Founder Stories: Melissa Moore, CSO of Moderna & mRNA as Medicine

We're looking like we're staying well in time, and I will therefore swiftly move on and introduce Melissa Moore as our next speaker. Melissa Moore is the Chief Scientific Officer Emeritus of Moderna. She did her PhD at the MIT and then started to focus on RNA biology at the MIT, working with Nobel laureate Phil Sharp. She had a stellar career as an HHMI investigator in academic RNA research, received many awards for this. Among them, for example, she was made a member of the National Academy of Science. But from, and relevant particularly to today, from 2016 onwards, she led the early-stage research teams at Moderna to develop their platform technologies in mRNA design and delivery. So thanks, Melissa, for joining us.

Thank you, Thomas. And again, thank you for inviting me. I'm really happy to be here. To share some, some of our research on mRNA medicines with you. So I also, I, as you know, have left academics and work full-time for a company, so I have to show you this disclaimer. I think you've had enough time to look at that now, so move on. So the kinds of molecules that Ross was telling us about are small molecule medicines, and small molecule medicines really have evolved over the less than 100 years. And here I'm showing penicillin and prontosil, which were the first antibiotics discovered. And then of course, we have many other small molecule medicines that we take every day. Now, the vast majority of these small molecule medicines interact with proteins. So they target proteins, they modulate the activity of proteins, just as Ross was telling us. But another class of medicines that has emerged in recent years is proteins themselves. So, and these are often called biologics. And the first biologic that was discovered was insulin, which was discovered in 1921 at the University of Toronto. But over time, we, many, many more proteins themselves have been used as medicines. And so just to illustrate this fact, last, earlier this year, no, it was last year, Nature published an article saying that the American FDA had approved the 100th monoclonal antibody as a medicine. And so they— monoclonal antibodies specifically have become really important medicines to fight disease. Now on the right-hand side of the slide, this is an image from that same paper. It shows the number of new antibodies entering the clinic every year. So this is not cumulative. This means that in 2020, there were 160 monoclonal antibodies that entered the clinic in that year. So that just shows you how important these have become. Now, the— as much as biologics and proteins made outside the body and then injected into the body are— have been proven themselves as effective medicines, they do have certain— a number of limitations. So one of the limitations is that they require very large dedicated industrial infrastructures. So this is a cartoon of a typical bioreactor for a biologic where you're growing, you know, large quantities of Chinese hamster ovary cells or other tissue culture cells to make the protein, and then the proteins need to be purified from that. Another issue with biologics is that each one is unique. So once the protein is made, and even different monoclonal antibodies, once they been made, you have to figure out how to formulate them, what their PK/PD properties are, how to stabilize them. And so that can take some time. And a third limitation is that, of course, the most proteins, especially secreted proteins, are post-translationally modified. And the post-translational modifications that are put on are different between different organisms. And so even though the Chinese hamster ovary cells that we use to make monoclonal antibodies are very similar in their glycosylation patterns to humans. They're not exactly the same. And then finally, the problem with biologics is they're really limited to proteins that can be delivered extracellularly. They have to be injected into the bloodstream or into the interstitial fluid. And so, and most of them cannot enter cells. So that really limits them to just a portion of proteins in the human proteome that are secreted proteins, but over 90% of the human proteome is either intracellular or transmembrane proteins. And so the biologics in general cannot— we cannot use those proteins as medicines if we make them outside of the body. So the simple idea of mRNA medicines is that instead of supplying the body with pre-made protein is to supply it with the mRNA instructions instead, so that then this can— the human body itself can make its own medicinal proteins. And it's, you know, it really is simple, but as I'll show you, it's taken us over 60 years to figure out exactly how to do this. But one of the features of both proteins and messenger RNAs that is really important and very similar to classic medicines is that they're temporary. They are not permanent changes in the DNA or genome. So to illustrate this, I like to use the example of the circadian clock. So of course, your circadian clock is driven by circadian clock proteins. And I'm just showing you a generic example here where the clock protein appears and disappears with remarkable regularity every 24 hours. And that's driven by the appearance and disappearance of the clock mRNA. And so what this means is that, you know, every day you're getting your daily dose of clock messenger RNAs and your daily dose of clock proteins. So mRNAs and proteins too, but mRNAs have all three attributes of classic medicines. That is that they have limited duration of effect, They have predictable dose-dependent effects. The amount of protein that is made is directly dependent on the amount of mRNA that is there, and then they clearly can be redosable. So if we could unlock