Hello, everybody. Okay, we're going to get started on our next session, so please take your seats. Okay, so I'm very happy to announce our next speaker, who is Stuart Barnscher, Senior Director of Preclinical Development focused on ADC therapeutics at Zymeworks. Take it away.
Thank you very much, and thank you for the opportunity to provide an update on Zymeworks. As you'll see throughout the presentation, I'll be making forward-looking statements, and I'll direct you to our website and SEC filings for more information to review at your leisure. So we're really excited about Zymeworks and what the next two years has in store, and there's three key messages I want you to take away from this presentation. The first one being is that we're on the cusp of a potential regulatory approval and commercialization of zanidatamab. That's our HER2 bispecific antibody that is in development with Jazz and BeiGene. The second line BTC BLA was submitted earlier this year, and we've got a first line GEA trial with pivotal phase III data set to read out at the end of the year.
In addition to that, our R&D team has been working very hard on our five by five, so that was the initiative to bring five new INDs into the clinic in five years, starting in 2022. So we're actually ahead of schedule, and we're bringing in these therapeutic modalities around ADCs and multispecific T cell engagers. And I'll go into our four programs that we've named, and we've still got a fifth to be named later this year. In addition to that, we've also got a strategy in place to move beyond oncology and also expand within oncology. So we're going to continue to develop technologies and innovative strategies around our ADCs and our trispecific T cell engagers. We're also going to look at ways to bring novel therapeutic modalities like multifunctional cytokines and dual checkpoint inhibitors.
Then we're also looking to take our learnings from bispecific engineering to autoimmune and inflammatory disease, and we're going to do that at a rate of two INDs per year, starting in 2027. This slide just represents the area where we want to practice our craft. We believe in bringing novel and innovative therapies to patients who need them the most, patients who have the lowest five-year overall survival. This strategy allows us to be therapeutically focused so we can focus on indication, gynecological indications, gastroesophageal indications, non-small cell lung, and think about the best way to design molecules across our ADCs and multispecifics to make the biggest impact for these patients. Underscoring our R&D strategy is a strong capital plan, so we have cash resources on hand in excess of $450 million, which gives us a runway out until the second half of 2027.
We've got additional opportunities for commercial milestones around zanidatamab with our partners Jazz and BeiGene, and we're always on the lookout to strike up new partnerships that can potentially bring in upfront payments that can fund our R&D efforts. Okay, so first thing I'm going to talk about is antibody-drug conjugates. There we go. So luckily for antibody-drug conjugates, we've got about 40 years of ADC design and development. So what we did is we took a pretty agnostic and objective approach to reviewing all of that data, taking insights and learnings from molecules that have succeeded and molecules that have failed, and devised a strategy for us to move forward with three novel antibody-drug conjugates. Our focus for these first three programs is going to be on validated targets or targets with clinical proof of concept.
That allows us to bring our novel and proprietary topoisomerase I inhibitor ZD06519, to those targets paired with an antibody that has been specifically designed for ADC use. So these are antibodies that internalize well and have good tumor penetration properties. Taking all of this together, we believe that our ADCs can really move the needle in these difficult-to-treat cancers, and we look forward to moving these molecules into the clinics. So underscoring our ADC strategy is the development of a novel topoisomerase I inhibitor payload. This is an incredibly hot space if you're not familiar with it. There are a number of different payloads being developed. You can kind of divide the development work into two different camps. There's people who are working with known experimental drugs and repurposing those for ADC use, and then there's people who are developing novel payloads.
Our novel payload was developed during a structure activity relationship campaign where we looked at 100 different compounds. Those 100 compounds were plotted on a potency versus hydrophobicity plot. Potency is going to get you your antitumor activity, but also determine your tolerable dose. And hydrophobicity is going to determine whether or not you can have bystander and pass into neighboring cells. So in that effort, we selected ZD06519, which has moderate potency and is a very differentiated approach from some of the other companies and strategies where they're trying to push the potency higher and higher. Like most ADC companies, we got our start developing auristatin-based therapeutics. We applied our auristatin drug linker technology to a HER2 program called zanidatamab zovodotin, and we also applied that to a partnered program with Exelixis that targets tissue factor.
