Moderna (MRNA) Annual R&D Day Transcript September 2020

Catherine: (00:01) Good morning and welcome to Moderna's Annual R&D Day. At this time, all participants lines are in listen only mode. Following the formal remarks, we will open the call up for your questions. Please be advised that this call is being recorded. At this time, I'd like to turn the call over to Lavina Talukdar, head of Investor Relations at Moderna. Please proceed. Lavina Talukdar: (00:22) Thank you, Catherine. Good morning, everyone. Thank you for joining Moderna's R&D Day. Today, we will present new data and updates of many of our pipeline candidates. You will hear from Moderna's management and clinical team leads, as well as from key opinion leaders. Lavina Talukdar: (00:40) You can access the press release issued this morning as well as the slides that we'll be reviewing by going to the investor section of our website. Presenting today from Moderna are Stéphane Bancel, our Chief Executive Officer, Tal Zaks, our Chief Medical Officer, Stephen Hoge, our President, Juan Andres, Chief Technical Operations and Quality Officer, Jacqueline Miller, Senior Vice President, infectious diseases, Lori Panther, Senior Director, clinical development, infectious diseases, and Allison August, Senior Director, clinical development, infectious diseases. Lavina Talukdar: (01:22) Before we begin, please note that this presentation will include forward looking statements made pursuant to the Safe Harbor Provisions of the Private Securities Litigation Reform Act of 1995. Please see slide two of the accompanying presentation and our SEC filings for important risk factors that could cause our actual performance and results to differ materially from those expressed or implied in these forward looking statements. Lavina Talukdar: (01:52) We undertake no obligation to update or revise the information provided on this call as the result of new information or future results for development. With that, let me turn it over to Stéphane to open. Stéphane Bancel: (02:08) Thank you, Lavina. Good morning or good afternoon, everyone. Welcome to Moderna 2020 R&D Day. I'm happy to share with you today the important progress our team has executed over the last 12 months. Stéphane Bancel: (02:25) On slide three, as many of you know, our vision since day one has been that mRNA could create a new class of medicines and impact the life of millions. We never thought it would be a one drug company. We thought it could be a very powerful platform with a very large product opportunity, being able to make medicines that are not doable using existing small molecules or large molecule technology. Stéphane Bancel: (02:55) Having a higher probability of technical success because mRNA is an information molecule. Having the ability for investment in science, in manufacturing process, in IT, in robotics to accelerate research and development timelines, we have [inaudible 00:03:14] ever since. And the greater capital efficiency over time this is recombinant technology. That's the vision we had. Stéphane Bancel: (03:24) On slide four, we shot that slide earlier this year to show kind of a development of our company. In the first few years, we focused on the science manufacturing to be able to enter the clinic safely, which we did in December of 2015. Over the last few years, we focused to understand [inaudible 00:03:46] clinical signal, what technology was working better, and we explored six different modalities in parallel, which was an unprecedented endeavor. Toward the end of last year and early this year in 2020, at the JP Morgan conference, we announced that due to the positive clinical data that were generated by our teams in 2019, we decided to nominate two of our modalities as call modalities. [inaudible 00:04:16] vaccine and IV systemic delivery. And we decided to double down in these modalities because, in our opinion, we believe that these modalities were risk from a technology standpoint. We announced five new development candidates in the January, February timeframe. And we say that we thought it will take us three to four years to get to filing our first BLAs before scaling up the organization from a commercial standpoint. Stéphane Bancel: (04:45) Of course, SARS-CoV-2 virus changed everything. We believe that COVID-19 vaccine or mRNA-1273 has the opportunity to accelerate the company transition to a commercial company by three to four years. As we'll discuss today, there's a scenario where we could file an emergency use of parole this year in 2020, just months from now. And we could receive a BLA parole in 2021. On slide 6, let me share with you a couple high level numbers of all the progress the company has done in the last 12 months. Since the day 2019 in New York. Stéphane Bancel: (05:33) We have, of course, one programming phase three now mRNA-1273, where we had no phase three program last year. And we'll talk about it later. Our teams are working very aggressively to prepare the launch ... of a potential launch of the product. Last year, we had two phase two candidates, and this year now we have four, which is doubling the size of our mid stage pipeline. And [inaudible 00:05:59] is still at 18, showing that we have a rich diversified pipeline when you add the one four and the 18 programs. We are still very active in infectious disease, immuno-oncology, cardiovascular, rare disease and we added this year auto immune disease, as we think are very important for our particular areas where we believe mRNA would significantly impact the patient's life. We're at a cross formation in a number of patients, and as the participants who have been involved in our studies from just above a thousand people last year at the same time, to more than 27,000 people today. Stéphane Bancel: (06:38) We doubled the cash balance compared to 12 months ago, and we have added significant team members to the team to be able to beef up late stage clinical development and regulatory manufacturing, of course, to be ready to manufacture, in case of a success of 1273 ... or at least 500 million doses, up to a billion dose of 1273. And of course, starting to build [inaudible 00:07:03] commercial teams. Stéphane Bancel: (07:06) I would like to thank and congratulate the Moderna team, they did all that and much more during a very complicated pandemic. We believe that Moderna is the most advanced mRNA platform in the industry. This kind of investment in science and in manufacturing process development that we have done over the last 10 years, we believe is unique based on the ability we have to set up partnerships with large pharmaceutical companies, as well as the capital that we have been entrusted by our shareholders [inaudible 00:00:07:43]. Moderna is now one of the most advanced in COVID-19 vaccine development. But Moderna is not only a COVID-19 vaccine company. It is a very large platform. Moderna has today, 24 development candidates across a range of infectious disease and [inaudible 00:08:03] areas. On slide eight, you see an update on the pipeline. For longterm shareholder, I would like to drove him to the right of the slide where for the first time we're adding a commercial column, which is an important milestone in the company development because the teams, as we said, are preparing very actively for the potential launch of a COVID-19 vaccine. Stéphane Bancel: (08:26) We are very happy to report today that the phase two of CMV is positive and we've picked over those, and we are preparing actively for the start of a phase three next year. We're also happy to announce today that the Oxford [inaudible 00:08:43] program is now enrolling the patients in phase two. On the next slide, you see the two big news over there are. The first one is, of course, on CMV. The team will be sharing with you in detail, the data over a phase two study, which we had anticipated having go without [inaudible 00:09:01] of this year. And we'll sign on seeing that all teams after consulting with the scientific advisory board, were as [inaudible 00:09:09] phase three as 100 microgram per those other vaccines. The very important clinical data we're going to share with you today