the possibility of using mRNA as medicines and, and make that into a platform technology, then we would actually be able to meet many unmet medical needs. And as I'll show you in a bit, it also will— it can accelerate, greatly accelerate the research and development pipelines. Ross noted in his talk that it's taken over 10 years to get through from a discovery to a Phase 1 trial, and that is pretty typical. The typical time for development of a new small molecule medicine is, is 12 years, and the typical cost is $2.5 billion. So it really is quite expensive when you get through everything. Now, why is it— if this idea is so simple, why has it taken us so long? Why is it only now that we are able to make mRNA medicines? And it really has been a, a long road. It required And I cannot stress enough the importance of foundational curiosity-based research, because one cannot figure out how to engineer a system or utilize the system to make medicines until you understand the basic principles of how the biology works. And here I'm showing you a timeline that is from a paper from the BioNTech folks who, who show the timeline of important discoveries that led to mRNA medicines. And I do want to give a shout out to some researchers from Australia, Suzanne Cory and Gerry Adams in Melbourne, and then Gerald Booth, who was a longtime faculty member in Sydney, who made very important contributions to the discovery of the mRNA cap structure. And so there have been many, many academicians all over the world who have worked since 1961. So mRNA was discovered in 1961 to really just understand the structure of messenger RNA, the how it is synthesized in the body, how it is translated and utilized in the body. And so I, we would not be able to do what we do today without all of that foundational knowledge that accumulated over time. And I'm a— as a previous academic myself, I'm a very big proponent on continuing to fund basic academic research because it will be crucial for our ability to make new medicines in the future. Now, having that said, let me show you the path to make in mRNA medicine today. So today, this is the entire path in, uh, one slide of making an mRNA medicine. It starts with an idea for a new therapeutic protein that, of course, then dictates the amino acid sequence. At Moderna, we've developed very sophisticated computational algorithms to, to back-translate that into an mRNA sequence. Now, that might seem like a simple thing, but because of the redundancy of the genetic code, there are many, many mRNA sequences. And when I say many, many, I'm talking big numbers. So a slide that I didn't bring today, but if you do the math for spike vax, for mRNA-1273, which encoded the protein, spike protein for SARS-CoV-2, there are actually 10 to the 632 possible mRNA sequences that could encode spike vax because of the the redundancy of the genetic code. And yet we were able to make just one and it worked. So we did that because we've put in many years of figuring out how to make an mRNA that will make good amounts of protein. This then, once we've decided on the mRNA sequence, we send this off to our manufacturing plant in Norwood, Massachusetts, where they make a DNA template. They make that in the form of a plasmid. That they grow up in bacteria and then purify and cut with the restriction enzyme. So we're going to do runoff transcription. And then we add the nucleotides, the polymerase, the capping enzymes, buffers, make lots of copies of the RNA, purify it, formulate that RNA with lipids to make lipid nanoparticles, and then it can be put in the vial, quality controlled, which is crucially important for clinical-grade material. And then it's ready to go into the patient where now the patient's own cells can make that same therapeutic protein that we thought about back here. Now, in comparison to biologics, where I showed you that same person, that was to scale, standing next to that huge bioreactor, this is the size of the clinical manufacturing equipment that we use to make mRNA medicines. And this particular one, which is no bigger than a, than a large, like, -80 freezer, you know, we can make a million doses of vaccines on something this, this small. So the other advantage of mRNA medicines is that once you figure out how to make a particular thing like a vaccine and how to deliver it to, let's say, the resident monocytes in your muscle, And then if you want to make a new vaccine, it's easy because you just swap out the sequence of the mRNA. You're not changing the PK/PD properties of the medicine. So all of the medicines within a particular modality, for example vaccines, can be, um, use the same raw materials and the same manufacturing processes, which involve no mammalian cell culture at all. It's all enzyme-based. And our, our, the manufacturing equipment is actually these big empty ballrooms that where we can wheel in and out different pieces of equipment very easily. So we can rapidly adapt the manufacturing to make many different products and not just have dedicated machinery. So in, when it came to making mRNA-1273, our vaccine for SARS-CoV-2, This is how fast we can move. Within— it took us 2 days after the sequence was posted online in January, January 11, 2020, to agree with our collaborators at NIH of exactly which version of the spike protein to make. And then it took us 1 hour to design that mRNA. Then we were able to make the mRNA, get all— do all of the quality control testing, and get it formulated and ready in 45 days. So it really has incredibly shortened the timeline. And if you got the Moderna vaccine, that mRNA that we designed in 1 hour is the one that went in your arm. So it's— it worked the first time. It's amazing. Now, one of the things I wanted to just talk about is that all of