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Cowen Infectious Disease Panel Transcript (Q1 2022)

Phil Nadeau (Cowen)  0:03  

Morning and welcome once again to counting company’s 42nd annual health care conference. Hopefully it’s last virtual edition. I’m Phil Nadeau, one of the biotech accounts here accounting. It’s my pleasure to moderate a corporate panel discussion of infectious disease. These are clearly exciting times for the field with the current pandemic entering its third year now, hitting a second anniversary. Maybe we’ll start the discussion there. Orion of dynavax Oh, sorry. Let me introduce the panel. First we have from dynavax Technologies Ryan Spencer, CEO from gritstone oncology, Karen gIass, the EVP and head of r&d from icass of x and M. Simpson CEO, and from Vir biotechnology, George Kangas, President, CEO and director. I thought we do probably about 45 minutes a company specific questions and maybe 15 minutes of thematic questions at the end. As I mentioned, Ryan, we’re going to turn to you first on the subject of COVID dynavax. His collaborators have supply agreements and in aggregate to deliver about $700 million 700 million doses of COVID vaccines by the end of the year. What is an update on the status of those vaccines at managing cluver by Ali, Val Neva?

Ryan Spencer (Dynavax)  1:15  

Well, I’ll have to give you the with 45 minutes, it’s probably give you the short version. But they all make continued progress in regulatory environments around the world, they’ll need us looking for their first approval here in the near term, Clovers continuing to manage through their regulatory approval process and targeting who EMA and China medicines approved in Taiwan and Paraguay and bio he received approval a while back in India and recently received approval for their 12 to 18 year old indication which is unique. It’s nice. It’s low in India, so they have a good opportunity there. The other key point is they all of those collaborators continue to work on additional clinical development to support a ditional utilizations of the vaccines, whether it’s pediatric elderly, or boosters across a variety of regions.

Phil Nadeau (Cowen)  2:07  

Last week, dynamex got to 2022 CPG revenue of greater than 550 million with a gross margin of 50%. Can you discuss the assumptions incorporated in that guidance? How much of the revenue is based on signing contracts? How much upside? What are the risks to guidance? Referring?

Ryan Spencer (Dynavax)  2:22  

Yeah, you know, we’re in the supply business here. For COVID, we develop obviously, other products, but here we made our adjuvant available very, very broadly. And as such, you know, supply arrangements are different than obviously product sales arrangements. So we have a good line of sight and that we have to have prior to ordered and supply and ahead of manufacturing for eventual sale. So that guidance was underpinned by contracts that we haven’t had non cancelable contracts we haven’t hand across our portfolio. It’s why we felt comfortable providing it. And so upside to that is obviously depending on needing to order more as as their programs progress. And in recognizing that, and we’ll probably get to this in the discussion. There’s some variability on how vaccines could progress in different regions over time. And to the extent that there’s more opportunity, as a result, they’re expanding utilization from these clinical trials I mentioned before or eventual regulatory approval. There’s, there’s upside as demand dictates. So we’re pretty excited to be able to lock in that level of revenue from a guidance perspective.

Phil Nadeau (Cowen)  3:29  

That is perfect. Adam, we’ll move to you. Could you take a minute to describe a cost of access approach to vaccine development? What are the advantages and disadvantages of virus like particles? And how is your technology differentiated from other DLT VlP platforms?

Adam Simpson (Icosavax)  3:45  

Phil, of course, I mean, that the easy way to think about VlPs I mean, they’re they’re not what you’re hearing about in the news, certainly in the United States in the context of COVID. We’ve all seen lots of pictures of the Coronavirus, right, there’s a ball in the middle and then the spiky things sticking out. That structure is exactly what we’re we’ve emulated with a VlP. When you think of the incredible advances of nucleic acids, or how vaccines are, for example, the Sanofi vaccine coming in line and COVID, they are in a manufacturing plant or in the body, making one of the spiky things you know, a bunch of them. But it’s not going to surprise you that the body we believe saves its most pronounced immune defense mechanism for something that actually looks and smells like a virus. And the problem has historically has been how you make that macromolecular structure in a scalable way. It’s a hard it’s a protein folding problem that the the antigens themselves have to be properly folded. And you have to assemble this three dimensional structure. So that’s going to challenge so what you’ve generally heard about is either naturally occurring we know a lot about this modality. There’s a handful that exist in nature. And so the challenge is been Applying that modality to other targets of interest. And that’s why we’re so excited about the opportunity to really advance something entirely distinct from what we all hear about.

Phil Nadeau (Cowen)  5:11  

While, we’re on the subject of COVID. Could you provide an update on IV X for 11? Year VlP vaccine candidate is SARS cov. Two, I think we’re actually expecting data over the next few weeks, what info will be disclosed in that initial data release? And how could it How could ultimately 411 be differentiated from the other COVID vaccines?

Adam Simpson (Icosavax)  5:33  

So we believe the LPs are, again, fundamentally different, which is the way we think different is potential for higher titers. And so we all know now now in the context of COVID, if we didn’t know before, that, you know, neutralizing titers are how you protect a brothel response, these VlPs have an attribute called heterospecific protection, which you know, could be important for meaning they can protect against related strains that are in the vaccine. So think, you know, flu and COVID, that’s important, we’ll be looking at that element as well. Ultimately, we’ll look at durability, which is a big VlP difference, that won’t be in the first dataset, and that’ll be coming later. But what we’re going to try to do is both the naive, in particular, because the clean background, as well as in the booster context, be as clear as we possibly can there’s there are techniques to use international units to try to help cross comparison studies. And so that’s one of the techniques and we’re going to try to lay out the data in a way that allows, again, will allow people to see the benefits of this modality.

Phil Nadeau (Cowen)  6:40  

And have you defined a hurdle or or criteria necessary to move? Move forward? 