is around the antibody against Chikungunya virus on a 1944, for which, as you know, we've enrolled additional cohorts in a phase one study. We have a very important new data set to share with you is that of two of those regimens of Chikungunya antibody demonstrates the platform's ability to safely repeat dosing. Stéphane Bancel: (09:43) The data is quite interesting as you'll be seeing. And the very important advancement in the company today is that we are now seeing that Madonna is going to enter the seasonal flu vaccine business. And the reason is very simple. If you go to slide 11, is we believe there's still a very high unmet medical need in seasonal flu despite, of course, commercial vaccines being available. But it's this gap in unmet medical need that is driving all decision. As many of you know, as reported by WHO there are three million to five million severe case of proof each year around the world leaving between 300 and 600,000 deaths. Just in the US, we have between 140 and 800,000 hospitalization a year leading to between 12,000 and 61,000 deaths per year. We believe we have a chance to change that. We believe we have a chance to bring a flu vaccine that could be more effective than the current vaccines in the light of the elderly data we have been able to generate so far across the platform with COVID-19 [inaudible 00:11:07]. Stéphane Bancel: (11:07) And in face of the significant challenge with matching the strain with the mutation of flu, which we think mRNA is a very well adapted for. So if you think about us entering the flu business and the other respiratory virus, as on slide 12, we believe that we have a potential to create very powerful combination, especially for older adults. If you look at it, we have already demonstrated in the clinic that we can have a vaccine that includes several mRNA's coding for antigens of different viruses. We've shown that with the H MPV and PIV pre combination, mRNA 1653. We have also shown that from a process development standpoint, we are able to even go higher, puts more mRNA in a single dose. And as you know, in the CMV vaccine, we have six mRNA molecules in every vile. Stéphane Bancel: (12:11) So these ability that mRNA have gives a unique, competitive advantage. And if you think about a few of the most deadly respiratory viruses, COVID-19, flu, RSV, H MPV to start with the most important ones, we have actually shown positive human data of neutralizing antibodies titer in all of those four pathogen. COVID-19 obviously, we did flu twice, for pandemic flu [inaudible 00:12:42] , this has been published and for the very high level of neutralizing antibodies and [inaudible 00:12:48] . So what if one day we could get the seasonal flu vaccine to market and we could combine it with a COVID-19 vaccine in a single shot to protect the elderly. What if we could combine it with RSV? Do you understand what we could do with different combinations. Stéphane Bancel: (13:08) We also announced last night, after the close of the US market, two new collaborations with industry players. The first one is with Vertex. As most of you know, that this is our collaboration with Vertex. Our first collaboration, which we signed a few years ago, the goal of that collaboration was to use mRNA technology and Vertex's deep, deep, scientific and clinical expertise in here to develop a drug, to bring it to a line of patients, to express the CFTR protein coded in the messenger RNA. That work is advancing very nicely as we've updated you over the last two quarters. But following the progress around that program, the Vertex team and the Moderna team I've been discussing quite a lot and become quite intrigued about the possibility to use mRNA technology and all delivery technologies into the lungs to go into a new field to perform gene editing. Stéphane Bancel: (14:18) And so, we are very pleased last night, to announce this second collaboration with Vertex, [inaudible 00:14:24] using our technology and Vertex expertise and Vertex massive investment over the years in gene technology to try to bring together a very innovative treatment for patients. The team came with a 75 million upfront payment, and that was the typical milestone regulatory and commercial going up to 418 million dollar. Steven will come back later this morning to walk you through that partnership in more detail. The second partnership we announced last night was a partnership with Italian pharmaceutical company Chiesi. Chiesi is a commercial company and I think this partnership goes exactly in line with what we're trying to do, which is to bring, using all technology, as many impactful medicines to patients as we can. Some drugs like CMV, like COVID-19 we will do by ourselves, but there are a lot of medicines for which we believe partnering makes more sense to bring a better solution faster to patients. Stéphane Bancel: (15:31) Because we are combining Moderna's mRNA technology, we even have a company expertise in the disease from both a scientific and the clinical standpoint. And so with Chiesi, we are going after pulmonary arterial hypertension, which is a rare disease, but these financials are 25 million upfront and up to 400 million dollar in the typical development, regulatory and commercial milestones. So this is where I'm going to stop my few words of introduction to start the day. I'm going to leave you in the good hands of the team and closing the meeting later this morning. We decided to set up the agenda in the following way this year. Stéphane Bancel: (16:12) We're going to start with [inaudible 00:16:13] therapeutics. We have talked a lot about vaccines in the last few months, and so we thought it would be good to start with therapeutics morning. We'll take a break after we've discussed systemic therapeutic, intracellular therapeutic, and [inaudible 00:16:30] immunoncology therapeutics. To come back and to discuss about the vaccines, obviously, we talk about the work portfolio first with non-Covid and then we'll finish the morning by giving you some updates on COVID-19 vaccine. After that, Stéphane will repeat what I talked about the collaboration I just mentioned. And then I'll say a few words for closing, we'll take your questions. [inaudible 00:16:56] Tal Zaks: (16:58) Thank you, Stéphane. And good morning, everybody. It's a real pleasure to be here today and start the deep dive into our programs with the antibody program against the Chikungunya virus. This is mRNA 1944, and this is really the first of our systemic secreted and cell surface therapeutics. This is a proof of concept program that we showed the initial data last year, and really a followup of the final cohorts today that will demonstrate the ability to repeat dose with our platform. On the next slide, as a reminder of what this medicine is about, this therapeutic, what we have here is really mRNA that is encoding for a monoclonal antibody. So we have in the LMP two mRNA molecules, one encoding for the heavy chain and one encoding for the light chain. And the idea is that when these go into cells, then they will translate into proteins. Tal Zaks: (18:12) There is translation that is occurring in close proximity, which allows these, the heavy chain and the light chain, to find each other in the appropriate manner as biology has designed it. And so, we have the formation of a monoclonal antibody and then secretion into the bloodstream. And so, for us to be able to measure the antibodies in the bloodstream, the mRNA has to get into the cells. They have to get translated. This is not a simple protein in the sense that two chains have to come together, which is, I think, an inherent strength of our platform. You'll actually see us do this with five different mRNA's when we come to CMV, but the salient point here is that we're measuring a secreted protein in the bloodstream that has the potential for a therapeutic benefit. So on the next slide, if just to remind people of the design, we started with three dose levels as predicted from our translational pharmacology 0.1, 0.3 and finally 0.6, migs per kig. Tal Zaks: (19:21) We describe the initial results from those cohorts here last year. And we