Biotech analyst here at BofA, welcoming everyone to this, our final morning. very pleased to be able to introduce Zymeworks and the Chair and CEO, Ken Galbraith, which is here with us today. Ken, thank you so much for joining me.
Oh, Jason, thanks for the invitation to come to Las Vegas and attend your conference.
Wonderful. Maybe let's start off a little bit more broadly for those who maybe aren't as familiar with the story and the platform. Can you talk a little bit about, you know, your platform, what separates, you know, your multi-specific antibody technology from competitors, and how is the ADC platform differentiated?
No, great. No, great, thank you. Zymeworks, in summary, is a clinical development stage oncology company, trying to make a difference for patients with the most difficult to treat cancers, today. We do that with multifunctional therapeutics, which are a combination of either a next generation antibody-drug conjugate or the other side of our portfolio, which is multi-specific antibody therapeutics, which is really, our next generation tri-specific platforms. I think what we're trying to do is trying to utilize these more complicated biologic structures to try and generate mechanisms of action and clinical benefit that we haven't seen with more traditional agents in going beyond bispecifics and antibodies and other approaches.
We do that with a portfolio that's from phase III with zanidatamab, which is partnered with Jazz in BeiGene, to our HER2 ADC agent, which is going to phase II, and a whole host of other new medicines that we're bringing into the clinic for us to as INDs next year. Fortunately, with the financial position we did last year, including the Jazz collaboration, we've got a cash runway through 2026 at least, which gives us the ability to build that type of company that I just explained, to provide us a really great clinical stage portfolio of novel oncology agents that are both ADCs or multi-specific antibodies. Hopefully can make a difference for those patients in really the most difficult to treat cancers that we can find.
Gotcha. Do you see yourself more as an ADC company or protein engineering company?
Yeah. I think since coming here, as a CEO January last year, what I found is that we do both equally well. That's what we're trying to do. I think we're great protein engineers, is where we started, but we also are fantastic medicinal chemists inside the company, and there is overlap between those two capabilities. I think we could equally design high quality next generation ADCs, high quality tri-specifics. Both are important. I like the diversity of the portfolio that builds for our investors. I also like the diversity of our approach for potential partners, where we can take a target of interest in a cancer indication of interest, and we can build multiple structures and then examine which one of those formats, might give the best.
We can design a monobinding ADC, we can design a biparatopic or bispecific ADC. We can design either one of our tri-specific platforms, whether they're costimulatory or build CD28 and CD3 or the checkpoint inhibitor tri-specific, where we build PD-1 into the mechanism. We can build all those formats in different geometries with people. Then we can allow partners to pick the best format against that specific target and that specific patient population. I think in that way, we hope that our own internal portfolio is of higher quality because of that and more diverse. We hope for partners, we can design more high quality products for them to move forward with.
Makes sense. What do you think is the biggest open question, at this point in time about the platform?
I think just, you know, more clinical data to prove out what we believe pre-clinically and where we're going scientifically, and we need more data for that. We've certainly proven our skills with zanidatamab, which is at phase III now, and we think is gonna be a really exciting drug in the HER2 antibody space for BTC and GEA, where we are now, and maybe beyond that, with Jazz innovation designing where to go with that agent. I think, you know, we've designed a biparatopic ADC in zanidatamab zovodotin, which again is not many people have done that. I think both of those have clinical data to support that we are good protein engineers. We're good developers of ADCs.
We've got an opportunity to do that with five new compounds we wanna move into the clinic over the next number of years, the first two starting next year and then beyond that. I think, you know, we've shown we have expertise through partnerships that are molecules. I think we have a really good strategy of how we're trying to build a portfolio and construct it with novel agents on their own that all fit together in some, in some strategy. I think we just need to move those into the clinic and get additional clinical data to show that we are on the right track that we think we're on.
Great. You've talked a little bit about efficacy, maybe in terms of safety and tolerability, you know, what have you seen in terms of the outputs here? Any meaningful changes in the therapeutic windows, improvements or detriments, you know, CRS toxicities?
