 Good afternoon, everybody. I'm delighted to welcome you to the 39th annual lecture series that's co-sponsored by the McLean Center for Clinical and Medical Ethics and by the Bucksbaum Institute for Clinical Excellence. As you all know, this year's lecture title is Ethics and the COVID-19 Pandemic, Medical, Social, and Political Issues. It is the deepest and greatest honor for me to welcome an old colleague and friend, James J. Bradner, who is the president of the Novartis Institutes for Biomedical Research. The home institute is in Boston, but it's an institute that is around the world. Jay will talk today on the topic of an industrial strength response to COVID-19. Let me just say a couple of quick words about Jay. He joined Novartis in November of 2016 and became president of the Novartis Institute of Biomedical Research in March of 2016. So between January and March, he's a member of the Executive Committee of Novartis internationally. Prior to joining Novartis in 2016, Jay was on the faculty of the Harvard Medical School in the Department of Medical Oncology at the Dana-Farber Cancer Institute and had been from 2005 until 2015. Jay is a co-founder of five biotechnology companies and has authored more than 250 scientific publications and has received 50 or more US patent applications. Jay Bradner is a graduate of Harvard University and of the University of Chicago Medical School. I have to say a quick word that's not official, but for four years while in medical school, Jay and I played squash, and three times he allowed me to win in four years. So I felt particularly proud. Jay completed his residency in medicine at the Brigham and Women's Hospital and his fellowship in medical oncology and hematology at the Dana-Farber Cancer Institute. He's been honored with many, many awards over the years, was elected into the American Society for Clinical Investigation in 2011 and the Alpha Omega Alpha Honor Medical Society in 2013 to name just a few. So today's talk, as I said, is going to be, quote, an industrial strength response to COVID-19. I am so delighted to see Jay and to have him with us. Jay Bradner. Mark, thank you so much for your kind invitation and also the really generous and hilarious introduction. I assure the attendees of this conference that no consideration has ever been given to Mark on a squash court. I hope that you can see my slide as well, Mark, is that correct? Yeah, beautiful. Okay, thank you. This was quite funny to put together some reference at this point in the global pandemic and how large pharmaceutical companies and how our biopharmaceutical ecosystem has responded to the present pandemic. An interesting, as I had not written a lecture on that subject, I really most hope that we can engage in a more meaningful dialogue after these slides are presented. Mark shared, I am the head of research at the Swiss University of New Vardis, headquartered in Basel, Switzerland. Our research headquarters are in Cambridge, Massachusetts and so I'm calling here from suburban Massachusetts, suburban Boston. Relevant disclosures for this academic interaction are on this slide and I would only add two additional disclosures. First, I'm a chemist as well as a doctor and so I may show some chemical structures. I will not get too technical, I assure you. Not to disrespect the experts on the call today but recognizing that this is an interdisciplinary center joined attending seminars at for many years in my time in Chicago. And my second disclosure is that I'm not an expert in bioethics, clinical medical ethics, moral philosophy but have tried at the end of this presentation to organize my own thoughts and those of my leadership team around what ethical circumstances tend to arise in biopharma uniquely or not uniquely and others that we've experienced and organized discussions around through the course of the pandemic. Those last two slides may be the most interesting slides to this group. Well, I think it's most important just to calibrate where we are in the middle of this pen. All of this information is surely well known in following the Johns Hopkins dashboard almost weekly since it started in the spring of 2020 and the global burden of this is just impossible to estimate it and the statistics are mounting and deeply, deeply concerning. And so it's hard to celebrate an industrial strength response to COVID-19 because we haven't cured this disease and because we have not as yet eradicated this disease and because the burden of this disease is still so challenging. For all the challenges we might face as individuals or as families, I'm just constantly reminded that there are others in truly impossible situations, elderly patients, vulnerable patients, patients with inadequate access to the first world vaccines and available therapeutics to manage the disease, challenges to healthcare workers less so now the fully developed world then in low and middle income countries and friends infected, some even going into intensive care and then all of the intangibles on the economy, on employee or on children raised at this time of disruption and isolation. I think that it's fair to say that we're still deeply in the weeds of this pandemic and the data in Illinois, in Michigan and in certain countries in the world remains deeply concerning. I'm relieved to hear that this spike is mostly mapping to young individuals who might tolerate SARS-CoV-2 infection. This is less true in Michigan and surely not true in Brazil where the death rate just continues to climb. And so it's hard to be too celebratory about some of the technology innovations that have a sense of optimism or perhaps exit from this pandemic. There is light at the end of the tunnel where her achievable as these updated data from this morning in Israel, there is a set that we might even with emergent variance see an end to this pandemic. And so let there be that beacon of hope in Israel that there could be some exit vector for this historic event that we're living through. Now the truth is we could have been better prepared. And before I talk about the response that I've observed within our organization where I can comment in some detail and in the community of biopharmaceutical leaders with whom I've engaged so closely the last 13 months and regulators and government officials. But I wanted to first calibrate by saying we really could have been much better prepared. It has been well appreciated now for over a decade almost to that the coronavirus family can transmit from animal reservoirs into the human species. This was true with SARS-CoV or SARS in 2002, 2003 with evident epidemic local spread and MERS which actually was a more lethal virus than SARS, albeit a little bit less infectious. And in the context of those two xenobiotransmissions, zoonotic transmissions from animals into humans a group of scientists and government leaders were organized from the institutes of medicine quite painful to read this online book shown on the right from more than a decade ago that spells out all that would be needed to mount a immediate response to a pandemic. What science, what technologies, what targets would need medicines and what can we do to prepare for this? As I was getting up to speed on the biology of the virus as I'm a cancer doctor, I was quite new to this field of study as February as the accounts from our Shanghai site started to trickle in and then through the expansive access to information through the mainstream. I took a look at this book and it defines the innovation of polymerase inhibitors and protease inhibitors and better diagnostics. And it's fair to say a very small community that had religion about coronavirus as a global public health threat took this charge seriously and thankfully built a strong foundation of research upon which some of the technologies I'll share in a moment and reflections on them more than that, but we were quite ill-prepared. The reason that there is a chance to get out of this pandemic with such expediency fundamentally maps back to hulking innovation platforms that were built for other purposes, but that created a technologic pandemic preparedness in certain pockets of the biopharmaceutical industry. These are hulking and inventive technology investments like the massive bioreactors on the left that can scale up immunoglobulins or antibodies as therapeutics and I'll share some