Aquestive Therapeutics, Inc. (AQST) Earnings Call Transcript & Summary

[Audio Gap] opportunities and progress relating to our epinephrine program. Before we start, let me make the obligatory statement that during the presentation, the company will be making forward-looking statements. We direct you to the risks and uncertainties affecting the company as described in the forward-looking statement page at the beginning of the PowerPoint presentation being shared with you all today. I'll turn the program over to the team you really want to hear from in a moment. But first, though, I'd like to take a minute to update everyone on the progress we're making in one of the other key programs at Aquestive, Libervant. As many of you know from our recent earnings call, the company's lead asset is Libervant buccal film. The work we need to do to prepare our NDA resubmission, inclusive of the agency's comments that we recently received is progressing as expected, and we remain on track for a near-term submission of this product with the FDA by the end of the second quarter. We're committed to bringing this product to market as quickly as we can get it approved. Let's turn now to the topic at hand. Today is about another very important program for the company, our epinephrine program. Over the last 120 years, the world has undertaken change at an astounding pace: Air travel, space travel, computing, cell phone technology, monoclonal antibodies, gene therapy, improved cancer treatments, the list goes on and on. While the progress bodes well for our world, it is more complicated for those of us at risk for anaphylaxis. Over the same 120 years, we've made almost no progress on how we deliver epinephrine. In fact, we're still delivering epinephrine in an injection form, the same way the previous generations did when Parke-Davis first started marketing epinephrine in 1901. The only innovation for the delivery of epinephrine has been improving a manual injection to an auto-injector. That innovation took almost 90 years to occur and is now over 30 years old. 90 years and 30 years, astoundingly slow marks for innovation. To complicate matters, at the same time, the planet has grown from 2 billion to 8 billion inhabitants. According to the Allergy & Asthma Network, 1 in 12 children worldwide currently have a food allergy. 25% of allergic reactions in a school setting occur without a previous diagnosis. The annual cost of food allergies alone is $25 billion per year in the United States. The implication of failing to pay close attention to these statistics mean that we, as an industry, continue to underserve a large patient population. It's for these reasons that we have 3 very strongly held convictions about moving forward. They are: first, innovation in the allergic reaction space is not only necessary but good for every stakeholder who's on the call today, especially for patients, health care providers, and caregivers. Second, something has to change, but change is not easy. There are barriers in every step in the process. And in the case of epinephrine, these barriers include significant scientific hurdles that must be overcome. And finally, our third conviction. We believe that Aquestive is uniquely positioned to enable the first orally delivered epinephrine product in the world. With that, I'll hand it over to Dan Barber to walk you through today's events. We're very excited about the progress we've made in the last year regarding this program. We think you will be as well at the end of the program. Thank you again for spending the time with us today. And I will hand it now over to Dan Barber, our Chief Operating Officer and leader of these efforts, to walk you through today's program.

Thanks, Keith, and thank you to all of the various stakeholders attending today: patients, caregivers, health care providers, investors, analysts and many more. We appreciate that you are using your valuable time in order to be with us today. We have an exciting program to share with you, and we are confident that you will be glad you made the choice to attend our R&D Day. As Keith mentioned, my name is Dan Barber, and I am the Chief Operating Officer at Aquestive Therapeutics. Joining me today is the Aquestive product development team for epinephrine, along with 2 very important key opinion leaders. My colleagues here today are Michael Arcara, our marketing leader; Dr. Steve Wargacki, our R&D leader; and Dr. Mark Lepore, our clinical leader. I am also joined by Dr. David Fleischer from the University of Colorado; and Dr. John Oppenheimer from Rutgers University. They will introduce themselves further during today's call. As Keith mentioned, we are uniquely positioned to deliver the first orally administered version of epinephrine for anaphylaxis. What you see on the screen right now is our PharmFilm technology. Only a few millimeters thick, the size of a poster stamp and weighing less than an ounce. This product can be carried in your pocket, can withstand submersion in water, temperature excursions and direct sunlight. The product is administered sublingually, or under the tongue, and dissolves in seconds. We are the leading innovators of oral films and have delivered billions of sublingual films to patients over the last decade. We have used all of our learnings, know-how and brain power to create and protect the first oral epinephrine film. Today, you will hear from Dr. Fleischer and Michael Arcara about the continued unmet need in the allergic reaction space. You'll hear about patients who refuse to carry an EpiPen as well as patients who refuse to inject themselves with a needle. Dr. Steve Wargacki will talk about the significant scientific challenges of delivering epinephrine and the breakthroughs that he and his team have created. He will walk you through the science behind AQST-108, and will introduce an exciting addition to our pipeline with AQST-109. Dr. John Oppenheimer will walk you through the known clinical data on epinephrine from a key opinion leader's perspective. And finally, Dr. Mark Lepore will walk you through our clinical results to date, as well as our upcoming clinical plans. At the end of the presentation, we will open up the line for Q&A. We are confident that you as our stakeholders will benefit from today's discussion by better understanding our technology and progress. And we are also committed to bringing the benefit of our technology to patients at risk for allergic reactions. When you leave here today, we are also confident that you will agree that there is a large, unmet need and a growing patient population in this area. Aquestive is the first and only company that has successfully demonstrated a repeatable and predictable capability for orally administering epinephrine, and we have a pathway to approval in bringing our product to the market. With that, I'm excited to introduce Dr. David Fleischer.

