Good morning, everyone. Thank you for joining us, both here at the Palace Hotel in beautiful New York and those on the live webcast that couldn't be with us here today. Before we get started, I'd like to refer to our forward-looking statements. If you can all take a moment to read them, please. Thank you. During the next few hours, we will focus on the scientific and clinical rationale driving Eagle's hospital-based pipeline and commercial products, and lay out for you Eagle's value proposition for patients, the healthcare system, and shareholders. We will showcase the strength of these development programs, as well as our recently acquired approved assets. Including Enalare's ENA-001, an agnostic respiratory stimulant being developed by Enalare for the potential treatment of postoperative respiratory depression, community drug overdose, and apnea of prematurity. As a reminder, we acquired approximately a 14% equity stake in Enalare earlier this year, and have an option to purchase the rest of Enalare in the event specified milestones are achieved. We'll make additional payments as previously disclosed. CAL02, a novel first-in-class broad-spectrum anti-virulence agent being developed for the treatment of severe community-acquired bacterial pneumonia. BARHEMSYS, the first and only antiemetic approved by the FDA for rescue treatment of postoperative nausea and vomiting, or PONV, despite prophylaxis, and also approved for the treatment of PONV in patients who have not received prophylaxis, and for the prevention of PONV. BYFAVO, for the induction and maintenance of procedural sedation in adults undergoing procedures lasting 30 minutes or less. landiolol, a short-acting beta blocker. Today, you will hear from a truly extraordinary lineup of world-renowned key opinion leaders and Eagle team members, as well as Enalare representatives, who will share their knowledge and perspectives about these exciting clinical programs and products. These KOLs as well are well-respected experts in their fields and have dedicated their careers to clinical and research endeavors to improve the lives and outcomes for patients, specifically acute care patients in the hospital and ambulatory setting. Remarkably, even though each has individual areas of expertise, they organically overlap in their pursuits, as Dr. Mike Greenberg, our Vice President of Medical Affairs, will explain shortly. What will also become apparent this morning is that Eagle's pipeline assets and hospital-based commercial products, notably BARHEMSYS and BYFAVO, also fit together organically to create a potential suite of solutions that address some of the chronic challenges faced by the healthcare providers and hospitals today. Before we get into that, let me take a few minutes to talk about how Eagle has evolved and where we are now, and how we plan to execute our vision for the future. We have historically focused our efforts on our 505 businesses, but now we're turning our attention to patented, longer duration, new chemical entities. We've come a long way. Consider that the Enalare study has 200 patients in a phase II study. For CAL02, we are planning a global phase II study with more than 270 patients. We're certainly not cutting any corners. With our investment in Enalare, we are making a major commitment to what we believe could be two blockbuster products as part of our transition into a more traditional branded pharmaceutical company with a diversified portfolio of assets. In a few short years, Eagle's become a research-oriented company with the ability to self-fund R&D and launch costs. This year, if we follow analyst estimates for the company, we are expecting to earn around $130 million of EBITDA, which translates into about $100 million of net income. We've already posted record earnings this year, and we think that next year will be another very strong year for the company. Looking at the big picture, we currently have eight products on the market split between oncology and acute care hospital. We anticipate expanding both segments of our business. Today, however, we will focus solely on the acute care hospital business. To be clear, we anticipate growing both segments as we transform from a specialty pharma company to a diversified pharmaceutical company. We believe, based on our cash build and the strength of our balance sheet, we are able to fund our R&D while still maintaining strong earnings. There is a gap between the low end of the range of the next few years' earnings expectations and the high end of those earnings expectations. I will point out that this gap, if we reach the low end of those expectations or the high end, will have no meaningful impact on this transition. Regardless of the range of earnings, we believe we are very capable of continuing to fund this evolution and at the same time continue to post strong earnings. Today, we are going to focus on the elements of that transformation and the NCEs and branded products both on the market and in development. Our revenue, earnings, and cash flow are strong, and we have put that money to very good use. In 2021 and 2022 alone, we have funded the licensing of landiolol, the acquisition of Acacia, the equity stake in Enalare, and the clinical development of CAL02, all with what we see as so much potential to elevate care for patients in the acute care setting and beyond. In our view, each offers us a significant opportunity upon regulatory approval and commercial launch. As we have stated before, we also plan to use our cash to make a significantly accretive strategic transaction to round out our portfolio with already marketed products where we can take advantage of both strategic and financial synergies of such acquisition. We believe we have put ourselves in a strong position to achieve all of this through our disciplined approach to managing our cash and our balance sheet. Between potential acquisitions and our pipeline, we believe that Eagle can grow significantly in both the short term and in the long term. I will now turn the program over to Dr. Mike Greenberg, who will introduce you to our esteemed KOLs and talk about how these various products and pipeline programs are highly interconnected. Enjoy the day. Enjoy the program. I'm looking forward to it. With that, Mike? Thank you, Scott. It's my pleasure to introduce you to the esteemed KOLs who will be presenting this morning. I echo Scott's enthusiasm for the opportunities for Eagle as we evolve into a branded pharmaceutical company with a diversified portfolio. Even as we diversify, I remain excited about our ability to develop a comprehensive portfolio in acute care with current and future utility across the hospital space, including emergency medicine, critical care, and peri and intraoperative medicine. These are important products with the potential to elevate the level of care providers are able to offer. We believe the medications and pipeline opportunities being discussed this morning address unmet needs across anesthesia and its subspecialties, including perioperative medicine, pain medicine, cardiovascular anesthesia, critical care, and infectious disease, addiction medicine, neonatology, and cardiology. Today, we have the extraordinary privilege of hearing directly from experts who will elucidate these topics for us. They will provide not only the scientific and clinical aspects of these products and programs, but also share their personal experiences with the challenges they face in their practice areas when they confront some of these unmet medical needs. We believe the products and programs we are focusing on today are, or have the potential to be, useful, not just in the acute care setting, but in the perioperative setting and procedural spaces within hospitals and ambulatory centers. When considering Eagle's full portfolio, it may be useful to think about the patient journey. In the beginning of the patient journey, we have BYFAVO, which offers distinct characteristics and is the first procedural sedative to be launched in more than 20 years. Moving along, BARHEMSYS is indicated for the prevention and treatment of postoperative nausea and vomiting, or PONV. It is the first and only agent indicated by the FDA to treat established PONV in patients despite prophylaxis. We know that postoperative respiratory depression is increasingly recognized as a challenge. ENA-001 is being developed to address this as one of our pipeline assets should we exercise the right to acquire Enalare Therapeutics. Healthcare providers are keenly aware of the risk of infection, particularly community-acquired pneumonia. For example, if a patient were to develop a severe community-acquired infection, CAL02, if successfully developed and approved, might be appropriate. CAL02 is a novel, first-in-class, broad-spectrum anti-virulence agent being investigated as an adjunct to the current standard of care in community-acquired pneumonia. In this case, we aim to improve patient outcomes, and we believe we will do so without contributing to antibiotic resistance and therefore potentiating antibiotic stewardship. We believe that ENA-001 for community drug overdose is a logical corollary to the initial proposed indication of postoperative respiratory depression. We will also hear about potential in apnea of prematurity, in which the etiology of respiratory depression is physiologic rather than chemical. We believe all of these drugs and drug candidates have potential utility in the perioperative and perial procedure space and beyond. Our panelists are eager to share their deep industry and clinical expertise with you today. To help us put all of these puzzle pieces together, let me introduce our panel of experts by topic. Presenting on Enalare's ENA-001, we have Herm Cukier, Enalare's Executive Chairman, President, and CEO. Mr. Cukier is a results-oriented leader and industry veteran who has held positions at BioDelivery Sciences, Allergan, Bayer, and Bristol Myers Squibb. Also from Enalare, we have Dr. Joseph Pergolizzi, Jr., Chief Research and Development Officer, Board Member, and Co-Founder. Dr. Pergolizzi is an internationally recognized thought leader in anesthesia, internal medicine, perioperative medicine, pain medicine, critical and palliative care, pharmacology, drug development, and regulatory affairs. Dr. Pergolizzi is the former Director of Business Development and Financial Affairs for the Johns Hopkins University School of Medicine Clinical Trials Unit and a former part-time adjunct faculty member in the Department of Medicine at Johns Hopkins University School of Medicine. Dr. Pergolizzi has published over 100 peer-reviewed medical articles. We will then have three KOLs who will address the three indications under development for ENA-001. Dr. T.J. Gan, who will speak about postoperative respiratory depression, is a distinguished leader in anesthesiology dedicated to defining best practices. Currently, he is Professor and Division Head of Anesthesiology, Critical Care, and Pain Medicine at The University of Texas MD Anderson Cancer Center. Prior to that position, Dr. Gan was Chairman of the Department of Anesthesiology at Stony Brook Medicine. Dr. Eugene Vortzman, who will speak about community overdose, is a practicing emergency medicine physician working for the largest provider of healthcare in New York State, Northwell Health. He rotates between large tertiary care academic hospitals as well as community hospitals and serves as the Clinical Director for Addiction Medicine and Disease Management while also functioning as the Chair for the Long Island Jewish Pain Committee. Dr. Prem Fort, who will discuss apnea of prematurity, specializes in neonatology with the Johns Hopkins All Children's Maternal, Fetal, and Neonatal Institute. He is co-lead for the institute's Research and Quality Network and a co-chair of its Research Council. Dr. Fort's research includes control of breathing and apnea in premature infants, specifically as it relates to its management with caffeine. Moving now to CAL02, Dr. Andre Kalil, Professor at the University of Nebraska Medical Center, Division of Infectious Diseases, and 2021 UNMC Scientist Laureate, will walk us through the challenges of treating severe community-acquired pneumonia and the potential therapeutic benefits of CAL02. Dr. Valentin Curt, Eagle's Senior Vice President, Clinical Drug Development, and Interim Chief Medical Officer, will explain CAL02's unique mechanism of action and provide an overview of the regulatory status and development plan. Moving now to the two FDA products that we recently acquired. Deb Hussain, Eagle's Senior Vice President and Head of Commercial, will introduce BARHEMSYS and BYFAVO. Ms. Hussain moved to Eagle from Acacia Pharma in connections with Eagle's acquisition of Acacia, where she served as Chief Commercial Officer overseeing BARHEMSYS and BYFAVO. Prior to that, she spent 22 years at Eli Lilly and Company. To speak in greater detail about BARHEMSYS and its utility in treating postoperative nausea and vomiting, we will welcome Dr. Gan back to the podium. That he is considered an expert in both realms, postoperative respiratory depression and PONV, is an illustration of the interconnectedness of the products and programs we are speaking about today, and the potential broad utility of these products and programs. Dr. Rick Dutton, a widely recognized leader in anesthesia quality management and Chief Quality Officer for USAP, will then provide his clinical perspectives on BYFAVO, as well as the challenges in anesthesia today. In the final segment, I will provide a high-level overview of landiolol, a beta-1 adrenergic blocker for which a new drug application has been submitted to the FDA, seeking approval for the short-term reduction of ventricular rate in patients with supraventricular tachycardia, including atrial fibrillation and atrial flutter. I'll focus on the unmet need for rate control in multiple patient populations. We will host a Q&A session in which all the KOLs will participate. In closing, as diversified as our drug portfolio is, the hospital space is the underlying commonality across and among all these key areas. As you can see, Eagle believes it is putting the puzzle pieces together with a robust portfolio and a potential pipeline of acute care products. I'll now turn the program over to Herm Cukier. Herm. Thank you, Mike, and thank you to the team at Eagle Pharmaceuticals for the opportunity to present at this important forum. It is my pleasure to be here representing my colleagues at Enalare Therapeutics and to be sharing the stage with an esteemed group of medical and scientific experts. We have made significant progress since founding the company in late 2020 and believe we have the potential to improve the standard of care for millions of patients around the world suffering from life-threatening and debilitating conditions, both in the hospital critical care setting and from community-based health emergencies. Our lead compound, ENA-001, is a clinical-stage, novel, agnostic respiratory stimulant with a unique mechanism of action, which has been demonstrated to successfully increase ventilatory capacity in five phase I human studies. This product is what we like to call an N of 1. There is no other product like this in the world today. To our knowledge, there is no other product being developed anywhere else like it in the global biopharmaceutical ecosystem. What makes this product unique is its mechanism of action. I will let our head of R&D, Dr. Joe Pergolizzi, describe it in much more detail in just a few moments. What I have the confidence in, having been leading organizations for over 30 years successfully in our industry, is that when we have a unique product with the potential to bring significant benefit clinically to millions of patients around the world, and at the same time, potentially reduce healthcare costs, we have the makings of a potential blockbuster opportunity which could be transformative for an enterprise. Let's take a high-level view of why I believe this to be true. First, we start with the medical need across multiple patient populations. Acute respiratory depression affects millions of patients around the world. At a basic level, as represented on the left side of the slide, this condition occurs when the body's natural ability to ensure we have an adequate supply of oxygen and removal of excess carbon dioxide is curtailed. Either condition, too low of oxygen, known as hypoxemia, or too high a level of carbon dioxide, known as hypercapnia, is debilitating, can lead to respiratory or cardiac failure, and even death. Our bodies have a sophisticated, integrated design to ensure that we have the harmonious balance between oxygen and carbon dioxide within our bodies. The vast majority of this responsibility lies within the brain, though there are other important components that become paramount when we speak of ENA -001 's mechanism of action. There are several reasons why this breathing system can be curtailed and create the condition of respiratory depression. Primarily, as you see on the right-hand side, the use of certain drugs, including opioids, anesthetics, and benzodiazepines, as well as underlying health conditions, including obesity, age, and underdeveloped respiratory system, are leading causes. There are many patients for whom this condition arises. We have focused our efforts to date on three priority opportunities. Patients coming out of major surgery, those experiencing drug overdose in the community, and neonates suffering from a condition known as apnea of prematurity. While I will let this esteemed panel of experts describe each of these conditions in far more detail, the fact that there are more than 40 million surgeries annually in high-risk patients in the United States every year, there are over 100,000 deaths due to drug overdose in the United States annually now, and such a delicate population in neonates, we believe there is clearly a major medical need for novel innovation. That is the potential ENA-001 holds with its novel mechanism of action. The most important elements to consider in this regard are, first, that ENA-001 is an agnostic agent, so it doesn't matter what has caused the respiratory depression, this drug is designed to help people breathe. Second, it acts very rapidly, potentially enabling usage in rescue situations. Finally, the chemistry allows for the drug to be crafted in various formulations, allowing for potential usage in different patient environments. While mechanistic theory is interesting, clinical data is what builds our confidence. In this regard, we have a very strong foundation of successful human exposure with ENA-001 that point to the potential of achieving our target desired profile. We have seen this compound's definitive ability to increase ventilatory capacity and the challenge of both various powerful opioid and the most commonly used globally anesthetic. The results in more than 100 human subjects have further been encouraging as the drug has been well-tolerated with no significant adverse events. Our excitement for this novel compound is further amplified by support from major scientific governmental agencies, BARDA and the NIH, which has included meaningful non-dilutive funding for the company. BARDA, in particular, is an important partner developing the intramuscular formulation for potential usage in combating the drug overdose crisis, and also as a potential medical countermeasure in case of mass casualty event through the weaponization of super potent narcotics and agents of unknown origin. We look forward to working with BARDA and their esteemed group of scientists in developing this compound. As you see here on the slide, BARDA has actually provided over $50 million to the company to develop the drug all the way through NDA filing. As I mentioned previously, with this unique product profile and a large addressable market, we believe ENA-001 has the potential to achieve blockbuster status. There are several product analogs to consider as useful barometers, which may be possible in this particular instance. For example, this reminds me of when I was overseeing the development of sugammadex, brand name Bridion, which has become a global blockbuster product. Back then, similar to ENA-001, we believe sugammadex had the potential to improve patient care post-surgery and reduce overall healthcare system costs. Finally, of course, we need to get the drugs approved by the regulatory authorities to ultimately realize this potential. Here, too, I am encouraged by our ongoing dialogue with the FDA, where we are treated with Fast Track status and have secured the highly coveted Rare Pediatric Disease and Orphan Drug Designations in apnea prematurity. Let me conclude before turning the podium over to Joe. In reemphasizing my excitement for ENA-001, if approved, this drug could potentially bring dramatic improvement to millions of patients around the world and potentially reduce overall healthcare system costs. I strongly believe, as I did with sugammadex, we have a global blockbuster in making and look forward to being part of this unique journey. With that, I'll ask my friend and colleague and Head of Enalare's Research and Development, Dr. Joe Pergolizzi, to share more of the science behind this novel compound. Joe? Good morning, everyone. How do we start this with Enalare? Real simple, and I hope the guys at Nike don't get mad at me. Just breathe. Really simple. It's very simple. Let me walk you through this, very much like Einstein said, and that is, if you can explain it to your grandmother, then you'll be okay, right? A little paraphrase. With Enalare, I think what we need to do is start off at the basic science level and then work our way up to the clinical utility. I think that will build the excitement that we have on our team and our partners, Eagle, have as well. When we look at this opportunity, we have to think about how it fits in to the paradigm of changing the dynamics of acute care, perioperative hospital, and ambulatory-based medicine, and how we can align with the various stakeholders. You're gonna hear from some of my colleagues today about how important it is to avoid sentinel events in a hospital setting. How important it is to achieve health economics and outcomes research goals so that the payers are aligned with the needs of the providers and the outcomes we want for our patients. In a perioperative setting, we're very limited with the amount of tools that we have in our armamentarium. Two of the biggest issues that we've always had to struggle with, you're gonna hear about today. One is postoperative nausea and vomiting. My colleague, Dr. Gan, and I have been working on that, and we were both involved with the major brands, including ondansetron, you know, as Zofran, when we were able to revitalize that by taking an existing product and turning it into an orally disintegrating tablet and ending the product life cycle at a $2 billion mark. That same type of enthusiasm brought to postoperative respiratory depression. With this particular asset, we go beyond that spectrum. Let me start with some of the science. If we look here, we can first get our arms around what is central, peripheral, and mechanical aspects of respiration. When we talk about respiratory drive, it's very simple. Put it into three buckets. You have your central control. That's everything in your central nervous system, like the brain you see over here. You have your peripheral sensory input. This is sort of a connection between what's happening out in the periphery, which includes your lungs, your muscles, your diaphragm, and it's sort of a throughput to how your brain is going to perceive different types of chemicals in your blood and changes that would translate to issue with breathing. In the neck, in your neck, you have your carotid bodies. The carotid artery, remember, brings blood up to your brain. It's uniquely positioned to surveil what type of constituents need to be adjusted for when it comes to respiration. At the bifurcation of the carotid body, you have this area that has a bunch of different channels and receptors. We call these