followed up then with two additional dose cohorts, one with the addition of steroids to see whether they would have [inaudible 00:19:37] some of the adverse events that we had described and test for their influence on the pharmacology. And finally, to see whether we could take ... administer 0.6 instead of in one bolus as a repeat dose. So 0.3 once, and then a second time a week later, and we chose a week of interval because when we did see adverse events, they were your typical infusion related reactions and they were all transient. And so it made sense that a week later would be a good initial interval to demonstrate the ability of this platform to repeat this. The utility of this protein as a proof of concept is actually that the protein is functional. Tal Zaks: (20:22) We can measure the activity of the protein because it's a passive transfer. I think in the year since then the world has come to understand much easier what a passive transfer monoclonal antibody is. In this case, it's the ability to transiently protect against Chikungunya virus. So on the next slide, let me start with the safety data. You will see here the same charts that we described last year for 0.1, 0.3 and 2.6 migs per kig. We saw very minimal adverse events until we got to the 0.6, migs per kig. And there, we started to see ... Tal Zaks: (21:03) So we got to the 0.6 mig per kig, and there we started to see grade ones and grade twos infusion related reactions, such as headaches, nausea, myalgias. These were all transient. They all spontaneously resolved without treatment. We did see one subject have a couple of grade three events, notably sinus tachycardia and an increase in their white count. We did not see any meaningful change in any other laboratory abnormalities, i.e. liver or kidney function tests. And so what you see here is what when we added steroids, there is perhaps a bit of blunting. It's hard to say, because of course these are very small numbers. We did not see any more grade three events across the entirety of the trial beyond that one case I described last year. Tal Zaks: (21:45) We continue to see some infusion related reaction. They are mostly mild to moderate. They are all transient and they are all of the same type of events that we had initially described. Notably on the next slide, if you take a deeper look at the cohort that received the 0.3 repeatedly, a week later if you come back and you re-administer it, you basically get the same thing, either nothing or you get some grade ones and the occasional grade two. These are nothing new and I think the salient point here is that none of these adverse events were exacerbated in any subject that experienced them in the first week. So from a safety profile, I think this bodes well to our expectation to be able to deliver potentially therapeutic doses at the range of up to at least 0.3 migs per kig repeatedly. Tal Zaks: (22:49) Now let's talk about the pharmacology. On the next slide are the data as we had disclosed them last year. As a reminder, we saw a nice dose dependent pharmacology. Importantly, the doses of 0.3 and 0.6, we see quite remarkable concentrations of potentially therapeutic levels of protein. These are now in the six to 10 microgram per mel in the blood at the 0.3 migs per kig. And this is a monoclonal antibody, so the therapeutic concentration from monoclonal antibodies are obviously well-known and depend on the application, but it's certainly within the range of what other therapeutic monoclonal antibodies have demonstrated. Tal Zaks: (23:40) Specifically to the application of passive immunity, we had extrapolated that one would need a trough concentration of at least one microgram per mel, and what you can see here is following that initial folus of translation, if you look at the inset, in the first two days is really where you see the buildup of protein, because it takes time for the mRNA to get in the cells and then we get translation, the mRNA degrades, you're left with a protein. And so the half-life curve on the right part of that graph post the peak is really a function of the protein half-life, not the mRNA or the lipid. I'll come back to the point of the lipid. Tal Zaks: (24:23) And so what you see here is that at the 0.3 migs per kig or above, we maintain trough concentrations above our target for at least four months or so. Now let's take a look at the effect of steroids. They don't really do much. There's a little bit of a blunting of the Semax. You can see the curves then come together and maintain a very nice and respectable half level above the trough, and so the data are up there with steroids. The really interesting part comes when you look at the repeat dose pharmacology, and this is on slide 23. What you can see here are the first three curves, as I had described them initially, the 0.1, 0.3, 0.6, and now look at the green curve of 0.3 migs per kig, so the total dose is 0.6 but we've given it now repeatedly. Tal Zaks: (25:25) And what you can see is at the second dose, protein translation starts again as if completely afresh, which from the sense of the body it is. And you can see the rise in protein on the second week is the same as the rise in protein after the first week, given this protein has a very nice half-life, what you really see is the buildup of the pharmacology. And now we're actually achieving Semax concentrations of up to eight to 16 microgram per mel. And if you just let the eyeball follow what happens a week later, I would anticipate that if we were to come with a third dose the next week, you would continue to see buildup of that protein pharmacology. Tal Zaks: (26:15) For the purpose of this target product profile, I think we're clearly there and we anticipate to have very long concentrations of a potentially protective antibody. So it may have relevance for this target product profile, but the salient point I think for us is the ability to show repeat dose in a tolerable manner, no adverse safety findings in the sense of no serious adverse events, nothing unexpected. It's all transient, no laboratory abnormalities in liver or kidney function tests and very nice dose dependent stackable pharmacology, if you will. Tal Zaks: (26:54) On the next slide is a look at what happens to the lipid, the lipid nanoparticle itself, because what I've showed you is the protein that gets translated. Well, what about the drug? Well, the drug practically disappears. We have engineered and invented this lipid and the entire lipid nanoparticle for this modality, it's specifically to have a short half-life. It is biodegradable relatively rapidly. And so what you see here are the lipids that we've invented, looking at the accumulation of it over time, and what you can see is you come back a week later. There's practically nothing of that lipid left and you basically start from baseline again, because you can think of what would happen with repeat dose pharmacology, I would expect that there is no lipid accumulation. I would expect that whatever transient adverse events happen, the infusion, when they do happen, they're gone by then and so I think this bodes well for our ability to have repeat dosing in this modality in the future. Tal Zaks: (28:03) So to summarize, I think this for us as a proof of concept has demonstrated the ability of our platform, the technology of our lipid nanoparticles when delivering these systemically a messenger RNA to lead to potentially therapeutic levels of protein in the blood, to do so safely, at least as demonstrated by this phase one trial. And we've shown that the property of the protein or exactly what you would expect, in this case, a long half-life IgG, a complex protein that requires two subunits to come together and be secreted. And importantly, to be able to repeat dose and build up pharmacology in the case of this application without building up any accumulation of lipid or drugs or adverse events. Tal Zaks: (28:59) With that, let me turn it over to my colleague, Steven Hogue, to walk us through the rare disease portfolio. Thank you. Stéphane Bancel: (29:11) Thank you, [Tal 00:29:12], and good morning and good afternoon, everyone. Before