Adam Simpson (Icosavax)  6:49  

So when we went public in July, what we told investors at the time was our our by Vaillant, RSP hMPV program, you know, as you as you know, Phil, there’s nothing on the market for RC, there’s there’s nothing on the market for hMPV. These are both we believe, is his biggest pneumococcal let alone stack together. So we told folks look, COVID, COVID. And upside, we were asked to get involved by the Gates Foundation, we’re going to do that, I think our conviction and COVID as an endemic opportunity has only grown. But as you know, our vision is to create this pan respiratory panel that’s been in the news, but to actually have a technology, again, from a durability and a reactogenicity perspective to do that. And so we continue to think about will be advancing COVID. And I guess I’m saying at a minimum in the context of the pan respiratory vision.

Phil Nadeau (Cowen)  7:47  

Perfect. I will move next to Andrew Allen and Andrew, I apologize. My script had Karen appearing

Dr. Andrew Allen (GRTS CEO)  7:54  

she’s much better looking than me. So I’m sorry, you have to just settle with me.

Phil Nadeau (Cowen)  7:59  

Well, thanks. Thanks for joining us. Maybe we’ll just start with a with a basic question on the importance of T cell responses and protecting against Super COVID-19 disease. Can you discuss the importance of those T cell responses one by memory T cells and maybe give a bit of an overview on how grid stones vaccine candidate can be differentiated through its T cell affects?

Dr. Andrew Allen (GRTS CEO)  8:20  

Sure. So the natural immune response to viral infection is to generate neutralizing antibodies and cytotoxic T cells. And they work in tandem to both obviously neutralize virus before it can enter host cells and then to kill virally infected cells if the virus makes it through that first wave of defenses. So it really is a belt and suspenders approach, which obviously naturally works quite effectively. And we know that we’re there are people who’ve been infected with Coronavirus who have durable, I’m talking about non SARS cov. Two but other related coronaviruses who have durable T cell memory against fragments of the virus that are conserved, both within that original viral infection the common cold, but also the same sequence is present in those nonstructural proteins of SARS cov. Two, and this nice paper came out from Oxford last year showing that in health care workers who had been exposed to abundant SARS cov, two in the early days of the pandemic, there were a group who just never it’s not that they never got sick, they didn’t even cero convert, they never showed any evidence of having even had to mount an antibody response to SARS cov. Two, the hypothesis was that this was because of their T cell memory against conserved regions of other genes. And they tested hypotheses and found it to be to stand up. And indeed there was there’s an enzyme called or a protein called NSP 12 which is a an RNA polymerase that’s found in all coronaviruses and that appear to be providing these targets which are consistent across different members of the family. So we’ve got lots of indirect evidence of the importance of T cells, but it’s hard to measure T cells. And they’re complicated to understand because you have, the targets are restricted by HLA molecules, which vary from person to person. And so I think largely for those reasons, we have actually limited data on the importance of T cells in vaccine responses to SARS, cov. Two, and what we are starting to see is that there may be differences between the mRNA vaccines and the adenovirus vaccines, the adenovirus is a very good way of generating a strong CD8T cell response. We’ve known this for years. And I think that’s what we’re seeing with with the j&j vaccine in particular. And when you look at their survival data, they have this remarkable flatline, it was just actually published in the New England Journal a couple of weeks ago, showing that this survival benefit is sustained and is high level as you know, whereas protection against getting virus in your nose and being PCR positive, has been lower because they make lower amounts of neutralizing antibody. So right there, we may be seeing a separation of these effects that if you want to have sterilizing immunity, then you need antibodies. And if you want to be protected from dying, T cells are very important and potentially more durable. And this stands on perhaps in contrast to what Israel has demonstrated in their publication recently, where at five months after Pfizer vaccination, the mortality from Delta suddenly took off. And that was protected against with a third dose of the vaccine, suggesting that perhaps the durable memory was just lesser with the mRNA vaccines, which is broadly consistent with some of the other published data. So we’ve got lots of reasons to believe that T cells matter. 

So gritstone, we’ve developed a self amplifying mRNA or second generation RNA product. It’s in similar to RNA because of course it ultimately it is an RNA, but it has a copying component derived from a different virus. That means that you can administer small amounts of mRNA and still get very strong neutralizing antibody responses. And our early human data suggests that with a 10 microgram dose of our vaccine, in a boosting setting, we generated neutralizing antibodies, that basically the same as Maderna, at 100 micrograms, so one log reduction in administered dose. But of course, the additional benefit potentially is those additional CD8T cells. And in our vaccine, we don’t just have spike, we have other conserved regions of the virus from other genes, which are thought to be very good sources of T cell targets. And we do our own work to validate that and Alex setti, in La Jolla has published extensively on this. So we know we’re administering good to have T cell substrate in the vaccine together with a spike. And so what we see is good neutralizing antibodies, and good CD8 responses to those novel components of the vaccine. The premise is that that could be useful to both provide us perhaps superior protection and more durable protection. Because the real unmet need today in vaccines is this constant antigenic drift in spike. And obviously omachron is the most recent example, where the protective capacity of the original Wuhan vectored vaccines has diminished pretty dramatically because of all of the mutations in the spike protein that are found in Omicron. So that the neutralizing potency of those vaccine listed antibodies drops off about 30 fold, on average, something like that. And obviously, George can speak to some of the interesting data they’ve generated with their therapeutic antibodies, which did retain activity against Omicron, because of some of the binding properties. But the vaccines, we certainly saw attenuation of protection because of Omicron. And the idea is that by having those conserved T cell regions, you may have a more durable, variant proof form of Clinical Protection.

Phil Nadeau (Cowen)  13:53  

That’s a perfect segway to George. George, maybe you could spend a minute on antibody therapeutics, what role do you think they’re going to play in the treatment and prevention of COVID in future years? And then, specifically, what place do you expect sotrovimab to occupy within the COVID antibody space?