insights into vaccine. These innovative technology platforms that are importantly built for scale, science at scale because to address even a rare disease as in some of the biotechs I was a part of starting several years ago can require hundreds of scientists 10 plus years, numerous trial and error experiments ultimately to make a medicine that might be scaled for a small number of patients to imagine such a rapid response for a disease that could affect and did affect millions of patients is quite a bit more challenging. I borrowed the next few slides from a colleague and friend at Moderna Stephon Bancel, their leader. Here in the Cambridge ecosystem and this is just to rate the scope of these hulking investments. The company Moderna was founded with the idea that if gene therapy is exciting to give DNA sometimes with a virus to add a gene back to the genome or to introduce a therapeutic gene that's been engineered well that may be giving mRNA which is the product of DNA transcription member DNA to RNA to protein could be even more exciting. And so this company was started to imagine ways of administering new genes to patients for illnesses more so than infectious illness. But it was learned along the way at Moderna as in our own laboratories that mRNA is very immunogenic meaning when mRNA is injected into muscle it's taken up by dendritic cells that present protein made from that RNA to the immune system eliciting a massive immunologic response. And we once had a DARPA contract to make antibodies for soldiers with mRNA but the anti-drug antibodies were so high and tighter that we had to consider this more vaccine platform as Stephon and colleagues did at Moderna. And so this platform that was built and this is I believe their Norwood manufacturing site is has brought the capacity to establish proof of concept for adaptive immunization to other viruses a programmable nucleic acid synthesis. Chemists like me might take a prototype and tinker with it once here it can literally dial up payload of interest this spike protein payload on a computer inputting the genetics but they also built preclinical models for clinical evaluation, lipid nanoparticle chemistry that has a long legacy in our field but optimized for the delivery of immunologic payloads and drug like prop designed also to scale. Well, these might make for proof of concept medicines but to make a real world nations around the world and healthy individuals around the world might take requires considerations of shelf life, storage temperature safety, tolerability, potency consistency of manufacture. And it's fair to say all of these technology investments were made without the knowledge they would become essential during a pandemic and that's not the least of it. There's commercial and manufacturing considerations like low exit requirements and non-product dedicated plants, smaller footprints and supply chain networks. The idea that one could once a medicine was innovated studied to be effective that it could be into multi-dose vials that there could be then cartons and cases and pallets for distribution around the world with storage conditions that would be compatible with broad clinical use. Very little of this was invented on the fly. It was reconsidered or repurposed context of this pandemic. And it's fair to say Moderna didn't undertake this research alone. They have many experienced partners that they built for their RSV cytomegalovirus and that were relationships that were very much in place to help respond to that pandemic. And I think that these I keep coming back to and understanding what might be place for the next pandemic the access and utility, the nimble repositioning of hulking technology platforms as well as enhanced connectivity, collaborative models, working relationships established, new and facile have proven essential to the pandemic response. Well, I could have told the same story in the context of the innovation of mRNA vaccines at BioNTech more similar than different to the Moderna technology and their partnership with Pfizer. Suffice it to say as presented in the New England Journal over the last few months that the efficacy of these mRNA platforms now having completed phase three trials in some cases with six or seven month follow up has proven quite remarkable, quite durable. Please know I have no conflict of interest to these vaccines. Like many of you, I await the arrival of these vaccines to have better penetration into our community here in Massachusetts. But I do find it incredible because if you had asked scientists as we did at our leadership team meetings to imagine what the efficacy of mRNA vaccines at this scale might be amidst an evolving pandemic with new variants, I think some of the most optimistic would have thought 70 or 80%. And so to see 90% efficacy durable in this way is quite applicable. In truth, the most thing about this preexisting infrastructure to deploy in pandemic times is just how quickly the science has moved built again on a strong foundation I'll mention in a moment. The genome sequence of SARS-CoV-1 only presented into the public domain in January of 2020 to the credit of those scientists in China in real time to the report of the clinical syndrome. And this led to in about 11 months the invention, the preclinical testing, the regulatory path and ultimately the clinical investigation of two highly efficacious mRNA vaccines. It's an unprecedented record in time approximately takes between four and 10 years and is most typically unsuccessful in its first approach to viruses. All these years later, we lack an efficacious vaccine say to the HIV virus despite intense consideration. Well, the vaccine space is not a story of Pfizer and BioNTech or of Moderna or Oxford, AstraZeneca or J&J these four authorized vaccine innovators and manufacturers. It's actually a story of a large field of study that it's converged down upon a very small number of highly credible and hopeful vaccines. And of course, not all of these have worked. This is required to consideration not just of a new platform like mRNA but the repositioning of inactivated viral platforms live attenuated viruses, DNA-based, not RNA-based non replicating and replicating vectors as traditional proteins with immuno-adjuvant small molecules or in organics built in. It's said COVID-19 commanded the full consideration of massive global R&D infrastructure. The principal second reason why the response of the pandemic was so quick maps less to the biopharmaceutical industry than to the quite mature fields of science in many different allied disciplines of therapeutics. The fundamentals of viruses is quite firmly established. Genome sequence of the new virus could be so quickly interpreted and understood. Shown here on this slide are a handful but not all of the critical structural proteins that make the capsid and structure of the SARS-CoV-2 virus as well as some of the non proteins, the machines that contribute to viral replication, infectivity and ultimately viral exit and further infectivity of virion expansion. Coronaviruses have been well characterized by a mature field of viral biology. They're typically innocuous, irritating and convenient but can be scary. They're in four sub-families. They circulated a massive animal reservoir, bats, livestock, other, as I mentioned, have seven times now jumped from animals to humans. It's an RNA genome as shown in red. One of the largest RNA genomes speaks to its outstanding proofreading activity of 30,000 bases. Now, many of these proteins might be considered for vex and others might be considered for therapeutic development and perhaps most famous among all the proteins in oranges is this spike protein. Here again, foundational science provided not only an understanding of the function of this protein to determine what hosts can be infected, humans and not mice with this first emergent coronavirus SARS-CoV-2. But what cell types might be prone to infection as they would be bound by this spring-loaded spike protein. Further functional studies from the NIH in particular had mapped the immunogenicity of this spike protein, describing it as an outstanding target to consider for vaccine innovation. And even in Kizzi Korbet's group had identified mutant that would build the immunogenicity of this protein. And those actual mutants mapped from SARS-CoV-2, the SARS spike protein