launching into a bit of a discussion about our systemic intercellular therapeutics, I did want to remind everyone that Tal has walked through an example of one of our core modalities, the secreted in cell surface therapeutics, and that there are three other programs that we won't be speaking of today, aisle two, PDO one, and relaxing in that core modality. The modality I'll briefly update you on today where we do have some news is the systematic intercellular therapeutics. This remains an exploratory modality where we're looking for the first proof of concept in the clinic in the near term. Stéphane Bancel: (29:50) So with that, I want to focus on two programs today on slide 27. The first are MOR82937, our mRNA against propionic acidemia, and 3705, against methylmalonyl mutase, so MMA for short. We have two other programs in this modality, a program for PKU and GSD1A, for which we're not providing updates today. So first on the organic acidemias on slide 28, as a reminder for those who are new to the story, organic acidemias are a set of metabolic, rare diseases that have to do with a breakdown of amino acids and fatty acids in the mitochondria, the energy factories in every cell. Stéphane Bancel: (30:33) These components are broken down and fed into the Krebs cycle by the pathway illustrated on the slide in front of you. There are a series of enzymes in that pathway, which are related to that metabolism, specifically the propionic academia PCC enzyme complex, and methylmalonyl CoA mutase, for MMA. Both of these enzymes are associated with rare genetic diseases which lead to deficiencies in the ability of the body to break down those components and feed them into the Krebs cycle. And unfortunately there are approximately one to 2,000 patients in the United States for each of those disease. And there's a lot in common between these diseases as organic acidemias, because they're in that same metabolic pathway. Stéphane Bancel: (31:17) And that includes both the biology and pathology of the disease, but also the treating clinicians and the centers of excellence for addressing the disease. We've developed two different programs that I'll speak about briefly, one against each of those diseases, MMA, MPA. And we believe messenger RNA has specific advantages in trying to address the organic acidemias. One is the ability to encode for intracellular proteins. These are proteins that are actually even inside the mitochondria within the cell, and we previously published and demonstrated our ability to deliver the enzymes to the right place in the cells in vivo. Stéphane Bancel: (31:54) Another is our ability to combine multiple different subunits, for instance, in a propionic acidemia context, and I'll speak more about that in a minute. And the last is the ability that titrates the dose response, and therefore perhaps address acute metabolic decompensations, which are a feature of both of these diseases. So double clicking on propionic acidemia on the next slide, just to give you a little bit of an overview of this disease, the PCC enzyme is actually a dodecamer complex made up of six PCCA and six PCCB subunits, and in fact it's two different genetic diseases are mutations, one arriving from deficiencies in PCCA and the other from PCCB. Stéphane Bancel: (32:36) As you can see, the prevalence is about one in a couple 100,000 births and there's approximately one to 2,000 patients in the United States. It is primarily a pediatric disease that presents early in life with significant morbidity and mortality. Often the metabolic decompensations that result from the inability to clear out those organic acids, amino acids, and fatty acids lead to neurologic complications, growth retardation, heart challenges, and even life threatening metabolic crises. So it's a terrible disease, significant unmet need. Unfortunately there are nonapproved therapies for propionic acidemia, and the standard of care so far has been dietary restrictions and palliative measures. However, liver transplants have in some rare cases been shown to improve the biochemical and clinical outcomes. And with that basis, it gives us some opportunity to proceed here. Stéphane Bancel: (33:35) So on the next slide, our program is mRNA-3927 in propionic acidemia, with the goal of replacing both the PCCA and PCCB subunits so the full dodecamer complex or propionic acidemia. mRNA-3927 has received an FDA fast track designation, an FDA Orphan Drug designation, and rare pediatric diseases designation, as well as an EMA, Orphan Drug designation, and has an open IMD. Now earlier this year, as we were preparing to initiate clinical work on propionic acidemia, the COVID-19 pandemic led to a decision that we previously announced to pause ongoing enrollment and recruitment in the study for the purposes of protecting the health of those patients and their caregivers and not bringing them into clinical setters during this time. Stéphane Bancel: (34:26) We've actually announced today that we've restarted some of that effort, but we've used the time during that pause to make some important improvements that we think will help advance the program more quickly as we re-initiate. The first thing that we focused on amending our protocol to a novel dose optimization clinical trial design, which I'll speak to in a minute. We think it will help us identify [inaudible 00:34:48] more quickly. The second is we've looked at the protocol, taken feedback from sites and from the patients and their families and caregivers, to understand how we make the overall protocol less burdensome on patients. I'll speak to that in just a minute. Stéphane Bancel: (35:02) We are looking now also to launch an extension study, which we had always intended to do but now we've had a chance to formally prepare, that will allow for the continued dosing of patients as well upon positive risk benefits for them in the phase one two trial, which is an absolutely important commitment in these rare and ultra rare disease conditions. So in the next slide I just want to spend a minute describing the revised protocol, the updated novel dose optimization design that we're taking forward for mRNA-3927. And this phase one two study has still the objective of evaluating safety and pharmacology in patients one year of age and up with propionic acidemia. Stéphane Bancel: (35:39) The primary end points, as before, are safety, PK, and PD, with secondary end points looking at the incidents in severity of adverse events or changes in biomarkers. As I said, we initially earlier this year paused activities around the trial, given COVID-19 disruptions, but those efforts have subsequently restarted and we're looking forward at the moment. Now the change has been in the dose optimization stage. While the prior design had been a standard dose escalation study, what we realized in reviewing our clinical experiences with programs like the mRNA-1944, the Chikungunya antibody program that Tal just described is that there are a number of different ways to think about optimizing the correct dose for individuals with metabolic diseases. Stéphane Bancel: (36:27) And the design, as shown here, is going to be more iterative as an approach. Patients will be enrolled and following a 21 day DLT observation window for each participant, we will take a cohort's worth of data and do innovative PK and PD modeling as well as safety review to select the optimal dose for the next cohort to come into the study. That could include dose escalation or changing the dose frequency in which we'll be treating subjects for that next cohort. That will continue until such time as we identify a dose that we think is optimal for the majority of subjects, and then we'll move into a dose expansion phase, enrolling a further four to six participants at that dose level, including a minimum of two participants from each subtype of the propionic acidemia disease, two with PCCA deficiencies and two with PCCB deficiencies. Stéphane Bancel: (37:22) We believe this approach to optimization will actually help us to identify most efficiently the optimal dose for treating this terrible disease. I want to move on to briefly give an