Geogre Scangos (VIR Biotechnology)  14:09  

Thanks Phil, first of all, thanks for having us. Nice. Actually, kind of nice in some ways to see a panel on infectious diseases and the area getting some attention says it’s so important. But anyway, look, we believe COVID is here to stay, right. It’s infections with Omicron are coming down. Everybody’s optimistic. But we have to be prepared for next wave of variance whenever whenever they come. The virus has shown an incredible ability to adapt to mutate. So almost certainly moving back and forth between humans and animals. So I think there’s every reason to believe that this is not the last wave that we’ll see. So we think that antibodies will have a critical role alongside other treatment options and obviously vaccines. And we see, I think, three different segments. One is prophylaxis, which of course is, you know, for most of us is achieved through vaccines needed. You know, as we just heard, I think there’s a lot of room for improvement over the current vaccines. But there are millions of people in the US whose immune system is impaired to an extent that they don’t respond very well and are not protected by the vaccines. So for those people, antibodies I think provide provided very good way to protect them from from COVID especially antibodies that have an extended Half Life and can provide protection over over months. There are a number of different antibodies been developed for prophylaxis and Abby shield from AstraZeneca has received as received and EUA terms of Sidorova map. There are multiple investigators sponsored studies going on right now for for prophylaxis and we’re begin to phase three trials for prophylaxis in q2. Once a platform trial, and the other is a company sponsored trial called common star, the endpoint of both is the reduction of symptomatic PCR confirmed COVID 19. And the say the comments star are company sponsored trial is an event driven trial. And so we could see results as early as the second half of this year. So the second need is early treatment. You know, in both antibodies and small molecules, Pio packs of aid from Pfizer have shown positive data in the outpatient setting. We believe that antibodies will continue to have a role there, even in the presence of small molecules. You know, we’ve done research and there are, you know, patients and physicians who would prefer a one and done antibody treatment, you know, they’re sick, they’re not feeling well, they can have the get an antibody and be done as opposed to taking, you know, large number of kills over over several days. So clear, the world needs both, but we believe antibodies have a continuing role in early treatment. Third is hospitalized patients, you know, and some major area of unmet need, and where there aren’t many treatments available. And so we are evaluated sotrovimab in the hospitalized patient population as part of a trial in the in the UK, it’s called the recovery trial. And we will expect to have initial data there in the second half of this year. Finally, all of that is enhanced with an IV. I mean, I am formulation as opposed to IV formulation. So we you know, we conducted two studies come at peak comet tail last year, and based on their data from those trials, we submitted an EUA requesting an amendment. So that’s approved map can be administered I am and that request is currently pending. So we we think anybody’s and Sutro have continued lates and the continuing problem with COVID.

Phil Nadeau (Cowen)  18:20  

Can you clarify the current data and sotrovimab efficacy against Omicron sub variant ba.2, where does the discussion now stand with the FDA as to why the sotrovimab retains efficacy? 

Geogre Scangos (VIR Biotechnology)  18:34  

Well, as you say, we published it in February, you know, demonstrating that so Trove MAbs neutralization potency was reduced 16 fold against the h2. And we did that experiment 10 times, error bars are small. So pretty, we’re very confident in that 16 fold number against pseudo virus right live virus data still pending? The same essay that we’ve used for other variants. The data was shared with regulatory agencies around the world, including the FDA, of course, and the FDA questioned our conclusion that the 500 milligram IV dose of Citroen Mab retains activity against the against b two. And they question that based on the assumptions, modeling assumptions about concentrations in the law. So the FDA are asked for additional information, additional data to support our position there. And they also asked for safety data for higher doses. So we’ve submitted all the data to the agency, and we’re awaiting further correspondence. So we’ll we’ll we’ll see. In the meantime, the FDA did note on its EUA website that’s a trove a map is currently authorized in all US regions. The FDA also updated a healthcare provider factsheet, to say that the two include the 16 fold change against pa two, and noted that the clinical relevance of the 16 fold change is unknown. And so they will, I’m assuming relatively soon form an opinion on that

Phil Nadeau (Cowen)  20:22  

that is very helpful. Ryan, we’ll go back to you continuing the discussion of COVID and COVID. Vaccines dynavax is partnered with some of the major international vaccine providers. What’s your expectation for the long term demand for COVID? Vaccines, particularly outside the US? How over how many years do you think vaccines will be necessary will have to be delivered to fully vaccinate the worldwide population?

Ryan Spencer (Dynavax)  20:50  

Yeah, I think there’s two, there’s a couple elements to this question. And one, I think you’ve heard from the penalty code, it’s here to stay in some form or fashion. And we’ve talked about prevention against infection versus prevention and severe disease and death. So there is an element over the long term that’s going to dictate be dictated by vaccine policy and goals, versus the short term, which was get everybody vaccinated. So in the near term, there’s still a large portion of the population that has not received their full course of vaccines, even the initial two doses, I think we all recognize that three doses is probably a better way to think about a complete series. And then that’s important, because in unique certain regions, there’s room for booster unique boosts or heterologous boosting. So for example, China, they did a great job vaccinating their population using an adjuvant inactivated products, and some add no products early on. But the reality is, from a boosting perspective, those that’s not exactly probably the right approach. So I think there’s probably an opportunity for China for a continue boosting through into 22 to 23. vaccinating Africa, there’s still a very low number of complete series given in Africa, even initial doses, given demand and challenges. So I do think that takes time to roll out in those in those regions. And so I think there’s 22 is an opportunity, I think it probably bleeds into 23, just given the challenges with extending initial vaccination globally. Beyond that, it does come down to the landscape, the policies, the economic realities, and then what the disease does. We have seen, I think some of the points here, the even the mRNA vaccines that did generally great protection early on the durability around protection against infection, it wanes as antibodies wait. However, we also did see that even with two doses, protection against severe disease was was quite good. And so I think there’s some time that’s going to, we need to see how well that holds up, especially in the highest risk populations. So these would be elderly, immunocompromised diabetic patients, how long does that immune memory or T cell response that was generated? How long does that last? And does that wane over time, which could have an impact on vaccine strategy? i And frankly, also how therapies evolved as well, alongside it. So there’s a landscape question here, Phil, which I would love to see if anybody else has the answer on exactly what’s going to happen in 2030. And beyond. I do think there’s opportunity, I think for dynavax. The fact that we’re positioned across different technological approaches, as well as different geographical areas, means, you know, the strategy to be available to be helpful as the landscape evolves, I think will play out well.