chemoreceptors. These chemoreceptors are constantly looking at your blood to check on the oxygen levels and the carbon dioxide levels in your pH. If they see that these levels are not right, they send an impulse directly to the brainstem to tell you to breathe better, more efficient breathing, deep breathing, or sometimes faster breathing or slower breathing. That's what this very primitive system does. It's a sort of a survival reflex that we have. When we take it down to the cellular level, what we find is that there are the task channels that you see here, and these task channels, as well as the big potassium channel, all work together. The way I like explaining it is driving a car. If your body sees that your oxygen levels are low and your pH is low, it's gonna step on the gas, right? It's gonna do more transduction through those TASK channels to feed the direct input to the brainstem and tell you to breathe better. Drugs like doxapram, which are a non-selective agent, meaning it works both peripherally and centrally, they try to augment that. What they're doing is if your foot's on the gas, they're trying to push it down even further. Now, I have the luxury of driving a 911 Turbo S, right? I could tell you it's only so far you can keep pushing it, right? What happens with a drug like doxapram is it tries to push that gas down even further. There's a limiter, there's a governor on it. That's what these big potassium channels do. These big potassium channels, when you antagonize them, what does that do? It lifts off the brake. Now you get even more of an efficient signal to the brainstem, and that improves the breathing. It only is peripheral. You don't have the type of baggage that you might see with doxapram and that we historically have. CNS issues, cardiovascular issues, the other doctors will talk about some of these in the rest of the program. It's very, very simple. What we have to realize is that the onset of action is almost immediately. It's one blood-brain circulation, right? Once it gets injected and gets to that receptor, it starts to work. What we find is that it's very specific for the central peripheral mechanisms that are surveilling your blood. That means that we're not gonna have off-target effects. I'm gonna show you that in over 110 patients. Human beings that we put this in, a very predictable pharmacokinetic profile and very directional pharmacodynamic profile. What does that mean? That means that when we studied it for safety, we also sorta hedged our bet a little bit, and we wanted to see when we challenged these healthy volunteers with opioids, which cause hypercarbia, meaning increase in carbon dioxide, they mask the ability of these receptors to pick up high levels of carbon dioxide. What happens in that case? You don't pick up the high level of carbon dioxide, all of a sudden you become hypercarbic, that causes cardiac arrest. Cardiac arrest causes respiratory arrest, you talk about things like overdose or in the PACU. Right? The ability to unmask that, the ability to take your foot off the brake, that's the excitement, right? To be able to do that in a clean and effective way, safety is very important. We did the same thing with propofol. All of you know propofol. It's the most ubiquitously used anesthetic in the world. It was mentioned by Michael just before is that it's something we take for granted in the United States, that here in the United States, propofol is administered by individuals who are trained in the production of your airway, the protection, right? You have to be a trained individual. That limits the ability of propofol to be used in a lot of different settings. Leave the United States like I have, as a visiting professor from traveling all over the world and seeing them administer propofol, it's not done by an anesthetist, meaning an anesthesiologist or nurse anesthetist. It's done by a group of individuals that are supporting a surgeon, and sometimes even just a surgeon. That means if you're able to make it safer, more predictable. The problem that we have with propofol is that it masks the receptor's ability to pick up hypoxemia, right? Low oxygen levels. Again, low oxygen levels increases carbon dioxide levels, then it goes into cardiac arrest, goes into respiratory arrest, and you die. That's what happened to Michael Jackson. For this particular drug, we're able to overcome that. I'm gonna show you data in healthy volunteers, 108 data that looked at both the pharmacokinetics and the directional pharmacodynamics. Why is that so important? As a drug developer, if I can get some insight into the pharmacodynamics of a drug before I start phase II, I have a good way of defining what I need to accomplish in phase II, including the dosing. When you go to the division, which we work with at FDA, they wanna hear this information, and they get excited. That's why we have essentially a Fast Track position with them. We're on the phone with them all the time, talking with them, 'cause this is a critically important drug to develop. To stay on time, I'm just gonna walk you through a couple things. A couple words I want you to take home. Agnostic. Well, you know, some people challenge me on that, the reason I like agnostic is because regardless of the iatrogenic type of reason for you not to be breathing, meaning drugs, right? It could be alcohol, propofol, it could be gabapentin. You may read some of my papers on those, right? Fentanyl, et cetera, anesthetic, inhalational agents. Regardless of what type of masking is happening at those receptors, we can overcome that. Neutral, meaning that we're using a primitive reflex. You know of some of these reflexes. If you think about cataract surgery, one of the biggest problems we had with cataract surgery is when we were starting to do it, if you press on the eye too much, you initiate the ocular reflex, oculocardiac reflex, and you go bradycardic, right? These are natural type of things. If you take... If you, if you ever think you're having an arrhythmia, take cold water, splash it in your face. The diving reflex, it'll drop your heart rate, right? This is the same type of protective primitive reflex that we're able to initiate. Peripheral, meaning that we're not going to have that CNS baggage that you have with a lot of these agents, and we're able to transcend the issues that are related to drugs for opioid overdose that are specific antagonist, right? Across the whole way, they're talking about one of those that I passed on, right? It's rapid, and it's ability to not compromise pain, analgesia, that's very important. After a surgical procedure, you want your patient to be breathing well, you want them to be out of pain. This is able to be done with our drug. At the same time, as Dr. Vortsman will tell you about combative patients, when you go and you bring them out from the verge of death for opioid overdose, they're very combative. You get this hyper noradrenaline overdrive when you give them a opioid antagonist. We can avoid that. You will just breathe. Well, what do we know about this drug? So far, what we know is very encouraging. I've been involved with probably, I don't know, my CV is long enough, but at least 45 NCEs across the globe. I'm extremely impressed with what my team is able to do with this drug. When we look here, we have over 110 subjects, these subjects we've given the drug single dose, ascending dose, continuous infusion for five days, 24 hours at three different doses. I mean, they've been pressed, right? We challenged them with an opioid challenge, and we challenged them with a propofol challenge. All of this allows us to get to the point where we believe our phase II is going to be very exciting. What have we seen again? Consistently, it's well-tolerated. It has this agnostic effectiveness. It has a therapeutic dose range that we believe will allow us to treat multiple types of disorders, including postoperative respiratory depression, which is a huge market opportunity. Opioid overdose or polysubstance drug overdose. Herm had mentioned that the NIH, it was a little convincing, you know, talking to Dr. Volkow, who is always the head of the spear. Explaining to them how important polysubstance overdose is and how we may have a remedy for that. Also apnea prematurity. The results have been consistent. If we look at the 104, and these again are published, and we also can present them through Eagle if you'd like the data, but these normal, healthy volunteers were administered both low and high levels of alfentanil. That is a potent opioid. Under very controlled situations, done in the Netherlands with Dr. Albert Dahan. Albert has tested every single drug in every single class, so at least 26 of them that I know of. Albert's group is the world-leading experts. The FDA goes to Albert's group, right? For help. Albert has been working with myself for the last 25 years. What did we see? What we saw in this particular study is, again, that these patients, when they were given a opioid challenge in a hypercarbic setting, that various doses of ENA-001 were able to overcome that challenge and return the healthy volunteer back to a normal breathing position. This is the 106 study. This is multiple doses, five days infusion. This is very important because we want to be able to expand the indications and therapeutic use of this drug. We do wanna see what happens when you give it over a long period of time. Here it was a double blind placebo-controlled trial. It was 12 hours, five to eight doses, three different dose levels. What did we see? We saw it was very well-tolerated. We saw that, again, there was this directional pharmacokinetic profile, meaning patients did better breathing, deeper breathing, more efficient breathing, looking at tidal volume, ventilation parameters, et cetera. What we experienced was self-limiting, non-serious adverse events in the dermatological aspect, like pain on injection. Most drugs in the anesthetic world potentially have pain on injection. A lot of that has to do with the pH of the drug, and we've been working on that aspect as well. When we look at the bigger organ systems, it looked very clean and no unexpected serious adverse events or expected adverse events. What do we walk away with? Well-tolerated, well-defined pharmacokinetics. That means both intra and inter variability is minimalized. That means I can give it to any one of you in the room and should expect a consistent, reproducible outcome. That is very, very important in drug development and very directional. This is the 108 study. Some people call this the Michael Jackson trial. Why? Because we gave these patients both a hypercarbic and a hypoxemic type of environment, and then on top of that, we gave them propofol, both low and high doses of propofol. We matched it with low and high doses of ENA-001. What did we find? That we were able to overcome the hypoxemic and hypercarbic events, and we saw that these patients were able to resume their breathing parameters as they initially started with. Well-tolerated, no serious expected or unexpected adverse events, and directional PK that allows us to go further with our modeling that we're doing with NDA Partners and IMA Clinical Research. NDA Partners is Carl Peck. You may remember him. He was the head of the division of pharmacokinetics and pharmacodynamics at FDA. He's the premier modeler, which is the method of drug development that we use to use pharmacokinetics to help model our dosing. I recently was asked at the beginning of last year as one of five anesthesiologists in the world, and particularly in the United States, to volunteer my time with the Anesthesia Patient Safety Foundation. They asked me to do this to look at respiratory-induced aspects of opioids, particularly in the postoperative setting. What we found is that postoperative respiratory depression is real, and it causes a problem, and Dr. Gan's gonna give you some of the deep dive on what that actually means clinically and economically to the various stakeholders. What we also found is that there was a big unmet need, and it's not just in the form of a rescue medication. Again, I go back to my days of helping develop ondansetron, where we looked at both prophylaxis and rescue. In discussing with the FDA and discussing with the internal team and other subject matter experts and key opinion leaders, we felt that there would be a huger market opportunity and a better way to serve patients around the globe by looking at prophylaxis, not just focusing on rescue, so that if we could mitigate the potential impact and probability of postoperative induced respiratory depression, that would better serve all the stakeholders. With that in mind, we've gone back with FDA, we've had discussions, and we're going to be conducting a small preclinical examination that will allow us to help get additional preclinical toxicology data so that we can extend the use in our phase II trial. That's very important because it opens up that bigger market opportunity of prophylaxis. We're gonna start that fentanyl study in early 2003. We're expected to start the phase II trial as early as Q3 2023, and then a potential top-line data in the second quarter of 2024. I think the trade-off with a delta of about four months is very acceptable because we're going from just a finite rescue opportunity, which we want, to a broader prophylaxis opportunity. That would also mean that we could apply it for pre-procedural perioperative respiratory induced depression mitigation strategies, meaning endoscopies, colonoscopies, things like that, where they're still using propofol and may not be using more exciting drugs, which you'll hear about today.When we look at community overdose, I'm very, very proud that our partners at BARDA awarded us not just a contract within 30 days, our initial one, but we were awarded a contract up, I think to the tune of about $50+ million, to develop this for community overdose. You know, it's funny because we're here in New York City, and when we were speaking with BARDA, they basically look at their the potential for these mass casualties, and they use New York as an example. What if someone drops something in the Hudson River water supply, let's say, right? How would that affect everyone? That's where we're working on. We're looking at community drug overdose. We're also looking at that opportunity to provide an agnostic respiratory stimulant. We have IM formulations. This is very, very unique for this drug. Similar drugs that have medicinal backbone chemistry to our drug, like almotriptan, have never been able to get in from the muscle to the cardiovascular system. We overcame that. I wanna thank Frank Diana for that, and the rest of the team. We did, we overcame that. My colleagues at the NIH and NIDA who I love, I worked with for many, many years, they were betting that I couldn't do it, right? We did. We overcame that, and we have three stable formulations, so we're real excited now. We're also looking at intranasal applications too. We're expected to start phase I enrollment as early as mid-2023. I want to also mention that five of the last six directors of this division of the FDA have worked with us hand in hand on this project since we've taken it over. There's a lot of confidence, and I give them a lot of credit because they are looking for solutions. Finally, Apnea of Prematurity. We have Prem here in the audience. He's gonna tell you a lot about that. When Prem talks about it, I want you to realize that if you've never seen a preemie before, premature baby, they're about the size of the lobster that you might order at one of the nice restaurants here. That's unfortunately what he has to take care of every day. When you think about it, he's gonna tell you about caffeine. We all like caffeine. We probably had some this morning. I need more. The equivalent dose in my experience of what we give to this little lobster-sized baby in order to make them breathe is 12 shots of espresso, right? Like every four hours. God bless you, Prem. We need opportunities. I've been going all over the country talking to my colleagues like Prem and others, and they're very excited about this. As Herm said, I think that the division and the agency has recognized that with the status that they've granted us. We are looking at designing our next stage of animal studies and then our clinical pathway for that exciting opportunity. Before I hand it over to my very esteemed colleagues, I just wanna give you my high-level overview. I think that the transformational footprints that Eagle and Scott and his team have put together for their company and their focus and direction are obvious. I think the tactical approach where they've corralled these various assets is going to define how perioperative, acute care, and ambulatory type of care is going to take place here and around the world. That's very important because the company needs the adequate support from the investors to be able to go out and find additional assets to complement that and to really be the leader in acute care, perioperative hospital, and ambulatory-based medicine. They have the ability to do that. With the cadre of assets that you're going to see, you should be as excited as I am and all of my colleagues that are around the world. I got an email just the other day that I had to share with Dan Motto 'cause I was amazed by it. A dentist said, "Dear Joe, haven't met you before, but I heard you're developing some drug, and I use a couple of drugs you've developed before. I heard that I might be able to give propofol in my dental office, and run this drug with it and not worry about respiratory depression. Is that true? How can I be involved?" It's that type of enthusiasm that we're getting daily. Along with that, we're also seeing a lot of potential opportunities that are outside the process that we hand off to Eagle to look at because I do believe that they are poised to be the leaders for acute care, perioperative hospital, and ambulatory-based medicines and strategies from here on. Now I'd like to take the opportunity to introduce Dr. TJ Gan. TJ and I have worked together, I don't know, we'll sound old, I guess, but at least 25 years or so. We've worked together on at least 10 blockbuster drugs together. He is the division head of Anesthesiology and Critical Care and Pain Medicine at MD Anderson. You may know him from Stony Brook and also Duke University. He's gonna talk to you about postoperative respiratory depression. Eugene Vortsman, Dr. Vortsman, right here, in New York, is emergency medicine physician. He is the Director of Addiction Medicine and Disease Management at Northwell Hospital, which includes, I believe, the Presbyterian group too, right? No, it doesn't. I know they're big. They're big. Yeah, they're big. He's gonna discuss community overdose. Then finally, Prem Fort is a neonatologist from Johns Hopkins All Children's, which is the largest NICU, Neonatal Intensive Care Unit, in the United States, right, Prem? One of the biggest. Well, I'm Johns Hopkins pro, so you know I'd like to say it's the largest, all right? One of the biggest. He's in Maternal, Fetal, and Neonatal Institute there, and he's gonna talk to you about Apnea of Prematurity. What I've asked him to do is give you some real-life experience, so you walk away understanding just how important ENA-001 is. I'll end it with saying it's just the beginning. When I was speaking to my colleagues up at SOCOM and USCENTCOM in Tampa, former four-star General Chad, he had said to me, "You know, Joe, there's a lot of other things. What about, you know, maybe high altitude sickness, all these other things?" I told him, "Let's just curb up enthusiasm right now. Let's get through FDA, and then we can figure out all the rest of it." It has that type of potential, and that's a great thing. With that, I thank you all for the time, and I'd like to invite up Dr. Gan. Good morning, everyone. Good morning. Good to be here in New York at this time of the year. My name is TJ Gan. I currently at MD Anderson Cancer Center. The hospital has been voted as the number one cancer center by U.S. News & World Report for the last six consecutive year. I believe we are either number one or number two for over 30 something years when the report first came out in 1990s. Dr. Pergolizzi had talked to you about the mechanism of the drug, as well as give you some preview of some of the early studies and the ongoing program. As a clinician, what I like to do is to tell you a little bit about what is the impact of postoperative respiratory depression, not only on the patients, but also healthcare providers and the hospitals. I would first of all say that postoperative respiratory complication or depression is significantly underappreciated and underdiagnosed. What is postoperative pulmonary complication? You can define as any event that occurs in the postoperative period that resulted in either physiologic dysfunction or resulted in clinical disease. Depending on the complication, it has been estimated even up to 40% incidence. In the NSQIP database, in non-cardiac surgery, they estimate it's about 3%-4% that suffer postoperative complication. Another set of data from the VA database, almost 10% of patient had respiratory complication after surgery. It is pretty common. The problem is that our monitoring and prediction is not, simply not very good. We are unable to predict accurately who are likely to suffer from postoperative complications. Many of the PACU nurses who look after these patients day in, day out, without a pulse oximeter, you can almost can't tell who are the one who have a saturation of below 90%. Even with a saturation of below 90%, because of alarm fatigue, often the nurses just turn it off. Imagine that. That really is the starting point. In some patients, they can then go down from there. Up to 62% transferred from floor to the ICU had serious abnormalities four to eight to 48 hours before the transfer. Now, if we can catch some of these patients, we can potentially prevent the downstream consequences as a result of postoperative complications. We know that those patients who had postoperative complication, they use more resources, they have increased length of stay. As a result, increase in healthcare costs. We have done a lot of things in terms of education, monitoring, but I think there is still a significant gap in doing a better job. How do these patients manifest? How do they appear? Well, it's a range of symptoms and sign from feeling dyspnea, short of breath, to having your airway collapse, atelectasis, hypoxemia, where the blood gas is hypoxic, pneumonia, developing chest infections, respiratory failure, where you are inadequate to be able to breathe by yourself, resulting in reintubation. Often unexpected reintubation is really one of the main problems in the postoperative period. When they are unexpectedly reintubated, what happened? They have a prolonged ventilation. What does that mean? They go to ICU. They stay in ICU. That prolongs their hospital length of stay. You can see that one thing lead to another, resulting in a significant increase in not only length of stay, but healthcare costs. We also administer naloxone if in the postoperative period when they don't breathe adequately. This list tells you some of the risk factors. Some of them are modifiable: smoking, body weight, habitus, hypertension. Some of them are not. Age, sex, frailty. Unfortunately, we see increasingly older populations get frailty, and frailty is one of the risk factors for developing postoperative complications. The more risk factors you have, the higher the risk of developing postoperative complication. As you can see here, these are some of the risk factors. These increase the risk by about 30%, 40%, 50%, 60%. In high-risk patients, increase the risk by five-fold compared to those patients without some of these risk factors. In this study, a large NSQIP database, what they did was to look at over 220,000 patients. They looked at the incidence of unexpected reintubation in the recovery room. Patient has woken up, had their surgery, get extubated, go to the recovery room, and at some point in the postoperative period, because of respiratory not able to maintain breathing adequately, they had to be reintubated. Reintubation unexpectedly alone, as you can see here, increased mortality significantly compared to those who did not require reintubation. You can think about reintubation in the PACU or postoperative is bad news. That means you are putting the patient back from their recovery track and often significantly. Another piece of data, this is from what they call the closed claim database. What is closed claim database? It is collected by the American Society of Anesthesiologists, all the lawsuits that the society know of when there's a payout. These are not the day-to-day event. These are when things go bad, really bad. It's the sort of cases that if you as a clinician probably most concerned about, and if one of these cases happen to you, these are the sort of cases that will keep you at night and probably many years, if not the whole life of your professional life. They found about 1% of these cases that be paid out was due to respiratory complication, respiratory depression. More importantly, 88%, almost 90% occur within 24 hours after surgery. 