the different possibilities of using mRNA, because it's just, it's amazing the kinds of things you can do. So for example, for that vaccine, the, uh, we only use one messenger RNA because we needed to just make one protein. That protein makes a trimer, but it's just one subunit. For other vaccines, for example, for our cytomegalovirus vaccine, the important epitope is a multi-protein complex of 5 proteins. And so the way that we do that is simply to put in 5 different mRNAs plus a 6th mRNA because we wanna target cytomegalovirus in order to have good immunogenicity for that. You have to target both the fibroblast and epithelial cells. So we are, this vaccine has 6 different mRNAs in it and 5 of them make a multiprotein complex. And so your body, your cells just assemble that complex the way they would if the virus had infected you. And it makes it much easier to, to make new vaccines. Another thing that we can do and that we're working on hard is to— you can multiplex our mRNA vaccines very easily. So here, one of the things that we're working on is an adult pan-respiratory vaccine where it would be a yearly annual booster for COVID, flu, and respiratory syncytial virus, which are all very important give a lot of morbidity and mortality, particularly in the elderly populations. So we're working on, on that. Another use of mRNA is that we can make personalized cancer vaccines. So here what we're doing is taking a sample of a patient's tumor and a sample of their blood and doing deep sequencing of both to find all the mutations that are present in the tumor that are not present in the blood. And then we can use bioinformatics genetics analysis to predict which of those mutations would be expressed in proteins in the tumor or in the cancer that are not expressed in normal tissue. And then we can, based on their specific HLA type, we can predict which of those peptides, those neoantigens would be presented on the surface of the cancer cells. And so we make an mRNA that encodes up to 34 of those neoantigens and give that back to them as a vaccine. And we're doing this in collaboration with Merck, but our goal is to provide the vaccine back to them within 45 days. And so you'll notice that 45-day window, that's the same window that it took us to make mRNA-1273. So we can, we can really make, we can make medicines for millions, hundreds of millions of people, or we can make medicines for just one person for, from mRNA. Finally, I just wanted to point out that here's the metabolic chart of the human body, and about 1 in 1,000 newborns are born without the ability to make one of the enzymes that's on this chart. And so these metabolic rare diseases right now have almost no therapies. They're managed by managing their symptoms. But they don't, we don't have the ability yet to give them back the ability to make the missing protein. So one of the medicines that we're working on is directed toward propionic acidemia. And this is a rare disease that affects between 120,000 and 250,000 individuals. That lack the enzyme that make the, so propionyl-CoA enzyme. And so the enzyme that metabolizes propionyl-CoA. And this enzyme is a multi-subunit enzyme. And so what we do is we have developed therapies where we now we can target the liver and deliver those messenger RNAs directly to the liver where the liver makes the, and the liver cells make the sub, the individual subunits. This is a protein that is actually in the mitochondria, so it can be imported directly into the mitochondria. And I just wanted to give you in those last couple of slides a little teaser. We've actually now been dosing patients, we've dosed 10 different patients with this for over a year. And we have very good safety that, and none of the patients have gone off of the trial. So they, they, it's, it seems to be working and we've been redosing them every couple weeks with this mRNA. And so just as a little bit of data, because I know I didn't show you any data in the talk, this, what this shows is each one of the lines on this this chart is a patient. So patients 1 through 9, and these patients tend to have metabolic decompensations. So they'll often end up in the emergency room because they just could not manage their disorder using their diet. So if they get— and also if they get a cold or something, they often end up in the emergency room. And so these red dots are in the year previous to them starting to take the mRNA medicines, this is how many metabolic decompensations they had. And so then this is the number that they had with in the year following starting taking the medicine. And you can see that, you know, there's one patient here that is, it's not working for everybody, but it really is being very helpful for these patients already. And this is, was our just initial cohort. So this is we're doing dose escalation, and so we are now escalating the doses to get to figure out what is the best therapeutic dose for each patient. So I'm very heartened by these data because not only can mRNAs be used to make vaccines for many different unmet needs, but now we can really treat patients and give them back the ability to make enzymes, to make enzymes that they're missing. So I just want to close by saying that Moderna has been an amazing place to work. We've been around for now since 2010. This was a picture of the company in about 2018. We were about 600 people at that time. At the time that COVID hit, we were 850 people. This is a picture from September this year. We're now over 5,000 people, and we are— none of what we do is the work of one person. It really is It takes an incredible team to get all of this done, and I just really want to thank my colleagues at Moderna. It's been an amazing journey, and I want to thank you for listening. Thank you.