sequence overnight led to the innovation of the Moderna vaccine. The spike protein is also the target of therapeutic antibodies which I won't consider in this conversation today. You might think of the non-scientists or side of this spike protein as like a broccoli floret that has this outer leafy domain covered in these sugars. And what this field of study has done is to give atomic resolution into the life cycle of the virus that has afforded opportunities for vaccine and therapeutic innovation. I won't go too deeply into this because I imagine much of this is already known. But I think of the life cycle of the coronavirus in sort of four fundamental stages, the first being viral entry where the spike protein engages receptors, the ACE2 receptor on the surface of a target cell say an airway up a cell and then is spring loaded to open and release fusion machinery to bind into the membrane of the target cell, creating a pore into which the viral genome coded in protein is then injected. The second step is protein production and processing. This mRNA has two open reading frames and some structural proteins from which like beads on a string, individual globular proteins are prepared. An essential protein that I'll talk about in some detail in a moment. So try to remember this called the main protease is one of these proteins on this string of pearls. And this protease functions to release itself, NSP5 and then clip off all of these beads to liberate these machines driving further infectivity. The next important protein functionally which is the target of this drug remdesivir is the RNA dependent RNA polymerase. With the profile fully synthesized, they form large molecular machines as shown here that combine to an orange with some primer material leading to a replication first of the sand strand and then this leads to amplifying the viral genome. So after infectivity, proteins are made liberated to form machines that replicate the viral genome and then form virions that are packaged with that genome for release into the bloodstream, into adjacent tissues and these so-called sense RNA in viral particles released through the ER Golgi intermediate compartment exocytic vesicle like a bubble that goes to the surface and pops liberating the virus around the body. I use over a couple of minutes the viral life cycle because I'll now make mention of some of these machines and how we and others have approached the invention of first therapeutics for SARS-CoV-2. Now it's fair to say that the literature has proven not only an important foundation to understand SARS-CoV-2, but it still proves it's directional. There are literally hundreds of manuscripts in just this last one year published on the subject of SARS-CoV-2 biology, reconsiderations of SARS and MERS as well. We have a full understanding of the virus, not just in isolation, but all of the emergent variants that are not missing. Variant viruses may emerge with infectivity, improved fitness like a new branch of the family tree. This variant B117 emerged even down in Southeast England leading to an increase in local cases. By the end of December it was 60% of new cases with 23 mutations, more infectious but thankfully not more lethal and more so thankfully responsive to many of these vaccines. And scientists are not very hard at work to understand each mutation structurally and functionally. This work is transpiring both in the academy as well as in biopharma with almost real time a publication of which I think is a great testament to the open access publication system today. For drugs like me and my colleagues at Niber, we need almost atomic resolution of these proteins because we are like molecular locksmiths that make small organic molecules that could be pills maybe taken as a taken orally that will fit into the little molecular keyholes in these proteins. And so we're always looking for a little pocket as shown here in red on the protease trimer in which we can position a small key to block say the function of this protease preventing it from clipping other proteins and contributing to the viral bio. There's a great conversation back and forth between the protein scientists called biochemists, ethicists who are mapping and tracking these new variants. This works to ensure that as we innovate new medicines that we're always working on the most threat to the human species. I'll tell you a little bit about our work at Niber but I thought first in fair balance just to describe in a few slides the massive global investment now in the consideration of therapeutics. I mentioned the large number of vaccines in development. It's a smaller number of antivirals in a slightly more expansive number of non antiviral medicines. These could be medicines to block the inflammation, attributable coronavirus infection in an ICU, but it's fair to say that out of the other end of this funnel there's a very small number of effective medicines to treat established disease. Seeing another way is the availability of vaccines and was very, very quick and early antiviral study was really quick but unfortunately we have yet to realize highly efficacious antiviral therapeutics and none really that can be taken orally at scale around the world to treat medical communities and in earlier stages of disease if not for prophylaxis. And so we believe that there is a real need for therapeutics but I will say that it is a very small coalition of the willing working on direct acting coronavirus therapeutics. The first effort in the heat of the pandemic last March we organized with all of our drug molecules that are already prescribable today FDA approved with molecules that are clinically staged so there is a human experience with them across the whole industry and together with the Gates Foundation we had Novartis and a couple of partner institutions set up a third accelerator where we would bring in all of these small molecule tools and study them in miniaturized Petri dishes looking for activity arts code B2. It's fair to say then not in humans but in tissue culture and Petri dishes and in some cases in animal models no stone was unturned to look for the activity of medicines invented for a completely other purpose to be active against SARS-CoV-2. There were a number of important publications in this space and I do think it's possible that some of these medicines might read through to clinical activity but I would be surprised if any are as effective as bespoke invented antivirals. One story that I found particularly appealing is the discovery by Kavan Chokat and colleagues that small target the BRD-4 protein might block not so much viral proteins but the human machinery required to amplify viral genomes and this appealed to me because professor at Dana-Farber as I last lecture when I visited the University of Chicago we invented the first molecules to target the BRD-4 protein called JQ1 shown here. JQ1 is a senodiazapine that binds to BRD-4 and pulls it off the human genome and what we discovered is using this molecule that BRD-4 concentrates at certain regions of the genome as a master on switch to turn on genes. Some of these genes it turns on we found are involved in inflammation. Others are involved in fibrosis and in animal models molecules like JQ1 might block fibrosis, might block inflammation, might prevent death from sepsis, might block damage to the heart muscle and in a series of manuscripts with a lot of collaborators we this over about a 10 year span. This side activated with that discovery and this now is not drug repurposing it's the mechanistic repositioning it's the understanding of the viral biology leads to a hypothesis about a mechanism and then molecules are used as tools in animal model systems so-called preclinical models and if they work they might be advanced into clinical trials and so this is all very early days and at least two publications now and a third I just read on bio archive this JQ1 molecule which we've made freely available to the community for research purposes has been shown to decrease the expression of the receptor ACE2 that the spike protein binds to and so maybe it's sort of like putting blinders on the cell and then secondly it decreases the of a protease that helps to activate viral entry and seen on a protein Western blot you can see this ACE2 in Shrull Erosionions laboratory and just this week in Cell Press a study of