97% were judged to be preventable with better monitoring, better management of patient. That is where I see the opportunity of what we do potentially with this drug. The median payout is about over $200,000. If you imagine the number of cases, over $20 million payout because of respiratory complications. Another important piece of data I like to draw your attention to. This is from, again, the NSQIP database, where they looked at the cost of an episode of hospital admission for those coming for surgery. If you don't develop complication, everything goes well, your cost is actually very predictable. If you look at this column here, without complications, your cost of that hospital admission is about $5,000. Even the range is pretty narrow, about $4,500 to just under $6,000. Once you develop a complication, whether it's infectious or cardiovascular, respiratory or thromboembolic, that cost goes up substantially. In the case of respiratory, you can see that that stands out compared to all the other complications, more than 10 x from $5,000 to over $60,000. How is that possible? Well, the scenario I described, unexpected reintubation. They go to ICU. They can stay there for a few days. They develop chest infection. Some of them may develop multi-organ failure, sepsis, that prolong their hospital stay, ICU stay, maybe sometime for weeks. After that, they became weak because their muscles weren't working, and therefore, they need a whole period of hospital stay. Imagine that cost significantly increase. The length of stay, again, without complication is average five days. Once you develop complication, especially respiratory, go up to 19 days. That is the impact of postoperative respiratory complications. It is underappreciated. This recently published study just last year simply look at the incidence of postoperative respiratory depression. How did they define those? Respiratory rate less than five breaths per minute. We normally breathe anywhere from 12, 13, 14, 15 breaths per minute. Oxygen saturation less than 85%. Hopefully, we all sit here will be around 97%, 98%. End-tidal CO2 less than 15 or over 60 for more than three minutes, suggesting there is inadequate ventilation. Apnea episode lasting more than 30 seconds, when you're not breathing for 30 seconds, which hopefully, unless you want to breath hold, is not in a normal state. Any respiratory event requiring intervention. Now, these events, they found that those patients with one or more than one of these events end up staying longer, about a day and a half longer, and as a result, resulted in a higher hospital cost. These are very common. These are things that we see every day. What does the future hold? Well, we know that we can't prevent every episode of postoperative respiratory depression. Often it's thought that opioid is the cause, main cause of postoperative respiratory depression. While it is a cause, but it's not the sole cause. Other drugs that we give are anesthetic, often have sedative properties, paralyzing agents, other sedative midazolam. Some of the antiemetics, which we'll talk about later, have sedative properties. These drugs, unfortunately, do not respond to naloxone because it doesn't operate on the opiate receptors. This is where I think another drug that stimulates ventilation can potentially cure this. In the old days, what we used to do at the end of the case, where patients at the end of surgery, trying to wake them up, they don't breathe, we often pull up doxapram, as Dr. Pergolizzi said, which works. Because of the central action, it also come with significant side effects. Apprehension. They wake up feeling that they are really anxious. Not a good state to wake up. They can cause hypertension. They can cause nausea and vomiting, diarrhea. There's a long list of complications. I think this potentially may be a drug where at the end of surgery, if the patient is not breathing, just a little bit touch of the drug to stimulate the respiration, wake them up, take them to the PACU, so that it would reduce the length they stay in the operating room and potentially have a higher throughput. I think we need a new approach to look at this problem, identifying the risk factors, but more importantly, having therapeutics to try and to manage when it happens. In summary, postoperative respiratory complications are common, but more importantly, preventable. This is something as a clinician we want to do. About 1% of these postoperative patients require unexpected intubation, and those are the patients who do badly once you get re-intubated. Postoperative respiratory complications increase length of stay, increase hospital costs, and in the context of apnea respiratory depression at the end of the procedure, that also increase costs and having a therapeutics potentially can work on these patients, I think will be very valuable. Thank you very much for your attention. I think I'm gonna call up my next colleague to present the next topic, Dr. Vortsman. Potential new tool for emergency setting. Dr. Vortsman. Good morning, everybody. My name is Dr. Eugene Vortsman. I'm an emergency medicine physician for Northwell. I function as a clinical director of addiction medicine, disease management, chair of the Pain Advisory Committee, co-chair of the Substance Use and Pain Advisory Committee. I'm gonna expand on all those roles, but first, I need to thank Eagle Pharmaceuticals for inviting me on such an important topic. Second of all, I hope everyone enjoyed breakfast. I hope the coffee has settled in. We're all awake and ready for what we're gonna be talking about today. While we have such significant industry leaders talking about how we're gonna get these drugs to the market, how are we gonna be able to start saving lives, how are we gonna be able to make this work, my responsibility to you is to paint a picture. What's a day in my life in each one of these roles? As an overall thing, if you open up the news these days, we see almost over 105,000 deaths a year in overdoses. That's more than homicide in this country, that's more than motor vehicle accidents. In the last 20 years, we've had over 750,000 overdoses. Understanding that opiate overdoses are due primarily and exclusively due to respiratory depression. When we think about this crisis, we have to think about it in many ways. One of the ways is that COVID did many things to us in the last two years, and we're still dealing with that emotionally, physically, and otherwise. We have to understand that it made it also harder to see your pain doctor. It made it harder to see addiction doctors. What we do know is that substance use disorder and opiate disorder has only continued to rise up. Unfortunately, we expect that these numbers to continue to rise up as well. When you think about the fact that even celebrities like Prince had a pressed pill that led to an overdose, you can begin to understand how this impacts everyone, rich, poor, in every socioeconomic status, in every neighborhood, in every community in this country. We're gonna start painting a picture of, first and foremost, my most important role is I'm a frontline emergency physician in a large tertiary care hospital. We're gonna paint a picture of somebody who comes in, friends brought in, said, "Hey, my friend took a Percocet and Oxy. He's not breathing." Gets pushed out of his car, kinda like what you see in the movies. Usually less dramatic, and the doctors aren't as attractive. What it is now we bring this patient into the emergency department, we bring him in. All we need to do for this patient is we need to maintain their respiratory rate and their tidal volume and their oxygen saturation. We have one tool, one medicine, naloxone. If anyone here has ever seen naloxone being used, it leads to a severe precipitative withdrawal. While we're looking for a sniper and what we hope ENA-001 is doing, what we really have at this point is napalm. What that means is we have an angry, agitated patient in severe withdrawal, vomiting, sweating, in pain, requiring all the resources of the emergency department. When the news tells you that we're on the rise and hospitals are being stretched thin, the only lie there is that we've been stretched thin for years. While we wanna take care of family members, we wanna take care of your family members, we have to utilize everything in this one patient. Just one month ago, I can remember very vividly, we gave a patient who was dying in front of us due to their respiratory rate, gave him naloxone. He woke up so angry and agitated that he started swinging and punching at people. We had to tackle him with a mattress because he was spitting at us, and he was trying to rock the bed to injure himself. What we're trying to paint as a picture to say, not only is he a danger to us as staff who are trying to take care of him, he's also a danger to himself. We have a responsibility to that patient. We have a responsibility to our staff. We have one tool. All we need to do is maintain their breathing rate. What we led to was this complete chaos. Extending out to... We have to take a few steps back. We think about the pre-hospital care outside of our emergency department, outside of the four walls where I have security and I have heavy beds that are really hard to rock. You start thinking about two people, two medics, true healthcare heroes, and one truck. I'll tell you honestly, anecdotally, I think any frontline doctor will tell you the same. If you see a patient who's breathing just enough, they're just enough in their overdose that they're still somewhat stable, they will wait until they can bring the patient closer to the hospital before they administer that one tool they have, that naloxone, because they know that they're gonna be angry and agitated while they're driving down a highway, while they're driving down a side road, while you again, our community, is just trying to go by around their day. Imagine what kind of chaos and danger that is to the patient as well as to these true frontline heroes. Even just two weeks ago, unfortunately, there was someone, they couldn't wait till they got closer to the hospital. What they did was the patient was breathing about twoone breaths per minute as Dr. Gan spoke. Not enough. They gave the naloxone, and about 15 seconds later, the patient woke up and threw the female medic against the wall, punched the male medic in the face, and they come to us with a mild concussion and a broken nose. Just to further show signs of what kind of heroes they really are, they went back on shift because there's more patients to take care of. That's what a big role for us, and that's understanding. That's We take care of that. As the chair of the Substance Use and Pain Advisory Committee, what we do is we create protocols. We try to allocate the proper resources for these patients at pre-hospital care. Our chair of the Pain Advisory Committee, in that role, we function as understanding the regulatory processes. We wanna identify the high-risk patients. I'll tell you that all the regulatory bodies that come into the hospital, Department of Health, the Center of Medicare and Medicaid Services, The Joint Commission, they all track trends, processes, and policies related to iatrogenic overdoses, which are overdoses that are due to us. Picture this, your family member, you yourself, have to go to the operating room for whatever medical reason, now you're having respiratory depression due to many different medications anesthesiologists have to use. morphine, fentanyl, carfentanil, very potent opiates. Now again, there's one tool. All you need to do is maintain a respiratory rate, your tidal volume. You have one tool to give them. You give naloxone. While this patient might not go into severe withdrawal, it's true, the most common way to manage their post-op pain, giving opiates, is now completely blocked off for almost three-four hours. While they're not suffering in their own addiction, they're suffering in their pain. When I think about these roles on a micro level inside the emergency department, while we're still trying to take care of everybody else, we have to completely allocate everything to that one patient because we only have one tool. We hope that ENA-001 will give us the opportunity to safely take care of the patient while safely taking care of my staff. Expanding out to pre-hospital, outside of hospital care, we wanna be able to safely take care of patients while maintaining their respiratory rate and tidal volume. Again, we have one tool, and we hope that ENA-001 can do better. When we think about our family members and our loved ones in the post-operative care area, we wanna be able to take care of them as well, make sure they're not gonna be in a bad situation. We have one tool, and I don't think it's enough. To summarize, we have a lot of work to do. I believe that ENA-001 gives us an opportunity to really take care of patients and keep our frontline heroes. You know, with the banging pots for about a few weeks that we had, it was a good time in our memory. We have an opportunity to do better. I think that ENA-001 gives us that opportunity. I hope everyone enjoyed my talk. Thank you very much. All right. Good morning, everybody. I'm Prem Fort. I'm a neonatologist. First of all, I wanna thank Eagle again for inviting me. It's truly an honor to be here and present in front of everybody. I am apparently gonna be talking about apnea of lobsters, it sounds like. I can't get that image out of my head now. I'm gonna have to go back and take care of these little lobsters. I am an apnea of prematurity and caffeine research neonatologist, scientist. I've been doing apnea prematurity now for over about 10 years, I've been studying apnea prematurity and caffeine, not because I love caffeine. Yep, actually I do, as everybody here. Because there's really nothing else, nothing else to treat apnea prematurity. When Joe contacted me and he said, "Hey, we are working on something that can actually work on apnea prematurity," I immediately said, "Yes. Let me tell you more about this." What exactly is prematurity? Prematurity are babies born that are less than 37 weeks gestational age. Normally, a normal gestational age goes to about 40 weeks. There are 50 million babies born premature around the world. Just in the U.S., there are half a million babies born every year premature. That is one out of 10 babies born are premature. Remember those numbers, 50 million per year born premature. What is apnea? Now, you've heard apnea the term already, but there are two types of apnea. There's obstructive apnea, commonly seen in the adult world. You see it with sleep apnea. When you go to sleep or you're laying down, you have an obstructive anatomical issue, something not allowing you to get the air into your, into your respiratory system. However, there's central apnea. This is what we deal with in apnea of prematurity, where essentially the central system forgets, if you will, to send a signal to the respiratory center. That's what we have to deal with respiratory problems in the premature baby, and this is very different to some of the other issues that we talked about already. What's the actual definition of apnea of prematurity? Apnea of prematurity is defined by the COFN, which is a Committee on Fetus and Newborn, as having apnea for 20 seconds or more, or if you have bradycardia, so your heart rate actually drops for less than 100 beats. In premature babies or actually in babies in general, a normal heart rate is 150. That would actually be really high for all of us in the room, a normal baby is actually 150. Less than 100 is actually bradycardia for a preterm. Cyanosis or blue color of the skin, blue color or hypoxemia, actually low level of oxygen in the blood, or pallor in a baby that's born premature, hence the prematurity. I mentioned remember that number of 15 million. Why? Actually 80% of babies that are born premature will actually develop apnea of prematurity, will actually have these pauses in their breaths. What does that mean worldwide? That means that 12 million babies around the world are holding their breaths or actually, you know, not sending that signal and are not getting oxygen to their brains every year. That's a huge number. The big problem. If we break this down a little bit more, the younger the gestational age, the more or the more events or the more apnea of prematurity we see. This is a study from Eichenwald, and what we see is that babies essentially that are born less than 30 weeks gestational age, pretty much every single one of those babies will have apnea of prematurity. If I have a baby that's born at 25 weeks gestational age, 100% that baby will not be breathing, will have apnea of prematurity. Okay? How do we treat these babies? You can treat mechanically. We use very similar to the adults, we use nasal CPAP, and you can also use actually a nasal cannula. We call it a ramp cannula. This is mechanical. We use this a lot of the times actually in the hospital, obviously these babies cannot go home with these devices. As opposed to the adults, babies for the most part do not go home on these devices. This is only a temporary treatment, if you will. We have to use something else. I've already talked about it. We use caffeine. Just like you folks have taken your caffeine this morning, maybe a couple of doses too, we actually do use caffeine to stimulate the respiratory center to actually send a signal to the central area, to send a signal to the respiratory center to take a breath. You can see this has been done for many years. The first study was done by Aranda back in 1977. He grabbed 18 babies. He gave them a dose of caffeine, and actually of these 18 babies, you can see a lot of these babies were having up to 44 events per day. You can imagine 44 hypoxic events where their brain was not getting oxygen a day. Now we were able to get down to maybe three, four events. I think that's still not good enough, but better than 44. Okay? What's really interesting in even this study back 30, 40 years ago is that you can see there was a still a very good subset. Half of those babies were still having five, six, seven, eight events, right? If I told you your baby is having one event where they stop breathing for 20 seconds, would you feel good about that? Probably not. If I told you they're having eight, you feel really bad about that. Okay? This is with treatment. This is actually treating babies, and I'd love to say that it's better. It's not. We're still using the same caffeine, but I'll tell you more about it. Is caffeine actually good though? Yeah, we're using this treatment, but is it actually good? This is a study from Chavez from Hopkins, actually. What he looked on the left and the right, these are actually inflammatory biomarkers. On the left column and the right column. The left column is TNF-alpha. This is essentially a pro-inflammatory biomarker. What it tells you is the body inflamed? TNF-alpha is what we actually, what stimulates our fever. When you get hot, that's your TNF-alpha going up. On the right side is IL-10. That's an anti-inflammatory biomarker. That's actually showing anti-inflammation. What you can see on the left and the bottom column actually on the x-axis is us being exposed to inflammation and then also higher doses of caffeine. On the left column, you can see that as we increase our caffeine, our pro-inflammatory marker doesn't change. We stay inflamed, if you will. But what you see on the right side is that the anti-inflammation actually decreases the higher the caffeine dose. What does that mean? If we keep on going up and up on doses in the babies, they are less and less anti-inflamed. You can think about it, they're more inflamed with higher doses of caffeine. Okay? Another way to look at this is that there is a caffeine sweet spot. If you look at this graph, all of these are saying exactly the same thing, on the lower doses of caffeine, which is, you know, if you look at again x-axis, lower doses of caffeine, this, y-axis is inflammation. Why actually is showing on the low doses of caffeine you have inflammation. You increase your caffeine dose, you actually decrease inflammation. This is why it is actually good even for adults, by the way. As a caffeine expert, I'll tell you this. Drinking some two to four cups of coffee a day will actually decrease your inflammation. If you actually increase too much your caffeine dose, you actually increase inflammation. This is what happens in adults as well. This is what happens in premature babies, okay. Don't drink too much coffee. Okay. This is all done in animal models, right? What about clinical? This is a meta-analysis. This is basically pooling a lot of different studies together, okay? In a meta-analysis, looking at high versus standard dose, we normally dose our babies 5 mig to 10 mg per kilo per day. In the high dose studies of these meta-analysis, they were doing double that dose, okay? They were using essentially 10 to 20 maintenance dose. Okay? Double the dose. What we actually found with these meta-analysis is that all these babies were tachycardic. We know, again, as cardiologists and everybody, even adult medicine, the longer you stay in tachycardia, that it starts changing the morphology of the heart. It's not good for your heart, it's not good for your brain for you to be in constant tachycardia. This is why there's a limit with caffeine. We know that caffeine helps, we know it helps to a certain degree, and we know also there's a limit. We can't go any higher. Not only is it that we have to deal with the caffeine, we also have to deal with, what about getting them home? I've talked about in-hospital management with devices and caffeine. When a baby's ready to go home, we actually now have to watch them for them not to have events for at least five-seven days. That's standard practice around the country. Most places will actually do seven days, some places will do five. You actually have to watch them for them not to have five days without apnea. A lot of the times, it actually cycles two or three times. That means they're on day four, they have an apneic event, we actually have to now recount a five-day count or a seven-day count. Technically, a lot of these babies will go through two or three cycles. You may be going on 15 days where you're watching. They're ready to go home, they're not on any device, they're just laying there. We're basically, I tell the parents sometimes we're really expensive babysitters 'cause we're just watching them. We're not doing anything. What we're doing is we're actually occupying an ICU bed. The ICU NICU bed can be as expensive as $1,000-$3,000 a night. You may be at the, you know, cheapest, if you will, you may be on $5,000 just for a five-day count, let alone that 15-day count I mentioned, which is pretty average. Okay? Just for watching. If we had something that could turn things around and get them home, that could be a lot of cost savings. Aside from obviously the emotional