Thank you, Dan, and good morning, everyone. My name is David Fleischer. I'm a Professor of Pediatrics and the Section Head of Allergy and Immunology at Children's Hospital Colorado and the University of Colorado School of Medicine. For the past 20 years, I've been managing patients at risk for anaphylaxis, especially relating to food allergies. I've also worked with various industry partners over the years on the development of different formulations and different delivery methods of epinephrine, the first-line drug for treatment of anaphylaxis. I'm pleased to be here this morning and to share with you why I believe Aquestive has the opportunity to make a substantial contribution to the protection and treatment of patients at risk for anaphylaxis. To begin, I'd like to spend a few moments reviewing for you what anaphylaxis is, its current treatments, and some of the improvements, I believe, can make a critical difference for at-risk patients. First, what is anaphylaxis? Anaphylaxis is a severe, potentially life-threatening allergic reaction. It can occur within seconds or minutes of exposure to something to which you're allergic. Medically speaking, anaphylaxis causes your immune system to release a flood of chemicals that can cause you to go into shock. Your blood pressure drops suddenly and your airways narrow, blocking breathing. My colleagues will provide more information on specific epidemiology a bit later, but I can tell you that anaphylaxis is relatively prevalent in the general population. Indeed, most any allergist or pediatrician these days will see numerous patients per week, if not per day, who are at risk for anaphylaxis. These allergic reactions can pose serious consequence for patients. As such, anyone at risk for anaphylactic reaction should be under the care of a health care provider and have a management plan, which includes immediate access to epinephrine. Many people are aware that foods such as peanuts can cost severe allergic reactions, but this next slide shows other common triggers of anaphylaxis as well. Specifically certain foods, including peanut, tree nuts and shellfish, insect venom and medications are all known and somewhat common triggers of anaphylaxis. Exercise-induced anaphylaxis is a less common condition, in which anaphylaxis may occur during or after a physical activity. In some cases of anaphylaxis, no trigger is identified. This condition is known as idiopathic anaphylaxis. Epinephrine has been around for a very long time, yet it remains the only first-line treatment of anaphylaxis and the sole effective and recommended initial treatment of anaphylaxis. My colleague, Dr. Oppenheimer, will speak more to the specifics of epinephrine in a few minutes. But in general, epinephrine also known as adrenaline, helps reverse anaphylaxis while stimulating different receptors in the body, effectively increasing blood pressure and reducing swelling, for example, in the airways. As I've been alluding to a few times this morning, failure to administer epinephrine to a patient in anaphylaxis can lead to death. Conversely, timely administration of epinephrine significantly improves survival and other patient outcomes. Importantly and perhaps sadly, failure to administer epinephrine, and I want you to underscore the word promptly, has been shown to be the most important factor contributing to death in anaphylaxis patients. Headlines such as the ones on this slide are often -- are seen all too often. And are unfortunately, given the vast majority could likely have been prevented if treated appropriately. I have seen the rapid response induced by epinephrine first-hand in a family member. My then 9-year-old son who has asthma and season allergies, who was getting one of his allergy shots. I was there with him in a few minutes after getting one of the allergy shots, he complained of difficulty swallowing and breathing. Immediately the nurse gave him intramuscular epinephrine, and within a minute or 2, he was fine. Having treated many patients with anaphylaxis over the years, watching your own child respond to epinephrine so quickly can only underscore the importance of it in managing anaphylaxis. We've now reviewed medical literature and real-life stories about the importance of immediate access to epinephrine and the potential consequences of not having immediate access to this life-saving medication. Let's now turn our attention to how some of the real world reasons patients can fall short of having immediate access to the epinephrine auto-injectors. Even for patients who carry [ the risk ] who have their EAIs with them, there is certainly no guarantee that they will use the medicine correctly. The EpiPen, for example, has a number of steps involved, as seen on this slide. Keeping in mind that weeks or months, if not years, are likely to have been passed between the day a patient receives and is trained on their EAI and the day they actually have to use it. This time lapse, coupled with a panic emergency situation, can and does lead to misuse of EAIs. Both my experience and data show us that correct use of EAIs, indeed -- correct use of EAIs is indeed surprisingly low. You can see from the data in the first bullet on this slide that correct use was achieved by 16% to 32% of patients. Either one of our allergy fellows who trained many patients and families on the proper use injected himself in the thumb when he actually held the EpiPen in the wrong direction. Remembering to take and even intentionally leaving their EAIs behind when they leave home is another issue for patients. Studies have shown that just half of people prescribed an EAI actually have it with them at all times, even though as I am speaking to this morning, exposure to an allergen for most people is unpredictable and can happen any time, anywhere. Additionally, both patients and caregivers have been shown to be reluctant to administer the EAI when it is needed, needle phobia being a large contributing factor to this. There are multiple reasons behind all the issues on this slide. Some are human nature and unavoidable to some extent. But I do believe that if patients had the opportunity to carry a medicine with them that was smaller than the current EAIs, took less steps to administer and could be given without an injection, there would be more patients taking their medicine with them more often, and less patients unwilling or unable to administer out the medicine in an emergency situation. Another pitfall of current EAIs can be seen on the next slide. From actual health care providers given an EpiPen upside down and injecting their own thumbs, to patients causing considerable damage to themselves with an incorrect use of the pen, as seen in these pictures, anytime there's a needle involved, there is room for human error. In one 13-year period measured by Poison Control Center, there are more than 15,000 unintentional reported injections due to EAIs, many of them in children. Talk to most any physician and he or she has examples of patients who incorrectly used an EAI and some, like my colleague, may have even done it to themselves. Before I turn it over to Michael, there is one more set of data I think you will find interesting and relevant to our discussion today. While some children may actually eventually outgrow their allergies, for many this is a lifelong diagnosis. As such, if you should have epinephrine with you at all times when first diagnosed, you should also have it with you all times in the future. Again, exposures and serious reactions are