Phil Nadeau (Cowen)  23:41  

We held COVID, expert panel, first thing Monday morning in we asked the panel this question, and we also surveyed 25 COVID experts as well as 10 pairs in the days leading up to the panel as to how often they thought booster doses would be necessary. What was interesting is that 80% of surveyed kols and 80% of Payers thought that this would actually become an annual vaccination panel brought up all the points he did in suggest we need to know a bit more about durability and antigenic drift, and weren’t quite as convinced. But but they found it could be could be annual. Any any thoughts on that server? I mean, yeah. Are you preparing for maybe annual booster doses being necessary?

Ryan Spencer (Dynavax)  24:23  

Oh, absolutely. I mean, that’s, that’s this whole concept of being prepared for what’s needed. So we position ourselves to be we’re there we’re able to support the demand as as it’s generated in the annual boosters, I think could very well be needed. I think the question will be maybe be there’s a layer down on annual boosters for whom, and I think that’s where we have to recognize we’re very early on in this disease. And we’re learning every month there’s more data that comes out around durability and, and age groups and so I do believe there’s going to be repeat booster is needed, especially For those at highest risk, I think and then expound to do we have vaccine candidates that can protect against infection? And do we want to protect against moderate disease? And how I do think you’re gonna see two different realities there, though, the number one protecting against severe disease, death and hospitalization? And then a second possible approach even on how do you protect against moderate disease and just general illness to be more of a lifestyle vaccine versus avoiding severe disease and death? So yeah, I do think there’s a room for a booster market. And the question is, for whom and how often

Dr. Andrew Allen (GRTS CEO)  25:35  

And with what, perhaps Ryan as well, because obviously, we’re assuming that there will be some new variant, we don’t know how effective revaccination With today’s vaccine will be, we know that Omicron attenuated protection dramatically. But if I got my antibody levels up high enough, they could still kind of overcome that loss of potency, we don’t know that will be true of whatever comes next. And so it’s not clear that you’ll be able to just give more of the same, you may need to generate global supply of a completely new product. And that’s obviously we’re potentially attacking top conserved epitopes with a more T cell tropic effect to complement the antibodies makes some good sense. Because otherwise, we’re going to be turning into a flu like scenario, which obviously, nobody finds very satisfying, where you either trying to predict what will be the next variant and with varying degrees of success, or you’re reacting to a variant, which then takes time and cost a lot of money, and then you have all the distribution challenges. So I don’t think we can just sort of simply assume it’s going to relax into a happy once a year, same old, same old kind of strategy that may not work here.

Ryan Spencer (Dynavax)  26:44  

Yeah, I mean, there is there is interesting data still being generated on it again, I think, Andrew, your point around different technologies, completely different technologies are interesting, the Omicron variant based vaccines didn’t necessarily won’t necessarily overcome, you know, how to might have something to say on this to the the original prime response to one type virus. And, and yet, we still didn’t see significant increases in hospitalization. If you were boosted with three doses, so there’s memory B cells, T cells, against even a wild type that still come into play. So I don’t know if it’s gonna be as simple as just doing variants either. I think, to Andrew’s point, it’s just a lot to learn.

Geogre Scangos (VIR Biotechnology)  27:30  

you know, it’s interesting that if you think about this, from an anybody point of view, whether they’re monoclonal or polyclonal response from the vaccine, that there are, and we’ve characterized, now, a lot of monoclonal antibodies against COVID. And the coronaviruses, there are a very small subset of antibodies that hit epitopes, that are conserved across all variants, and across many coronaviruses. And so, and so not all coronaviruses. But and so those antibodies in the epitopes, that they hid, define regions, that could elicit a broader response if included in a vaccine. And so I think there are ways to get to a vaccine that will have broader, potentially longer lasting coverage. And we’ve got some preclinical data along those lines to show that we can protect against Corona viruses that are not included in a vaccine, not just variants, but different viruses.

Adam Simpson (Icosavax)  28:35  

Yeah, I mean, just add, you know, from a from a VLP perspective, and I agree with you, George. And, again, what we’re what we’re really looking forward to digging into with our clinical data is mean there’s fascinating data about VLPs. And in the context of flu in the cockpit with this idea of hetero subtopic protection, we can see the ability to protect against related strains in noreau, that’s in development HPV, so it’s not a it’s not a new idea that something about the immune presentation of VLPs gives you a different technique to protect. And then just to explain to the group, and I certainly respect the comments about the role of T cells going forward. In our case, what’s what’s unique about VlPs because they look and smell like a particle, you end up with this long list these long live plasma cells that their job is to pump out neutralizing antibodies over time. And so that is to extend the neutralizing antibody response. Because completely agree that, you know, particularly in the context of the variants, you know, there’s there sure seems to be a need for for durability.

Phil Nadeau (Cowen)  29:57  

And maybe we’ll stay with you integrate your other respiratory vaccine for a second, you have IV x 812. In the early stages of clinical development, he provided an update on that. When might we see data? In many, maybe any challenges in the ongoing studies? Because of COVID? In enrolling patients? 