part, a lot of the times the families, we tell them, "Your baby's getting ready to go home." On day four, they have an event. We say, "You gotta watch another five days." That's very emotionally hard. Okay? Are there other options? I mentioned caffeine's really the only thing we use. You know, we actually published this. There are other options, but they're not really well-studied, and we don't really use them as much. Doxapram has already been mentioned. In some areas, in some units, they have used doxapram. It's something we don't use. It's rarely used, and it has to do with a lot of things already mentioned in adults, but we see it in premature babies as well. In premature babies, I've done multiple studies, and it's not recommended 'cause it actually decreases the oxygenation in babies. It's actually counterproductive. You're trying to stop them from not having apneas. You give doxapram, it actually decreases their oxygen in their brain, so it's not recommended. The other thing they can do is actually cause arrhythmia, a type of arrhythmia called long QT syndrome. It actually prolongs their actual rhythm in the heart, which actually can cause a lot of problems, including death. It's very risky, most places do not use doxapram. There are other things that have been studied: blood transfusions, devices, and sensory simulation. They don't really have very good data behind them, and they also do come with a risk as well. It's not really used for apnea prematurity. We may use it for other things, but we don't really use it for apnea prematurity, okay? Let's drop the science for a second, and let me just show you about what I have to deal with on a daily basis. Just put yourself in a room for a moment where you're dealing with a family. You have a baby who may be, you know, two pounds, even a pound and a half, who's small, who had a breathing tube for maybe one week, two weeks, maybe even longer. You've successfully been able to extubate that baby. You've been able to take that breathing tube out. That family may have enjoyed two or three days where now they've been able to hold their baby without a breathing tube. They've been able to do what we call skin-to-skin. They've been able to enjoy that baby. On day two, day three, that baby begins to have apnea, begins to have more apnea, begins to have more progressive apnea. They maybe actually have already gotten to start feeding, maybe even, you know, some breastfeeding, not nutritive 'cause it's still pretty small, but maybe some attempts. Now with the baby having apnea, you now have to put that medical device I talked about, that CPAP, 'cause you cannot leave that baby having apnea. You've already given your caffeine. You might even be tempted to go up a little bit on the dose. We talked about there's a sweet spot, so we do sometimes double the dose, just like the studies did. Even doubling the dose, you may still have four or five, maybe even more events. Now you're approaching the family, and you're telling them, "I am sorry, but I have to put that breathing tube back in." The emotional stress that leads to the family. Finally, you've given them that hope, you've given them that contact, you've given them that skin-to-skin, you've given them that baby that feeding, and now you're having to take that all away. That emotional stress, that to me, when Joe came and told me about the possibility of another thing, if we can have a medication, if we can have something, a product, an asset that can help where I can come in, a different picture to say, "Hey, your baby's having four,five, six different, you know, events, but I've got this drug. We're gonna go ahead and infuse. We're gonna go ahead and give. We're gonna do something with this so that we can keep that breathing tube away from your baby, so that you can continue skin-to-skin, so that you can continue feeding that baby." That's what I'm here for, and that's why we do what we do. Thank you for your time. I have to listen to Dr. Fort. I think I'm gonna have to decrease my caffeine intake. This is not good news. Thanks so much for your invitation. It's a pleasure to be here. My name is Andre Kalil. I'm a practicing clinician and professor of medicine at University of Nebraska. I'm a critical care, infectious disease trained doc. I've been in the front lines for over 20 years. As part of my practice as well, I do clinical research. I've been involved in phase I, II, and III trials for all these years, I believe that my motive is that, you know, combining my, you know, clinical bedside approach to clinical research is key for us to really find new diagnostics, new treatments. That has been really, something that I've worked really hard to make this happen. Trying to actually educate this new generation to enjoy doing both sides 'cause I think sometimes you hear the stories of people doing research are not on a bedside, people at bedside aren't doing research. I believe that doing both makes a huge difference. I'm a better physician because I do research. I'm a better researcher and scientist because I am at a bedside. This is who I am, and that's why I'm here. I think that if you can get these lights. Sure, here. Here is the slides. Okay. Let me just. I'll do a little bit of a disease state of review, and Curt 's gonna talk about CAL02, but I'm gonna introduce you to the concept of community acquired pneumonia, what that means, and what's the burden of the disease in our society. This is in the left side, you're gonna see a normal chest X-ray. Basically, what you see there is all the dark part is air in the lungs, and this is pretty much what you're supposed to see. Lots of air, lots of oxygen going in, and CO2 coming out. In the middle one, you see a patient with pneumonia. This is a patient actually developed a severe pneumonia, end up in the ICU, very severely, and really required a lot of intensive care. You can see in the very right side, this is a CT scan showing a little more, a better resolution of the lungs. All this white part actually is all inflammation. It's all the fight between the bugs and the patient's immune system. This, all this white part are basically parts in which it's gonna be very hard for any air to go in, any oxygen to go in, it's become really hard for the patient to breathe. That's a situation where you end up going to the hospital with short of breath and also with hypoxia. You know, I mean, you've heard the term hypoxia a little more than ever in the last two or three years because of COVID pneumonia. Hypoxia, silent hypoxia, no silent hypoxia, this is exactly what I've seen for over 20 years. Any pneumonia is gonna cause, can potentially cause some severe degree of hypoxia. This is just to show a little bit of the history behind, you know, how we made improvements but still lots to do. You can see here in this graph that patients that were. You know, this is early 20th century. You can see that the mortality basically was incredibly high in patients that developed pneumonia. This is mostly the pneumococcal pneumonia, but it can be other streptococci or a bug. There are many, many bacteria that can cause pneumonia. Basically, what you can see here is that if you are early in the 20th century, and you were like in your 70s and 80s, basically, you're dead if you got pneumonia. If you're in a middle age, you know, maybe you could have about 40%, 50% chance to survive. The point is there were no antibiotics, there was nothing, and at that point, it was a sentence of death if you got pneumonia. If you look in, you know, back in history, you're gonna see so many of the historical figures that we go through our history books that died from pneumonia, and that was incredibly common cause of death, and you're gonna be surprised how common it is you know, even up to this day. Just to give a little bit of a sense what I see every day, I mean, these are the three kind of classifications that we tend to use syndromically. Community acquired pneumonia, CAP, hospital acquired pneumonia, and ventilator associated pneumonia. At the end, they all, you know, end up with this, you know, inflamed lung with fever, with cough, with hypoxia, with, you know, chest discomfort, and sputum production. All these things are. At the end result is very similar. What changed here is the type of bacteria, the type of microorganisms that are gonna affect. At the end, the lung gets severely affected, and once the lung gets severely affected, you're gonna see now in the next few slides that actually other organs can get affected as well. In the U.S., the annual incidence of CAP is about 2.4 per 1,000 adult patients. Global mortality with CAP is up to 50%, and you must be thinking, "Oh, this must be from last century. That's ridiculous." Well, it's not. This is basically what you see today all over the planet. Severe CAP is killing about, you know, half of the people that end up, you know, with severe CAP in ICU. Probably you must be asking how that's possible. We have all this incredible improvement in medical care. We have all these antibiotics. It is exactly what's happening today, and that's why we're here talking about the need for a change in the way that we approach these patients. CAP is the second most common cause of hospitalization and the third leading cause of hospital readmission, with, you know, costing about $17 billion just, you know, in just in in the situation related to this specific disease. We are not talking about any other disease. This is a massive problem both in the U.S. and in the whole world. This is a German data just showing that actually the mortality goes up with, you know, with the severity of the disease. You know, the more severe, the more advanced is the pneumonia, the higher it's gonna be mortality. Just to show this is something that we take very seriously, and we try to use this a little bit of a prognostication. As previously was talked, I mean, prognostication is not a big strength that we have in these patients. A lot of times it's very hard to know, you know, which patients are gonna progress and which ones are not. Here is just an example of a pneumococcal pneumonia. Pneumococcus is one of the most common bugs causing pneumonia all over the planet, and this is a patient that had pneumonia, and the bug actually, it spilled over the bloodstream and caused bacteremia. We call bacteremic pneumococcal pneumonia. You can see that, you know, either monotherapy means one type of antibiotic or more than one type, the mortality still runs to about 20%, 30% with the best ICU care. The reason why I'm showing this graph is because this graph, like the next one you're gonna see, when you combine medications and different antibiotics, still you double the mortality of these patients when they develop severe CAP, severe community-acquired pneumonia. The mortality is about twice as much as they would be if they had a mild disease. The reason why I'm showing this slide is because no matter how many antibiotics you give, patients will die. No matter how right you are with antibiotics, patient will die. Here's the thing, there's two reasons for your antibiotics not to work. Me as a clinician, you know, I have to choose antibiotics before I know which bugs are causing the pneumonia. I never know which bugs are there. All I know, I have the patient's symptoms, I have the X-rays, I have the CT scan, correct? I don't have the name of the bug. I don't have anything when I'm seeing this patient by the first time. I have to make the best educated guess choosing the antibiotics that likely are gonna cover the bugs that are causing the pneumonia. There are thousands of bugs causing pneumonia, correct? First of all, I can be wrong in my empiric choice, and that's gonna be in part a situation that can make the patient's outcome much worse. Let's say if two days from now I learn that I used the right... the wrong antibiotics when the patient came to the ICU, basically, it's gonna be very hard to change outcome, change antibiotic, 'cause now it's two days in the course. The patient is more critically ill, much more difficult to go back to that situation two days ago. Even changing antibiotics unlikely gonna change how severe it's gonna be and potentially even the risk of death. The other situation is that I chose the right antibiotic. Everything's beautiful. You know, I'm a great clinician. I got the right antibiotic. I got everything. You know, the culture came back, you know, 24, 48 hours later. I find the bug from the sputum. I see the bug. I see the culture. I see the MICs. I say, "You know what? I am using the right antibiotic for the last two days. I got the right drug. I'm killing this bug." Actually, the bloodstream clears with my antibiotics, okay? I'm using the right drug. I have the culture. Turns out the patient still gets intubated, and the patient still dies. Why this is possible? This is possible because even if I choose the right antibiotic, there is a point when the CAP is so severe, the pneumonia is so severe that all these toxins, all these things being released by the bug trigger this massive inflammatory dysregulation of body, that the patient basically is gonna die from this dysregulation of the immune system, even though I killed the bugs with the right antibiotics. What I'm telling is that even if I choose the right antibiotics, still there is a large proportion of these patients are gonna die if they're already that advanced. The reason not is not because I'm not killing the right bug. It's because the release of all these toxins from the bugs already triggered a massive immunological inflammatory dysregulation that actually leads to organ failure and sepsis and death. That's why we have to do better than what we've done for the last 100 years, even with antibiotics. Here's to show what happen when you use the wrong antibiotics or use the right antibiotics, but the patient's already too far on the process of severity of the pneumonia, that these patients here develop shock. Septic shock is one of the consequences of severe pneumonia. The bug spill over the lungs, goes all over, you know, bloodstream, goes to other organs, and the blood pressure goes... you know, gets very low, and the patient needs vasopressors in order to keep the pressure up. This is called septic shock. It's one of the most severe pictures that you're gonna see with pneumonia. When you reach that point, you can see the mortality here in patients that didn't receive the proper antibiotics was about 46%. Guys, this is 2010. This is not 1910. This is not 1910. This is 2010. This is embarrassing. I'm telling you, this is... I really feel incredibly embarrassed when I see this data because, you know, it's... we've made so much progress in ICU supportive care using antibiotics, and still people are dying. People are dying, and we're talking about one in two of these patients are gonna die. This is why it's so critical for us to really have to make progress and potentially even change the paradigm how we treat these patients. The other thing that I wanna mention here that's really important is that even, you know, with all the best care that we can provide to these patients, about 16% of these patients will have treatment failure for multiple reasons. Sometimes the antibiotics are not gonna reach the lung in a proper way because of too much inflammation, sometimes because the cultures show a different bug, or sometimes because the patient, really the bugs, the burden of the infection is so big that even with antibiotics, the burden of infection could not be fully cleared. For many reasons, about 15%-20% of these patients will have treatment failure, that's a big problem because now the patient is gonna stay longer in the ICU, the patient potentially can get reintubated, and that adds a tremendous burden of morbidity and mortality to our patients. Other things that people don't think, most of you probably never heard about this. This is critical. After even if you survive, you know, if you're one of the two that survive that severe bout of community-acquired pneumonia, you left ICU, you got extubated, you went home. Unfortunately, for the next one or two years, you're gonna be more prone to have strokes and heart attacks. There's something that we still have to understand better that actually leads to long-term complications from the community-acquired pneumonia. This is very serious because strokes and myocardial infarctions are not something that we take lightly. On top of that, if you had a bout of severe community-acquired pneumonia, you are more prone to have heart failure in the next one or two years as well. That adds morbidity, adds chronically, chronic illness, and on top of that, it's gonna add readmission, right. You can see here, this is not rocket science. If you have a higher chance of developing heart failure, myocardial infarction and stroke, there is no questions that you're gonna be back to the hospital. Your chances of being readmitted is gonna be much higher, all because you developed a very severe community-acquired pneumonia that was... that we are not able to curtail that whole process that, you know, led to a long, a prolonged and a very difficult admission and discharge. That's why this, you know, we show this figure showing that actually you not only have a mortality from the time that you're in the hospital, 40%, 50% mortality, but also you have the mortality and morbidity that follows in the following two years. There are both short-term and long-term consequences from the severe pneumonia. To add to the problem, I don't need to tell you that this is all over the news in the last few months. I mean, this is old, this is not new, but you know, it takes a little long sometimes for, you know, for the media to pick this up. You know, for me, in the trenches and seeing patients all these years, this is a reality. We are seeing way more antibiotic resistance. Basically bugs, bacteria that are becoming resistant to antibiotics, you know, we keep using, overusing. There is a point where by selective pressure, these bugs learn our tricks. In the last two or three years, this problem got even worse because, you know, we've never used more antibiotics in the entire planet than in the last two or three years. If you remember when we start having the COVID patients come in the beginning and middle of 2020, we didn't know if these patients were coming just with COVID or if they had some other bacterial infection. If you look at the x-rays and CT scans, a lot of times these things are very difficult to distinguish. People were throwing antibiotics in every patient coming with COVID then to the hospital for months and months, up to this day. Somebody come with in the monitor hospital, you're not sure if this is COVID, get two antibiotics, three antibiotics. We've used antibiotics more than ever in the last two or three years. If we already had a problem of increasing resistance before the pandemic, let me tell you the bad news. This is gonna get much worse in the next two or three years. There's no questions about. It's selective pressure is something we've seen for 100 years in our practice since the invention of penicillin. The more we use, the more the bugs learn our tricks, the more bacteria resistance we see and the longer it's gonna happen for us to re-reach a point where we can treat these bugs. These bugs come, you keep using the same antibiotics, but these antibiotics are not as effective or even ineffective compared to the same bug that we used two years ago. This is a big problem because now even antibiotics are gonna become less effective. To top it off, you know, here's another issue that I've seen daily for the last two and a half years with the COVID, you know, pandemic, is that once the patients admitted with COVID and progress to a situation where sometimes the patient needs one or two weeks in ICU being intubated because of a severe COVID pneumonia, now the patient becomes more prone to develop pneumonia from bacterial sources. You know, because the longer you stay in the ICU, the longer you stay intubated, you know, the more prone you're gonna be to get hospital-acquired infection. This is a simple fact. Hospital is a place that has the worst bugs imaginable, right? Because all the sick people come to the hospital. The longer you stay in the environment, in the hospital environment, the higher the probability of acquiring bad infections. Now we're seeing more pneumonia because of COVID as well. Not only patients come with COVID, but they develop bacterial pneumonia after having COVID as well. Here to conclude, you're gonna see this next three slides, the complexity that we have in order to treat these patients. You know, this is something that we, you know, we have specific guidelines both for community-acquired and hospital-acquired pneumonia. And I've worked a lot on this for many years, is how to educate our clinicians, our colleagues, to approach these patients in a way they can choose the right treatment, choose the right antibiotics, choose the right supportive care for these patients at the moment they need, at the moment they're getting hypoxemia, at the moment they're being admitted to the hospital. It's incredibly complex to really make the right decision. The reason why I'm showing you this is because we need therapies that minimize that complexity. We need therapies that will be much easier to be administered, and is gonna be much more effective in combination with these antibiotics. This is part of the reason why we are here today. This is just a summary of the burden of pneumonia in all of us. Most common cause of infection, hospitalization, admission to ICU. Third most common cause of death globally, 2.5 million deaths per day. I'm sure a lot of you never saw these stats. This is a massive amount of people dying every year. This is really important because we tend to think about one bug or two bugs. This is a syndrome, and this is a really situation that can be caused by many, many types of bacteria. About 1 million adults seek care for pneumonia just in the U.S. 50,000 die just from the disease every year. Admission to ICU and length of hospitalization is very close related to pneumonia complications. The more severe the pneumonia, the longer you're gonna be in the ICU, the longer you're gonna be in the hospital, the more complications you're gonna be prone to. High mortality, as we talked, despite all the antibiotics and supportive care that we have. The complications that come after the patient leaves the hospital are critical as well. Unmet needs in severe CAP include a unknown bacterial speciation. As I told you, when I have to see these patients the first day of admission, I still don't know which bugs are causing the pneumonia. Current treatments are really very limits to address the propagation of that whole immunological inflammatory response that's related to the toxins of the bug. Even though sometimes you are right there, you're getting the right antibiotics, the right supportive care, still, we are limited by this progression. This progression can be really serious and leads to death. We still have about a 15% rate of treatment failure and 40%-50% mortality in this patient despite all the care that we provide. Just to finish up, emphasize again what I told you before, that it is a massive problem worldwide, the growth of bacterial resistance to our antibiotics. We are getting very close to limit the amount of antibiotics that we have and the types of antibiotics that we have. You can look in every piece of media, industry, academia, that we are getting too short on antibiotics development. We don't have the same time to develop antibiotics as we had in the past. It's a very complex, difficult task, and the bacteria are becoming resistant much faster than the time that's taking for us to develop these new antibiotics. I'm gonna close here and give the words to Dr. Curt. Thank you. Thank you, Dr. Kalil, good morning, everybody. I'm gonna spend some time to talk to you about CAL02, our answer to what Dr. Kalil just described as an unmet need. I'm gonna tell you about the asset itself, and I'm gonna go a little in the data package, the