update also on MMA, where we provided some news today as well. And focus on our new program there, mRNA-3705, against methylmalonic acidemia. So quickly on slide 33, just an overview of the disease, it is also a rare autosomal recessive organic acidemia, as I said before. It is a progressive disease that leads to multiple organ systems failing, and ultimately can lead to life threatening metabolic decompensation episodes. The prevalence is similar to what we described for propionic acidemia, approximately one in 100,000, except in the Middle East where it's even higher, maybe five to sixfold higher. Stéphane Bancel: (38:12) During the neonatal period, there can be quite severe compilations from this disease, including neurologic complications, high mortality due to life threatening metabolic crisis, and other disease manifestations. There are currently no approved therapies for MMA, despite this incredible unmet need, and the majority of the current interventions are dietary restriction, co-factor therapy, and palliative support. However, liver and/or kidney transplants have been shown to be effective when they've been pursued even in infants as long as one year of age. Unfortunately, a transplant has not been curative to date. Stéphane Bancel: (38:49) So our program on the next slide for methylmalonic acidemia was originally an mRNA-3704, but has been updated per the news today to mRNA-3705. It is a chronic treatment for patients with MMA that replaces the faulty enzyme by putting the mutated enzyme, or [mute 00:39:07] for short, back into the mitochondria of the patients suffering from the disease. And due to COVID-19, as I said before, we paused enrollment and initiation for MMA earlier this year in early spring, and specifically that was for the program that we previously published on, which is mRNA-3704. Now the update today that I'll give a little bit more information on in a moment is that we've leveraged that pause these last few months rather than waiting to make some important improvements that we think will help accelerate the MMA program. Stéphane Bancel: (39:41) The first have been improvements to the clinical trial design that are similar to the ones that I described previously with TA, specifically looking to make the initial experiences more friendly for patients and more operationally successful at the sites. And the second is we've identified a next generation project, an improvement in mRNA-3705, that given the delay, we have decided to advance that into the clinic instead of 3704. So slide 35 briefly summarizes some of that data around the next generation MMA candidate that we're announcing today. Stéphane Bancel: (40:17) And the mRNA-3705 is a superior mRNA, specifically it is a new messenger RNA that otherwise uses the same lipid nanoparticle, and importantly the same lipid nanoparticle for 3704 as well as propionic acidemia, but also the same with the nanoparticle that was used and described previously by Tal, mRNA-1944, the Chikungunya antibody program for which we believe we are building some tangible evidence of the safety, tolerability, and pharmacology. As you can see on the graphs on the right, mRNA-3705, the next generation product, produces significantly higher levels of the human mutase enzyme in the liver of rats in the red versus the black at the top graph. Stéphane Bancel: (41:02) And that translates into greater potency and more prolonged lowering of the toxic metabolite MMA in the mute in all mice, as you can see, they're comparing the red line versus the black line at the 0.5 MPK dose in the lower right hand side. That improved pharmacology we think is an important reason for why we've decided to make the change and bring forward 3705 in place of 3704. Now those aren't the only changes we've made over the last number of months. We've also taken the opportunity to revise the clinical protocol, as I described, primarily to improve the patient experience and ensure the operational feasibility of the study is at the utmost. Stéphane Bancel: (41:42) The next steps for this program, we will be filing a new IND, because it is a new messenger RNA, and UCTA applications for 3705 and will provide those updates at the appropriate time. The closing on our rare disease pipeline on slide 36, we believe there are a number of advantages to mRNA and rare diseases and we are strategically committed not just for the- Stéphane Bancel: (42:03) ... mRNA in rare diseases, and we are strategically committed, not just for the organic academia programs, but for the other programs on our pipeline to advance them, to try and help people with these debilitating diseases. The advantages for mRNA, we think, are the ability to target intracellular proteins and the ability to target protein complexes with multiple subjects, as best illustrated by both the MMA and PA programs that I just described. We also think the ability of mRNA as a drug with drug-like pharmacology will allow us to tailor dosing to clinical response, with repeat dosing, increased dosing or increased dosing frequency, as is required to meet the needs of individual patients and their diseases. Importantly, mRNA, again, does not require entry to the nucleus or do anything to modify the genes, which we think is an advantage. Stéphane Bancel: (42:52) The next steps in rare diseases would be looking for the proprionic acidemia study with its new revised protocol under existing INDs to have the first patient dosed. MMA, the 3705 program, will be filing the IND and CTAs for that, building on the successful filings of 3704. Then we're looking for the IND filings of our two other rare disease programs, GSD1a and PKU, as previously described. We're looking forward to hopefully clinically de-risking the systemic intracellular modality with proof of concept in any of those studies, which would move this from an exploratory modality in our mind to a core modality and cause us to double down as we have in other therapeutic areas and continue to build our commitment in rare diseases. Stéphane Bancel: (43:39) We will then, of course, continue to develop new development candidates and new modalities in the rare disease space, and look forward to providing updates at the appropriate time. With that, I'm going to be handing it back to Tal Zaks to begin discussion on our oncology pipeline. Tal? Tal Zaks: (43:54) Thank you, [Stephen 00:00:43:54]. Let's talk about oncology. Our pipeline, as you can see on slide 38, is really composed of the vaccine approaches and intratumoral injections. What they share is a basic scientific hypothesis that says that if you can translate proteins into the human body, which we now know we can and we've shown it time and again, then the question is, how do you leverage that ability to make a dent in cancer and improve the lives of people living with cancer? What we've learned over the past several years is that our immune system is potentially capable of recognizing it. In fact, if you can unleash it with checkpoint inhibitors, then you can mediate cancer regressions, and in some cases, very longterm remissions, perhaps even cures, but that's still only in a minority of patients. Tal Zaks: (44:53) Our goal has been, whether it's through personally vaccinating people with a personalized cancer vaccine or through intratumoral approaches to try and spur the immune system, so that in combination with checkpoint inhibitors, we will have a higher benefit. Tal Zaks: (45:14) In the cancer vaccines, which I won't be discussing today, suffice it to say that we are in a randomized phase two for the treatment of adjuvant melanoma in combination with Keytruda, and given that Keytruda has a proven benefit in that setting, of course, a randomized phase two is the right way to demonstrate proof of concepts. That trial is enrolling. As in all randomized trials, you can only talk about results when you really get to the end game here. Tal Zaks: (45:46) In terms of our intratumoral approaches, the OX40 ligand program, which is the one we've started with first, I'm happy to say today has started dosing the first patients with ovarian in the phase two component of that trial. Behind that, in