Adam Simpson (Icosavax)  30:20  

Just step back for a second, if I, if I can’t, I mean, we, we raised our a round in 2019, we, we knew we had access to this incredible technology from from the Institute of protein design and could actually, you know, make VLPs at scale where the engineering does the trick, so to speak, on on, on the VLP. And what we were looking at at the time, of course, pre COVID was flu, where you can see really clearly, flu vaccines work about half as well in older adults as they do younger adults. And so when the when the market bifurcates, by the way, in the context of COVID, I agree, it’s going to bifurcate, we think it’s going to look a lot like flu, where there’s going to be kind of an all comers market and a specialized older adult market where that’s going to be the need. And so And of course, so we’re looking at flu COVID has come up, you know, unfortunately to society, that’s where the deaths are, you know, 85% of deaths are in this older adult population. And what was really kind of fascinating whole to us in the market was RSV, and hMPV. And, you know, we really believe when you look at older adults, you know, before COVID, it was shingles has an hcip recommendation flew pneumococcal. And when we looked at the prevalence of each of hMPV, and RSV, and think of hMPV is kind of the cousin of RSV, it attacks the cell the same way. Again, we think each of these is going to be as big as pneumococcal. So that was the idea. And that’s where we see that the need, we think by combining them out of the gate with a VlP. There’s multiple ways to win. And the technique to your question, Phil, is to first get RSP data, once again, we’re using international units, we’re going to do the best we can to compare the modality to a soluble protein, which we think is representative of what’s out there today. And then from there will be you know, our intent is to add hMPV on top of that and get into the clinic with the combo later this year.

Phil Nadeau (Cowen)  32:34  

What is the status of the RSP component? I’ve explained to you why when could we see data and what can talk maybe a bit more about the insights you hope to gain from that initial data? 

Adam Simpson (Icosavax)  32:44  

so we’ve said that we’re going to release data in the second quarter of this year. So our second, our second data set both an important diseases but on the platform. And again, what we’re going to be looking at is first with international units trying to compare our modality to to a soluble protein. So fortunately for us, the NIH was the innovator in this space originally used international units. So on the basis of comparison, the VLP compared to the soluble protein, again, the way we view the world, whether you make the soluble protein in the body or in a manufacturing plant, it’s it’s the same to us. And so we think that that’s representative. And then the other important thing is we’ll be looking at our titers in older adults versus younger adults. And so again, why we really focused on the older adult population is thus far VLPs had been resistant to drop offs and titers in that immunosenescence population. So when you look into some of the data that’s come out in the RSP space, or otherwise, that’s not certainly not always the case. And so we’ll be really interested in again, you know, an immaterial drop off and titers, it won’t be in this data set, again, filled but will be coming. The The other thing, of course, is durability, where I think that we’ve had lots of conversations on on that and think there’s going to be an opportunity to to potentially improve durability independent of, you know, higher titers, which we would think would correlate to a potentially a better label.

Phil Nadeau (Cowen)  34:20  

Andrew, could you discuss in a bit more detail, your progress in the coral program? What trials are you currently running? And can you review the initial data that’s been produced?

Dr. Andrew Allen (GRTS CEO)  34:35  

We’re in a, the first trial we started was actually in partnership with the NIH. They’re obviously attracted to the elements of differentiation that I’ve alluded to. It’s been run through they’re not through the Vaccine Research Center, but through the Infectious Disease Research Consortium. So moving at a slightly different kinetic. And so we then started our own study in the UK as a boost. And those are the centers the source of the data that we showed in January of this year, and so in subjects over 60, who’d received a primary series of AstraZeneca vaccine, we administered a boost of 10 micrograms of our self amplifying mRNA. And as I said, we observe neutralizing antibody titers consistent with Moderna, which is, you know, is best in class currently, in terms of magnitude of neutralizing antibody response. We also observed a boost in T cells against spike as you’d expect. And then the key differentiation was that we then saw induction of de novo CD8T cell responses against the conserved additional non spike epitopes, included in the vaccine. And that obviously, is was the key elements of novelty in the vaccine, because we’re not trying to just make me to this is trying to be a differentiated superior product in principle. So now we’re expanding that trial in the UK and dosing more subjects, including younger subjects, and after an mRNA primary series, as well as after a Novartis primary series. So that’s ongoing as we speak. 

We’re launching a study funded by Cepi and Iactually came away from the the Cepi. Big summit in London yesterday, where they’re looking to raise $3.5 billion to achieve the goal of delivering a vaccine against the next disease, disease x so called inside 100 days, which is a fairly aggressive challenge. But we’ve made enormous progress. And there’s a lot of good context setting at the summit yesterday, when COVID-19 first surfaced in January of 20. There were a lot of sophisticated people saying this will take about 10 years to make a vaccine because historically that that’s been the timeline. And of course, we accomplished it, thanks to the efforts in particular of Moderna and biotech, Pfizer, we accomplished it in about 320 days or there abouts. So really extraordinary progress. And I think the the near term goal that Cepi spoken to, and they wrote a nice piece in the New England Journal just published, suggesting that we’re basically now at the 250 day horizon. And the goal is to then shorten that further, as I said, so enormous interest, obviously, in driving this forward. And they’re interested in our platform because of its novelty. Those sparing in the early stages of vaccine, a scale up and when supplies a limiting obviously is attractive, because you can obviously dose 10 times as many people if you’re using a 10 times lower dose. But really, I think the T cell component is what really matters here. T cells have just been under studied, because they’re hard. And they’re hard to understand. Which is not a good reason, of course. But that’s it’s a practical reason. Traditionally, the assays have required live cells, which means you can do a 30,000 subject clinical trial, you’ll get T cell data on about 50 subjects, because there’s only a very specialized units where they actually have the ability to collect blood centrifuge, and then snap freeze it in liquid nitrogen. And so that’s been a huge impediment to progress. There are now some newer techniques that can work using standard blood samples. And that I think, is really a game changer. So we’re all interested, I think, in how to really start to understand the role of T cells more fully, not to displace the importance of neutralizing antibodies. Of course, those have been demonstrated to be very important, particularly for sterilizing immunity. But perhaps we can really meaningfully add to that. And the attractiveness of conserved epitopes means that you may have an easier prediction problem. So for example, as we’ve talked about spikes by keeps changing, but if the next pandemic is MERS, we basically have to go back to a completely different product because MERS uses a totally different spike protein with a different receptor compared to SARS. So there are some conserved epitopes between cells immerse, but they’re only T cell epitopes. So if you want something that’s truly pan Corona, for example, Pan Corona, meaning all of them, then you have to go after T cell epitopes there’s really no choice. So I think we can leverage the T cell side of the house in concert with B cells and set these interests for that reason. Now, they wanted to see the performance of the product in vaccine naive subjects, which basically means you can’t do it in a developed country. So that study is due to start in South Africa imminently. It’s been through all the regulatory approvals, as just literally about to start dosing subjects in South Africa. 