Now moving forward, our next three programs are really going to focus on our topoisomerase I inhibitor platform. The first molecule I'd like to introduce you to is ZW191. This ADC targets folate receptor alpha, and this was built from the ground up at Zymeworks. We discovered and developed the antibody to be an ADC antibody that had superior internalization and tumor penetration properties and didn't just focus on affinity. We used a proprietary ZD06519 payload, which inhibits topoisomerase I. That has bystander activity, and we conjugated that to a DAR of eight with our validated peptide cleavable linkers. We've presented data at AACR both last year and just last week, actually, at the most recent AACR annual meeting that highlights the compelling antitumor activity in preclinical models and also the compelling tolerability profile.
So this data here shows that ZW191 was tolerated all the way up to 60 milligrams per kilograms, three doses given every three weeks. So that's the highest non-severely toxic dose. The PK profile was linear, and this gives us a lot of confidence that we can move into clinical studies and we can think about this molecule being well tolerated in patients and potentially combined with standard of care to be able to move up into earlier and earlier lines of treatment. The folate receptor alpha ADC space is incredibly competitive. There are a number of different molecules being developed that utilize a topoisomerase I inhibitor payload. Here are five of them that I'm highlighting. And you can see when you organize these molecules based on payload potency and drug linker stability, we have a unique opportunity to differentiate from our competitors.
We like to call it kind of the sweet spot effect. We have sweet spot potency, moderate potency, not ultra potent, and we have moderate stability, so not ultra stable. And we think that these properties paired with our best-in-class antibody can really make a difference in folate receptor alpha expressing indications, both folate receptor alpha high but also moderate and low, so that gives us the ability to move outside of ovarian cancer into other indications like endometrial and lung where folate receptor alpha is expressed at lower levels than ovarian cancer. The next ADC I'd like to introduce you to is ZW220. So this targets NaPi2b. Again, same story as 191, homegrown at Zymeworks. The antibody was discovered for ADC use. It's not a repurposed antibody. For this program, we selected a DAR of four instead of a DAR of eight .
At last year's AACR, we presented preclinical data that highlights the rapid internalization compared to other benchmarks. We also highlight the potency profile in ovarian and non-small cell lung cancer cell lines that express a range of NaPi2b. We also highlight the antitumor activity in ovarian cancer models. These are patient-derived xenograft models where we see with a single dose of ZW220 at 6 mg/kg, we give good, strong, efficacious responses in models that are both high in NaPi2b but also models that are low in NaPi2b. NaPi2b is not a novel target in the ADC space. There have been a few other companies that have gone after NaPi2b as an ADC target, and we believe that the design is paramount to getting the design right.
So there are a number of different design features on ZW220 that we think are unique, but I'll just highlight a few here that we think would make a difference with NaPi2b. NaPi2b does have some normal lung expression, and we would really want to avoid any sort of on-target toxin in the lung. So to tackle that, we've selected our moderate potency payload with moderate antibody linker stability. We've also lowered the DAR from 8 to 4, and we've also silenced the Fc gamma R binding. We believe all of that taken together will be able to target NaPi2b in an efficacious but, more importantly, tolerable way. Okay, and the third ADC I'd like to talk about is ZW251. This is a glypican-3 targeting ADC. Glypican-3 is probably the best and most validated target in hepatocellular carcinoma. It's expressed in the majority of hepatocellular carcinoma cancers.
The design here, again, was centered around our topoisomerase I inhibitor platform, and for this program, we selected a DAR of four. Last year's AACR, we presented preclinical data showing the compelling antitumor activity profile. But again, I'll highlight here that this molecule is very well tolerated. We dosed all the way up to 120 milligrams per kilogram three times every three weeks, and the PK profile was good. And we think that this strong tolerability profile will be really important for this patient indication, as most hepatocellular carcinoma patients have impaired liver function, and having a drug that is tolerable and not only efficacious will be paramount for these patients. It also provides an opportunity for us to combine potentially with standard of care and move up into earlier lines of treatment.
HCC has been a very underserved cancer with only recently some new developments and new therapies being available to patients. First-line treatment is usually Atezo Bev, and second-line is typically sorafenib. There are no other ADCs in the space being developed for hepatocellular carcinoma, and we believe this could really move the needle for patients that are sorely in need of novel therapeutic modalities. Okay, now I'm going to talk about the other arm of our research, which is multispecific antibody therapeutics. We got our start engineering multispecifics with zanidatamab, our HER2 bispecific antibody. We took those learnings and built ZW171, which is a mesothelin targeting two by one T cell engager. We're also working on two other programs where we're looking at adding in a co-stimulatory arm or a checkpoint inhibition arm to create trispecific T cell engagers.