bromodomain inhibitors including JQ1 was shown to potentially block the progression of cardiac disease all in preclinical models but I just show you the way that the scientific world has organized around mechanistic considerations built on the strong foundation of biology in the space. Just John Charles Sorin colleagues published in Cancer Discovery a systematic review of all cancer medicines to ask the question could cancer medicines maybe work to treat COVID-19 as a clinical syndrome and there are a couple of ideas that we and others will already deeply working on like Janice kinase inhibitors that could block cytokine storms and inflammation, BTK inhibitors that might silence toll like receptor signaling and B cell activation and the like but there was no stone on turn in the mechanistic repositioning of medicines. This happened not just on the host factors that I described but it has happened and it's still happening on the viral proteins as well. You might know that the successful treatment of viruses can include direct acting antivirals like the treatment of HIV whereas I said there's no effective vaccine but there is highly active antiretroviral therapy small molecule therapy. In the case of HIV just like in the case of hepatitis C two targets that sort of bubble to the top of interest because they've given the biggest medical benefit are polymerase in the protein machine that turns A into more RNA or DNA into RNA depending on the virus and protease inhibitors. And I've introduced the concept of both polymerase and protease inhibition already. Well, as the genome of SARS-CoV-2 is RNA it has dependent polymerase and molecules that tend to inhibit polymerases which are nucleosides were then studied against polymerase. And in fact, a number of them none of which were invented for coronavirus were shown to have some activity in petri dishes. And these were advanced into clinical trials and as surely you know right now the intravenous administered remdesivir as shown here which to the scientist looks a little bit like the ADP nucleoside were shown to have a meaningful clinical benefit in this disease. Now remdesivir over activity on decreasing viral load and so we and others believe that we can do a lot better than remdesivir but this medicine is now approved and helping patients in particular vertical care settings. Could we imagine protease inhibitors from HIV or hepatitis C crossover activity for the coronavirus protease and so a large number of those molecules were tested. Here's a molecule from local to Chicago Abbott laboratories now called ABV, Coletra with lopinavir and ritanavir, a combination medicine and there was some weak activity of the SARS-CoV-2 protease and potentially even the tempers to cellular protease. Unfortunately, the protease inhibitors read as coronavirus medicines have not shown as yet the efficacy of remdesivir but a new candidate from Pfizer has just completed the first part of a clinical trial by their own report. This intravenous medicine was made for human rhinovirus 14 which has a protease that is structurally similar to SARS-CoV-2's protease and so we're hopeful that that might work but beyond vaccines the biggest contribution to coronavirus therapy came in clinical intuition and investigation. The use of high dose steroids in people with profound lung disease led to the consideration globally but as studied in the UK of the steroid dexamethasone. Now this isn't the muscle building steroid but an immune suppressing steroid that has shown a dramatic improvement in invasive mechanical ventilation in oxygen requirement and overall mortality compared to best supportive care. And many other potential were considered. You probably know the story of hydroxychloroquine I'll only make the briefest mention of it here but there was an early suggestion that the deacidification of lysosomes that are part of viral entry into the cell with hydroxychloroquine might work in COVID-19 and this received exhaustive consideration regrettably not demonstrating consistent activity and possibly increased toxicity. There's been a huge amount of innovation beyond biofarm trying to just acknowledge that there have been creative adaptive responses in so many industries to the present pandemic ties to those innovators. I'm only gonna talk about medicines here today. In this next section, I wanted to share with you a little bit inside baseball about how did we as a leadership team responsible for a company that is significant in size $220 billion market capitalization and 160 civil associates get organized internally to protect our associates and then get organized to contribute to this pandemic with our sleeves rolled up as part of the solution. Just a brief description of where I'm calling from if you're not familiar with Novartis or Nibber Novartis is similar to many pharmaceutical companies access to medicines with hundreds of approved products between our innovative medicines and our generics but different than a lot of drug companies today we still believe you have to invent your own medicine sometimes that some drugs are so hard to realize that it takes a generational strategy which is hard to execute in the biotech sector. And so about half of our medicines derived from internal drug hunting and half from partnering and that makes us a little bit unique. We've got almost 6,000 discovery scientists on in the Institute and 90 clinical stage molecules clinical trials are more and every year we devote about $9 billion to R&D. I'm not trying to impress you with scale because you can't beat coronavirus or cancer or Alzheimer's disease with muscle it takes working nimbly in a really ingenious mindset to move from the concept of a drug to the proof of concept in phase two clinical trial. Now we were a little bit hamstrung in this present pandemic because we sold our vaccines unit to GlaxoSmithKline in 2014 and we exited infectious diseases as a coordinated area of research in 2007. And so we weren't in a great place to contribute and so we went deep on where we might matter. And without a vaccines unit we stood up right away a drug discovery unit against the viral proteins themselves. And we did this at an institute within Niber called the Novartis Institute for Tropical Diseases which is a small fraction of our project investment at Niber but is home to some of the most promising and two of the most advanced allerials in clinical study today together again with the Gates Foundation. We have a long legacy of contribution in small molecule drug discovery and that's probably our strongest area. And so we put a huge investment into the coronavirus drug discovery with our chemist but just for completeness there are five types of therapies that we're interested in like biotherapeutics but it seemed that Regeneron and Veer and Eli Lilly and molecular partners had the biotherapeutics covered and we wanted to make a contribution that would be in that way quite unique. This is not at all intended for advertisement just to share with you that for internal research engine to exist it has to be productive especially in the commercial marketplace of today's pharmaceutical companies where most companies have advocated their responsibility for drug hunting and probably 50% of our rent maybe 60% of the value in our late stage clinical trials are all internally invented molecules. We don't suffer from a not invented here syndrome I just intend to show you that this group is highly productive and has made some really important medicines so quite experienced. So I wanna take you through these five threads of our industrial strength response to COVID-19 at Nibir and first and foremost is associate safety. It has felt like quite a real responsibility to the 106,000 global associates who work beyond research and manufacturing and finance and really all operational functions. And we kept our labs open throughout the whole pandemic and we took this decision not quickly but in the recognition that patients with cancer can't wait for a pandemic to be over that patients with heart disease the still the number one killer globally can't wait for a pandemic to be over and we tried to, in March of last year make the research environment safe for our associates but allow them, enable them, equip them to do this around each other in their collaborative way but with an intense degree of individual