And then finally, as George said, there’s a heavily immunosuppressed population, particularly those who are patients who’ve received therapeutic B cell depleting antibodies such as Rituxan or Obinnatuzamap. And those patients don’t make good antibody responses because they have no B cells. And you can keep giving them doses of mRNA vaccine but they’re just they won’t make antibodies. There are no B cells. And so there we’re actually using our adenovirus platform for the reasons I articulated earlier that it’s really good at making CD8s. And so we have good CD8 epitopes and we have Good CD8 vector. And so that may be useful to those subjects who today, as George alluded to, are still acting unfortunately, they have to as if it’s March of 2020, they they are effectively completely naive and exposed to risk. And so it’d be wonderful to be able to do something helpful for those. It’s pretty large population. So that’s a study that we’re starting as well. So those are the four ongoing trials. And then, of course, they’ll they’ll will have data mid year, that should then be the basis for a potential pivotal. And again, depending on the context, you can think about different pivotal designs, one of the key challenges we’re getting will be, how do we measure T cells. And so as I say, there are some technologies out there now, I mentioned adaptive bio technologies, who who have an approach that uses ordinary purple top blood shoots, and looks at T cell repertoire. So it’s T cell receptor sequencing. And they actually have an FDA approved test, it’s an emergency use authorization, but the approach has passed muster in terms of the quality of their analytics. And so that is quite an interesting way of assessing T cell responses, not by looking at T cell function, but by looking at the magnitude of the T cell receptor repertoire change after disease or after vaccination. So there are some new approaches that I think will help unlock the power of the T cell compartment.

Geogre Scangos (VIR Biotechnology)  41:22  

So so far, maybe I can follow up on that, because I agree completely with everything that they just said. And I think the T cell importance has been under estimated by the field. And I also think that the effector function of antibodies, which is the ability of antibodies to bind to FC gamma receptors in myeloid cells, including dendritic cells, which then can induce T cells, that’s underestimated, and not all antibodies are equal in those properties. And so some add some, like syndrome has very good effector function, we’ve actually have a version that we’ve enhancing texture function even further, other companies have taken a different approach, which is just to eliminate that affected function completely for fear of causing inflammation. But I think having that activity there, and interacting with myeloid cells, which then can kill infected cells, is an important property that also helps protect against variants, right. And so I think for both the vaccines and the antibodies, those properties have been grossly underestimated and importance.

Phil Nadeau (Cowen)  42:33  

George, maybe you could actually go into a bit more detail on 7832 How the effector function is different. When we’ll see data on that, and whether the data that we we will next see could demonstrate the clinical clinical value of different infection effector function. And I also wanted to hear your response to Andrews comment about the epitopes. Between SARS MERS and others in the difficulty in finding finding ones that are similar, I know you’ve done a lot of work there, a massive database on that. So I’m curious if you could maybe expand on that topic as well.

Geogre Scangos (VIR Biotechnology)  43:09  

Sure. To two separate questions here, I think for 7832, it’s the same antibody same FOB as 70 is Citroen Mab, but it has an A an alteration in the FC region that enhances binding to dendritic cells and enhances binding to the FC gamma receptors that are stimulatory receptors. And in virtually abrogates binding to a negative regulatory receptor. The result is in a animal models, that you do get more interaction with dendritic cells, you do see a T cell response that the antibody can can generate, which results again in animal models have a several fold increase in potency in the near term, and long term protection of the animals even after the antibody is gone. And so this is an approach that can enhance the potency of the antibody and has the potential to provide long term protection through through activation of T cells. And so, we are, you know, doing the work now to see if what we see in the animal models also happens in humans. And so seven 832 is in a you know, and face clinical studies right now, and we should have some information about the immunology later on this year. You know, as Andrew said, it’s much harder to get assessed activity against T cells and it is against the antibody formation and so you need specialized centers. And so we are you know, we hope that those stay to that later this year. But that’s it you know if that if that works in humans has it doesn’t animals. I think VIR is potentially a very interesting molecule.

Phil Nadeau (Cowen)  45:04  

Great, a couple commercial questions. Before we move on to genetic questions, first one to you, George, you have noted that were there in GSK binding agreements for 1.7 million doses of Sotrovimab. And there’s about 1.025 million doses to be delivered. In 2022, you’re talking about the risks to the delivery of doses and the recognition of revenue. Is there any way for those contracts to be broken? And then maybe commercially, what is the upside potential came here, and she’s gonna continue to sign new contracts in the next several months? 

Geogre Scangos (VIR Biotechnology)  45:44  

So in total 1.7 million doses. And we announced that you know, that we are, well, we expect a revenue of about 1.1 billion to VIR in the first half of this year. And that 1.1 billion comes from binding orders that are already in hand. The, and we, you know, in our 600,000 dose sale to the US in q1, that’s included in that number. We had about 350,000 doses delivered to other countries, that’s included in the 1.7. Number, the US government has an option to buy another 700 I think 715,000 doses in q2, that’s not included. So the 1.7 billion is just based on hard orders that we have the 1.1 billion in revenues for 22. First half, are based on hard orders that we have right now. We recognize the revenues when the doses are delivered. So some of that revenue will be recognized in q1, some will be recognized in in q2. So we’re confident about that we’re in discussions with the US government and other governments about additional orders for the second half of the year. But so far, it’s 1.11 point 1 billion.