preclinical, clinical package, and I'm gonna end with our proposed clinical development plan. As Dr. Kalil just described, pneumonia-associated complications are many and severe. The toll it takes on patients and their families, as well as the strain it puts on the healthcare system, is significant. Besides the direct effects on the lung themselves, there are multiple serious complications associated with severe pneumonia, including the ICU admission and the need for mechanical ventilation, sepsis, multi-organ failure, and ultimately death. Many bacteria can cause structural tissue damage that favor ongoing bacterial growth, as well as evasion of the immune response. One mechanism that many bacteria leverage is the secretion of virulence factors or VFs. These virulence factors are key in the pathogenesis of acute disease and the resulting complications, and their effects may persist, as we heard from Dr. Kalil, as infected bacteria are attenuated by antibiotic therapy. CAL02 is designed to neutralize these bacterial weapons acting on this trigger, as opposed to downstream mediators. It acts really high up in that cascade that you see on the slide. Our hope is that CAL02 will have a protective effect on multiple disease complications parameters, and ultimately a positive effect on patient outcomes. Why is this the case? Bacterial infection, as I just said, can be made more severe through the release of virulence factors by the pathogen. These virulence factors play a significant role in the development of the complications that Dr. Kalil has been discussing. They trigger a multi-pronged process that disrupts tissue barriers, facilitate tissue penetration of the bacteria, and result in enhanced bacterial growth. They can lead to bacterial immune evasion, and all of these effects at the tissue level are expressed clinically through edema, inflammation, and ultimately organ failure. While there are many classes of bacterial virulence factors, the single largest category, the pore-forming toxins, comprise 25%-30% of cytotoxic bacterial proteins. We would be referring to them today in today's talk. As you can see in this slide, in severe bacterial pneumonia, pore-forming toxins can be produced by a wide range of organisms, they're on the left of the slide, including Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, E. coli, and Haemophilus influenzae, all which are common pathogens that cause pneumonia, be it community-acquired, so, from outside of the hospital or hospital-acquired pneumonia. Targeting pore-forming toxins is agnostic to the specific bacterial pathogen causing the infection, and thus has the potential to attenuate the virulence of the offending bacteria even before the specific pathogen is identified by the clinicians. This is an important distinction because healthcare providers often don't know which bacteria to target early on in the treatment course. Now let's take a slightly deeper dive on virulence factors. Virulence factors, as you've heard, are universal bacterial weapons, regardless of the, of its resistance profile. They are, however, species or even strain-specific. Typically, as illustrated on this slide, pore-forming toxins are secreted by bacteria as a soluble monomer. These monomers target particular membrane lipid platforms where they aggregate and oligomerize to ultimately form a pore or a hole in the, so in the host's cell membrane, killing the host cell and releasing its intracellular components. This leads on a macro level to increased inflammation, tissue destruction that promotes bacterial growth and can lead to those severe complications that we've been talking about. CAL02 relies on the fact that the vast majority of virulence factors produced by the most common pathogens, which cause severe pneumonia, they all target particular lipid platforms that are ubiquitously present at the surface of human cells. This allows the bacterium's attack on the host cell to be unspecific and widespread. CAL02 mimics the lipid platforms that the pore-forming toxins require to bind to and to attack the host cell. Binding to CAL02 instead neutralizes the pore-forming activity, drawing the toxins away from the host cell. In this way, CAL02 is designed to act as a competitive inhibitor of the virulence effector or factor, or as a trap disabling the action of the toxin. That's in a nutshell the mechanism of the drug and the value proposition. Disabling these virulence factors prevents some of the downstream effects of the whole host cell damage, which can eventually lead to the significant morbidity and mortality we've heard about. Until now, drugs targeting virulence have been limited by specificity to a given pathogen or a given strain. These drugs cannot be administered empirically because you need to know what bug to target and can complicate an already complex treatment algorithm, as Dr. Kalil has showed us at the end of his talk. Importantly, CAL02 may potentially help overcome this limitation. When added to standard of care, we believe it may help improve clinical outcomes. What is CAL02? CAL02 consists of a liquid injectable solution containing engineered empty liposomes, which are designed to capture and neutralize virulence factors secreted by bacteria. It is intended for use in patients with severe infection. Eagle has taken the next step in the development of CAL02 with the initiation of an adaptive phase II clinical trial in patients hospitalized with severe community-acquired bacterial pneumonia. We also plan to pursue regulatory designations such as the Qualified Infectious Disease Product or QIDP that could provide for 10 years of market exclusivity. To recap, CAL02 is designed to target the virulence factor secreted by infecting bacteria that create pores or holes in the host cell walls, causing tissue damage, immune dysregulation, and inflammation, all of which increase the severity of the disease. CAL02 binds to these pore-forming toxins with greater affinity than the host cell, thus preventing them from reaching their target and doing their damage. Our lead indication is severe community-acquired bacterial pneumonia. There are significant complications and sequelae that prolong suffering and death from this disease that we believe CAL02 has the potential to address. Looking ahead, we anticipate that CAL02, if approved, could be used as an adjuvant therapy in conjunction with conventional antibiotics. It's an add-on to antibiotics. That's important for you to remember. What's exciting is that we think that as long as there is a suspicion of a pore-forming toxin-secreting pathogen, CAL02 could be used empirically without the need to confirm the identity of the offending bacterium. Because of its composition, we do not foresee the possibility for negative interactions with traditional direct-acting antibacterials, thus making CAL02 use potentially therapy agnostic. It could be used with standard of care antibiotics in any clinical situation. You've heard this before from Joe's talk, yes? About the agnostic. There's a theme here throughout our pipeline. The risk of antibiotic resistance development, a huge challenge, as we've heard, for direct-acting antibacterials, does not seem to be significant with CAL02. Other advantages of CAL02 include that in the first-in-human study, and I'm gonna show you the results shortly. While small, in that study, we've demonstrated a compelling safety profile as well as encouraging efficacy trends. In addition, interactions with the European Medicines Agency, or EMEA, as well as the U.S. FDA, indicate that CAL02 may be eligible for special designations and review processes, thus accelerating the development. Finally, the Eagle team believes that we have a scalable manufacturing process that would be able to supply both phase III and commercial launch if CAL02 is approved. Let's move into the data package. I only have a few slides to pique your interest. This slide shows us an overview or an introduction to the comprehensive non-clinical package, which includes extensive peer-reviewed in vitro and in vivo efficacy studies. In vitro studies demonstrated the ability of CAL02 to neutralize virulence factors of various classes of bacteria, including gram-negative and gram-positive bacteria, those that are highly relevant in pneumonia. In vivo, as depicted on this slide, CAL02 was tested either in monotherapy as the only treatment or as an adjunct to direct-acting antibiotics, the way it's meant to be used in the clinic. In all cases, CAL02 was administered within several hours after the infection, infectious challenge in order to mimic the real-life clinical situation. As you can see, CAL02's protective effect was observed to be dose-dependent, and the protection was compelling on tissue damages such as pulmonary edema and on inflammation. Remember the CT scan Dr. Kalil showed us with that white area, that's all due to an inflammatory process and edema that doesn't allow the air to get to the alveoli. CAL02's effect was shown on edema and inflammation as it abolishes the rise of signature pro-inflammatory cytokines and acute-phase proteins, such as those that are involved in fatal sepsis cases. The results were compelling on survival as well, and CAL02 proved to safeguard immune defenses. Why is that important? The beneficial impact of neutralizing virulence factors with CAL02 was evident regardless of the resistance profile of the pathogen. Now moving on to GLP compliance, safety pharmacology, and toxicology, as well as pharmacokinetic studies. These studies have shown that virulence factors are entrapped by CAL02 and once they are entrapped, they lose their toxic capability. Toxicology studies show that CAL02 has an acceptable safety profile, even at the highest administrable doses. Remember, it's a mixture of liposomes. Of note, while the degradation and elimination of the CAL02 toxin complex occurs via the liver, it is not expected to cause any added toxicity, even in patients with impaired liver function. On this slide, you can see a snapshot of the first-in-human clinical study, which was conducted in 19 patients with severe community-acquired pneumonia, exploring two doses of CAL02. Results were published in The Lancet Infectious Diseases. This study was a multicenter, randomized, double-blind, placebo-controlled study, so very well and robust design, well-designed study. All patients received standard of care plus either placebo or CAL02 administered as two IV infusions 24 hours apart. A sentinel cohort of patients received CAL02 at a dose of 4 mg per kilogram or placebo to confirm appropriate safety and risk benefit, after which CAL02 dose was increased to 16 mg per kilogram for the remainder of the study. Results showed favorable tolerability for CAL02, which was the primary endpoint. Numerous efficacy parameters were also assessed, and some of them are summarized on this slide. At the high dose, there was a trend of improved early cure rate, decreased mortality, decreased time in the ICU, and decreased days of mechanical ventilation, all of which are important clinical and health economic parameters and endpoints. In addition, the SOFA score, which is a well-established tool to assess the clinical severity in pneumonia patients who require critical care, decreased by 65% after seven days for patients treated with CAL02 versus 29% in the placebo arm. This indicated a rapid recovery for CAL02-treated patients. Also, within the first week of treatment, the APACHE II score, a mortality predictor score used in ICUs, steadily decreased by 60% in patients who received CAL02 versus 22% in the placebo group. While the sample size in this phase I study was small, we believe that these trends indicate the potential benefit of CAL02 for parameters related to organ dysfunction and dysregulated inflammation, and thus justify studying CAL02 in a larger clinical study. Guess what we did at Eagle? Based on the results of the phase I study, we in humans are continuing the development of CAL02 with a robust phase II study in patients hospitalized with severe community-acquired bacterial pneumonia. This slide summarizes the key design elements of the study protocol, which was included in the October 11 IND filing to the U.S. FDA. Roughly 30 days later, as you know, on November 10th, the FDA notified us that the IND filing was accepted. They issued the study may proceed letter. We are in position to initiate sites as soon as all the local regulatory approvals are received and the contracts are in place. The study is an adaptive, randomized, double-blind, placebo-controlled study, which will assess the efficacy and safety of CAL02 administered intravenously in addition to standard of care in patients with severe community-acquired bacterial pneumonia. We're not asking the physicians to change their care for these patients. Patients who will be randomized in this study will receive CAL02 or placebo study medication in addition to what they would normally get for their pneumonia. The estimated sample size for this study is approximately 276 patients. Through an ongoing, robust feasibility program, we have identified the pool of centers that we believe will yield the approximately 120 study sites needed to complete patient recruitment. We expect to begin initiating sites in early 2023, and as you see on this slide, we have two interim analysis planned at 33% of subjects completed and at 50% of subjects completely. We believe that approximately one year after the first patient is enrolled, we should be at the point where we can carry out the more robust of the two interim analysis. This is my conclusion slide before I turn it back to Dr. Kalil for some parting thoughts. As you have heard today, there are many reasons to be excited about CAL02's potential to make a significant impact on this severe disease. We believe both the preclinical and clinical data generated to date support further development and investment in this program. In this slide, we have outlined the potential competitive advantages of CAL02 for the patient, the prescriber, and the healthcare system. We believe that ultimately, the use of CAL02, if approved, could be less restricted than direct-acting antibacterials, as the anticipated resistance generation should be much less. As a result, because of its potentially broad empiric utility and use as an adjuvant to any standard of care, we believe the potential impact of CAL02 could be quite significant. Now I'll turn the program back to Dr. Kalil for some quick parting thoughts and clinician's perspective on what you've just heard. Thanks, Dr. Curt. I mean, I have just one slide to show you and it is, I believe it is a very exciting slide because I think it links what I talked before with Dr. Curt 's presentation on the molecule. I think this is where we need to move forward. The, you know, the potential benefits that we're gonna see now, looking back into our talk, you know, my talk into Valentin's talk is one thing that to me caught my eyes when I read his Lancet paper, the one that he, you know, the phase I that he just showed a few minutes ago. The phase I study is even though as small as all these phase Is are, I was pretty impressed by the safety profile of the drug. Not only clinically, but bench-wise, because think about this is a literally a glob of fat, you know, that is not gonna interact with the other medications. It's not gonna decrease the level of antibiotics. It's not gonna change the levels of vasopressors. It's not gonna change oxygenation-wise. This molecule has no other biological activity. When you look at the basic mechanism of the molecule with the phase I data, everything fits in the sense that it seems to be a quite safe drug. Sure, we're gonna have to prove that safety in a phase II and a phase III study. There are no questions of that we need larger studies. To me, as an investigator, as a clinician, to be able to offer a study in which I believe to have so much more safety than a lot of the drugs is critical. It's really important, number one concern I have and when I start any clinical trial in my, in my hospital. The other thing that as infectious disease docs scare the hell of me, and you've heard, you know, about 20 minutes ago, is resistance, correct? This is something that we fear 24/7. We not wanna lose our antibiotics. Adding CAL02 to antibiotics will not change how these bugs are gonna, you know, respond to CAL02, because CAL02 literally is gonna just bind the end product of this bacteria. CAL02 is not gonna be interacting with the bug themselves, correct? This will there is no reasons for us to believe that the bugs are gonna come up with some kind of resistant mechanism, 'cause all we are doing is misleading the toxins that were already produced by the bug into a different direction, correct? The point here is that, hopefully, if this works, we're gonna become much less dependent on antibiotics. That's really important because we already talked before, the antibiotics alone are not doing everything that we need. Still people are dying despite this. We need to do more than that. That's the beauty of acting in conjunction with antibiotics in order to killing the bugs and preventing the toxins to cause all that inflammatory process. The other point, very important, is, I'm gonna come back to the flora, the fifth bullet, the non-immunogenic. You've learned during the COVID pandemic that now we have the benefits of what you call immunomodulatory drugs. Steroids, baricitinib, tocilizumab, all these drugs that were discovered, and I was part of some of these studies in the last two or three years. It is a major shift in terms of trying to help the host, the person that has the pneumonia, to deal with the immune system dysregulation. I think we've made a huge progress in the last couple of years for this. The key point is that all these immunomodulatory drugs that we use nowadays, they have some degree of immunosuppression. They cause some degree of immunosuppression. Specifically, when you hear about steroids, that we've used for close to one century, it's a drug that can blunt inflammation, can bring the fever down, can bring the inflammatory marks down, can cause more immunosuppression and can lead the patient to sometimes to a more dire situations because the immune system gets too low. With CAL02, there is no interactions with the immune system. Zero, correct? This again, it's simply a molecule with lipids. There's no reasons to believe that this drug would immunosuppress any patient. There is no reasons both from the biology and from the clinical perspective. This is really important. Now you literally are given a drug that is gonna immunomodulate by trapping the toxins, not by decreasing the immune response. This is really a very interesting twist that we are seeing with this molecule. Last, not less importantly, is that we're not gonna kill the good bugs as we do with antibiotics, correct? Remember, when we give antibiotics to our patients, we are definitely wanna kill the bad bugs. Unfortunately, we end up killing a lot of good bugs and say, "Well, what's the big deal with good bugs?" I wanna remind you that in your body today, you're here sitting, you have 10 more bacterial cells than human cells. You are 90% bacteria. Me too. I'm no different. Why I'm telling you that? Because when we give antibiotics, we are killing a lot of good guys. These bugs, we need it. We would not be here today as humanity if we didn't have these bugs in our body. We have the microbiome in our bowel, we have the microbiome in our lungs, we have the microbiome in our skin. We have bugs all over our body. They are incredibly helpful to our body response, to our immune response. They're part of who we are. We have to start relying in other therapies that do not change our microbiome. This is the beauty about this molecule. If this molecule works, it's gonna work about in a way that's not gonna change a nod of our microbiome. For us, as infectious disease docs, this is fantastic. My hope is that this trial is gonna really be a paradigm shift, is gonna change how we approach the treatment of severe community pneumonia, and we're gonna save more lives by adding that to the standard of care that we have today. Thanks so much. Okay. I think we're taking a little bit of a break now. Let's see. It is 10:23 A.M. If we can be back in 10 minutes at 10:33 A.M, that'll be great. There are restrooms right around the corner. Next up, you know, we made this acquisition of Acacia Pharma, BYFAVO, also two incredibly special drugs that haven't been given enough attention yet. We did a remarkable amount of diligence when we acquired the company. I think you're gonna leave here as excited about the two new products that we have on the market now as the products that we have in development. Stay around for that. It's gonna be remarkable. Still a little bit of time to go. Thank you. See you in 10 minutes. Appreciate it. All right. Welcome. Welcome back, everyone. We have a tight schedule. Still have so much to speak about before we end here today. With that, let me introduce Deb Hussain, our Head of Commercial. Great industry leader, doing wonderful things with these two great next products. With that, Deb, go do your thing. Looking forward to hearing all about it. Excellent. Good morning, everyone. As Scott said, my name is Deb Hussain, and I am the Senior Vice President and Head of Commercial here at Eagle. Today, I have the pleasure of introducing our two newest FDA-approved and marketed products, BARHEMSYS and BYFAVO. After a brief overview, I'll then hand it over to our key opinion leaders, Dr. Gan and Dr. Dutton, to provide more detail. As most of you know, earlier this year, Eagle added BARHEMSYS and BYFAVO to its portfolio with the acquisition of the Acacia Pharma Group. BARHEMSYS is a selective dopamine receptor antagonist that's indicated in adults for the prevention of postoperative nausea and vomiting, also known as PONV, as well as for the treatment of PONV. BYFAVO is a benzodiazepine indicated for the induction and maintenance of procedural sedation in adults undergoing procedures lasting 30 minutes or less, which addresses really an unmet need by offering a fast-acting agent and a favorable safety profile versus other treatments that are available today. Before discussing the products any further, let me take a step back first and touch upon the hospital environment that is undergoing some fairly significant change when you think about it. Many hospitals are facing challenges with profitability due to margins being eroded. Not only are supply costs rising due to inflation, but hospitals are also experiencing major staffing challenges with early retirements and employees just leaving the healthcare industry altogether. In turn, there is a reliance then on locums that is further driving up these costs. To compound the issue, the reimbursement remains an ongoing challenge due to diminished Medicare and Medicaid reimbursements. Hospitals are struggling with how to balance a focus on patient satisfaction and driving efficiency and ensuring patient safety. The industry is also seeing a shift of surgical and procedure volume to outpatient sites of care. Advances in clinical approaches and advances in technology, including new developments in anesthesia and pain control, have enabled numerous procedures such as knee replacements and tonsillectomies to migrate into the ambulatory care setting. This trend allows a greater number and variety of even more complex surgeries to be performed outside of the hospital, serving an aging population and at a lower cost. Additionally, patients are actually increasingly choosing this out-of-hospital medical care because of these lower costs, because it also provides well improved access for them and an overall better experience. We believe that both BARHEMSYS and BYFAVO can help alleviate some of these strains and deliver value to the health system. As you'll hear over the next 30 minutes or so, we believe these products have the potential to improve patient throughput, to drive satisfaction, and to potentially positively affect the health economic system. Now let's turn to