unpredictable. Even so, over time, many patients begin to worry less about a reaction and become less diligent about carrying their EAI with them, especially the longer it has been since they may have had an allergic reaction. I think out of sight, out of mind begins to eventually take over. For example, a few months after diagnosis, that EAI goes everywhere the patient goes. Then a few months later maybe the EAI stays in the kitchen drawer a quarter of the time, then half the time. And before long, leaving home without the EAI actually becomes the habit, and the habit leads to a lack of refilling the EAI when it expires. As seen on the slide, data have shown what I've just talked about to be the case for many patients. In this study, less than half the EAI patients refilled their prescription at least once. Just 25% refilled multiple times and just 11% refilled once for 5 years. I'm not going to claim that a pocket-sized film can solve human nature, but I do believe that a product with more easily -- which more easily travels with a patient in a wallet or a pocket, for example, it's more likely to stop -- stay atop of patient's mind and therefore, have an opportunity to do, in fact, remind and encourage patients to refill their prescription when it becomes dated. In summary, anaphylaxis is unpredictable and rapid in onset, which means at-risk patients should always have immediate access to 2 doses of epinephrine. Indeed, a delay in administering epinephrine can lead to mortality. Despite all of these points, too few at-risk patients actually carry their EAIs with them, refill their EAIs on a regular ongoing basis, are confident, timely and accurate in the use of an EAI during an emergency situation. While not a magic bullet when it comes to carry and refill rates, I do believe, again, the film product has an opportunity to improve a patient's ability to carry and appropriately use epinephrine. Also not having to use an injectable form of epinephrine might lead to more rapid, appropriate use of epinephrine and eliminate the injuries that can occur with a needle-based device. As a treating physician and researcher for anaphylaxis, I do believe the film dosing could represent a significant advancement in treatment. I would now like to turn the presentation over to Michael Arcara, who will talk to us about the commercial opportunity for the epinephrine in film.

Thank you, Dr. Fleischer, and good morning, everyone. My name is Michael Arcara. I'm heading up commercial development for PharmFilm. I've been working in the pharma industry for more than 25 years now. More than a decade of that time has been spent in the epinephrine space, including a number of years on U.S. marketing of EpiPen. I've paid a fair amount of epinephrine market insights and knowledge over those years, and over the next few minutes, I'm looking forward to sharing some of those insights with you, which I hope as analysts will be helpful in your evaluation of this opportunity. Let me start by providing some background on this market and this market's potential. Unfortunately, when you go back to the office and begin looking into this market, you'll find the epidemiology to be somewhat imprecise. Even so, there is some recent literature, which can help us start to quantify just how large this market and market opportunity is. So let's start with the lowest common denominator, patients who have actually reported having an anaphylaxis episode. A recent paper estimates that at least 1.6% of the U.S. population, and perhaps closer to 5% of the population, has had at least 1 allergic reaction severe enough to be classified as anaphylaxis. To put that into numbers, those estimates translate to between 5 million and 17 million people in the U.S. who have had an anaphylaxis episode. Looking at my graphic on the right side of this slide, please note that even if you split that 5 million and 17 million down the middle, say 11 million people who have had anaphylaxis, we have a very large patient pool. And we are still not including people who are at risk for anaphylactic episodes, but have not yet had one. Let's pause on that statement for a moment. People at risk, but have yet to have had an anaphylactic episode, because this patient segment adds to our base number of 5 million to 17 million. To this point and noting the third bullet point on the left side of the slide, published data has indicated that people dying from food allergy often had previous reactions, but these reactions were not severe, i.e. they were not anaphylaxis. What does all this data mean for us on the call today for our take homes? It means that many millions of Americans have had an anaphylactic reaction, again, between 5 million and 17 million, and many more are at risk for a very severe reaction but have not yet had anaphylaxis. If you put both of these sets of patients together, we have a patient set that all should be prepared for a severe reaction by having immediate access to epinephrine. Just one quick note before I move on, the bottom bullet on this site -- on this slide, excuse me, cites some additional data, showing that food allergy, as prevalent as it is, has been and continues to rise in children. Let's now take a minute or so to look at the recent EAI market. I know as analysts, this is some of the most important information for you. What you see at the top of this next slide is the data on total epinephrine auto-injector prescriptions going back to 2014. What I will ask us to focus this morning is on the years around 2016, as noted on the slide, where you will see that the U.S. market was getting close to 4 million prescriptions per year. Though not a true apples-to-apples comparison because epinephrine auto-injectors expire and have to be refilled about once per year, let's roughly assume that each prescription in this market equals 1 patient, in other words 4 million RXs equals 4 million patients on and filling drug each year. If you were to go back and analyze the 2016 time frame, you would find heavy EpiPen promotion, including TV advertising and the use of celebrities. From this, it's apparent that Mylan was putting fairly significant marketing efforts behind EpiPen in that time period, and that this market is, therefore, promotionally sensitive. Looking at the right half of the table, you will see the prescriptions did begin retreating in 2018. Given what we know about the increasing prevalence of food allergies, it's safe to assume that this retreat coincides with EpiPen losing patent protection and Mylan withdrawing most, if not all, promotional efforts from the brand. As I just mentioned, this market appears to be highly promotionally sensitive and it's important to keep that in mind. For those of you that have not already done the math, please remember what I told you on the last slide about the estimated 11 million plus at-risk patients. When you take that 11 million patients and subtract the peak 4 million that were prescribed the medicine, you see that this market has significant room to grow, even beyond what was being achieved in 2016. Of course, it's hard to have any kind of EpiPen discussion without mentioning price. As I'm sure you know from press coverage, there was slight controversy over EpiPen pricing before it went off patent. There's no need for us to rehash that today, but what I do want you to take away from this slide is that the current price of a generic EpiPen 2-pack is roughly $300, which has been steady for a few years and is off the branded price of roughly $600 per 2-pack. So