Good afternoon, and welcome once again to TD Cowen's sixth annual Oncology Innovation Summit: Insights for ASCO and EHA. I'm Phil Nadeau, one of the biotech analysts here at Cowen, and it's my pleasure to moderate a fireside chat with Vir Biotechnology. We have with us today Marianne De Backer, the CEO, and Mika Derynck, the Executive Vice President of Therapeutic Oncology. With that, Marianne, I thought I'd hand it to you for a brief overview. What's the state of Vir today? Biggest strengths, biggest challenges, and what do you think Vir needs to achieve to drive outperformance over the next year or two?
Hey, great. Thank you, Phil. Really excited to be here. It is also a really important time for our company. As you know, we have sharpened our strategic focus. We are really focused now on two core areas where we believe, you know, the unmet need for patients is truly high, and we can also create a significant difference. One is hepatitis delta infections, which is a disease where patients who already are infected with hepatitis B progress really fast to liver cirrhosis or hepatocellular carcinoma. We have a treatment in our ECLIPSE program, which is in registrational trials, that can really, you know, significantly impact that disease. There are no approved treatments in the U.S. for hepatitis delta infection.
The other one is addressing, you know, the unmet need in metastatic solid tumors, where we believe that our masked T cell engager platform is, you know, creating very exciting data. We have shown proof of concept already in two clinical studies targeting validated oncology targets, one being HER2 and the other one being PSMA, and we're due to start a third program targeting EGFR. Your question on our strengths, yeah, definitely our pipeline, also our platform. We have this differentiated PRO-XTEN dual masking technology that really allows a T cell engager to be masked in the circulation and only be activated in the tumor microenvironment. That creates, you know, for a much more advanced safety profile, allows you to achieve a much better therapeutic index. Again, we have shown proof of concept of this already in two clinical programs.
We are progressing a third one to the clinic this quarter, and we have also started seven preclinical programs really taking advantage of that platform. And then, you know, we have a very experienced leadership team. Mika is one of the people we brought in through the deal with Sanofi on the T cell engagers. Underpinning all that, maybe also important to note that we have a very strong financial position. We have approximately $1 billion in cash, providing runway into mid-2027. That, you know, obviously gives us the resources to advance all our key programs through a number of value inflection points.
To dive into the TCE platform in a bit more detail, can you remind us of the terms of the deal that brought those compounds into Vir?
Sure, yes. We acquired the worldwide rights to the PRO-XTEN masking platform in oncology and infectious disease. That was last year in September. We struck this deal with Sanofi, which really has three components. One is the platform. As I mentioned, we have acquired the rights in oncology and infectious disease. Sanofi retained the rights in other areas, for example, INI. We also brought in three clinical stage T cell engagers, and they are masked T cell engagers, as I mentioned. In addition, we have brought in a group of about 50 Sanofi former Amunix employees who have very deep expertise in the platform, in the assets, in the manufacturing. As mentioned, Mika is one of those employees we brought in. As it relates to the deal terms, the deal closed in September last year. We paid about $100 million upfront to Sanofi.
There is also, as we have shared, a $75 million escrow payment. It is a milestone for when we progress our EGFR program to first in human dosing. The deal also includes other milestones and tiered royalties on worldwide sales.
You noted that the TCEs are masked. Can you discuss the structure of the masking?
Yeah, Mika, you want to take that?
Sure. Yeah. So these are, this is a universal T cell engager platform. At the core of the molecule, there's a bispecific, which is the T cell engager itself. It's sort of like a BiTE where one binds to the tumor antigen and the other binds to T cells, the anti-CD3 component. Surrounding the T cell engager are these long protein polypeptide masks, which are the PRO-XTEN masks. These have been developed over a decade to perfection in order to not have any secondary structure, so they don't fold. They're hydrophilic. They basically wrap around the T cell engager and prevent any protein-protein interaction with the T cell engager.