Phil Nadeau (Cowen)  47:12  

That is very helpful in writing a commercial question for you on Hepilsav. Can you give us an update on Heplisav where’s the process of driving adoption at targeted accounts? What’s your current market share? And what are your expectations returned? 22?

Ryan Spencer (Dynavax)  47:28  

Yeah, I mean, we keep at it, I think that’s the key here, vaccine sales is one of you know, time and pressure. Implementing a new product in a buy and build model requires a lot of system change and education. So it’s, it’s something we do over time. COVID had some disruption, obviously, in the market size and our ability to get decision makers to implement new things. So we’re very excited about the fact that we ended up with 34% share in our in our targeted business. So that’s the customers that we target with our most with our most of our field force. And that’s up from 26% in q4 of 2020. So it’s nice growth during kind of disruptive time, overall loading the entire market. We’re about 26% market share in q4 of last year. So you know, we’re pretty pleased with our continued growth. What we see going forward is the impact of the Universal Recommendation where they moved away from a risk based recommendation to a all adults 19 to six years old or 15 years old, should be vaccinated against hep B. It changes the paradigm significantly. Actually, with that recommendation, it’s about 130 million adults that are now recommended to be vaccinated. That’s the largest adult recommendation next after flu, it’s more people than pneumococcal is more people in shingrix for shingles. And so that becomes a big tool to increase the prominence and the importance of adult Hepatitis B vaccination within our health systems, which we believe is something that will help us continue to drive institutional interest and physician interest in utilizing in evaluating new products, especially ours with a two dose regimen, which provides a significant amount of efficiency in implementing such a broad recommendation. And it actually comes with higher levels of certain protections. So you kind of get both. So we’re pretty confident about our ability to continue to rev share, ultimately, to get this product to be majority have majority share across the whole book of business. 

Phil Nadeau (Cowen)  49:32  

That’s a great update. I do want to turn to some thematic questions. And Adam, I’m going to direct the first one to you that’s on the attitude of regulators towards developing new vaccines for infectious diseases. Do you think the COVID pandemic has changed that attitude and make make the regulator’s a bit more willing? I think I have a fair number of my gray hairs for covering dynavax for a number of years through at least a couple of complete responses. and negative FDA panels where if he was just so focused on every little nitty gritty detail about safety, it was, as Ryan said, a real slog to move forward. Are you running into that today as you deal with the FDA today? Or do you feel like it’s a new day of course?

Adam Simpson (Icosavax)  50:17  

The the famous loaded question here, I mean, I think I would, I would just make the point that our initial clinical work has been actually us. And so we’re coming. We’ve been in Australia, for COVID and Belgium for RSP. We’re coming into the States as part of our combination program, and so look forward to continuing interactions there. I think the thing that I could do a better job of commenting on Phil, is what certainly I think is changing is the public perception about vaccines. And just to just to a little prediction here, I mean, perhaps this panel would actually know the answer to this question, which is, you know, what flu vaccine you got three years ago, before COVID? The general population, you know, probably wouldn’t, right. I mean, I think historically, you know, this has been such, you know, vaccination has really been the last bastion of pharma, you know, you think of incredible capex needs for these really, you know, unusual technologies. And so it really, you know, prevented other technologies coming in my, in my view, and I really think that the public is going to be involved going forward, and that in vaccination, it’s going to ultimately look like every other indication out there where, for example, you know, take asthma, oh, that’s, that’s the rescue modality versus this is the modality that you want for long term disease prevention. And, and, you know, in every again, in every other body of indication, there’s this treatment paradigm. So I really think that that’s coming. And I think it’s been amazing to watch the recognition of the need for biotech in this space. And you know, the technologies that generally we’re talking about that have been so important in the pandemic, are biotech driven technologies. And so I think there’s, you know, lots of lots of change that’s been recognized.

Phil Nadeau (Cowen)  52:11  

In her in her remarks, you reference the efforts of Cepi to accelerate vaccine development, that does seem like a paradigm shift to me. Do you have the same opinion, do you think COVID is really fundamentally changed the way people whether the public or regulators are in the scientific community development of vaccines?

Dr. Andrew Allen (GRTS CEO)  52:31  

For sure. Yeah, I mean, if you look back prior to pandemic, the vaccine space was highly concentrated, very conservative. There was a fixed size to the pie. It was obviously for big companies. And then CSL and dynavax, doing their best, a couple of other smaller companies. That was it. And that has all changed. Obviously, Moderna went to went alone and clearly successfully commercialized, which was quite amazing when you think about what they had to do in that short timeframe. So the pie I think, is about to get a lot bigger. Now, I think obviously, the pandemic did have some particular peculiar properties, which have now dissipated. But I think some of the changes that were inspired by the pandemic are here to stay. I think the technology innovation that we’ve all been talking about is not going away. And so I think the the market for vaccines is going to increase because of so many innovations coming diseases where we didn’t have vaccines before, I think we will have vaccines before too long. So I think this this industry, the segment of our industry is going to expand pretty significantly. I think the receptiveness of the public has increased dramatically, as well, as we’ve discussed, for obvious reasons. And UNICEF has been successful in raising a lot of capital. You know, this is their attempt, as I mentioned, to raise 3.5 billion. And in their, on their website, they’ve announced they’ve already got over 1.5, with commitments from many different governments, gates, foundation, welcome Foundation, etc. So I think there is a general recognition that we need to spend time and energy preparing for what comes next because of course, there will be another epidemics slash pandemic, and we don’t know exactly where it’s going to come from. So I think that the forces are all moving in our favor. And it’s an exciting time for biomedical innovation to really address excellent unmet need with hopefully great public appreciation for the work that we do.