Dr. Fleischer and I spent a little bit of time reviewing for you the background and the potential of this medical and market opportunity. But if I'm sitting in your seat as analysts and investors, I'd also like to see some voice of customer data, and that's precisely what I'd like to cover for you next. Let's start with some physician research. This slide shows data from an online quantitative survey we did with 500 allergists, pediatricians and primary care doctors. We first asked these doctors to what extent they would prefer an alternative dosing to EAIs. As the results of this slide show, close to 90% of the 500 indicated at least some preference for alternative dosing. In that same study, we asked respondents how concerned they were that patients do not have their EAI with them when they leave home, another really high percentage. Again, close to 90% indicated concern here. Patients are important, of course. So let's now look at some patient research we've conducted. For the patient research, we conducted an online survey of 150 epinephrine patients and caregivers. The first thing patients told us before we revealed anything about the film was that they too prefer alternative dosing. In this data set, you see 88% of respondents at least somewhat prefer a new method of dosing. 88%. For our next question, we actually exposed respondents to pictures of PharmFilm and asked about their interest in the product. As you can see here, 80% expressed significant interest and a full 99% expressed interest -- at least -- I'm sorry, excuse me, expressed at least some interest in the film. Again, 99% expressing at least some interest in learning more about the film. Perhaps even more encouraging is this slide. Both commercially and medically speaking, 94% of respondents felt that the smaller film package would make it more likely for them to have the film with them when they needed it. Again, that is medically important because people have access to the medicine. And it's commercially important because people will have this product with them and refill it every year. Importantly, the last question we asked respondents in our survey was how likely they would be to ask their doctor about the film if it were available. Close to 70% said highly likely and 96% said at least somewhat likely to ask their doctor. Really amazing and encouraging numbers. Before I leave the customer feedback section, I just wanted to share a quick story with you that sticks in my mind and this is some market research I did a couple of years ago. In that market research, we were interviewing a mom, and this was a well-educated, articulate mom, of a son who had severe peanut allergy. There was a day when that son -- or when her son got exposed to some peanut residue and was starting to have a severe allergic reaction. What that mom told us that day, and she was almost embarrassed to say it, that she was driving to the emergency room, she had the steering wheel on one hand, the auto-injector on the other, and she did not want to give her son that auto-injector. She was willing to take a chance and get to the ER and have someone else do it for her rather than stick her kid with that needle. Luckily, that day turned out fine for the mom and the kid. The son was fine. But how eager and anxious do you think those parents would be to have an alternative to an auto-injector for their kid? Let me now begin to summarize why I believe you as investors, you as analysts and why we all should be optimistic and indeed enthusiastic about Aquestive's PharmFilm opportunity. The left side of this slide depicts why we firmly believe an oral film dosing of epinephrine delivers on unmet needs and can take significant share from the in-market auto-injectors. We're smaller. We should be easier to carry, for example, in a wallet, purse or shirt pocket. In terms of usability, patients and parents won't have the needle issue to deal with. As part of our product development program, we will also be striving to develop the film and packaging such that we improve on some of the temperature and moisture control issues that auto-injectors are faced with. For example, temperatures below around 60 degrees and above -- around 90 degrees can be an issue for auto-injectors. And I believe that temperature range covers just about every county in the U.S. during certain times of the year. So on the left side of this slide, we should take away the potential for a better product to capture share of the existing market. Now let's go over to the right side of the slide. Here, you will see why we believe PharmFilm, bolstered by Aquestive sales and marketing, can deliver financial value above and beyond capture market share. For example, there are patients who just will not fill an EAI because of its needle or its size. We believe we can bring these patients into the market. We are also confident that by calling on physicians, working with KOLs and patient advocacy groups and running patient promotions centered on PharmFilm's attributes, we can grow this market not only to where it was at peak, but to even higher levels. Let's now take a look at what potential net revenue could look like for a new, incrementally better product in this market. Recall that at its peak, the U.S. market was roughly $2.4 billion and 3.8 million prescriptions. For sake of analysis today, it's probably better to focus on RXs [Audio Gap] this had dropped since 2015 given the generic conversion of EpiPen. On the left side of the slide, for a low case scenario, let's assume that post-launch of a film product, the Rx market simply returns to where it was in 2015, '16. Under this scenario, assuming no price premium to the current generics, and taking just 30% market share or so, we could generate close to $250 million in annual net revenues at peak. For a base case, let's now consider what I believe is a much more likely scenario. If we assume that film Pharm (sic) [ PharmFilm ] will deliver a more patient-friendly product that drives market share, that Aquestive driven physician and consumer marketing creates some incremental market expansion and that PharmFilm can command even a relatively small price premium versus generics, we can model net revenues at peak closer to $500 million. For an upside scenario on the right side, which is by no means out of the question, let's paint a scenario where PharmFilm becomes EpiPen like, when EpiPen held the market. Under a scenario like this, we could see net revenue generation in the range of $750 million annually. All right. That's it for my section. So I'd like to close now with what I believe are the main points from a business perspective, which are most pertinent to those of you tuning in today. As analysts and investors, please keep in mind, there is a large and growing at-risk population. And right now, just a fraction of these patients are carrying epinephrine with them, which translates to a large existing and potential market for new entrants. Secondly PharmFilm, because of its friendly dosing, has the potential to deliver on physician and patient articulated unmet needs in the marketplace, resulting in an opportunity for significant market share. So tying it all together, I hope you will agree with me that Aquestive's PharmFilm technology represents an exciting and significant pipeline opportunity. With that, I'd like to thank you all for your time and attention this morning. I would now like to pass the presentation to Steve, who will walk you through an update on our PharmFilm development activities.