responsibility for sure but I think strong support from the organization as well. Now knock on wood here we're a year into our essential research workers on site and we have not yet experienced on-site workplace transmission although we have had a few cases of coronavirus from community exposure and this has required real efforts from our associates on site as well as many of our leaders to take contact tracing and isolation quite seriously. The second way we worked to respond to the pandemic was with access to medicines. You know, even with remdesivir the medicines that actually keep patients alive who are in ICU's in 19 require sedatives and bacterial fighting medicine to prevent ventilator associated pneumonia and the injectables were in short supply. Now, wealthy countries like the United States might have access or even compete for access but we were worried as a global company that cares a lot about drug access and has a generics company that we could work to ensure this. And so we identified the 15 essential and difficult to access medicines and provided them at a no profit basis to low and middle income countries until that point where either curative therapies or available vaccines arise. And this was one of our biggest I think contributions to this pandemic. We also have hydroxychloroquine as one of these genes and there was a time last spring when hydroxychloroquine was even recommended for use by some medical systems and we were uncomfortable that there wasn't strictly a dataset robustly supported. And though we would take no profit on hydroxychloroquine as a generic medicine, we stood up a very expensive and well-designed phase three clinical trial in order to ultimately test this hypothesis. Hydroxychloroquine wasn't our idea we didn't regard it as the very best idea but there was an urgent thing to understand and explain whether it could work in this disease. And so we set up a multi-center randomized double blind placebo-controlled phase three clinical trial for hydroxychloroquine monotherapy and even with a zithromycin which was postulated by some to work. Thankfully through the course of this trial that we set up and globalized in record time for our own company teaching us a lesson on how to transvestigation swiftly. It failed to recruit because the virus became less a concern with vaccines but also because it's arose. We gave a full reconsideration of our anti-immune medicines like interleukin one beta targeting canokinomab and Jack two kinase targeting Ruxal could we block immune cytokine storm and set up large phase three clinical trials regrettably those two medicines and even back in our early pipeline we took our leading novel anti-immune medicines such as first in class inhibitors of the so-called inflammasome testing more of a myeloid compartment and I need immunity and less adaptive T and B cell immunity. These clinical trials are ongoing but we're so hopeful that they could help patients. And part of pandemic response wasn't coming up with our best ideas but just listening to the community and responding to investigators at medical centers around the world for initiated trials and in the time more than a hundred proposals were received more than 30 trials were stood up overnight and we worked with any number of organizations around the world. But the doomsday scenario is this virus changes or that this virus comes back vaccines prove in effect and we can't be caught on our heels the next time. And so in our laboratories we set up a program to target coronavirus protease. And as I shared this protease is an essential gene and it's also a gene that does humans suggesting that we might be able to make a medicine for it that would have strong efficacy and be very well tolerated. Now why do we pick the protease? Like Moderna with their mRNA vaccine platform we had made big investments in creating a chemistry discovery platform that's called COVID proteomics. Normally we make drugs by picking a protein developing bioassays for it introducing libraries of molecules in search of a good point for drug discovery. And a lot of actually most medicines are discovered this way. We thought to just turn that on its head and just take a library of proteins that are very sticky what we call electrophiles and just throw them at the human proteome and say what sticks to what? It'd be like mapping all of the footholds on El Capitan to then decide how to climb that face. We do this work and an open science strategy with Dan Nomura and colleagues at the University of California Berkeley. We've made now millions of molecules that are sticky in this way and have mapped thousands of novel protein starting points. Citing chemistry. These molecules tend to bind a single amino acid called cysteine and we can map cysteines that are drugable in the human proteome and so we wonder, does the coronavirus have any important cysteines? And it turns out that the main protease is able to clip other proteins and pull beads off the string using a cysteine active site. And so deep in this pocket there's an amino acid on the protein called cysteine and that's essential for the protease's function. And so we started to map with our libraries of small molecules. Do we have any starting points for drug discovery? These wouldn't be new drugs. They would be prototype drugs that we could then optimize with our really sophisticated and experienced group of now more than 800 chemists. And we found some outstanding starting points some of which we've started to publish so that others can work on them too. It's best not to do pandemic discovery research in isolation. And so in our case, we want this molecule not only to work against SARS-CoV-2 but also SARS and MERS. And we need to even imagine what a resistant protease might look like and try to anticipate that with a new drug and we're doing that in collaboration with University of Massachusetts computer modeling. This is going really well. We now have molecules that suppress viral load in pre-clinical models are very potent, low nanomolar to the scientists on the line inhibitors of the protease. But as an insurance policy against our own success or failure, we actually did not do it before. We've opened up the drug discovery platform to scientists from academia like Stuart Schreiber at the Broad Institute and even other pharmaceutical companies like Andy Plump and Takeda. Send us your molecules. We'll test them against them. And we'll send you the data back without even looking at the structures. This is a new way of working. It's like the rising tide. And we think that it has a chance to be applicable well beyond this pandemic to other severe and life-threatening disease spaces. This type of open science and public-private partnerships is something I became passionate about back with that JQ1 molecule. And I think is really underutilized in biopharma today. Through the pandemic, so many groups were self-assembling. And we've enjoyed connectivity amongst leaders of R&D in the industry together almost every Wednesday night in the heat of the week comparing notes on how to take best care of associates, how, but also to plan collaborative ways that we could interact, platform studies that we might interact with undertake together. And it's fair to say that third-party groups did a lot to keep the dialogue moving and heading to the table with their best intentions. And I credit the FDA, the Heaver Group, believe it or not the pharma organization as well as the NIH with its active program. And we've been contributors to the active program which sought to bring medicines together for comparative study that might normally live in the isolation of individual clinical trials. And then lastly, contribution. We are a big global company, but we work in communities. We have six communities where we do discovery research and from friends on the wards, we learned about everything from needs for viral nucleic acid purification kits to PPE, protective equipment for clinicians, as well as just concrete financial needs. We created a $20 million global fund for communities in and around those spaces where we work and actually increase the investment, ultimately reach even larger global communities. We're not unique in this way. I'd like to think that many pharmaceutical and other industries have done similar things to try and help. The most powerful ways is that we have