completing the phase one dose escalation, again, in combination with checkpoint inhibitor, we have the triplet of OX40 ligand, interleukin 23 and interleukin 36 gamma. Our collaborators, AstraZeneca, are progressing mRNA encoding for IL-12 with [inaudible 00:46:20] also in phase one. Tal Zaks: (46:22) In these approaches, really we've shown that as expected we can translate protein. The question is, can you really translate the biology of the protein expression into useful pharmacology, i.e., an effect on the immune system, and then translate it into clinical benefit? To discuss that, we've invited somebody who is much more facile and is actually treating patients and translating that science into clinical research at the University of Colorado Cancer Center, Professor Jimeno. It's a real pleasure to introduce him to the audience. I will invite him to discuss the findings that we've had and where we are in the clinical development of our intratumoral immuno-oncology programs. Dr. Jimeno? Dr. Jimeno: (47:18) Good morning. Hi, Tal and everyone. Thank you for the invitation to be external scientist presenting this very important research. Disclosures, my institution has received research support from the NCI and over 20 sponsors for research on the principal investigator [inaudible 00:05:32], including Moderna, but I have received no personal remuneration or support from Moderna for these or any other activity. Dr. Jimeno: (47:41) Major advances have been made with the advent of checkpoint inhibitors, and in particular PD-1 PD-L1 inhibitors over the last 5, 10 years, as witnessed by the multiple tumor types that are sensitive to them. However, overall, it's estimated that only about 18, 20% of all patients that receive benefit from PD-1 inhibitors or PD-L1 inhibitors do actually derive an objective benefit. Most of these patients eventually develop acquired resistance. A major question and unmet need by cancer researchers is, what can we do to improve patient responsiveness to PD-1, PD-L1 axis inhibitors? Next slide. Dr. Jimeno: (48:35) According to the seminal papers describing the cancer immunity cycle by Chen and Mellman, there are three essential elements that are key for successful adaptive response to cancer, as exemplified by the responsive tumors to checkpoint inhibitors. The three things that need to happen are we need to have at least a presence of immunogenic neoantigens, needs to be a presence on proper function of the [inaudible 00:48:59] cells that will present the antigens to other immune cells, and we need to have active functional T cells. Functional or absolute deficiencies in any of these steps or components can result in primary or acquired resistance to PD-1, PD-L1 inhibitors. Dr. Jimeno: (49:23) The next slide very nicely summarizes the stimulatory and inhibitory factors that can enhance or inhibit the adaptive immune response to cancer at every stage of the cancer immunity cycle. By administering agents, either systemically or intra-tumorally, one can supply the missing factors or inhibit inhibitory factors to elicit the desired immune response. It is also evident that if one supplies multiple targets, and one can [inaudible 00:49:58] interference in multiple of these processes across a variety of mechanisms of resistance, that is going to lead, like in classic chemotherapy from the 70s and 80s, that is going to increase the chance of success when giving a backbone of effective inhibitors such as PD-L1 inhibitors across a wide variety of tumor types and/or individual immune phenotypes. Next slide. Dr. Jimeno: (50:27) Intratumoral therapy can get single or multiple nodes of this cancer immunity cycle, as seen in the cartoon, depending on how many components are contained within the investigational product. In the case of the Moderna portfolio and its intratumoral therapies, they are evaluating both individual and multiplex, so multiple combinations of components of the cancer immunity cycle to come up with two products that are currently under active development. Dr. Jimeno: (51:01) First one is mRNA 2416, we will referred to it as 2416 thereafter, which encodes the OX40 ligand. The second one is mRNA 2752, that encodes both the OX40 ligand, as well as IL-23 and IL-36. With the introduction of OX40 ligand alone, four of the seven key nodes in the cancer immunity cycle are opened up. With the addition of the other two cytokines, we add an additional node and the three synergize substantially compared to individual or even doublet combinations, as we will show in the data a few slides below. If we go to the next slide, slide 45, summarizes the principle behind, or the rationale behind intratumoral therapy. As opposed to systemic therapy, where the principle is to achieve a systemic effect, intratumoral aims at focusing a or eliciting an immune response in a specific area of our patient, in this case, in one of the tumors available for injection. With systemic therapy, evidently the toxicity can be multi-organ and can be substantial. Immune therapies are better tolerated than cytotoxic gauges, but still can lead to significant and sometimes devastating autoimmune processes, whereas local administration should minimize the toxicity and exposure by eliciting a more focused immune response. There are also differences in who can access these drugs. Evidently for systemic therapies, the only limitation is intravenous access, whereas for intratumoral you need to have a tumor that is detectable either by physical exam or radiology and injectable. There are less differences in terms of ... I mean, we can now safely combine multiple targets with both systemic and intratumoral therapy, although the overlap of systemic toxicities can be more limited in the former than in the latter. We'll go to the next slide. Dr. Jimeno: (53:45) In oncology, multiple intratumoral regions are approved for in development. In general, one of the most best known examples is the T-VEC, which is the oncolytic virus for melanoma now approved, or several immune agonist in development, including OX40, cytokines, PLR, STING and [inaudible 00:54:11] agonists, but if you look at this more from an internist drug rather than specifically an oncologist, I mean, essentially, this is how we have been giving vaccines with the localized for viruses, for using localized injections rather than giving vaccines by systemic or parenteral administration. The toxicity premise holds in that field too. Dr. Jimeno: (54:47) In the next slide, you can see that the first agent that we will be discussing is 2416. That is an intra-tumorally administered mRNA encoded OX40 ligand. Next slide. Generating optimal T cell responses requires T cell receptor activation and co-stimulation, as seen in the cartoon here on the left, which can be provided via ligational binding of tumor necrosis factor receptor family members such as OX40. As you can see in the cartoon on the right, 2416 encodes for the ligand of OX40. That is a homotrimeric protein regularly presented on APCs. Upon binding of OX40 to the ligand in the presence of a tumor neoantigen, there is an expansion of both CD4 and CD8 T cells, and an imprinting of T cell memory, and also a secondary inhibition of T regulatory cells which maintain a pro tumor microenvironment. Local expression of the native [inaudible 00:55:58] form OX40 would allow to achieve this activation. Next slide. Dr. Jimeno: (56:06) In preclinical models, the efficacy of the surrogate mouse OX40 was tested intra-tumorally in a syngenetic mouse model with hepatic carcinoma, age 22, shown here on your left. The spider plots show tumor volume in mice above and the survival graphs are below. These show that three weekly doses injected to the tumor resulted in reduced tumor growth in most animals, and about a 50% complete response rate. On the right, OX40 ligand was tested in ID8, which is an intraperitoneal model of ovarian carcinoma, and a single dose of mouse OX40 ligand, dosed IP, was combined with concurrent systemic anti PD-L1, and whereas neither single agent demonstrated any meaningful efficacy in these mice, combination resulted in an over 80% response rate. Dr. Jimeno: (57:09) This pretty striking preclinical proof of concept experiments prompted, and next slide, the launch of the first in human program with 2416. This is a first part of what we'll be discussing today. This first in human study evaluated this investigational product in incurable solid cancer patients, including dose escalation phase with cohorts of three to six patients based on toxicity, as well as a confirmation cohort as needed in patients with tumors accessible to the injection. Primary objectives included determining the safety and tolerability of [inaudible 00:57:51] intratumoral 2416 in patients with said solid tumors, and to define the maximum tolerated dose and subsequent dose for expansion. Exploratory objectives included assessing the correlation of other investigational serum based protein, such as ADAs, with PK efficacy and safety endpoints, and to test the biomarkers of immunological response to 2416 in tumor on blot. Next slide. Dr. Jimeno: (58:20) A total of 39 patients have been enrolled in this protocol, 38 in dose escalation, one in dose confirmation. Patients were heavily pretreated and the most common tumor types were head and neck and ovarian cancer, with breast cancer melanoma and sarcoma being also represented, as you can see in the chart on the left. Treatment was overall well tolerated with seven grade three toxicities, mainly of fatigue, nausea, myalgia and injection and local reaction observed. Mild one to two local and systemic injection reactions were the most common toxicities observed in seven patients each. Of 39 evaluable patients, 14 patients had stable disease as best response. Dr. Jimeno: (59:07) The next slide, as you can see, shows a swimmer plot of timeline study which ranged between 6 to 24 weeks with several patients on study long term. Time on study did not seem to be associated with dose level, which is not an unusual event in immunotherapies. Dr. Jimeno: (59:35) The next slide shows an interesting distinction that this study design allowed, since patients had some but not all of their lesions injected. We were able to dissect where we were seeing efficacy. In this bar graph, we're seeing the percentage growth or response of tumors, and we can see that injected and uninjected lesions that are plotted separately, in the 14 patients that had an overall response by resist, there were 4 patients that had tumor shrinkage in injected lesions and 5 patients that had some degree of tumor shrinkage in uninjected lesions. There was an interesting mix, because there were patients with tumor shrinkage in both injected and uninjected, patients with shrinkage in injected lesions only, and even patients with shrinkage in uninjected lesions only, so in a number of very thought-provoking hypotheses, but overall, this shows that 2416 was able to induce both a directing end response and a distal systemic effect. Of note, the four page arrows are those four patients with ovarian cancer that had stable disease. In the next slide, we can see the schemata of the biopsy and biomarker translational analysis that were carried on a subset of patients, where paired biopsies were collected pre-imposed therapy from the same lesion, either from injected lesions on the second day of therapy, from injected lesions on the second cycle of therapy, or from uninjected lesions at the end of cycle one, so that we will be able to address those hypotheses separately. Biomarkers from biopsies included the evaluation of OX40 protein expression, which is proof of concept that the drug is doing what it's supposed to be doing, and T cell abundance by multiplex [inaudible 01:01:49] analysis and changes in inflammatory markers by RNA-Seq. Dr. Jimeno: (01:01:56) The next slide shows that in injected lesions, there was an increase in OX40 ligand, documented as you can see, in the plot on the left. The case with the most marked increase was an ovarian cancer patient that had stable disease, shown here in the left, in which the post treatment biopsy was collected 48 hours after injection. Her OX40 score went from 558 to 7, 050 in just 24 hours. That was approximately a 14 fold increase in expression of the protein. Dr. Jimeno: (01:02:39) In a separate funnel, T cells were also evaluated using cytokeratin staining and it was documented that CDT positive cells significantly increased both treatment in injected lesion both within the tumor and in the surrounding stromal compartments, indicating an engagement and trafficking of an adaptive- Dr. Jimeno: (01:03:02) And engagement and trafficking of an adaptive immune response in the T&E of these tumors. We can go to the next slide, we can see that in post-treatment biopsies, and this was a strikingly relevant finding, there was an increase in the levels of PD-L1 mRNA in these post-treatment biopsies with the greatest fault change observed in a sarcoma case who had a stable disease and was actually the patient that was longest in the study, both on a veteran and a breast cancer patient also with a degree of tumor shrinkage that did not meet a criteria for partial response but that had objectively strong, had amongst the greatest increases in PD-L1 transcripts. And this is important because this can be hypothesized as a consequence of an influx of T cells into the tumor. PD-L1 levels were compared with levels from the TCGA, the Tumor Cancer Genome Atlas study. Dr. Jimeno: (01:04:12) And by this analysis, the majority of patients increased their PD-L1 scores post-treatment. Next slide. Lastly, in these tumors, a general in information or inflammatory states index was calculated, it's called GEP scores, T cell inflamed gene expression signature, that has been shown to be predictive to PD1 inhibition in some settings. So in this analysis, out of the nine cases that were analyzed, there were increased rank scores in six out of those nine in where the biopsies were taken from injected lesions. The three patients with the greatest increase in this inflammation score were the three patients that had shown the greatest clinical benefit on study, which again, it's an indication that good things are happening in the [inaudible 01:05:19] of these tumors. And then the next slide shows the conclusions from this first study, that 2416 was in our population and will tolerate it when given a smaller therapy with no DLT reported. Dr. Jimeno: (01:05:39) 14 out of 39 patients achieved stable diseases best response, and six patients had stable disease for over 14 weeks. Four out of six ovarian cancer patients achieved stable disease along with clinically significant tumor regression in both injected and un-injected lesions, supporting further investigations in this tumor type. In patients treated with 2416, had increased OX40 protein until T cell infiltration in the tumor microenvironment as well as upregulation of PD-L1 transcript and activation of a proinflammatory gene expression response, suggestive of an anti-tumor immune response. These observations together with the preclinical data support the evaluation of 2416 with anti-PD-L1 inhibitors in certain tumors, which is right now, as discussed earlier, ongoing in part B with a focus on advanced ovarion carcinoma, of which one of my patients will be dosing soon. Dr. Jimeno: (01:06:49) In the neck slide, we are showing the second protocol that we will be briefly discussing and summarize as the OX40 ligand, IL-23, and IL-36 study with a product called 2752, which we will refer to us Triplet in subsequent slides. Next slide. Dr. Jimeno: (01:07:22) So Triplet, or 2752, it's a therapeutic, mRNA-based, that encodes both OX40- L as we discussed before, but also the pro-inflammatory side events 23 and 36 because it was hypothesized, as was discussed before and will not go over the table again, that in using these proinflammatory cytokines along with the T cell stimulation would include T cell activation but also would promote a TME that would shift from pro-tumor to anti-tumor and induce a better response. Next slide. This mRNA encodes these three components and, as discussed before, it is injected directly into the tumor, which can be done either directly in clinic as we've done many of the patients, or