Thank you, Michael, and thank you all for your time and attention today. It's my pleasure to get to walk you through what we feel is the really exciting and innovative science behind our epinephrine program. My name is Stephen Wargacki. I'm the Vice President of R&D for Aquestive. I have a PhD in Polymer Chemistry, and have begun my career in the defense industry prior to transitioning into pharmaceuticals approximately 12 years ago. I've been with Aquestive for 6 years. And during that time, as the R&D leader, we have developed and obtained approvals for both SYMPAZAN and Exervan, as well as filed over [Audio Gap] As well as filed over 47 patents. Now on to epinephrine. Epinephrine is a complex and powerful molecule. Also known as adrenaline, most of you are aware of the amazing things it can do in the body. Taken as a medication, as my colleagues have just ultimately highlighted, epinephrine has life-saving potential. However, it also presents a variety of challenges to drug product developers. Because of these challenges, all of you today may have heard many companies claim to be developing an alternative to the EpiPen and then not deliver. This means each of you may be rightfully skeptical right now about Aquestive's ability to deliver on this promise. But what we will present to you today is our novel approach to sublingual epinephrine that will result in an elegant and effective product that is both highly differentiated and highly protected. I want each of you today to walk away from this presentation understanding why our science is different from those who have tried before. In sharing our belief that this team has the vision, the know-how and the path to bring this innovation to market. Each of you listening will then have the ability to let your stakeholders know that Aquestive has some really exciting technology and is on the path to bringing true innovation to what has been a historically stagnant space. Let's step back for a moment to the challenges that epinephrine presents drug product developers. Some of the key challenges, anyone who develops an epinephrine product must face are: one, that it's endogenous, which is to say it's constantly present in and produced by the body; two, it impacts multiple organ systems; three, it's short acting, which means it clears the body very rapidly; and four, importantly, there is no known relationship between the concentration of epinephrine and the resulting efficacy, or PK/PD with respect to what's required to properly harness the power of this medication; and lastly, epinephrine is highly variable from person-to-person in both PK and PD, which in the absence of efficacy and/or a PK/PD relationship, creates a moving target. This brings us to the alternative administration of epinephrine. You've heard earlier today, alternative administration of epinephrine has been studied extensively throughout the years and yet innovation remains stagnant. As early as 1927, Meringer reviewed the state of oral epinephrine, and concluded, after many trials and investigations, epinephrine is entirely ineffective when administered orally. And that was almost 100 years ago. Despite this and despite continued work throughout the years, all have failed to produce meaningful systemic epinephrine levels. And this begs the question, why? Why have so many failed at delivering noninvasive epinephrine? From a practical perspective, without the ability to study anaphylaxis and its efficacy due to ethical constraints, matching the pharmacokinetics of the existing epinephrine therapies is a requirement. This requires matching both the speed and amount of epinephrine absorbed through the injectables. In order to do this, one must overcome specific attributes of the molecule itself. The most challenging of these features that I want to talk to you about today is vasoconstriction. Once in the body, vasoconstriction or the shrinking of the arterial walls by epinephrine, served to increase blood pressure, a desired effect. However, at the site of absorption, this can close off the capillaries and prevent the rapid absorption that's required. This is like trying to trip rapidly through a straw but squeezing the straw while you do it. You're fighting yourself. And without innovation, the standard solutions to these challenges will simply create new challenges. I would first like to tell you about Aquestive's initial solution to sublingually administered epinephrine. This utilized our PharmFilm technology. PharmFilm is a film technology that enables drug delivery through oral, buccal and sublingual routes. The technology creates a unique environment that not only stabilizes a molecule, but upon application rapidly releases the drug in conjunction with PH modifiers, permeation enhancers and whatever else you need to drive absorption. And it does all this in a film the size of a postage stamp, as Dan has showed you at the beginning of this presentation. Our first epinephrine film also included a novel penetration enhancer designed to compete with the receptors that cause vasoconstriction, as a way of blocking the vasoconstrictive effect. Our first-generation epinephrine film was tested preclinically and then eventually in man. The study found a dose proportional response and reached encouraging levels of epinephrine systemically as well as encouraging speed. While partially successful, the penetration enhancers alone could not fully block the vasoconstriction. This led ultimately to dose-limiting side effects and required a different solution. That solution -- the solution of vasoconstriction that I want to share with you today is the utilization of prodrugs. Prodrugs are an increasingly common approach in drug development. While some of you may have a light bulk going off saying, "Oh, of course, prodrugs," others may be asking, well, what are prodrugs? Prodrugs are the reversible modification of a drug substance that alters the molecule's properties. The prodrug is converted back into the parent molecule at a designated time once the intended purpose of the prodrug is achieved. Prodrugs can be used to increase solubility or improve bioavailability, prolonged half-life of a molecule, void side effects are simply just to absorb better. Simvastatin, which some of you may know as a very effective cholesterol medication, is one of the oldest and most well-known pro drugs on the market. But