a lot of clinicians still with medical licenses at Nibber, of one of whom here is Florencia Stiegel. We train together at the Brigham and Women's Hospital. She remains on her disease faculty. And like Florencia, many, including myself, re-enlisted for emergency management of the pandemic. Now, thankfully, the pandemic at the Brigham never got so severe that they needed a stem cell transplant physician from the pharmaceutical industry to hit the wards. And so I was not calling the florist as well as several others. And her stories from the wards were a source of energy. I think actually be supported keeping these labs open and working on COVID. Perhaps we can talk about this in the Q and A. I'm frequently asked these days, were there learnings about how to run a research institute about keeping a large company safe, about new ways of doing business? Will you change your global real estate footprint? And Lainey and Mark share that there are members of the business school community here who might have ideas, I'd be all ears, or could have curiosities about how we intend to come out of the pandemic once we're able to with a new way of doing business. And I've spent a lot of time here today talking about technology, the request. But if I've learned one thing in leading this, sorry, most productive and biomedical, private research institute in the world, these years is that this is not as much a molecules and atoms and dollars and indications business as it is a people business. And in this moment where we're quite actively recruiting new leaders at every stage of the company, I'm just consistently reminded by this group, my leadership team, well, what a privilege it is to work around people who are post ego, who are purpose oriented and who, despite their perhaps lack of awareness of coronavirus biology or biochemistry, really rolled up their sleeves through the pandemic to try and make a difference. There are challenges. So I've listed a few of them here, you can surely read the slide for yourself. We're lacking appropriate animal models to test medicines that are rising. There are new variants that will infect mice that will be helpful to us as we can't do monkey challenge studies and we shouldn't do Sinnoh challenge studies with every rising medicine. Access to diagnostics and therapeutics is still a great challenge and we still don't as yet fully understand risk beyond age and a handful of indication. I'm gonna finish where I ended. I'm sorry, finish where I began with a little bit of a future outlook. We just simply don't know what to expect. There's a range of real possibilities. It's our responsibility in the present pandemic to be prepared for a doomsday scenario. The world is increasingly turning its attention to therapeutics with the availability of vaccines. And we might reflect on the influenza myology following the 1918 swine flu epidemic as reported by Fauci and colleagues back in 2009. Go back and read this article 90 years later we can still see traces of the 1918 flu genome in patients infected today with H1N1. And so I think we really do need to get organized around preparedness. Well, I'll slides to you but as this is an ethics I thought to share a couple of reflections on the space of bioethics and ethics in biopharma and during pandemic times. And this is a quite a hot subject now. And so you can count on me, Mark and Laney to tune in to future seminars in this series. I won't read this to you. But as we gathered with my leadership team to prepare for this lecture and to imagine what this community might have real expertise on there are bioethical considerations that are so central to our function in biopharma that we've actually hired an ethicist from Harvard Medical School, Roberta Driscoll to help us to assess the challenges as they arise to connect to consult services extrinsic to our organization when and to really start to build a framework for bio pharmaceutical ethics. It sounds I know like an awkward term but we have just an obligation to execute this important work in just the most ethically appropriate way. I can imagine being in this audience today and hearing someone from a drug company talk about bioethics and you're rolling your eye. As I used to bristle when I would hear industrial scientists talk about patients what do you know about the patient? I see the patient every day and how wrong I was. There are really important business reasons that we should care about doing this work in an ethical manner, our license to innovate and to provide medicines utterly depends on this. It's not only just the right thing to do but it is the association of the associates that work with us who are oriented. Against these many I think established but some interesting challenges like permanent agents, Lainey and Mark and gene therapies and it's like cartoon therapies and ambiguity of long-term follow-up even as innocuous as MRNA all the way through to issues of access and awareness and confidentiality connected to clinical investigation. But this is the last list I wanted to share with you which I find really provocative. The many ethical considerations that we either observed or experienced pandemic times. Patients and healthcare workers and those needs will be better known to you than to me and I'm certain your list will be longer for healthcare workers. But we really struggled with helping give direction to our associates around managing personal and professional response creating a much more inclusive work environment than we had before. A much more adaptable when we ever had before catalyzed by the pandemic. Who is an essential worker in R&D? Is it because you move it or if you work on cancer? What about the stage of R&D? Are you essential if you're in the clinic or if you're doing discovery research or is it just supply chain researcher or supply chain workers who manufacture medicines as the Massachusetts state guidance suggested? How do we test associates? Can we mandate it? How do we provide vaccines? Can we access them? How will we return to work and how will vaccination status influence that? Can't bring people back to work where office space workers fully vaccinated or is it inappropriate to ask them and not just in the United States but in the 45 or more countries around the world where we practice research and development. Animal model studies, the dialogue really changed. If you talk to our pre-clinical community, they will say that there is an appreciation now more than ever for the use of challenged studies in Sinnoh because studies in humans was ethically untenable in many circumstances. And this narrative is quite evolving. On the flip side, it's notable that so many therapeutics were developed without animal model studies. As well, we've had some clinical trial ethical considerations. Can we do healthy volunteer studies of immunosuppressants which are required by regulatory guidance at a time when there's a circulating prevalent virus? Sister to that was no. Now I'm not an expert in commercial considerations but the pricing models that have been proposed and executed for vaccines and therapeutics and that will evolve, I assure you as the vaccines start to outstrip demand in their own supply healthcare, practitioner engagement, the appropriateness of those interactions and so many more. In any event, thank you very much for the opportunity to visit today. I would say we're getting increasingly organized around ethics at Novartis. It's core corporate strategy, society. It is a business imperative. It's also the right thing to do what our associates expect. And with that, I say thanks and we'd gladly stay and take any questions. Thank you. Thank you very much, Jay. That was an incredible science lesson and I love the ethics part that you brought up. I wanna start with one science question by Dr. John Fung who's the head of our Transplant Institute here. He says, wonderful talk on the role of Pharma in addressing COVID. Your approach to looking at the active enzymatic side of the protease is exciting. Has there been any evidence of mutations in these critical enzymes or has mutations only been demonstrated in spike protein? Thank you. Great question, critical question. As yet, the naturally occurring endemic viruses, notably those that are of the greatest global concern do not have meaningful mutations or even polymorphisms arising in the