This physicochemical structure, just in that hydrophilic nature, really prevents it from binding into any hydrophobic grooves, which makes it ideal for a universal platform because you could just basically attach it to any protein and T cell engager and just swap in and out your tumor antigen of choice. At the base of these X10 masks are these protease-cleavable linkers. These are linkers that have also been designed to be cleaved by multiple different types of proteases, three different classes of proteases. Again, it's the same protease linkers that we use across all of our platforms, all of our PRO-XTEN platforms. There is this nice clinical validation that occurs with this universality that you learn from, for example, from our HER2 program that can apply to the PSMA program and now to the EGFR.
As Marianne has said, seven other potential molecules coming into the clinic. The way that these things work is basically in circulation, the masks stay intact. Protease inhibitors is the most abundant protein in plasma. Once it gets into the tumor microenvironment, they are cleaved by the tumor-activated proteases. You have a very potent bite that is able to T cell engage T cells to synapse with tumor cells to cause that potent cytotoxic killing.
Earlier this year, data were released for the PSMA targeted T cell engager as well as the HER2. Maybe we'll talk through those two data sets now. Can you remind us of the design of the trial for VIR-5500, the PSMA targeted T cell engager, and the top line efficacy data that were disclosed?
Yeah. There are four parts to the study. The first part is dose escalation as monotherapy. The second part is expansion cohorts looking in different set lines of prostate cancer as a monotherapy. The second part is in combination with standard of care agents. The fourth part is expansion cohorts with a combination. What we've reported most recently in January is the early portion of our dose escalation. We're currently still in dose escalation in part one. That's currently where we are today.
Can you go through the highlights of the efficacy data? What were the PSA 50, PSA 90 rates, and whether in Vir's opinion, there was a dose response?
The PSA response rates, we were very excited to see at this very relatively low dose, a 58% PSA 50 out of 12 patients. We had an 8% PSA 90. This was, we saw responses across multiple dose levels. You know, we have not used any prophylactic steroids, which is certainly required for other T cell engagers. We are the only T cell engager program that does not require this. Despite that, we are seeing with a really nice safety profile, we are seeing this really encouraging data. Now, in terms of dose response, you know, our numbers per cohort are like three or four patients per cohort. It is really hard. We are still at the really early parts of the dose escalation. Certainly, at the very lowest doses, we did not see as much activity.
As we're getting up to the higher doses, we're beginning to see some more PSA responses. We are very encouraged on the prospect of dose escalation. We've seen a dose response within the HER2 program. We have a patient also who interpatient dose escalated from what we would consider an inefficacious dose level at 60 micrograms per kg in the HER2 program, who then dose escalated into the efficacious dose range and showed a nice dose response where he had a nice confirmed partial response. Continues on study for now with a duration of response of 18 months. Nice proof of concept of a dose response there, and we hope to see the same. With other competitor programs, we do see a dose response. Janssen did report a dose response early on, but they did see a higher dose response at higher doses.
We're encouraged. We're still early. You know, we've got a huge therapeutic index, and we're encouraged to see that at the efficacy of the higher doses.
Yeah. I would just add, Phil, that, I mean, these were all heavily pretreated patients, right? Patients who had exhausted all prior lines of therapy. To see that above 120 micrograms per kg, really all patients showed some level of PSA decline was really, you know, remarkable to see.
On the therapeutic index and prospects for higher efficacy at higher doses, some of Vir's potential competitors note that there was data disclosed in the 5500 patent filings that suggests the masked T cell engager has an activity at 5.6-47 nanomolars based on preclinical assays. Those competitors argue that since Vir's already achieving more than 10 nanomolar plasma concentrations at current doses, any additional dose escalation would yield levels at which the masked T cell engager will have activity even in the circulation. What data do you have that refutes this interpretation? How are those potential competitors misinterpreting the preclinical findings in the patent?
Yeah, thanks for the opportunity to address this question. We've heard this before. The preclinical data, and I do think it is a bit of a misinterpretation. The preclinical data that I believe they are referring to is the in vitro cytotoxicity assays, where we do believe there are some artificialities with that assay in that it underestimates the actual dose required to see cytotoxic activity. If you actually look at competitor masked T cell engagers, they similarly, using a similar in vitro cytotoxicity assay, are in exposures where you would potentially predict there might be some cytotoxic activity. Where I think is probably the more relevant in vitro data is the T cell activation assay that we use preclinically.