many others have followed. And now they're quite common. In fact, since 2015, approximately 10% of all small molecules that have come to market have been prodrugs. This is in [ par ] because despite being a new molecular entity, prodrugs can be eligible for the 505(b)(2) pathway and potentially even some exclusivity. The regulatory pathway can significantly reduce some of the developmental hurdles as the safety and efficacy of the reference product can be leveraged in support of marketing applications. What this ultimately means to you, the analysts, is a faster path to market. I would now like to introduce to you the molecule behind AQST-108. This is known as Dipivefrin. This was our first proof point of our innovative solution that I want to share with you today. Dipivefrin was chosen because the racemic form of this was -- this molecule already existed. And it was used in propine, an ophthalmic drop used to treat -- increased intraocular pressure. This allowed Aquestive to leverage additional safety information available to rapidly develop and explore the prodrug concept. Dipivefrin, however, was more than just a known prodrug of epinephrine. Our in vitro study showed that the structural modifications of the prodrug should not trigger the receptors responsible for the vasoconstriction. As we discussed earlier, this is the primary barrier to successful epinephrine delivery. Additionally, the scientific analysis of the molecule found that the increased lipophilicity, or nonpolar nature of the molecule, would provide favorable permeation through the sublingual mucosa. Now I know all that may be highly technical, but it's necessary to acknowledge the breadth of the innovation that we're presenting to you today. I will now show you how AQST-108 compared to similar doses of unmodified epinephrine. What's important for you to take from this is that when tested clinically in men, the prodrug allows for significantly greater epinephrine exposure when compared to unmodified epinephrine. The Cmax and the AUC are both significantly improved, all meaning that the prodrug approach allows for more drug to be delivered through the sublingual space. You may be looking at this graph and saying, yes, but the speed of the profile is not fast enough. And you may be right, but the profile confirms that AQST-108 and the overall prodrug approach significantly improves the resulting epinephrine profile. And we'll talk about speed on the next slide. This is a profile that I'm very excited to show you today, and one I want you to remember. Here is the average profile of AQST-108 in the blood from one of our pilot studies. What's important to take from this is that the profile is smooth. It's fast, it's smooth and the Tmax is at 20 minutes. And 20 minutes is well the fastest Tmax of a sublingual product that I'm aware of. The resulting conversion rate of this particular prodrug in men, it creates a lag between the absorption profile you see here and the resulting epinephrine profiles I showed on the previous slide. The data, however, is a strong confirmation of the scientific approach. Absorption of the prodrug occurs rapidly with no bimodal bouncing of the peaks typically associated with vasoconstriction. This is strong evidence that we have appropriately unlocked the door to delivering epinephrine, past the most significant hurdle. My colleague, Mark, will discuss this data in much greater detail shortly. But the connection between the observed profile and the validation of the science that drove it provides a road map to the successful sublingual delivery of epinephrine. It's also very important for each of you to know that Aquestive is confident that we already have the solution to the delayed conversion rate I just described. Aquestive has continued to develop and refine multiple prodrugs of epinephrine to optimize its performance for anaphylaxis. The prodrug development strategy involves balancing features that control the absorption rate, tailor the conversion rate and all the while providing known safety of the byproducts from the prodrug that ultimately get released in the body. And with that, I would now like to introduce to you AQST-109. The structure of AQST-109 is not formally disclosed here, but it's structurally similar to Dipivefrin with key modification. That modification greatly improves the ability of enzymes to access the ester linkage, which drastically speeds up the biotransformation. This means it has a much faster conversion rate. It's found to also have a better permeation rate than Dipivefrin. In our in vitro model, the conversion rate of 109 was so rapid that the half-life cannot even be estimated. It also achieved similar peak exposures to Dipivefrin or AQST-108 at 1 quarter of the dose in our nonclinical model. And it also has a better local tolerability profile. The last thing I want to show you today is that when our development team achieves these goals, Aquestive will be in a strong position to protect the resulting assets. We have been diligent in securing our innovation with multiple patent filings that encompass epinephrine, prodrugs of epinephrine, multiple routes of administration, optimal penetration enhancers for each. The enzymatic conversion rate, pharmacokinetic profiles resulting from the pro drugs as well as the potential for pharmacodynamic effects of the prodrugs themselves. Aquestive intends to continue to protect our innovation as it evolves and ultimately provide asset protection well into the future. With that, I hope you now have a good understanding of why we are so excited and believe so strongly in the innovation that I've presented here today. You've heard from David and Michael that the market is large and the need for a product with alternative delivery is great. I hope you take away from your time with me that our novel prodrugs are an elegant solution to the vasoconstriction challenge that has stunted so many prior attempts out of alternative epinephrine delivery. Importantly, these prodrugs have the potential for a 505(b)(2) regulatory pathway in the patent estate around them and their adjacent technology is established and growing. With that, I'm really excited to hand things over to one of the most knowledgeable people in the world with regard to epinephrine, its pharmacokinetics and the effect it has on the body, Dr. John Oppenheimer. John, the floor is yours.