protease and those that we have mapped and we follow this very, very close for Emeryville, California site, none of them mapped to the active site. So as yet SARS-CoV-2, as we know it today in this pandemic should be uniformly sensitive to the medicines we're making. Now with that said, one way to anticipate resistance is to do it in vitro evolutionary studies and more and more of these are being done with medicines like remdesivir and resistance mutations to remdesivir have been functionally realized in laboratories and that might predict for resistance in the future. We are at the point now with our lead optimization campaign where we can do selective pressure experiments to try to anticipate resistance with a series of protease inhibitors. It's unlikely to be only one. So no prevalent mutations today but we're working hard to discover them even in advance of their arising. That was the first was a research question. Then I'm gonna hit a clinical question which was asked by Martin Chan who said use of high dose corticosteroids in Hong Kong to treat SARS, the previous coronavirus left many with a vasculinocrosis. Is its use justified this time? That's a great question. Well, I would typically call you and Mark to answer this question. So Laina, I welcome your opinions here. I would say that the dexamethasone in this context is now well supported by properly controlled and blinded randomized studies but beyond this demonstration of efficacy of course, this issue of drug effectiveness. And for a medicine that's not a licensed medicine with evidence of a drug that we bring to the market for the first time but an established medicine, a lot of times those post marketing studies are not undertaken. And so I do believe not only for the point that you raised but about the extensibility, its utility to patient groups that who might have been ineligible for use in the context of a first clinical trial perhaps they have a immunocompromise or an active malignancy or any one of a number of exclusion criterion. I do think that a real world evidence at least understanding of dexamethasone is required to provide that doctors are used to a critical care management strategy. Great answer. We have an anonymous attendee who asks how do big farmers prevent their research from being stolen by foreign governments? Whoa, firewalls I guess. I will say that we have a very organized enterprise risk organization that we have even risk management in R&D that thinks about everything from tornadoes and earthquakes to intellectual property loss. And we do have some safeguards to prevent or at least to diagnose the migration the inappropriate migration of data. I will say I'm not kept up at night with the fear of foreign governments stealing our trade secrets. We have a but I do think we're pretty organized around knowing where our crown jewel data sets are and migrate to. Well, you pushed me there. So what does keep you up at night? Wow, I think understanding disease biology I think that when we know, hey, it's KRAS it might take us a couple of decades but we're gonna make a KRAS inhibitor. But there are so many people we don't know because there hasn't been a genetic lamppost to look under. Alzheimer's, what's the cause of Sjogren syndrome? What's the cause of lupus? We don't know. And so just the atomic resolution of disease and maybe the second one is talent is I do believe this is a people business and in Cambridge here, you know there's unprecedented biotech company growth and people are, I don't know having great scientific experiences and making a lot of money before humans even lived a day longer. And those are the companies that pull our talent from Nibbert into leadership. And so I just am constantly thinking how do we make this the most exciting place to contribute your career to finding science? Those are the two. Beautiful answer. I have two ethics questions. The first is from one of our current fellows Esther Berkowitz. She wrote, I'm aware of a few pharma companies that have formal ethics committees but it doesn't seem to have permeated industry as a routine phenomenon. Do you see a role for formal ethics committees that meet regularly within pharma and medical device companies? I do. And I think with Roberta and Ezy Garfinkel and Klaus Moosmeyer and many other new artists, we are I think increasingly pretty organized around this. Nibbert doesn't have a chief medical officer but the head of our translational medicine, our clinical trials group for the non malignant diseases called Evan Beckman. And Evan has just a personal interest in the ethical conduct of research mapping back to his days. I share that with him having a little bit of time with all of you at UFC. And really because we had an internal champion with legitimate curiosity, we started to get more organized around research ethics. I will say it doesn't arise every time but when I put out the call for some ethical considerations that I might share with all of you, I do that a lot with new technology ideas, things I've read, articles I've read and usually it's radio silence. I got back 40 emails in like five minutes. So I think that there is probably at companies like ours a legitimate and pent up interest to talk about these issues to triangulate them and to provide better guidance to parent organizations. In our case, grad CEO, Voss Narasimhan, Voss is a clinician scientist, mobile public health leader in H1N1 vaccine response. And he just happens to be like a really moralistic and I think balanced and ethically minded guy. And so under Voss's leadership these last three years we now have Klaus on our executive committee. We have an ethicist in chief who manages also risk management. Now, Novartis, like many pharmaceutical companies has had some tough experiences in data integrity with the business that we acquired with sales practices that were either regrettable or perceived enough to be regrettable to prompt serious compensatory. And so we have really an imperative to get this right to rebuild trust with society in the industry but in our company especially. Wow. We have an anonymous attendee who wanted to ask about do you think pharma companies have an ethical obligation to ensure their products are distributed in equitable ways both domestically and abroad? Yes, I do. And more importantly, our commercial leaders do. And so the narrative in Novartis is always drug access, drug access, drug access. We operate in Sub-Saharan Africa. We have a member of our executive committee who ensures that the discussions always culminate to a global health conclusion. And we've even made I think some pretty bold public statements our CEO around ensuring drug access. In R&D this is a great challenge. For example, I have an idea about how you might cure sickle cell disease by taking hematopoietic stem cells, by introducing permeable genome editing machinery, turning off, editing out the switches that keep fetal hemoglobin off, turning it back on and doing a bone marrow transplant to get the cells back in. That's a mouthful. And even as a data transplant doctor that's a complicated procedure even at University of Chicago or Harvard. And so how are we gonna do that in Ghana? And so built around this idea of access to medicines, Jonathan Spector and I, this goes back now five years. So right when I arrived, we wrote a 10-year strap plan because we knew we were gonna make this cure but we knew that things had to be in place ultimately for it to read through to patients around the world. And that's the amazing thing about working at a big global company is this five-page document triggered unbelievable institutional responses. A fast forward three or four years and we were working with companies with drones dropping hydroxyurea to medical centers that can try to use small molecule therapy, building clinical trial networks so that the infrastructure is in place to ultimately bring sickle cell disease into the environment. Again, medicines first for those who need them most. And then we get to pricing. And our pricing strategy, which I'm not the expert on has always the narrative as I have a front row seat for those discussions on the executive committee about value basis. There has to be a value basis and it's a dialogue. We don't set the price, it's a dialogue with payers. And so if we go in with an access mindset and if we're disciplined to follow