There you can go up to a level of 1 micromolar and see no evidence of T cell activation with a masked molecule, where, of course, you do with the fully unmasked molecule. We are definitely not achieving any exposures. You know, we're logs below 1 micromolar exposure. We don't believe that that assay, the cytotoxicity assay, really is a good way to assess this. The last thing is, you know, the proof is in the pudding. I mean, we've got great PK. We don't show any evidence of cleavage. There's a very low level, as you might expect, with natural metabolism. We see really minimal CRS. We're seeing 25% grade 1-2 CRS. We, again, are the only ones that don't require prophylactic steroids or any prophylactic anti-IL-6. That really tells you that we do have this pretty good therapeutic index.
We're continuing to dose escalate. We're pretty excited about the potential for the really extended therapeutic index. That, I would say, those preclinical data is really not really informative.
How does the preclinical assay you just referenced differ from the one in the patent filings? Are there basic?
It's the same. We're basically the same. You do get single digit, double digit nanomolar EC50s for the cytotoxicity assay. I didn't want to get into technical details around it, but needless to say, in the assay itself, you bathe the tumor cells and your human lymphocyte cells, your T cells over three days and basically look at increasing concentration of your drug. Over those three days, as you get tumor lysis, you get activated proteases. Those activated proteases then cleave off the mask. You get an artificial system, which then underestimates your EC50s. If you look at T cell activation, though, in vitro, same sort of format, you incubate tumor cells with lymphocytes, increasing amount of drugs, and you look for evidence of T cell activation. With a fully masked drug, you see no evidence of T cell activation up to one micromolar.
I think that there's an inherent flaw with the cytotoxicity assay saying exposure to exposure is going to be the same in patients. The other thing I did not even go into is, you know, patients, it's a dynamic exposure. It is not like you're going to get those exposures for three days at that high level.
Got it. When could we see data from 5500 next? Kind of what does Vir want to see before releasing the data? Following that data release, what would be the next steps for the program?
Yeah, Phil, so our phase I study is well on track. As Mika mentioned, we're in the midst of dose escalation. We're also exploring different dosing frequency, as you know, every week, every three weeks. I mean, the half-life of the drug being 8-10 days allows us to explore less frequent dosing, which is going to be really important if we go into earlier lines of therapy. You know, we have a waiting list for patients. We are executing as expeditiously as we possibly can. The team is working very, very hard. We plan for success. We last presented data in January. We will be sharing more data as soon as, you know, we have efficacy, safety, dose response, frequency of dosing, all those insights.
As soon as we have that meaningful data set in hand, we will be sharing it with the public, either through a major medical conference participation or through a focused investor event, as we have done a couple of months ago.
Sorry, go ahead, Mika.
Just to add, you know, and I didn't mention this in the trial design, you know, we're looking at a Q3 week dosing schedule. We hadn't presented that in January. We will, you know, we're dose escalating currently in this Q3 week. We're very encouraged. We are already doing Q3 week in the HER2 program, and we're seeing efficacy and safety in that program. We do think that that's going to read through well nicely. Our half-life is 8-10 days. That Q3 week is, I think, a big important differentiator for us.
Moving to the HER2 program, VIR-5818, can you briefly describe the efficacy data that were presented from that program in January?
Yeah. In that study, we looked at HER2 positive from IHC2+ and above in a similar format with a four-part study. Our combination is with pembrolizumab. What we share with you is dose escalation data at the monotherapy. We looked at both the Q week, and then we opened up subsequently a Q3 week dosing level. In the HER2 positive patients who were dosed above what we think is a minimal efficacious dose, which is 400 micrograms per kg, we did see about 50% of those patients have some form of tumor shrinkage. In the colorectal, the HER2 positive colorectal subset, we were very encouraged to see a 33% confirmed response rate in that setting.