Thank you, Steve. Let's talk about anaphylaxis and epinephrine or epi, clinical lessons from today's injectable products. I'm John Oppenheimer, Clinical Professor of Medicine at UMDNJ Rutgers and Chair of Research at Pulmonary and Allergy Associates. As has been discussed by prior speakers, epi is a highly effective treatment for anaphylaxis and the only recommended first-line medication in anaphylaxis management, though proving why has really been quite challenging. Due to the acute unpredictable and life-threatening medical condition associated with severe allergic reaction, there's not been a clinical model developed to ethically conduct randomized placebo-controlled studies in patients with anaphylaxis. To this point, the independent Cochrane Collaboration, a network of trusted experts in tracking intervention studies, could not identify a single trial, assessing the effectiveness of epi on anaphylaxis. The treatment of anaphylaxis is at best based on indirect and observational studies. And primarily, guidelines are based upon consensus. Because of the challenges associated with clinical models, regulators have instead focused on the pharmacokinetic, or PK, and pharmacodynamic, or PD, comparability for approved or new products in this area. As a direct result of the challenges inherent in conducting anaphylaxis clinical trials, it's important to note that the optimal dose of epi is unknown. There have been no published dose response studies documenting that the suggested dose of 0.01 milligrams per kilogram is indeed the correct dose beyond anecdotal reports. And actually, the origin of the suggested doses regimen can't even be found. Variations of the dose have ranged from 0.2 to 0.5 milligrams in the treatment of anaphylaxis as early as 1978. In adults, a dose of 0.5 milligrams was well accepted as optimal treatment for anaphylaxis until the advent of automatic injectors. Similarly, no dose-ranging or optimal dose injection data is available for any of the FDA-approved epinephrine auto-injectors or EAI products. Despite the absence of dose-ranging data to guide optimal dosing, epi nevertheless has a long record of safe and effective use when administered at currently approved doses for the treatment of anaphylaxis. Before I review the data on this slide, I think it's helpful to provide a few definitions for some of the medical terms I'll refer to in the next few slides. Again, we talked about PD or pharmacodynamics, which is a term we use when discussing what a drug does to the body. Conversely, PK or pharmacokinetics is what the body does to the drug, things like absorption, metabolism and excretion. Cmax is the highest concentration of a drug in the blood while Tmax is simply the amount of time it takes to reach Cmax. In this slide, and some that will follow, I want you to note the uncertainty around the expected Epi PK and PD values. You can see them here in the boxes. To date, the public data are sparse on PK and PD of epi administered via an auto-injector. EAIs have been designed to administer epi in the lateral thigh, the vastus lateralis muscle to obtain rapid response in anaphylaxis. However, there are challenges of delivering effective doses based on product design and usability. Current published studies suggest a wide variation in maximal plasma concentrations, which is due to many factors. To better understand these factors, following a few fatalities in 2015, the CHMP or Committee for Medical Products for Human Use, part of EMA, recommended that additional PK and PD studies were needed for EAIs to understand how epi penetrates the body when given with different devices. More specifically, CHMP report noted several potential patient-centric challenges in EAD -- I'm sorry, EAI dose delivery, and these can be exemplified by such things as comparison of pressure difference between device use, differences in weight, gender, age, say an adult versus child of study subjects, differences of patient populations, such as sex and BMI. Possible influence of human factors, an example would be the injection technique or even endogenous epinephrine values having an influence. Any of these factors may have a significant impact on how much epi is actually being delivered to an individual patient. In turn, these factors could explain the wide variation in PK values that we see on this table. To further emphasize this point of variability, I'd like you to look at the following graph, which is the injection of epinephrine into the muscle, looking at a study from Aquestive recent clinical trials. This plot represents plasma concentration of epi over time for 28 healthy subjects up to 4 hours after injection. Let me orient you: The vertical axis represents concentration of epi in the plasma, while the horizontal axis represents time. The blue circles along this graph represent an average data point for all subjects at specific time points. What I'd like to really draw your attention to, however, is the vertical lines, which recommend -- represent error bars, and they extend above and below each circle. These really show us the range of spread of values and a reflection of certainty or uncertainty of the circle averages. Where there are very short error bars, such as the 3-hour point, this means there's very little spread of values around the average. On the other hand, if you look at the earlier time points, such as the half-hour mark, these are large or long error bars, and this means a wide range in values around the average. And therefore, average value were calculated from a range of much higher and lower values. So speaking to the individual, it shows the variability between individuals when giving the same dose of epinephrine in the same location. On this slide, we're looking at what epinephrine does to the body, its PD profile. Remember, once administered, epi acts in multiple ways. It has an ability to prevent mast cell degranulation and release of chemical mediators, which are important in the development of anaphylaxis. Epinephrine also positively impacts cardiovascular and respiratory effects via its action on alpha and beta adrenergic receptors, the end result being pharmacologic actions that reverse anaphylaxis-related events, leading to an increase in the PD measures of, up top, heart rate, middle, systolic blood pressure and lower diastolic blood pressure. Which in layman terms means that epi when given quickly and correctly to a patient in anaphylaxis is good at reversing the life-threatening reactions in a person having such vital effects as improving heart rate, breathing, et cetera. So it really can be a lifesaver. In terms of the expected range of Cmax values, which would be observed following administration of 0.3 milligrams of epinephrine given in the thigh muscle, generally, these values range from high 200s to mid-500 range. Of course, the data could fall outside this range. However, these values that I show here are drawn from observed data in the published literature. Likewise, the Tmax range of median values is generally less than 20 minutes. However, there are published reports of a medium Tmax value of as high as 40 minutes. These ranges, and specifically, the variability in these ranges, will be important for you to keep in mind, as our next speaker, Mark Lepore will soon walk you through the data Aquestive has generated from AQST-108. So let me summarize what I've shared with you thus far. As outlined in this presentation, epi is a life-saving treatment for anaphylaxis with a long history of safe and effective use. Pharmacokinetic and pharmacodynamic measures following epinephrine administration are variable and represent a moving target. We saw the variability in Tmax, Cmax, et cetera, reinforcing this concept. There's significant variability in the reported plasma concentration following an injection of epinephrine, even using recommended routes, doses and devices licensed for treatment of anaphylaxis in adult and children. However, none of these studies were performed during anaphylaxis, where patients are likely to drop their blood pressure due to dilatation or leaking blood vessels. Now that you have a better understanding regarding the use of epinephrine for anaphylaxis, please consider this as you listen to the next presentation, which will take you through the development of Aquestive's new product. For that presentation, I would now like to turn to Dr. Mike -- Mark Lepore. Thank you.