Yeah, I think we've, you know, I think we've taken a look at both the ADC landscape and also the bispecific landscape, which is now we think going to tri-specific and beyond. We pay as much attention to tolerability factors for patients as we do with efficacy. I think if you look at some of the earlier programs which have gone forward and have been able to generate, you know, jumps in efficacy for patients and improve the standard of care, but the cost of tolerability for patients is pretty significant. I think in our ADC structures that we have, we think very seriously about potency and tolerability.
I think when we pick the DAR of an ADC, which we usually do at the very end, we think about the nature of the tolerability aspects for patients, the ability to use in combination with other agents, which is kind of a new thing for ADCs as opposed to monotherapy. On the tri-specific side, we're using a brand new low affinity CD3 antibody that's never been used before in our mesothelin two plus one T-cell engager, which will go in the clinic next year. I think if we're right about that selection, we'll use that CD3 antibody in all of our tri-specific platforms. I think that will do a lot to deal with CRS intolerability that's been holding back multispecifics, in this case, bispecifics against certain solid tumor targets of interest.
I think we've thought a lot about the mix of getting efficacy for patients, improving standard of care, but what we can't do it at an extreme cost to tolerability. We need to find agents that patients can stay on, not get discontinued, not get dose reductions, and also be something to be able to use in combination with immunotherapy or other standards of care in combination with either of those two structures.
Actually, I think that's a great segue into maybe zanidatamab, your first asset here. Can you tell us what's the advantage of a bispecific targeting HER2, especially compared to maybe some of the other monoclonal antibodies or small molecules that are out there?
Yeah. I think the approach we took with zanidatamab was to find a mechanism of action that was quite different from the nature of the antibody and the binding. That's why we designed this biparatopic or bispecific binding with two epitopes. I don't think we truly understood the differentiated mechanism of action you would see with that against other HER2 antibodies or HER2 ADCs, we published that recently. I think the way that it works is quite different. It's not surprising that when you look in BTC or GEA or other patient populations we studied it, you can find some significant differences in clinical benefit to patients that was not possible with our first generation HER2 agents. T-DM1 has not been seen with some of the other agents in development moving forward.
I think you know, that taught us to really focus on unique and differentiated aspects that might drive mechanism in a different way than seen before. zanidatamab is certainly that. I think when you look at our top line data in biliary tract cancer patients we got in December, those were amazing results in a patient population that truly needs an improved standard of care. There is no HER2 target therapy in that patient populations. When you see the detailed data coming up at ASCO shortly, I think you'll get a better understanding of how that mechanism relates to the clinical benefit we saw in a patient population that has not seen a benefit from other HER2 agents being applied.
Hoping that when we see our top line data from the first line GEA study next year, we're hoping we can see that also with zanidatamab plus chemotherapy, and zanidatamab plus chemotherapy plus BeiGene's tislelizumab added, that we'll be able to see the same mechanism in the clinical results for that patient population go well beyond Trastuzumab and chemo that's been used as the standard of care.
Absolutely. The added benefit of an ADC form, zanidatamab, you know, and how does that fit against say, you know, a number of the other ones out there in HER2, KADCYLA?
Yeah, we think it's interesting. It's the same backbone, so you still get the same biparatopic nature, and we think that's important for internalization and other things. We did put out some mechanism action poster in April at AACR, which you can take a look at for more detail. I think it's a unique mechanism. I think also what we've seen from Zani-Zo or HER2 ADC is it has a completely different mechanism of action than KADCYLA or in HER2 in the marketplace right now. I think the positioning right now is that I think KOLs appreciate being able to use an ADC in a HER2 patient. When they progress, which they always do, they're looking for what's next. I think when they're looking for what's next, they're looking for something that's completely different.
They don't want to use a trastuzumab antibody 'cause there might be some concerns about using one after the other. You know, we're starting to see posters being presented about DXd acquired resistance with the lead agent, so they're trying to find a payload that's not DXd or not a topo payload. Again, Zani-Zo's not that payload. I think the linker strategy we have there is a very stable compound with a low DAR, seems to work extremely well from a tolerability perspective with other agents. Because of the mechanisms of action of the auristatin payload with immunogenic cell death, there's some good synergistic action with immunotherapy agents. We're looking at positioning it as, you know, the second choice ADC in a post-T-DXd marketplace, which right now is defined in breast cancer and non-small cell lung cancer.