BARHEMSYS. BARHEMSYS, while it has been studied in and approved for both prophylaxis and for treatment, we are strategically focused on the treatment of PONV, where there is significant unmet need for patients. In prophylaxis, there are several very good generic options that enable clinicians and hospitals to try to cost effectively prevent PONV with a multimodal approach. Even when following guidelines, approximately a third of these patients are going to have breakthrough PONV after surgery and they will need to be treated. This is due to the complexity of PONV, which Dr. Gan will go into in more detail here shortly. According to the 2020 consensus guidelines, an antiemetic from a different class than the prophylactic drug that was used should be used when it fails. Until now, however, because of the lack of innovation and the lack of options, common practice has been to repeat the same class of drug within six hours despite the lack of clinical benefit. BARHEMSYS is the first and only antiemetic approved for this rescue treatment of PONV despite prophylaxis. It is the only drug to demonstrate efficacy in PONV rescue in a randomized clinical trial with a favorable safety profile. It is non-sedating, which is a common complaint of standard antiemetic options today. In addition, it really addresses in a significant unmet need. While PONV is associated with increased length of PACU stay and greater hospital resource utilization, BARHEMSYS has the potential to reduce that PACU stay and overall hospital stays, potentially offering significant economic savings to hospitals when compared to the current standard of care. Better efficacy and safety of the product mean better recovery and patient experience. This is playing out in the real world. We continue to hear patient success stories from PACU nurses who administer BARHEMSYS. Later you'll hear two real-world examples highlighting the benefits of improved PACU throughput. Now let's turn to BYFAVO. BYFAVO is indicated for the induction and maintenance of procedural sedation in adults undergoing procedures that are lasting 30 minutes or less. We believe it truly addresses an unmet need. There hasn't been innovation in this space for well over 20 years. In order to improve throughput and discharge times, clinicians are looking for a predictable sedation effect with a fast onset and a rapid recovery to enable more efficiency. As I said, BYFAVO is indicated for those procedures lasting 30 minutes or less, and it has broad applicability across a range of procedures and patient types, including for the least physically fit, with the clinical data package showing compelling efficacy and safety in both colonoscopies and bronchoscopies. As with BARHEMSYS, BYFAVO also has the potential to provide economic health benefits as it was intentionally designed for rapid onset and rapid offset to offer clinicians that predictable level of sedation using an easy to administer dose that is not dependent upon the patient, and potentially enabling that greater patient throughput while maximizing patient comfort and satisfaction. Next, I'd like to turn it over to Dr. Gan, who will speak more about BARHEMSYS. Dr. Gan, who spoke earlier about postoperative respiratory depression, is a distinguished leader in anesthesiology. After Dr. Gan, you'll hear from Dr. Dutton, who's a widely recognized leader in anesthesia quality management, who will provide his clinical perspectives on BYFAVO as well as discuss the challenges in anesthesia today. Dr. Gan. Good morning again. Hope you are now caffeinated and waiting to listen for the next phase of the presentation. I've been in the perioperative field for probably 35 years, over the years, really my focus is trying to see how can we get the patients who have a good experience, come for surgery at the same time, help them to recovery to get back to their baseline. I think this whole area of perioperative medicine has really not well been focused for the last probably 10, 20 years. We are finding a lot of opportunities, number one, to identify these patients. Some of them may need to be worked up because they are not in a fit state to have surgery, because surgery is associated with incredible amount of surgical stress. How do we identify those patients? How do we work them up? How can we prepare them, be more physiologically robust to be able to undergo surgery? Intraoperatively, how do we tailor the anesthetic with better pain management, with better anti nausea management? More importantly, post op, how can we get them back to their normal, you know, with all the enhanced recovery that many hospitals are doing? That is an incredibly exciting area, and I think the new therapeutics coming to this area will help our effort to trying to make them better. I'm gonna talk to you about the role of this drug, amisulpride or BARHEMSYS, in potentially management of postoperative nausea and vomiting. Now, PONV, as Deb said, it's very common. On average, if you take all comers, one in three is gonna throw up. Even in high-risk patient, there is gonna be more, and I'll show you some of the risk factors. Even with prophylaxis. If you want to think about PONV, think of 30%. In general, 30% throw up. Even with prophylaxis, 30% is going to fail and throw up again in the recovery room. This has been the most unpleasant thing that patient tell us that they don't want to experience. We all know that if you have PONV, guess what? You stay in the PACU longer. We have found that if you have an episode of PONV, on average, you stay in the PACU 30 minutes longer. 30 minutes longer, take up PACU space, patient from the OR can't come up, come into the PACU. All those are associated with increased costs. You can see the data here. Almost 50% of the patient said the common reason for dissatisfaction is because of nausea and vomiting. In fact, some people say, "I don't mind having a bit of pain, but I hate to be sick." Those of you know, who may have the experience understand what I'm talking about. We know that healthcare is moving from the volume-based care to value-based care. What does that mean? Well, value, as you know, is quality on top over cost. We want to increase quality, that means that better efficacy of drugs, better efficiency, at the same time reducing cost. This is where we are focusing on. In fact, the government CMS now have a new incentive system where they reward you if you do the right thing. One of the metric is called the MIPS 430 metric-based incentive payment system, where in high-risk patient, if you were to provide appropriate antiemetics prophylaxis, you get rewarded. If you don't, you get penalized. This can run into millions of dollars. Imagine if you have a healthcare at a hospital which has got a lot of high-volume surgery. We also know HCAHPS score track patient satisfaction very carefully, and most hospital value that increase in patient satisfaction so they can attract more patients. If you were to look into a literature, put in PONV in a PubMed search, you will come up with over 10,000 articles. A staggering number of papers. Over the years, in order to advise clinician, I have been the primary author of four consensus guidelines starting from 2003. Over the last 20 years, we updated it every five years because for a consensus to be up to date, you've got to periodically update it because there are new drugs coming, there's new strategy. The most recent one was published in 2020, which is most well-recognized internationally because that is really the only consensus that have been updated on a continual basis. First of all, who are more likely to throw up? Now let me ask you, in this room, who has got motion sickness or has history of motion sickness? I see a number of hands goes up. Who unfortunately have postoperative nausea and vomiting who have the experience? A number of hands goes up. If you have one of these two factors, you are at an increased risk. If you are female, there is three times the risk compared to men for post-op nausea and vomiting. Interestingly, if you are nonsmoker, you have an increased risk. Not that I would advise a patient to smoke before surgery. Let's put that clear. Interestingly, acute smoking. Let's say a patient who are nonsmoking, having surgery two weeks time, you're encouraging to smoke doesn't cut it. You got to be a chronic smoker because of the mediation of the nicotinic receptor. We'll talk about the mechanism. Obviously opioids increase the risk for nausea and vomiting. Now, you can see that often these patient have a number of risk factors. If you are female, you have a history of PONV or motion sickness, invariably, your anesthesia are gonna use opioid. You are already, and you often are nonsmoker, guess where you are? 80% risk of developing nausea and vomiting. That's why it's so common. Let's take a look at the mechanism. Again, I'm just going to really broadly describe. Essentially, there are two component. One is the peripheral and one is the central. Peripherally, in the stomach, there is a very rich source of receptors that are very sensitive to the things that you ingest, you know, for teleological reason, because, you know, we need to survive as a species, and therefore, if you were to ingest any poisonous material, you expel it, which is a good thing. Unfortunately, many of the drugs that we use also stimulate these receptors in the stomach, causing unnecessary, I would say, nausea and vomiting because it's not really beneficial. In fact, you just experience the horrible side effects. In the middle ear, there's also the input. If I were to spin you around or if you go on a boat ride, motion sickness, it's all about middle ear. Then there is also the supratentorial input. The classic example is that patient who unfortunately have cancer, have chemotherapy, who get really sick. Right? The next round, even before they get to the hospital, the moment they approach the hospital, they are starting to feel sick. No chemotherapy yet. You can imagine that central supratentorial input is also important. This area called the chemoreceptor trigger zone is where all the receptors... There are five of them. You can see here, acetylcholine receptor, dopamine, histamine, serotonin, NK1. Those of you who have done biochemistry, biology, you vaguely remember these receptors in this area. The drugs that we commonly use acts as antagonists on one or more than one of these receptors. There are many generic drugs, as Deb mentioned earlier, that we use to trying to prevent postoperative nausea and vomiting. These are some of the examples. Transderm Scōp acting on anticholinergic, droperidol, haloperidol on dopamine, dimenhydrinate, Phenergan and Benadryl. Zofran is probably one of the most widely used antiemetics. NK1 is a new drug, aprepitant, and also steroids. There are many antiemetics which are effective. Now, unfortunately, many of them come with side effects. Sedation, problem with extrapyramidal side effects, and we'll talk a little bit more. How do we, as a clinician, manage patient with high risk? Now, there have been a lot of study, as I showed you earlier, 10,000 articles, and this has been pretty well worked out. If you have a, let's say, a baseline risk of 50%, so you got two, three risk factors. If I were to give you one drug that act on one receptors, I will reduce your risk for developing nausea and vomiting by about 25%. If I add a second drugs acting on the different receptors, I will further reduce that risk by another 25%. You can see here, if you give one, two or three drugs, you reduce that risk proportionally. 25% for each antiemetics. It also show that it does not go down to zero, right? You can give as many antiemetics you want, unfortunately, there will be some patients still going to throw up. High-risk patient, 80%. In general, 30%. Patient who fail, most amount are nausea, because nausea is particularly difficult to treat. Vomiting is about one in five, those who fail following prophylaxis. As I mentioned earlier, all the drugs come with some baggage. Even when ondansetron came on the market, it was thought to be, "Wow, this is a new class. It's the probably the best antiemetics at that time," which was true, but then later found that it does cause QT prolongation. Also we know that if you give Zofran for prevention, which we now do all the time, if the patient throw up again in the recovery room, by giving another dose of Zofran does not help. It's no different from giving placebo. While it's good for prevention, it is not effective for treatment for those who have been given Zofran. Metoclopramide are drugs commonly used to empty the stomach. A great drug, unfortunately, it does not have good antiemetic properties. Dexamethasone, steroids, used widely. Problem is that it doesn't work straight away. It takes about three to four hours, therefore is good option for prevention, not so much for treatment. Phenergan or promethazine cause sedation. Unfortunately, also, if you inadvertently inject outside the vein, you get tissue necrosis. You can see in the case report, fingers dropping off, hand dropping off. In fact, our pharmacy have banned the use of Phenergan in our hospital. Droperidol, dopamine antagonist, it does cause QT prolongation. FDA put on a black box warning in 2001, the use has really dropped off significantly. Dimenhydrinate, histamine, again, sedation is the problem. Aprepitant, until recently, is only available orally. All right, what does this drug, amisulpride, offer in the context of all the other generic antiemetics we have? Let me tell you a little bit about this drug, amisulpride or BARHEMSYS. It belongs to a class called dopamine antagonist, but it's a little bit different from droperidol and haloperidol. Because if you look at dopamine antagonist as a class, there are two subclasses. One is what they call butyrophenone, the other is what we call benzamide, which what amisulpride belongs. There are subtle differences between these two subclasses. Generally, you'll find that butyrophenone tend to have much more extrapyramidal side effects, tend to have a higher tendency for QT prolongation, higher tendency for sedation. Whereas benzamide tend to have less of those side effects. The other unique feature about this drug is that it most drugs are metabolized in the liver by the cytochrome P450, and this drug is not. This drug mainly excreted in the kidneys, and it also have a low plasma protein binding. What does that mean? Well, what it means is that you have lower chance of interacting with another drugs, because in the perioperative environment, we give five, 10, 15 drugs. Therefore, the likelihood of one drug interact with another, especially if both drugs are metabolized in the liver, goes up substantially. Having a drug that is not metabolized in the liver reduce that drug interaction. That is another uniqueness of this drug. How did the drug approved? Well, in the typical FDA manner, you gotta do two large study. Usually, most of the antiemetics that come to the market have two large prevention study, which is what these two studies were reported. This drug also went through another indication, which is the treatment when failure happens, which is these two papers. The reason that most drugs did not go through the treatment pathway is because it is fairly expensive to do a treatment study. Let me show you this treatment paper. Now imagine if I said to you about 30% of the patient will likely develop nausea and vomiting, right? That means that if you want to do a treatment study, you got to enroll three times that population to enrich that population, so that you can then randomize those who throw up. Let's say you enroll 100 patient, only 30 something patient is gonna throw up. You randomize those 30 something patient, and therefore, it's very costly. Previous drug approval has really not taken this path because as you can see here, you gotta enroll over 2,000 patients. Over 2,000 patients to enrich that population to finally get about 700 patients who will enter into the trial. 702 patients from 2,200. These were then randomized into three different groups. BARHEMSYS 10 mg, 5 mg, and placebo. The primary endpoint was what we call complete response. What does complete response mean? Complete response means no vomiting, you don't throw up, and no need for rescue medication. Now, you said to me, "What happened to nausea? How come it's not in part of the complete response?" The reason is that nausea is very subjective, right? We typically assess nausea from, which is no nausea. 1, very, very minor, all the way to 10. The FDA basically saying that if you need a rescue, that means that your nausea is severe enough to require rescue. It's a surrogate for severe nausea, so to speak. No vomiting, no use of rescue. Let me show you the demographics before I show you the results. Again, not surprisingly, most of them were female. Many of them had another preventative antiemetics, most commonly Zofran and dexamethasone or Decadron. Many of them have two antiemetics or more than two. Most of the PONV happens in PACU. You see that about three-quarter of the PONV happens in PACU. That give us an opportunity to better manage PONV in the PACU, so that when you can be free of PONV in the PACU, when they get out of PACU, they are likely not develop nausea and vomiting after that. What was the result? Well, this is for the 10 mg that shows that the complete response rate over 24 hours is 42%, compared to 29% in the placebo group. This was statistically significant at P = 0.003. That is over 24 hours. I think what is more relevant is look at within two hours in the PACU, what happens to these people in the PACU? Again, this is another way to look at the results. Over 24 hours, 42% over 29%. Again, this is two hours. If you look at two hours, if you were to give these patients BARHEMSYS versus placebo, 70% had complete response versus 50%, which is a bit like toss of a coin, right? Head or tail is about 50%, whereas you get much better efficacy with the BARHEMSYS. Specifically, if you look at the length of PACU stay in those patients who are given BARHEMSYS, they were able to be discharged earlier. Again, how earlier? How much earlier? 30 minutes, as we said, because each episode of nausea and vomiting extend the PACU stay by about 30 minutes. At the same time, in fact, this group also have a slightly shorter duration of hospital stay. Now, I want to finish off with two recently presented abstract at the American Society of Anesthesiologists. One of them was from my previous institution at Stony Brook, when the drug first came out, I think we were the first one in the country, because we did the multiple phase III study, so we have experience with the drug. We went to the pharmacy and we said to the pharmacy, "Okay, we know that we have a lot of inexpensive generic. We are going to use that for prevention, but when the patient fail, we know that some of the generic antiemetics either do not work or they have side effects. We will reserve these patients only when you using amisulpride for these small group of patient." As a result, the pharmacy felt more comfortable that this is not going to break their bank, break their budget, so they approved it, and this is how we used it. We collected some data, and we found that patient who were given amisulpride, about 75% of the time we can get them out of PACU. One of the comment from nurses that in the past, before we introduced BARHEMSYS, that they had to cycle around two, three, four different antiemetics, because this doesn't work, patient throw up, they're going to go drug B and then drug C. As a result, they prolong the PACU stay at the same time trying to get the patient under control. Where with this drug, they give amisulpride, and they're able to discharge the patient from the PACU. Another abstract actually came from Dr. Dutton's, one of Dr. Dutton's institution that looked at the impact of amisulpride in a everyday PACU. What they did was they collected some baseline data before introducing amisulpride for three months, how long the PACU stay, what was the cost. They undergone through four months of education, introduced the drugs, had an algorithm, when to treat the patients, and then they collect subsequently another three months of data. This is before and after. Before that, on average, patients stay about 90 minutes in the PACU. Following introduction, that went down to about 68 minutes, and there's also significant cost reduction, mainly because of the reduction in PACU stay, also using less subsequent antiemetics. In summary, PONV is common. Significant factor of patient dissatisfaction. PONV is multifactorial, and we have drugs available to prevent them. About a third is still going to likely develop nausea and vomiting despite prophylaxis. Amisulpride is a new dopamine antagonist, belongs to the benzamide subclass. Four studies have shown efficacy, shown safety of the drugs, no insulin or QT prolongation. This is a drug that I think add to our armamentarium in an everyday practice in the, either hospital, ASC, as well on the floor. Thank you very much for your attention. We're gonna welcome Dr. Dutton to talk about BYFAVO. My thanks to TJ. I have followed him on any number of speaking engagements over the years. Always a pleasure. Let's see. Here's me. I am Rick Dutton. I am currently an adjunct professor at Texas A&M, the Baylor Scott & White system. I work clinically as an anesthesiologist at Baylor University Medical Center in downtown Dallas. My day job, I'm Chief Quality Officer for U.S. Anesthesia Partners. I'll tell you a little more about that in a second. My history is here on the slide. I am a recovering traumatologist. I worked in Baltimore at the Shock Trauma Center there for about 17 years. I was a professor of medicine anesthesia at the University of Maryland. I worked six years for my professional society, the American Society of Anesthesiologists, as their first Chief Quality Officer. We set up our national anesthesia registry, had the chance to see the scope and scale of anesthesia practice in the United States. I'm still heavily involved with the ASA. Since 2015, I've had the present job as chief quality officer for USAP. Here is USAP. We are the largest private practice probably in any specialty in the world. I am chief clinical officer for about 5,000 clinicians, about half doctors and half CRNAs and AAs. We work in 16 cities across the United States. 