Ryan Spencer (Dynavax)  54:24  

Yeah, Phil on let me just piggyback on that real quick, because you did mention the trials and tribulations we had about getting up to seven proof which I want to be clear is very clear that we overcame those because we demonstrate the product was safe, and we’ve done it in post marketing studies as well. But all the comments that Adam and Andrew made I agree with, but if you realize what what we weren’t saying is that not traditional vaccine development. I mean, I would caution everybody in the industry to remember that safety is paramount. And that is one of the reasons why vaccines as they’re developed, the FDA and other regulatory bodies take a really hard line on that. I think the The public is going to demand that as well, as they become more aware of new vaccines. I think as Andrew pointed out, clearly, the pandemic space is changed dramatically, and is going to have continued innovation. But I think as we all work towards developing new vaccines for different diseases that outside of the pandemic space, I do think our long history of having to develop vaccines very clear clinical and regulatory pathways demonstrate safety and efficacy, and painted the risk benefit will mean to be maintained. So it’s, I don’t think anyone should expect that there’s going to be a shortcut, and developing new products. And I think that’s why being diligent and thoughtful about your clinical regulatory paths is going to be a big part of driving the innovation forward.

Geogre Scangos (VIR Biotechnology)  55:49  

So yeah, so I look, I agree with Andrew and Ryan, and I share their their view, but I just a cautionary tale, you know, we had SARS, epidemic, there was a lot of energy around being prepared for the next pandemic. And when SARS went away, the energy went away. And then we got a gentle reminder with MERS, you know, which had, by the way, 10% mortality rate higher than 50, higher than that mortality rate. And there was some energy there, and then it went away. So hopefully, this is a big enough event, that the energy that we’re all feeling now. And if that is shared among a lot of the world, we’ll, we’ll we’ll keep going. And then once the pandemic becomes endemic, and it’s not in the news every day, that we’ll be able to keep up the momentum and keep enthusiasm for developing new products, because you know, they will come there will be more variants, there will be more viruses, they may be more coronaviruses. There may be other viral families. But I’m hoping that this is a wake up call that finally keeps people awake rather than a snooze alarm. Wake up and go back to sleep.

Phil Nadeau (Cowen)  57:09  

George, could you maybe discuss how you’ve seen the environment change from the early days of beer, where you were raising money and constructing clinical studies pre COVID, to kind of what you’re experiencing today? Whether whether it’s the public, or the regulators or even investors like how dramatically different is the environment today versus when we first met a few years ago?

Geogre Scangos (VIR Biotechnology)  57:31  

Well, we are here on an infectious disease panel, I’m not sure we would have had that for four years ago. So you know, there is more interest. I might be this I’m not sure investors know yet. How to interpret everything. You know, what’s going to happen to the pandemic? how generalizable is it? How easy will it be to translate this to other diseases? And so I there’s more interest for sure. I think there’s, it’s not an established field like cardiovascular or where investors are familiar with the treatment guidelines, they know the new drugs come in they, it’s easy to slot them in, I think there’s still more uncertainty, as to, you know, how either therapeutics or vaccines will be used and what the market potential is, and what their criteria for success will be. And so I think there’s still some more questions, but certainly more interest.

Phil Nadeau (Cowen)  58:28  

Great in the last minute, want to conclude with one final question to each of you. And this is something that we ask most of our panels, that’s over the next 10 years, what do you think will be the biggest surprise in the field of infectious disease? Certainly, 10 years ago, I’m not sure many of us would have predicted the COVID pandemics. So this is a field that is prone to surprise. But Andrew, will we’ll start with you what could surprise us?

Dr. Andrew Allen (GRTS CEO)  58:51  

I think there’s likely will there will be another epidemic slash pandemic, just to keep us reminded. And obviously George’s cautionary note is well taken that there is a danger, we just hit snooze button. This was clearly a much more disruptive event than than SARS or MERS. So I’m optimistic that that won’t be the case, there will be some loss of energy, but I think we will retain sufficient energy to drive the field forward. So I think the surprise to many people will be Oh, there’s another virus.

Phil Nadeau (Cowen)  59:20  

Ryan, any thoughts?

Ryan Spencer (Dynavax)  59:22  

Yeah, I think given the broad success of mRNA with COVID, I think there’s there’s obviously a place in that, you know, Andrew gave us a good a lot of detail on ways it can be continued to be developed. I don’t think though, that one technology is going to be the answer for all of our future vaccine needs. And there’s a lot of I mean, across VlPs, adjuvants, mRNA, there’s price is going to be we’re going to continue to see innovation across the spectrum, depending on the diseases and the challenges at hand. And I think it’s actually gonna be good for the field, but I do think there’s a general sentiment that the momentum game by mRNA will continue to be the solution to everything. And I don’t I don’t think that’s going to be the case.

Phil Nadeau (Cowen)  1:00:05  

Adam, have you any thoughts on surprises?

Adam Simpson (Icosavax)  1:00:06  

Yeah, my answer is similar to Ryan, which is, you know, we’re there’s been such a dearth of technologies deployed in infectious disease vaccines historically that I think we’re in the first inning in this game. And as you look at other, you know, look at oncology as we’ve progressed over time, I think that that, not that. I mean, there will be different technologies, different modalities that will have a significant role in the next pandemic. It’s my belief.

Phil Nadeau (Cowen)  1:00:35  

George will finish with you what could surprise

Geogre Scangos (VIR Biotechnology)  1:00:38  

but I think the biggest surprise to me would be if we don’t have another pandemic in the next 10 years, because they’re coming. The the other I think thing that is probably underappreciated is that, you know, COVID, kind of a newly emerged virus we didn’t know existed before, there are a lot of viruses we know exist, and they’re tropical. And you’ll see good Dengie and yellow fever and lots of others. And as the globe warms, those viruses find a more hospitable home in parts of the world that they previously didn’t infect. So I think we have to watch out for new viruses like COVID that pop up, and we have to watch out for viruses we already know about whose geography may spread.

Phil Nadeau (Cowen)  1:01:28  

There’s a perfect ending to the panel. Thank you so much for a very interesting discussion, and thanks to everyone who’s listening out there.

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