We're looking at doing that where we can in combination with other agents. In this case, we'll be using PD-1 plus Zani-Zo in non-small cell lung cancer HER2 amplified patients, HER2 overexpressing patients. We hope that's a really, it's a really attractive economic opportunity. There's a real pressing need from KOLs to use another ADC sequentially for patients who progress, but use something that's quite different than they've used before to avoid cumulative toxicities, to hopefully get a different mechanism on top of a patient who's progressed. I think our position there is good. We just need to generate the data to show that that thesis is correct.
Gotcha. Maybe just briefly pivoting to the commercial aspect, what was the rationale for the Jazz partnership and what does it bring to the table?
Yeah. I think from our perspective, you know, we think zanidatamab is gonna be an excellent drug, and I think we're well on our way for that. We had an existing partnership with BeiGene in Asia Pacific. I think the company was unsure about whether to take a commercial opportunity themselves or not with zanidatamab. My preference from 35 years is to find a way to take a lead compound, partner with people who can do well commercially, not take on the execution risk, build up a good financial base to build a company. I think if you can be a very productive R&D company, which means doing it more than once, then I think that's the right chance then to try and take a commercial opportunity focused in the U.S. I think we're quite comfortable with having BeiGene and Jazz market zanidatamab.
I won't report $1 of sales, we will get a tremendous financial benefit from the success of zanidatamab. I think the Jazz collaboration we struck last year allows us to not take the commercial risk. Jazz is providing their commercial infrastructure. They're continuing to fund all the future development costs. We had a nice upfront payment last year, which allowed us to give us the balance sheet and the cash run right through 2026 to build a broader R&D portfolio in the company. I still think that's the right decision. I think if zanidatamab does well, we'll share in the economic success of that with BeiGene and Jazz, and I think we can focus on being a really productive R&D company with these five medicines coming forward, with moving Zani forward.
Then we'll have an opportunity to be a commercial biotech company in the future, and maybe a way that we're better financed with a better portfolio, and we can do it in a different way that hopefully might be more successful in the end. That's just the I brought to the CEO job last year.
Makes sense. Then, you know, to what extent, and maybe this is somewhat of an overlooked dynamic, does the Zani data by itself de-risk Zani zo?
You know, they are two different molecules. They are looking at different indications. I think there's still work for us to do to get clinical data to prove the thesis we have. Obviously, the experience we have with zanidatamab using the same biparatopic antibody gives us some comfort on that part of the mechanism in the ADC. I think it does de-risk it somewhat. You know, we're moving in indications, especially in non-small cell lung cancer, where zanidatamab is not currently under development. I think in that context, there's something to learn. Obviously, combination with PD-1, with the auristatin payload, we need to understand how that works in the clinic. We know preclinically there is a synergistic combination of the dual blockade of HER2 with Zani and PD-1.
We wanna explore that in clinical studies in the non-small cell lung cancer setting. To that extent, you know, we haven't done that yet. We've only got monotherapy data on Zani. We need to understand its use in combination with PD-1. We've done that successfully with Zani, with chemo and with immunotherapy, but we just need to see if that repeats itself with the ADC format of Zani.
Makes sense. We are almost out of time, but I did wanna ask you, I mean, you have a fairly rich platform and early stage pipeline. You know, what makes an indication worth pursuing? What's the strategy here, and how do you think about these things with, you know, specifically your capabilities?
Yeah, we, you know, we have a chart that we use back in our offices where we have a big circle around the most difficult to treat cancers that we still have today. That's defined by the lowest five-year overall survival rate. The areas where innovation has not transformed life for a patient, that's where we work. Gastric cancer is one of those, biliary tract cancer is one of those, non-small cell lung cancer in the HER2 population is one of those. Pancreatic cancer, where we're going later, ovarian cancer, where we're going, like triple-negative breast cancer, those are the areas specifically we wanna apply our multifunctional therapeutics and novel biologics to make a difference with those patients. That's our starting point.
It's interesting targets, then it's product format, and then it's the real work of getting things into clinical studies.
Wonderful. We are out of time. I do wanna thank you so much for joining us.
Well, thanks, Jason. Appreciate it.