you a value basis for payment for medicines that be a path for most medicines to reach the patients in need. One of the challenges that we found though, medicines aren't approved for world use. They're often approved by the United States regulators first and then perhaps the European regulators and then perhaps the other countries. And there's this pregnant pause as we learned with our spinal muscular atrophy gene therapy, Zolgensma, where the US has it approved where we're ramping up global supply and where overnight every parent knows that their infant needs this medicine. And so I won't say we haven't all figured out and that there have been some really tough learnings along the way, but ours is a company that's built around value-based pricing and drug access and hold us to that account. Teresa Williamson is another current fellow and she asks, you mentioned unprecedented collaboration and sharing of scientific information to help patients. How do we continue to incentivize this behavior outside of the pandemic? The ultimate way to incentivize behavior in the private financial incentive. And so I think about this a lot, right? Because I'm really closely with the Gates Foundation and when Sue Desmond Hellman was leading, she had this really memorable statement and we were having a coffee one day and she said, you know, we were talking about what projects we might do and the budget that I have available to do corporate social responsibility and tropical diseases. And she said to me, she's like, let me challenge you. She's like, I'm gonna miss paraphrase her, but she said, the part of your budget that I wanna access is not the corporate responsibility budget, it's the profit-motive budget. That was really insightful. And so I think that we can for certain types of projects very seamlessly build public-private partnerships pre-competitive work. And we've been really good at that. What was interesting about the pandemic is there was a sense given how ill people get, the global economies, the individual toll, the death of young people, the recognition that these could be profitable medicines. And what's interesting to me about the pandemic is that the narrative in all of these meetings where it's just R&D pharma executives on the phone, their narrative was all about access. It was all about equitable access. It was about having diversity on clinical trials so that people could believe the data. The closed room narrative was always sort of on the high road. And so I find that like the door getting cracked open a little bit because here's the case where it wasn't corporate social responsibility. Everybody wanted to do the right thing. Everyone wanted to improve the reputation of pharma, but those aren't big enough drivers to command the investment of a $250 million face through clinical trial. So if there's a way to incentivize cooperative behaviors, early disclosures, I think you see a real response from the industry, look like the government voucher system for broken diseases. There are diseases that we do clinical trials on not because we want to get a voucher, but we can justify it and trade off discussion for another investment because the voucher exists. And it doesn't have to be only governments that trigger these sorts of incentives. But to really put into perspective your question, there are more people right now working on COVID-19 than are working on antimicrobial resistance which over a 10-year span is probably a bigger public health crisis. And I'll bet you a year from now there's less than a 10th of number of people working on COVID-19. And so how do we convert this from a passing fancy to a sustainable, incentivized R&D community? And I don't have an answer to that. But your comments, I mean, your comments which were very powerful was about what's an essential worker and is it the person who's doing the cancer research? Because well, we've had over 500,000 deaths here in the US from COVID alone. We also know that we've had an increased death rate for many other conditions because of lack of access to care and because we converted our surgical wards into COVID units and things of that sort. I'm gonna give the last word to the second generation. So Richard Siegler asks, Jay, thank you for your talk today. You've probably seen from the Gates Foundation's 2020 Goalkeepers Report that many average primary health outcomes in low to middle income countries rolled back to circa 1995 levels last year. With the rise of malarial deaths, this included, could you speak to your partnership status on a malaria vaccine that will address some of the broader global impact of COVID-19? Thanks, Richard. And great to almost see you here. I miss our time together. So we have part of the Gates Foundation on anti-malarial small molecule medicine as the bulk of our work together. This is a like-minded group that we've worked with for more than a decade now. And KAE and KAF, these two medicines in phase three clinical study in malaria treatment and prevention, prophylaxis are from our labs with cryptosporiosis and dengue virus. The thinking here is that we could kind of check but then who spends the money to make a medicine? Why don't we just make it and then give the world a medicine? And that's been our strategy. Malaria vaccines are a very exciting area of study. I think that mRNA starts to emerge as a pretty interesting platform for malaria. But as we're no longer as focused in the vaccine innovation that our work with Gates is principally around neglected tropical diseases, said. We recently announced with the Gates a partnership to do a kind of science out of regard as like just science fiction in sickle cell disease. What if we can't figure out a way even with this decade long strategy to do a genetically engineered, bone marrow transplant in Africa, that might not work. And so together with the Gates a very open, very engaging and forward thinking, scientific partnership that we just announced to try to imagine you surely know, Richard, but others might not. There's this idea of one dose radical cure. What would one dose radical cure for sickle cell look like? We're hard at work with them on that. They've been a great partner. But in malaria vaccines, we nearly have less work going on. Well, I wanna say thank you. This has been a fascinating talk. I'm gonna hand it over to Mark to say the last words. We're gonna stop now because the fellows are gonna be meeting with you and thank you again for agreeing to meet with them at 1.30 and I just wanna give everyone nine minutes to stretch, bio break and come back to meet with you at 1.30. Mark, do you have your last words? Last words are very few. This is a extraordinary talk, Jay. And I was deeply moved by it. I had one question myself and that was going back near the beginning of your talk on the achievement within 11 months of reaching four sets of potential vaccines that could change the COVID-19. Impact on the world and that no one had ever done anything quite that quickly by a factor of eight or 10 times. Will that somehow be a model to go forward with as we work on other areas or was it just on this one time that it took place? Well, thanks, Mark. I think that for the space of vaccine innovation, it's just changed. And the path forward now for these validated platforms like MRNA, the path from concept to proof of concept to phase three is a timeline that shouldn't be anymore as short as it was. And if there were two dominant MRNA vaccine players, there's a third back and there'll be probably 20 by this time next year because the lagging strand of innovation and pharmacology really fast is an established business model. And so I do believe that the space of vaccines is forever changed. We're looking very hard for faster paths for small molecule delivery. It is another artisanal process. I believe that once we get to phase one clinical investigation and trial designs that allow us to move efficiently and seamlessly arm in arm with regulators and investigators and patients from phase one to phase two B can take 18 months off of traditional timelines. But you know me well enough to know if there's a faster, cheaper way to do drug discovery, I'm in. It's just a little harder in small molecule therapeutics. Thank you so much for the talk. It was extraordinary. We'll see you in a few minutes again. Thanks, guy. Thank you. Thanks, everybody.