60 different small groups have joined us over the years. You can see the interesting feature of our company is it is somewhat more than half owned by the physician partners. This is physician-led healthcare. Physicians own all of the clinical governance in USAP, all the hiring, firing, contracts, policies, protocols, and so on. We do have private equity support. This lets us make investments. It lets us find leadership and talent. It lets us build big scale systems to be a very effective business. As I say, I joined in 2015, which was the third year of the practice. We're in year 10 now, and we've grown substantially over the years. My specific job is to make USAP the highest quality anesthesia group in the country, and I get to do lots of different things toward that aim, including identifying and sharing around best practices. I talk to all of the vendors in the anesthesia space, both equipment and pharma, to find emerging new things that are gonna make our care of patients better. That is my job on a large scale. As you can see, we do about 2.5 million anesthetics a year. I'm gonna talk the next couple of slides on the big issues confronting anesthesiology right now. I'll talk about my specific job in demonstrating the value of what we do to our customers, hospitals, payers, patients. Then I will get to BYFAVO and why I think this is gonna be a very big deal for our specialty. The biggest problem in anesthesia today is too much demand and not enough people. We've been very successful at convincing the rest of the house of medicine, every other specialty in medicine, that they need our help, our support in getting procedural care done. Whether this is psychiatrists doing ECTs, gastroenterologists doing colonoscopies and endoscopies, pulmonologists or surgeons, our traditional customers, we now touch just about every other part of medicine. The provision of particularly non-operating room sedation is a huge business with a current unmet need where the hospitals are requesting us to be there and provide sedation for their patients of 40 million to 60 million cases a year in the United States that we just can't cover today. A very big gap, and this is putting a lot of pressure on anesthesia departments and hospitals around the country. Every hospital wants more points of service from their anesthesia department. Every one of us has more work to do than we can possibly do. This is a big driver in our business right now. We suffer the same downward pressure on payments as other physicians and other physician groups, as well as hospitals. Increasingly, what it costs to have an anesthesiologist or a CRNA in your operating room or your procedural suite can't be recovered in fee-for-service payments. Increasingly, hospitals have to make up that gap in what we call stipends or physician service contracts, where the hospital is paying us specifically to be there providing anesthesia. Obviously, as the hospital writes those checks, they find that very painful, and that comes with a lot of demand for performance metrics and demonstration of the value that we're bringing. That is a big part of my job. For hospitals, the value proposition of a good, effective anesthesia partnership is probably best measured on the bottom of the slide in decreased length of patient stay because that, first of all, that's very easy to translate into dollars for the hospital. Every patient they discharge lets them admit one more, all right? That is a key driver of revenue for hospitals. That, it also captures all the reasons why a patient might not leave the hospital quickly. TJ talked about one a second ago, postoperative nausea and vomiting, good pain management, and you can see some of the other bits and pieces of value creation that anesthesia, anesthesiologists bring on the slide. Reducing transfusions, using medications wisely, increasing the efficiency of the OR. For payers, commercial, insurance companies, it's a similar roster. They are very focused, as you heard Deb say, on moving all eligible patients and procedures from an inpatient environment to an outpatient environment. That same knee replacement costs Blue Cross of Texas about half as much if it's done in a surgery center on a same-day basis as if it's a hospital inpatient. The savings there are enormous. Anesthesiologists are the big gatekeepers of that who can have their procedure on an outpatient basis, and we bring a lot of facilitating technique to that in terms of how we manage the anesthetic. Use of adjuvant regional pain medicine, for example, blocks, nerve catheters, that kind of thing that have enabled that switch. You can see some of the other things, other ways we bring value to the payers. One of the important ones emerging now is if we do our multimodal pain management right in the OR, if we follow best practices, we can significantly reduce opioid dependence in the long term. This is an enormously expensive problem for payers. Another one you see on the slide is reduction of readmissions. We USAP actually has national contract with gain-sharing incentives in it from a payer that for every readmission we don't have after a procedure that saves the payer $27,000. We know this from their own actuarial data, and we basically split that with them. Our group has an incentive to work with the hospital to reduce readmissions, and both we and the payers benefit from that. In terms of our workforce problem of the moment, there are lots of solutions that are being put on the table. We are trying to train more people. Unfortunately, in the past two years, partly as a result of COVID and partly just the demographics of our specialty, more anesthesiologists and CRNAs actually left the full-time workforce than joined it. Unfortunately, that's moving in the wrong direction. There are many ways in which we need to work smarter and in which we need to empower new solutions for covering those 60 million sedation cases every day. You can see some of them on the slides. We need to extend our ratios, so one doctor supervising more CRNAs, providing safe coverage to a broader number of operating rooms. The line on the bottom, we need to expand non-anesthesia nursing services. As we start talking about BYFAVO in a moment, you'll see how that plays in. If we were gonna design the perfect sedative medication for all of those cataracts and screening colonoscopies and knee arthroscopies under regional, and you name it, everything that we need to do that needs sedation, it would have the characteristics on the slide. It would work like a light switch. Wrap it on, wrap it off, right? You're awake, you're asleep, you're awake. When you're awake again at the end, you feel just as good as you did before you started. No hangover, all right? You can see that in so much science, terms there on the slide. Ideally, the perfect sedative would be free as well, that's not going to happen. Presently, this is what we got. Propofol and midazolam. Propofol you've heard talked about already today. That's the white stuff, the milk of amnesia, as we call it. It is the most commonly used sedative by anesthesia clinicians. It's how we start all our general anesthetics. More important, we use it alone as the medication for a lot of the sedation we give. It has many of the characteristics you see there. Rapid onset when we give it IV, goes away fairly quickly, doesn't leave much of a hangover. The problem with propofol is it has a very narrow therapeutic margin. If you give a little too much, all right, and too much is a relative term based on the patient's age, comorbidities, frailty, they stop breathing. As Michael Jackson demonstrated, that can be a problem if the clinician managing that isn't prepared to breathe for them. All right? This is why propofol comes with a big black box warning from the FDA that says that bolus administration of propofol, as for sedation cases, has to be done by an anesthesia clinician. This is something that has limited its use to anesthesiologists and CRNAs in the United States. We do this very safely. We have the right equipment. We have the right training. We have the experience to do it, but it is not a skill it's easy to translate to others, and that's a big safety problem. Where anesthesia clinicians are not present for sedation in the United States, which is a lot of those, tens of millions of cases today, the common cocktail is fentanyl and midazolam. Fentanyl, a short-acting narcotic, and midazolam, a benzodiazepine, given IV, again, has some of the characteristics of the perfect sedative. It comes on fairly quickly. The problem is, the next slide gets into this, midazolam's on the left here, that midazolam is metabolized by that same P450 system you've heard talked about into two active metabolites. Both of those products are also sedatives, and they hang around in the circulation for a while after the procedure. Furthermore, that whole P450 system is subject to a lot of external influences. There's genetic variation in how well that works in different people, and it can be affected by diet, by the other medications you're taking. Consequently, midazolam becomes very unpredictable how long the patient's going to stay asleep, how deeply sedated they're going to be. This is why it comes with that, "Don't operate any heavy equipment or make any expensive investment decisions, you know, after your sedation procedure." Right? Remimazolam, BYFAVO, the product we're talking about here, has been custom-built to get around some of those problems. It's the same benzodiazepine. It's hitting the same GABA receptors in the brain. It has the same kind of onset as IV midazolam, but it falls apart spontaneously in the circulation. It's metabolized by tissue esterase, which is an enzyme you have throughout your body. Consequently, it arrives in the bloodstream, it hits the brain cell it needs to hit, and it goes away in a very quick and predictable fashion. As you can see, its metabolite is inactive. It's not a sedative. All right. It's solving that hangover problem we have with sedation right now. Rapid onset, within 30 seconds, and I will tell you that in the whole house of medicine, anesthesiologists are the most impatient people. We go into anesthesia because we have a strong desire for immediate gratification, right? We're the only docs who give our own medications. We pick up the syringe, we give it, something happens, and that's usually within a matter of seconds. That's our personality. This is the perfect kind of drug for us. All right. We give BYFAVO, the patient goes to sleep. Similarly, when we stop giving it, turn off the infusion or let that initial dose run out, the patient wakes up very quickly and very predictably and without a lot of the hangover or secondary effects we see with midazolam. There's a bunch of preliminary data out there to support this. Currently, remimazolam BYFAVO is indicated for sedation cases lasting less than 30 minutes. This is a common, two common models, bronchoscopy and colonoscopy, that we do thousands of every day across the United States. You can see the green bars there are BYFAVO. Rapid drop to an acceptable level of sedation, three out of five in this. The patient's not responding. They're unconscious. All right. Then rapid recovery, as the procedure's completed. In this case, it's being compared to giving midazolam by protocol, where you pick a dose and give it. That's the yellow bars, and you can see you get sedation but slower. It lasts a lot longer, at the far side. Incidentally, that 10-minute gap at the beginning while you're waiting for the drug to work well is time you could be doing the procedure. One advantage of a more precise sedation protocol for hospitals is they get more work done. All right. Then finally, the gray bars is the part of the study you don't wanna volunteer for, where they just started the procedure and then gave sedation if the patient complained. As you can see, they did complain, and it took a while to get to an adequate level of sedation. Why do we like it? It is very predictable in its onset and offset. It appears, based on the preliminary data we've seen and some of my own experience with it, at Baylor, that it has less hemodynamic compromise than either midazolam or propofol. One problem with giving sedatives, the blood pressure goes down, and in your older and frail patients, that's an issue. A medication that does less of that's more hemodynamically stable, as we would say, is an advantage. All right? We are very interested in it as a starting point in older and fragile patients where that hangover is a big problem. I'm actually engaged in a national quality improvement effort with USAP right now, partnering with the University of Pennsylvania, to reduce the use of midazolam in older adults. We commonly give it as preoperative sedation for patients having general anesthetic, because of this hangover effect I've been talking about, it contributes to what we call postoperative neurologic dysfunction. That can be anything from a little delirium after the operation to grandma's just not the same ever since she had her knee replaced. All right. It's a major problem. We know that we need to reduce the amount of benzodiazepines we use. It's part of what ASA calls the Brain Health Initiative. We're working on this now, and I am very interested in studying BYFAVO in that population, specifically as a way of reducing this problem while still getting the benefits of sedation. I already mentioned the throughput problem, but if you look at the third line, this is forward-looking statement, to quote the investors. All right, no promises. One possibility is that BYFAVO will have a safe enough profile that after the anesthesia community has had some experience with it, we've had the opportunity to figure out how it works, who it works on, what the right cases are, what the right doses are, and so on, how it should be used, that we will be able to hand that off to non-anesthesia sedation nurses, which will meet a vast unmet need in American medicine right now. This is where we're starting with it. I mentioned I'm using it at Baylor, just in a couple of pilot projects right at the moment. We're looking at patients who need a cardioversion. They need to be asleep for about three minutes and then wide awake at the end. Often, these are patients, obviously, with heart disease, all right, who are somewhat frail. We're using it for transesophageal echocardiography. We're starting to think about it for our frail patients coming to the GI lab for endoscopy, colonoscopy. All right. We're going to ease this into our practice. We'll find out where it's right, where it really adds a benefit. As I say, the potential market for this, just in the anesthesia, what we're touching is 50 million, 60 million patients a year. This is a big deal. With that, I'm gonna wind up. Thank you all very much for your attention. Thanks, Dr. Dutton. Good morning again. The last pipeline product being discussed today is landiolol. Landiolol is an ultra-short-acting cardioselective beta blocker that results in rapid control in patients with supraventricular tachycardia, including atrial fibrillation and atrial flutter. Landiolol has simple intravenous dosing and utility in multiple care settings, including the ICU, the perioperative space, and the emergency department. Safety and efficacy are qualified by approved marketing authorizations that already exist in the EU and in Japan. Landiolol is not approved in the U.S., but the NDA is currently under review by the FDA. The proposed indication for landiolol is short-term reduction of ventricular rate in patients with supraventricular tachycardia, including atrial fibrillation or Afib and A-flutter. What's interesting and an important distinction to note in this space is that we are seeking to treat a condition, not a specific disease. Currently, there is not a single standard of care for patients with this condition. landiolol potentially addresses an important unmet clinical need, particularly among critical care patients. In these cases, providers need to safely and rapidly reduce heart rate without impacting other physiologic parameters such as blood pressure or cardiac inotropy, which is the squeeze of the heart. Examples of these patients include patients with sepsis, patients with heart failure, and patients with underlying organ dysfunction. As noted, there is no single care standard for these patients today, and when treating patients who are more frail or who have more comorbidities, healthcare providers have a limited therapeutic armamentarium. Comorbidities common include heart failure, renal impairment, hepatic dysfunction, as well as respiratory disease. One of the characteristics that makes landiolol unique is that it's ultra short acting. Onset is less than one minute. It clears within about 10-15 minutes, and the half-life is about four minutes. Importantly, landiolol has a limited impact on blood pressure because it's a pure S enantiomer. This is in contrast to esmolol, which is a racemic mixture. Landiolol also has a minimal impact on inotropy due to its lack or less of an impact on the cardiac action potential. Landiolol has a low volume of distribution. The benefit here is that there is less opportunity for toxicity or off-target effects. Landiolol also is compatible in more patients with respiratory disease, and it is the most cardioselective of common beta blockers. The beta-1 to beta-2 ratio is 255 to one. Lastly, landiolol is metabolized by esterases, much like BYFAVO, which was also discussed today by Dr. Dutton. Notably, landiolol is potentially more useful for patients with underlying liver and/or kidney disease, as it does not rely on the kidneys or the liver to clear the drug. Let's look now at how landiolol compares to other agents that are available for rate and/or rhythm control. This slide shows the ways that landiolol is differentiated in this class. It has the shortest onset of action versus commonly available options, as well as the shortest elimination half-life and the shortest duration of effect. When compared just to the beta blocker class, landiolol is also more cardioselective with minimal impact on blood pressure and inotropy. In conclusion, landiolol is intended to be a differentiated, ultra short-acting, cardioselective beta blocker resulting in rapid control of ventricular rate. It potentially addresses important unmet clinical needs, and if approved, landiolol has the potential to provide clinicians with a unique therapeutic option. I'll now open up the program for questions and answers. We'll be available to do that both in the room as well as online. Thank you. Well, thank you everyone. That was. Well, I enjoyed the morning so far. Let me open it up for some Q&A. I think, Tim Lugo, you have your hand raised. Sure. Thank you. Yeah, I'll start from the end and kinda work my way forward so that's how my notes are. I believe Dr. Dutton mentioned about 50 million to 60 million patients. For BYFAVO, can you kind of dig into that data? That's the kind of broad population you mentioned for GI, pulmonary radiation procedures. So the... Right. Right. We I think we need to turn it on the back on here. Are we on? Oh, there we go. Okay. Yeah, we wanna let our online folks hear as well. The question is about where does the 60 million procedural sedation cases come from. Right now in the United States, there are between 100 and 120 million procedures done a year for a broad definition of procedure, everything from colonoscopies to cataracts to heart transplants. Of those, about 35 million-ish are the traditional anesthesia, gallbladders, transplants, cardiac surgery, C-sections, where you have to have anesthesia in a major way. General anesthetics, major regional blocks, that kind of thing. All the rest of it, so that other 65 million cases are in this more discretionary category where the goal is often sedation. They're minimally invasive procedures like the colonoscopy or the endoscopy that aren't really gonna leave a big mark afterwards, where we don't need muscle relaxation to accomplish the procedure as we do when we're operating in the torso. That $65 million discretionary category, $65 million-$85 million, right now, anesthesia covers a certain amount of it, right? We do a lot of work in the GI lab, the cardiac cath lab, invasive radiology, typically for patients who are difficult to sedate for one reason or another. A lot of the rest of it is done, as I say, with midazolam and fentanyl and prayer. The patient gets a much better result when they get professional sedation with an anesthesia clinician and propofol, for example. They are more reliably asleep during the parts they wanna be asleep and awake at the end when we want them to go away. Anybody who's had colonoscopies or this kind of procedure over the years recognizes this, that although we talk about twilight sleep or moderate sedation, what the patient really wants is anesthesia, right, for that period of time. That's where this market is coming from, and the potential impact of BYFAVO in that space is enormous. Follow-up. For you, Scott, I guess maybe a broader question. I believe one of the speakers talked about the MIPS measure 430 incentives. Just in general, we've seen kind of a lot of, you know, those of us who follow drug launches, we've seen a lot of tough hospital-based drug launches over the past few years, besides BENDEKA, by the way. You know, I think BENDEKA was a great one. Can you just talk about, you know, kind of this franchise of products you're putting together in the hospital setting, and how should we think of it as, you know, they launch throughout the year and as you've assembled them? You know, should we be... You know, I guess, how, you know, how excited should we get about them when we start modeling them and looking at Eagle over the next couple years? Yeah. Thank you, Tim. You know, look, as you can imagine, we've modeled and modeled and modeled and looked at a number of analogs before we put this type of money into it. What we found is there's actually a tremendous number of extremely successful hospital products. This entire thought process that it's difficult in the hospital, although it's difficult in the hospital, the common theme running through all this has been deliver a good product that has meaningful benefits for the patient, and then at the same time provides value financially to the hospital system. Those are the products that seem to be rather large, and some of these are blockbuster products like the product that Herm launched in his history. When we look at this, and I hope the case was made today when we looked at all of our speakers, that the products that we selected fit the category. They are meaningful, very meaningful improvements for patients, and they also have the common thread of being economically positive to the healthcare providers. That's what we've tried to do, is work on products that have both those attributes, and if we're correct, we expect these to be very large products. In fact, potentially CAL02 and ENA-001 in the U.S. and worldwide would be blockbusters. Rick, do you wanna add something? If I can throw down on that. I was ironically amused by looking at Dr. Gan's slide set from the poster he put in from our recent ASA meeting from Baylor about BARHEMSYS. I engaged in trench warfare with the Baylor Scott & White P&T committee to get that drug approved and get it available for our clinicians. Baylor Scott & White's a very large not-for-profit healthcare system, and they're no pushovers. It took me six months to get that on the formulary with a very specific protocol for how we were gonna use it for rescue. I was very amused when that nurse from their P&T committee then wrote the paper showing the value to the hospital that it had provided. Tim, let me add, if we go back to Dr. Pergolizzi, to Dr. Gan, who have developed many drugs for the hospital, many of these drugs have become extremely significant products. I don't know, Herm, Joe, TJ, you wanna make a comment about the market opportunity, we believe we've done our homework, or we wouldn't be investing the way we have. Yeah. This is Gil Pergolizzi. Yeah, it may be complex, but it's not complicated, particularly now that you have independent delivery networks and GPOs and places where you can have one focal point to capture a large audience. I think that and then, you know, these massive anesthesia groups which are becoming more and more prevalent, they're competing for bids. They're really being judged by a value-based performance. There's a step up in the game for both the providers and what the payers are expecting, and it's opportunities like this that cross the chiasm, and they're able to satisfy the needs for all the stakeholders, particularly the patients. I think Scott mentioned one word very quickly, and that is international. All of these issues are global. As we sit here, we think about what's happening in the United States. Remember, I'm fielding these emails from dentists from around the world, from plastic surgeons. When I was able to help GSK with ondansetron orally disintegrating, that really was a play to the non-traditional prescribers. When you look at the ability to provide sedation with this new compound, I think it does meet a lot of those additional needs in a very safe and effective and co-cost productive manner. Herm? I think it's been well said. Okay. All right. Maybe for Herm or some of the other folks. Actually, probably not for you, Herm. This is a CAL02 question. It sounds like through the mechanism of action, with 25% to 30% of cytotoxic bacterial proteins classified as PFTs, this sounds like a relatively kind of narrow therapy for what's a very multifactorial condition. The preclinical data suggests that maybe it has broader effect. I know it's a limited kind of human, kind of data set you have so far, but, I mean, what we see is the highest dose looks good. Can you just maybe comment on CAL02 and, you know, how, you know, how broad is this therapy? It seems like kind of a blockbuster if indeed the clinic kind of, you know, reads out positively. Go ahead, Valentin. Thank you. Sure. Thank you for the question, and I'm sorry if I created any confusion. CAL02 is a broad-spectrum agent, so it captures all virulence factors. The point I made on that slide is that there are many types of virulence factors, and we focused on the pore-forming toxins because, you know, their mechanism of action is better understood. It's very simple. They poke a hole. What's in the cell comes out, the cell dies. That group of pore-forming toxins represents 25%-30% of the totality of the virulence factors. However, CAL02 targets and entraps all virulence factors that bacteria would produce. Not all the bugs rely on virulence factors to be more effective, but those that do, even if you give, as we heard from Andre, those that do, even if you give the right empiric antibiotic, you can still have this very complicated evolution of the disease because of the dysregulation of the inflammatory response. One way in which you can think about CAL02 is it addresses this dysregulation of the inflammatory response that leads to complications. 