So just real quickly on zanidatamab, HER2 targeting bispecific antibody targets two distinct epitopes on the HER2 protein. This allows for the driving of multiple mechanisms of action that are unique in the HER2 space. The clinical data has continued to be impressive for this molecule, both in second-line biliary tract cancer and in first-line GEA in combination with chemo. That data has really supported the pivotal trials that are ongoing in HERIZON-BTC-01 and HERIZON- GEA-01. And we have upcoming milestones, as I mentioned earlier, about seeking regulatory approval in second-line BTC. There's confirmatory phase III trial initiated in first-line metastatic BTC, and top-line data for our phase III HERIZON- GEA-01 trial is expected later this year. We're about a year into our partnership with Jazz, and we're really encouraged by how the development plan is evolving with Jazz.
We expect zanidatamab to enter the market in biliary tract cancer, and there's a path to approval within GEA as well. Additionally, and excitingly, Jazz is also guiding on indications outside of BTC and GEA, namely in breast cancer, where there's opportunities post-DXd and in combination, sorry, in novel combinations. Additionally, even past breast cancer, they're thinking about other indications where HER2 expression is prevalent. So now I'll talk about ZW171. I mentioned earlier, that's our mesothelin targeting t wo by one CD3 engager. Two by one means that there are two binding arms that engage mesothelin, and there is one binding arm that engages CD3. You'll notice that the design is fairly unique. The binding arms that engage the mesothelin are actually scFvs, and the Fab arm engages CD3. The CD3 engaging arm is a low-affinity CD3.
This design was selected from a number of different designs, and we believe this design allows for optimal targeting of mesothelin high, mesothelin moderate, but not mesothelin low expressing cells. So mesothelin does have some normal expression, and we want to avoid targeting normal cells that express low levels of mesothelin. Our CD3 paratope has low affinity. We're trying to limit cytokine release, but we're also trying to support the antitumor cell killing, and we think we've done that with our low affinity CD3. At last year's AACR, we presented data that supports the preclinical development or the clinical development of ZW171, and we're excited to move these into clinical studies this year. Okay, so where are we going next with our trispecific T cell engager is around introducing a co-stimulatory signal two in a single molecule.
So where we engage the tumor-associated antigen, we're also looking to engage CD3 and simultaneously CD28. We believe that this TA-dependent T cell activation can provide more durable responses and reinvigorate T cell responses in cold tumors that have lower levels of T cell infiltration. Just last week at AACR, we presented two posters that looked at our T cell co-stimulatory programs, and we're really excited about the progress we're making on these programs. And we believe our strategy is superior to some of the other strategies that are being used out there, and we're excited to nominate a molecule at the end of this year as the final molecule of our five by five strategy. Okay, now moving beyond the five by five , the next molecules to come after that wave would be the advanced portfolio.
So this is building upon our ADC and our T cell engagers or our multispecific cell engagers, but also thinking about additional modalities where we can utilize our expertise and our engineering in cytokine engineering and multifunctional immune cell engagers or, sorry, multifunctional immune modulators. But then, excitingly, we're also thinking about expanding beyond oncology and into autoimmune and inflammatory disease, really bringing our learnings of the design of bi- and multispecific antibodies to that space. And we're looking to do that at a rate of two INDs per year from 2027 onward. So as you can see, there are a lot of things going on and a lot of things to look forward to in 2024. I think, excitingly, the zani partnership with Jazz in BeiGene is going very, very well. And in addition to that, our five by five programs are ahead of schedule.
We have two molecules set to IND this year, and we're going to continue with our presentation and publications in peer-reviewed context. Into 2025, we're really excited about the progress that zani will make as well as the IND filings for ZW220 and ZW251. So just real quick in summary, we have enough. We have a strong capital plan to be able to execute on our R&D strategy. Our partnership around zani is going very well, and we have the opportunity to provide additional business development opportunities for some of our novel compounds. Our R&D team has been extremely productive. We're ahead of schedule on our five by five , delivering our 5 INDs expected in 2026. Beyond that, we're looking to expand outside of oncology with 2 candidates a year starting in 2027. So thank you very much, and I'll take any questions.