinion there...

I mean 2 of 6 is not competitive. I mean how can you say that -- what the profile is going to be?

I completely respect your opinion on that, but in reality and to be accurate, our rate is not 2 of 6 because you're talking of multiple different tumor types. So as you've heard us, we haven't said that the 2 are the same tumor type. And I think it is inaccurate to drive the 2 out of 6 in a dose escalation because similarly, we can argue if we were to reveal the actual tumor types, that we may have a 1 out of 1 in a particular tumor type. Is that 100%? And in fact, our competitors in several times on this call, our colleagues at Daiichi have come out, they have 2 different response rates between gastric and breast. So I completely appreciate where you're coming from, but we are developing an asset that has -- is meant to address the needs of patients, and that includes safety and efficacy. And we believe our safety as supported by our sites, as supported by the wait list, as supported by enrollment that is ongoing, speaks for itself, and we have an active agent. We set out to develop this asset a -- long ago. And as I mentioned, we developed -- we set out to develop an asset that did not compromise safety. And based on what I provided, hopefully, you're convinced that we did not compromise safety.

And have you disclosed what the next dose levels will be in the expansion cohort? What -- how much higher are you planning to go?

So let's take a half step back. We've initiated the expansion at 2.5, and we're continuing to escalate at 3 mg per kg in the Q3W and potentially higher. So while we are enrolling patients into the 2.5 mg per kg Q3W and we start to have a homogeneous patient population enrolled and as we escalate higher, we are quite possible to up dose these patients as the escalation continues. So what I'm specifically saying is that escalation -- or expansion is starting at 2.5, but it could very easily go to 3 or higher.

Okay. And the question of -- there's no waterfall plot that you presented, but if we were to see one, would most of the tumors to different doses be going south?

That's the kind of information that we specifically did not want to get into because everyone is trying to extrapolate a rate and personally, humbly, as a scientist, I don't believe extrapolating a rate from an escalation study is an accurate measure of a go-forward point. So that's precisely why we're not showing that information, and that information belongs at a medical conference in totality, especially when we reach an MTD.

No, no, I'm not trying to extrapolate a rate, I'm just trying to see whether the drug has incremental activity that's broad across different tumor types and that you're seeing incremental activity at the different doses. I know that there's no way to...

The simple answer to your question is yes.

Our next question comes from Ben Shim of Canaccord Genuity.

There's a lot of moving parts in this, and I'm sorry if I missed this earlier, but can you maybe review what the broad time lines or what you call priorities are for potential data readouts? I think you mentioned you would have some data at the end of this year or by the end of this year at a medical conference for what you have now. What about when do you expect to complete enrollment of the expansion cohorts and when might we hear about that data at some point?

Yes. Thank you, Ben. You are correct. We've mentioned that our next update would be at a medical conference. We haven't provided anything more specific at that. And our objective, point in time, is to put the spotlight at that medical conference on the expansion data on essentially what everyone is asking for here today. But there is a study to be done, we have an escalation that is ongoing, there is data that is ongoing, so we will do our best to inform everyone on a go-forward basis. And I want to remind everyone that the reason we're having this call is because we promised a while ago that should escalation continue, we would provide an update. And that's exactly what we're doing.

This concludes the question-and-answer session. I would like to turn the conference back over to Dr. Tehrani for any closing remarks.

I just want to conclude by thanking everyone for today's involvement, and thank you for the questions. As discussed here, we look forward to providing our next update on this program at a future medical conference this year. Thank you very much.

This concludes today's conference call. You may disconnect your lines. Thank you for participating, and have a pleasant day.