'Cause otherwise, pneumonia in itself, it's pretty easy if you don't get a nasty bug that caused it and if you don't have this dysregulation of the inflammatory response. Andre, I don't know if you'd like to add to this or draw any comparisons with COVID and in that cytokine storm. It's not quite the same thing, but it may be easier. No It's a great question. I think that the, this is one thing that I'm, you know, I'm looking forward to see in the trial. The, you know, we wanna see. I mean, we know that all these bugs that cause pneumonia have the properties to, you know, to release toxins. We wanna know exactly the extent of the problem that can be treated by CAL02. This is why we're doing phase II trial, correct? The idea here is to make sure that we are somewhat broader in the sense that we are taking all the bugs. I think this is, you know, a very bold move for a phase II, that we are taking literally everyone coming with a severe pneumonia. You could argue that you could pick and choose certain bugs, you know, to get a, you know, kind of more targeted approach. Because the molecule really has this property of binding toxins, independent of whatever, you know, what type of toxin is coming from these bugs, I think that makes much more sense to be a little broader in the phase II and try to catch all these patients coming. If toxins are indeed what we've, you know, what we've seen for the last 100 years, the reasons for why our immune system gets so dysregulated, I believe that CAL02 has the potential to really shift the paradigm how we treat these patients. I think that's what we hope. Maybe a quick follow-up. Is that why the over 200 patient study is so large, so maybe if you see sub-subpopulations that can move to phase III? Yes. Thank you. The question was related to the size of the study, and whether we are aiming to enroll over 200 patients in order to see trends in subgroups. Yes, that's what. That is a great question, but no, we're taking a different approach. We need to be very disciplined in order to get CAL02 through the regulatory process, because we are equally excited about the potential. That is a pitfall. If we let ourselves be distracted about all the possibilities, then, you know, the road to approval is gonna be long and complicated and maybe not lead anywhere. In this particular case, we focused on severe pneumonia, severe community-acquired bacterial pneumonia. The reason why we focused on the community-acquired pneumonia is because the types of bugs that normal or usually give this community-acquired pneumonia is limited. We know that the majority of them, and the prototype for that bug, is the Strep pneumoniae or pneumococcus, as Andre indicated. We know that pneumococcus relies on these virulence factors to be more effective at infecting the host, so we know that CAL02 is gonna work on it. As you know very well, when you go to the regulators, you pick an indication that is significant in terms of unmet medical need, and where you can clearly demonstrate whether your drug works or not. The size of the study comes from, in a way, from the execution of the study. First of all, we wanted to replicate the results of the smaller phase I study that you saw. At the same time, we want to move ahead with the development. For that, you need to go to more sites. You go to more study sites, you introduce diversity. Diversity drives the sample size. The 276 subjects was calculated by the statistician, taking into account the diversity introduced by all these sites that, by the way, are both in the Northern and Southern Hemisphere. The information I presented on the slide will be on ClinicalTrials.gov when the time comes and we post it. At that time, you'll have a better idea. Thank you, Valentin. We have a follow-up question, similar. I have two questions online here. The CAP population, I think you had just gained this, highly heterogeneous and fragile. How did you design the entry criteria for the phase II trial to optimize the likely outcome? A great question. You know, with all these syndromic diseases, infectious disease, you always have some degree of heterogeneity. You cannot avoid that. Even, you know, even if you say we chose to say we're gonna just enroll a patient with the one specific bug, let's say pneumococcus. You know, if each one of us got infected with pneumococcus today here, we would have a different clinical picture, right? The point is, You know, targeting one bug is not the goal for a drug that actually target toxins, correct? We gotta be careful about this. We really have to focus on the big picture. We don't wanna lose, you know, the big picture here. The, the way that we designed this trial, I think it's gonna be really a novelty, is that we are looking for patients that match the severity of the disease by either having acute respiratory failure, that means these patients are either intubated or requiring a intense respiratory care that we call high flow and positive pressure. These are patients that clearly are in a different level of severity or if these patients are in septic shock. These patients are very specific. They are relatively homogeneous in the sense that all of them are gonna have severe respiratory failure or severe hypotension. That, to me, is a key point to really include patients that have a commonality. The commonality is that they are losing the track of controlling the infection. They are losing because they have too much toxin release, they have too much toxin causing damage to the immune system. I believe that is gonna bring some degree of homogeneity that's gonna make this trial much more targeted in terms of knowing if these toxins, the inhibition of these toxins by CAL02 will change the outcomes. I think that's one of the novelty of this trial, is 'cause no other trial has done such a good job in terms of looking for this very specific inclusion criteria in CAP. Dr. Kalil, keep the mic in your hand for a second. We have another question from Brandon Folkes over at Cantor Fitzgerald, who asks another wonderful question. He says, 'Targeting these large markets in the hospital, do you expect the hospitals to run their own experience trials before adopting the drugs we spoke about today? Or how do you think about the adoption of these products? Asked another way, do you expect any of these products to bend the normal hospital drug adoption curve?' Before we answer that, maybe what we should do here is break it out because CAL02 and ENA-001 are very unique first-in-class drugs impacting these diseases that really need help. Before we get to BARHEMSYS and BYFAVO, if we can segment these. I guess another way to ask the question, Andre, is if the data in the phase II study bears out what we've seen in the small early studies, how likely do you think infectious disease physicians like yourselves and around the world would use the product? In fact, also assuming how we price it. Mm-hmm. assuming that the pricing works out favorably, what would you predict the pickup would be? No, it's a great question. The one advantage of being first in class is that, you know, this drug will not be used, just randomly by, you know, by clinicians like myself. Just, "Oh, you know, I wanna give a try to see what's gonna happen to my patients. I read a paper in some place." I mean, this drug is not available, right? Being first in class mean this drug, in order to be, you know, to be at the bedside, the drug is gonna have to be approved by the FDA. There is only one way to approve by the FDA, is doing the good science. I think the good science is gonna come with this trial. That being... that situation being, you know, kind of completed, the trial is complete and the drug shows exactly what you expect to show. That means patients they're gonna have better recovery from septic shock, better recovery from respiratory failure, and they will have a better survival. I think that's gonna be easily adopted by clinicians all over the world because, as I mentioned before, remember, this is a molecule that will not cause more bacteria resistance. This is a molecule that will not cause more immune suppression, even though being immunomodulatory. This is a drug that's not gonna affect the patient's microbiome, the good bugs. I honestly think that if phase II is positive and the FDA moves ahead with approving the drug conditionally or unconditionally with whatever more data is needed, I think that would be quite a easy process to move forward in terms of applicability at the bedside because of the safety profile and the lack of interaction and harm as we talked before. I think from the infectious disease, from a critical care perspective, I don't see hurdles in terms of adopting this drug as long as the good science brings the results that we expect. Thank you, Dr. Kalil. I think the same question pertaining to ENA-001. Who's best to respond to that? Maybe Dr. Pergolizzi, how you feel about... Maybe, you as well, Herm. Herm, why don't you start? Absolutely. I really appreciate Brandon's question. One thing that I'll add, or actually two points going first back to Tim's question. Remember, the funnel, the top of the funnel is so enormous. These aren't categories where you need extraordinarily high market shares to really build significant economic value for an enterprise. That's just one thing I wanted to follow up with your point. That's something to think about from a modeling perspective. When you look at price analogs in the current market, even at very reasonable, economically interesting points for the institutions, you get to very large numbers at the bottom of the funnel. Going back to the point, Joe, maybe you could talk a little bit about repeating some of the things that you exemplified during your presentation earlier in the day, is how we're actually going to be pursuing with the FDA the development of the drug. I think Joe pointed out earlier, our phase II study is in and of itself a prophylactic study. Not only are we demonstrating the clinical benefit to the patient, but think about the fundamental structure of the study is actually showing that the drug enables patients to flow through the theater in a much more expedient manner, much healthier and much more expedient. Less time in the PACU, less time in the hospital, and less readmission rates. Not only is that an essence of how we're gonna get the drug approved, but by de facto, we're gonna be building a health economic model during the clinical program itself. Maybe, Joe, you could expand on that a little bit. Certainly. Thank you for articulating that, Herm. Yeah. When we look at the indication of postoperative respiratory depression, Enalare is hyper-focused on using its funds and human capital resources to advance the lead indication, which is postoperative respiratory depression. In doing so, we put on a global provider and, quote, "purchaser" hat. Meaning we look at guidelines like NHS England, and we look at CMS and HHS guidelines here in the United States, those which are all being supported through the American Society of Anesthesiologists, the perioperative nurses, College of Surgeons here in the U.S. and abroad. We decide that being able to provide a way to mitigate postoperative respiratory depression and also rescue it if necessary on the floor or in the unit or in the PACU is very compelling for these institutions to be able to reach a positive ROI and for us to achieve those health outcome measurements that Dr. TJ Gan mentioned with the MIPS and the MACRA that are, you know, economically credentialing physicians and at the same time providing the opportunity for hospitals to even do better on their reimbursement. Aligning with those strategies of improved patient care and outcomes and incorporating those into what we try to capture in our endpoints for the various studies is the way that we're gonna try to answer that economic positioning statement. I hope that helps. Thank you, Joe. We have another question online. What is the marketing push and penetration for BYFAVO? What is the timeline to sales growth? The comment I'll make there is I thought Dr. TJ Gan and Richard Dutton did a great job today, along with Deb, explaining the really significant positive differentials between the value of the two drugs to what's on the marketplace now. What I would point out is that we have very good hit rates with the P&T committees for both products, Deb, and we're relaunching the drug now. With our sales team, I won't quite say it's like starting over, but we're seeing really very encouraging results, and I think it's gonna ramp up as we anticipated, and we're pretty excited about it, and we've put more people behind it. I don't know how that looks to a typical analog about how it ramps up. Based on, again, the value to the hospital systems and the clear differentiation and benefits of the products themselves, we see some really very positive results, and we expect today even more enthusiastically than we did when we made the acquisition, that we expect to get to the levels that we anticipated in the work that we did to make the decision to buy the company. Deb, I don't know if you wanna make any comments about how we're handling the marketing in addition to what you said during your presentation. Yeah. I can just comment on that a little bit. Obviously, we have the sales force that's out there, calling on these health systems and the IDNs and the hospitals. For BYFAVO specifically, it kinda goes back to some of the comments made earlier by Dr. Pergolizzi. Some of those dentists, you know, they're looking for options too because they do endodontists when they're doing, you know, crowns or not crowns, but when they're doing certain procedures. We have quite a few dentists anesthesiologists who have adopted BYFAVO. We're looking at potential to expanding outside of that as well with plastics and some of the others where these are quick procedures, and they need something safe and effective because they don't have the support of the anesthesiologist readily available. From a marketing perspective, we're really ramping up our digital marketing efforts and our presence at different conferences. In fact, part of the team is at one this week right now. We'll also be at one later this week with PGA. We're very much present and participating in those conferences and enhancing our digital marketing efforts as well. Thank you, Deb. Any other questions in the room? Yes. Thanks so much. Thanks, guys. Thanks, Isaac. Piggybacking off of Tim's questions and a few of the other questions we've heard, it's clear that hospital-based chronic launches have definitely struggled in the last few years. This is in relation to BARHEMSYS. I mean, you guys have talked about the economic benefit of using a product like that. It looks like there is a market. Patients do fail on one or two options. I mean, there is a patient population out there, but again, we've seen a sluggish launch so far. I guess what I'm really getting at this is what are the specific headwinds to the BARHEMSYS launch? I mean, can you give us some details on how the conversations with P&T committees are going? I mean, I know you mentioned that you've got a pretty high hit rate, but can you give us some more details on what you're seeing there? Is it a matter of educating docs? You know, where I'm really going with this is what gives you confidence that you can give this more TLC and some more love relative to what the Acacia guys were doing to really pick the product off the ground. I guess my second question is more for the Enalare guys. I believe you mentioned an intranasal formulation of ENA-001 in development. Can you give us some more color on that and where it is in development? Thanks. Deb? Sure. So for BARHEMSYS specifically, you're correct. We are having a very good hit rate with the P&T committees. We're at over 85%. The couple headwinds, one is launching in a pandemic, and the second one is launching without appropriate resourcing. We were limited in our ability to fund the launch. What happened is, we had a very, very small sales force who was going out and trying to call on these health systems. The other thing too is, during the pandemic, the P&T committees, they either shut down and didn't have them or they delayed them, we saw multiple delays. When we were able to get in front of the P&T committee, that over 85% hit rate was very encouraging for us because it meant the value proposition was meaningful and could add value. The other thing that gives me a lot of excitement is you saw two of the examples between Stony Brook and Baylor Scott & White, where they did their own, you know, clinical trial. It wasn't a clinical trial, but their own trial and evaluation of the drug, and it came out better than our clinical trials showed. We know that, and based on the feedback we're hearing from the PACU nurses from these places, we know that the drug is delivering as we would expect it to. Really, it comes down a little bit, to use your words, it needs a lot more TLC. Because when we are able to have those conversations, then we're able to see the results and see that get driven and see the patient benefit. I think that's really. Once they see the patients benefiting from the drug and then seeing those results, that's when they wanna replicate it and leverage it more. The headwinds are really subsiding, I would say, from a pandemic perspective. Really what we're trying to do is get out there now with our voices and really secure that positioning for the drug. I would add that we really do need to think about these drugs as being launched now for the first time. The amount of effort that the former Acacia company was able to put together behind it was really insignificant. You know, which was our good fortune, that we were able to acquire these two products as cheaply as we did. I will say that as you see the usage building here, if we look to January as the point in time where we say, "Okay, we laid the foundation, we've expanded our territories, we've hired new reps, we've gone through training," I would look to the first quarter of the year coming up as the place where we can really say, "Okay, the products relaunched. We're out. We're getting the message out. Greenberg, who spoke a few times today, who heads up medical affairs and has our MSLs, I speak to Mike pretty frequently about this. The feedback we're getting from what I would call the wider audience of not just somebody like TJ Gan, who's a KOL, who you bring in to speak today, who has all this knowledge and background. We're getting the same feedback from the multitude of physicians that we're speaking to out in the marketplace. I believe, Mike, we have a good group of MSLs who are not as strong as our KOLs today in being able to make this presentation or the time to sit for 45 minutes and make a presentation. They are capable of making the same as well as Deb's salespeople, the same activity as we saw today, and the feedback has really been very positive. To your point, I expect that we're gonna start to see a very nice ramp of these products based on the feedback we've seen, both for BARHEMSYS and BYFAVO. We're holding firm to the forecast that we've given previously. If anything, we're more encouraged today than we were six, seven months ago when we bought the company. Any comments, Mike, or anything from anyone else? Agree. The proof will be in the pudding. We'll see over the next few quarters, but we're feeling good. Yes, Isaac. I guess my follow-up to that is, I mean, I know that you talked about structural issues with the hospital system now. How do you see those issues resolving in the next, let's say, six to 12 months? Okay, Deb, you wanna take a stab at that maybe? Can I clarify what you mean by structural? I mean, I know that there's, of course, well-documented staffing issues. Obviously, the financial constraints associated with the hospital system. How do you see those issues resolving in the next six-12 months? Yeah. I can't predict how they'll resolve, but what I can tell you is how I believe we can help be a part of the solution. We're not a magic bullet, but a part of the solution. Really, that is with that enhanced throughput. That 35 minutes less in the PACU time, the six hours less in the hospital, that really helps them be able to then continue to have the efficiency. The heartbeat of the center is that surgical room, right? That's where the best profitability comes. If we can take them out of OR and move them along, we've had cases where people were able to skip the first level of PACU and move on because they were doing so well. Our ability to help with that throughput and with that efficiency is where we can be a part of that solution. That is a big piece of what we're doing. In terms of the staffing, obviously, that's not something we can solve for, but our solve is actually then through the increased headcount and representatives out there. It means we actually have to do more in-servicing because there is rotation of nurses. You have the same PACU manager typically, but then you have quite a few different nurses who are part-time coming in and rotating through. Our job is to then make sure that it's on the order sets and it's on the protocols to help with that, and then to educate more broadly, so that the other nurses are aware as well that there's a new solution and availability for it. Herm, would you like to make a comment on the IM? Yes. The intranasal. Yeah, on the intranasal. Question... Just very quickly. That is in the early concept stage. That is part of our relationship with BARDA. BARDA, as we mentioned earlier, is very eager, as expediently as possible, to develop an immediate solution in the marketplace. Intramuscular is our top priority at the moment. Intranasal is certainly a consideration for the long term as well. Do we have further questions? Okay. Well, let me conclude this way by first saying thank you to everyone that joined us today live here in New York or online, and to our incredible, wonderful, talented, experienced KOLs who flew from around the country to be here today and/or have decided to be partners with us in trying to help bring these great products to the market. I am most proud of everyone at Eagle and the work that we're doing, that a company our size can amass these types of products, this type of a pipeline, and have these incredible KOLs interested and desirous in helping us bring these products to market. I couldn't be more pleased with the short-term opportunities for this company and the long term. I think we're unusually well-positioned being a company with cash, a strong balance sheet, strong earnings, and still being able to fund these really exciting first-in-class products and launch twop wonderful products. It's a very exciting time for the company. Thrilled that everybody spent time with us today. Appreciate it. More to come. Thank you very much.