guided by imaging, ultrasound, or CT, which is straightforward as well nowadays. And take the mRMA inside of the tumors and upregulate these three proteins. Next slide. Dr. Jimeno: (01:08:31) Prior preclinical studies showed robust antitumor activity in mouse using this Triplet product, while introduction of these components was more effective in an immunologically sensitive model, and as we can see by the 100% survival rate in the plot below, compared to either of the components alone in both injected and non-injected lesions in this very elegant Science Translational Medicine article. Next slide. Dr. Jimeno: (01:09:03) Even in the difficult to treat, immunologically-barren B16-F10 model combination treatment of Triplet with a PD-L1 antibody was synergistic and effective, as we can see here, where with PD-L1 alone had no effect individually, the Triplet have also no effect individually, but there were a 40% complete response rate in these mice in the left panel, the proper panel with the combined Triplet plus PD-L1 Dr. Jimeno: (01:09:40) So these preclinical data and this body of immune knowledge let to the translation, next slide, of this concept into a clinical trial that is also ongoing. And that is a dose escalation study using 2752 plus minus the PD-L1 inhibitor, development was approved for a wide array of cancers. And this is a study that is currently ongoing and actively enrolling at multiple institutions including Colorado. Three objectives of this clinical trial is to evaluate safety and tolerability, determine the maximum tolerated dose for subsequent phase two studies, and also intends to assess anti-tumor efficacy, protein expression in tumors, and the pharmacokinetics of these drugs. The dose escalation arm of the monotherapy is complete and currently it is a combination that is ongoing which will be anticipated to expand into four different contraceptive indications in five arms once those findings of the combination is completed. Dr. Jimeno: (01:11:06) In the next slide we will go over, briefly, the data that was presented earlier in the year at ASCO. As of the cutoff data for that report, it was around April 2020, and of course the enrollment to some of these programs has been impacted, like everything else, by the COVID-19 epidemic. So in that sense, some of testing centers, we had to come up with different approaches to continue seamlessly our service to these protocols and these patients. But as of the spring of 2020, 29 solid tumor patients have been treated with either 2752 alone or in combination, which has been well tolerated with no DLTs or grade four or five toxicities. As you can see in the plot on the table on the right, out of 23 patients with full anti-tumor evaluation for resist and I resist, a patient had a partial response, nine patients had stable disease, and 13 patients had a progressive disease as best response for a overall disease control rate of around 40%. Dr. Jimeno: (01:12:34) Tumor shrinkage was observed in seven patients in both injected and un-injected lesions in both monotherapy and combination, so not would be the discussion that we had before, showing that this not only elicits a local immune response, but that immune response then expands and can reach other tumors that were not injected, just as in many other areas of immunology and vaccine biology. The patient that showed the deepest response was a squamous cell carcinoma of the bladder that received this combination and showed a 81% reduction of dark lesion, which is remarkable. In the next slide you can see the [inaudible 01:13:23] plot for the data as tabulated where you can see in the upper half the part A of the study, which is the single agent, and in the lower half, the part B, which is a combination where longer time on study is suggestive of more sustained anti-tumor effect of the combination. Next slide. Dr. Jimeno: (01:13:50) This is a waterfall plot. And again, injected and un-injected lesions were plotted separately to tease out that different biology questions, and the overall response is indicated at the bottom. You can see that the greatest reduction in injected and un-injected tumors occurred in the patient with the partial response both were in sync and shrunk by about 70 to 80%. Next slide. Dr. Jimeno: (01:14:24) This slide shows a schemata of the very complex and involved biopsy and biomarker collection schedule during this study, which was similar to the prior OX40 ligand alone study. An included measurement of IL-23, 36, that are the target of the product, as well as indirect proinflammatory cytokines proteins in both pre and post-treatment tumor biopsies in plasma. Chemistry for PD-L1 and T cell markers was also used to further characterize the baseline status and changes to the tumor microenvironment with treatment. Next slide. Dr. Jimeno: (01:15:09) As we can see here in this vision slide, in both mono and combo therapies, 2752 enhanced the percent of PD-L1 positive cells, particularly of tumor-associated immune cells and to tumoral cells, and sustained increases were seen throughout cycle one. A notable case with the partial response highlighted here, the bladder cancer patient showed that PD-L1 levels in both tumors and immune cells post-treatment increased significantly with immune cells shifting from negative expression at baseline to 25% expression after treatment in just a few days. And a subsequent accumulation of proliferating T cells, not just resident or passing through T cells, but active and proliferating T cells, CDH positive, was observed post-treatment, which again suggests a shift from an immune pro-tumor to an anti-tumor microenvironment profile. The next slide shows that IL-23 and IL-36 gamma were elevated in a dose dependent matter in both tumor and plasma, in figure A, plot A, which is in the upper left corner, throughout treatment, which again, it's nice to see that you put the mRMA and you actually do see the protein. Dr. Jimeno: (01:16:50) And associated to this, there were other pro-inflammatory side effects with anti-tumor activity including interferon gamma and TNF alpha that also increased 24 hours and one week post-treatment, both in parallel and inside the tumor and then in the plasma, circulating, indicating that this local effect, it's made systemic by the circulation, which does support the approach. Most importantly, all post-treatment plasma cytokine levels evaluated were well below what has been or what we know or interpret as toxic levels when given systemically, supporting the hypothesis that when you give something intratumorally, the cytokines can achieve effective levels locally, percolate systemically but without reaching levels that could be construed as clinically dangerous or significant for our patients. Next slide. Dr. Jimeno: (01:18:04) Here we summarize the conclusions of this earlier combination study. mRNA 2752 given as monotherapy as well as in combination with Durvalumab was tolerable at all those levels studied with no DLTs, dose limiting toxicities, reported, and the majority of related adverse events were grades one and two. The administration of intratumoral 2752 was associated with tumor shrinkage injected and non-injected lesions in both monotherapy and combination with a partial response in a PD-L1-low stoma cell bladder patient. Increased IL-23 and 36 protein expression were seeing both in tumor and in plasma, and analysis of biomarkers suggest a sustained anti-cancer immunomodulatory effect of treatment that includes elevated PD-L1 interferon gamma, TNF alpha levels. These levels of cytokine systemically were documented but were below what is considered to be clinically toxic, and this data support the ongoing testing of the combination of 2752 and Durvalumab in our phase one study. With that, I want to thank you for your attention, and I will pass it on to the next speaker. Thank you. Lavina Talukdar: (01:19:43) Thank you, Dr. Himeno for that very in depth review of both the OX40 ligand and Triplet program. We are running 10 minutes ahead of schedule, so why don't we go ahead and take our 10 minute break starting now, and we will get back on at 9:30 AM. Operator?