That included that patient that I talked about earlier, which is a patient who started at 60, went up to 600 micrograms per kg, was on study for over two and a half years, very well tolerated, confirmed his response when he got up to that 600 microgram per kg dose level, and has a duration of response of over 18 months. Really nice in a very heavily pretreated patient population. Similarly, the safety profile was very, very impressive in that we are seeing very low levels of CRS. We do not mandate prophylactic steroids. We are still evaluating and continuing to dose escalate. We have opened up the combination with the pembrolizumab combination, and that is currently dose escalating as well.
What did you see in HER2 positive breast cancer, and when do you think you'd be in a position to make a go/no-go decision on further development there?
No, go ahead.
The HER2 positive breast cancer, we did enroll both IHC2+ and above, as well as IHC3+. We did see that one very impressive response in a patient with very extensive chest wall involvement, had multiple prior lines of treatment, including in HER2, who had a really dramatic response. Other than her, we have not actually had a lot of HER2 positive breast cancer patients at the upper cohorts. I think one of the challenges of this study is that we enrolled sort of a very heterogeneous patient population across 10 or so different indications. Really hard to make an assessment in breast. You know, we had this one collection of the colorectal cancer patients, and that was because of that early responder that we saw that the investigators put these patients on.
Other than that, we only really have a handful of patients in any given one indication who are bona fide HER2 positive. Having said that, you know, we did see a CT DNA response in a HER2 low patient. And so, you know, I think if once we are able to do a concentrated effort and a homogeneous indication at a homogeneous dose level, the recommended phase II dose level, I think that's when we're going to really be able to assess fully the activity.
When could we see additional data from 5818, and what would be the next steps for the program generally?
Yeah, Phil, a little bit similarly, right? We are waiting for the data really to mature. So Mika talked about the results we saw in that subset of metastatic colorectal cancer patients. Importantly, those were also microsatellite stable patients where you typically don't see, you know, immunotherapies to be working. We really want to investigate that further. We obviously want to see more mature data across a more homogeneous set of types of tumors. The way that the study was set up, as Mika explained, is a basket-style study. You don't sort of know which kind of patients you're going to get in. You know, as the trial matures, you're getting more meaningful data across certain tumor types. That's why we got this very interesting insights into CRC. We want to see some early data on the combination approach with Pembro as well.
We're also exploring, again, both weekly and Q3 weekly dosing. As soon as that, you know, package all comes together again, we will be sharing it with the public.
You referenced VIR-5525 in your opening comments. Can you give us a brief status update on that EGFR CD3 T cell engager?
We're really excited that, you know, again, it has the same platform. We do think that the clinical validation that we've seen together with the first two programs will read through the EGFR program. It has really a pretty exciting preclinical data set. We anticipate FPI in the first half of this year. We're very encouraged about seeing the data come out of that program.
I know that today we're focused on oncology, but Marianne, as you mentioned, in HDV, you have a pivotal program ongoing. Could you give us a brief update on the status of the HDV program? When could we see initial results from those pivotal trials?
Sure. Yes. We're actually making excellent progress in our hepatitis delta program. We announced in the first quarter that we have dosed the first patient in the ECLIPSE 1 trials, and we are targeting completion of enrollment by the end of this year. We also have shared that the primary completion date is December 2026. That gives you a little bit of insight as to when the top line data might become available. Our ECLIPSE 2 trial is one with a shorter 24-week endpoint. We could potentially see data in a very similar time frame. It is the combination of ECLIPSE 1 and ECLIPSE 2 that forms the package for both the FDA and the EMA for registration of our regimen. We're also in full preparation for starting ECLIPSE 2, for starting ECLIPSE 3.
ECLIPSE 3 is a study that we are doing comparing head-to-head with bulevirtide in countries where bulevirtide is available, mostly Europe. That is going to be important for, you know, pricing and reimbursement, again, in Europe, for example. Maybe just also to mention that, you know, this is a program that addresses a very high need. We have breakthrough designation, fast track designation, prime designation, orphan drug designation. Our teams are working very collaboratively with the agencies to bring this regimen to patients as quickly as we can.
Great. With that, I think we are out of time. Thank you for a very efficient summary of all that's going on with Vir, and best of luck with the second half of the year.
Thank you so much, Phil. Appreciate it.
Thank you.