Thank you, Dr. Oppenheimer, for sharing your insights. Hello, everyone. I'm Dr. Mark Lepore, Chief Medical Officer for Aquestive's allergy franchise. I'm an allergist, clinical immunologist and pediatrician by background, and a fellow of the American Academy of Allergy, Asthma & Immunology. My career has included 10 years in private practice and experience as a clinical researcher, working on over 100 industry-sponsored trials. After leaving practice, I held industry roles at Teva and Lupin before joining Aquestive late in 2020. While I'm pleased to have all the credentials, certainly, the most pertinent bullet for today is that I'm a dad with 3 children who have suffered from food allergy-related anaphylaxis. I'm very excited to be helping Aquestive on its mission to change the treatment paradigm in anaphylaxis. As you've heard today, alternatives to injectable epinephrine are sorely needed. While companies have been working on these alternatives for some time, the only real changes have been incremental improvements still requiring injection. The pathway for getting a new product approved for anaphylaxis is a challenging one as it relies on pharmacokinetic similarity. This is a challenging development pathway. Aquestive has made significant progress in the development of an effective alternative anaphylaxis treatment, which can be dosed as a simple film under the tongue. As discussed by Steve, the 2 key considerations for this sublingual film treatment are whether it can be absorbed substantially through the sublingual mucosa and whether it can be converted systemically into active epinephrine. In the next few slides, I would like you to consider some of the data we have generated, which addresses both absorption and conversion in humans and its implications for the future. I'm very pleased to tell you that Aquestive's product will be the first and only treatment for anaphylaxis, given via the sublingual route. This will provide significant value, both to patients and our shareholders. With this prodrug strategy in mind, Aquestive developed several lead compounds. And took the first of these, AQST-108, also known as Dipivefrin, into clinic. The clinical program thus far has consisted of 2 pharmacokinetic trials in healthy volunteers. I realized that while the type of information on this slide might be familiar to some, I would like to take just a moment to detail it for this audience. The first of these, the 299 study, was a single ascending dose study, which looked at various dose levels of our AQST-108 sublingual film. The 203 study was a 4-treatment crossover pharmacokinetic trial, which advanced our lead film formulation at a 24-milligram dose and included various injectable epinephrine comparator treatments. All treatments, except the 0.5 milligram subcutaneous injection treatment, were replicated in the trial to allow better estimation of the variability. In both trials, pharmacokinetics were assessed as were the pharmacodynamic measures of heart rate and blood pressure. The information I will be presenting in the slides will focus on the results from these 2 trials. On this slide, we look at the levels of Dipivefrin, from both the 299 and 203 pharmacokinetic trials. For those of you who are less familiar with the terms, pharmacokinetics, or PK, are terms used to describe what the body does to the drug after administration. The figure displays the concentration of Dipivefrin following dosing. The vertical axis represents the plasma concentration of Dipivefrin, with the horizontal axis representing time from dosing to 2 hours post-dose. The plot with the open blue circles represents the concentration time profile from the 203 study and the plot with the solid blue circles and hatched line represents the concentration time profile from the 299 study. The table on the right displays the values for Cmax, AUC and Tmax. Cmax represents the average of the maximum plasma concentrations across all subjects. The Tmax represents the median of the time to reach maximal concentration across all subjects. The AUC represents the average of the calculated value for the area under the concentration time curve across all subjects. There are 2 things I would like to draw your attention to regarding the figure and table. First, you can see how large in magnitude the maximum concentrations are for Dipivefrin across both studies. Second, and as highlighted by the arrows, you can see the rapid time to peak plasma concentration for Dipivefrin. Across both studies, the median values for time to maximal concentration for Tmax were 18 and 20 minutes. This indicates that epinephrine prodrug delivery, via sublingual film, can result in very rapid drug absorption. This is obviously a critical feature for a life-saving drug. On this slide, we look at the levels of epinephrine from both the 299 and 203 trials. The figure displays the concentration of epinephrine over 2 hours following dosing. The vertical axis represents the plasma concentration of epinephrine, with the horizontal axis representing time from dosing to 2 hours post-dose. The plot with the open blue circles represents the epinephrine concentration time profile from the 203 study, and the plot with the solid blue circles and hatch line represents the epinephrine concentration time profile from the 299 study. The table on the right displays the values for Cmax, AUC and Tmax. Cmax and AUC values of this magnitude provide clear evidence to support the proof of concept, that Dipivefrin, following absorption through the sublingual mucosa, is being converted to active epinephrine in the systemic circulation. I realize this is a little dense so I hope you are all still with me. And just remember, there are questions and answers following our presentations. I would now like to turn our attention to the pharmacodynamic effects we have observed in our trials. As you likely know, pharmacodynamics represents what the drug does to the body. The 3 key pharmacodynamic measures we specified were heart rate, systolic blood pressure and diastolic blood pressure. These PD measures are known to increase in response to epinephrine administration. On this slide, we have 3 different figures from the 203 study. The figure on the left represents the PK and PD responses following AQST-108 administration. The figure in the middle represents the PK and PD responses following 0.3 milligrams of epinephrine delivered via intramuscular injection. The 2 vertical axes represent plasma concentration and systolic blood pressure, with the horizontal axis representing time from dosing to 4 hours post dose. Starting with the figure on the left from the AQST-108 dosing, the lighter blue line with closed circles represents Dipivefrin plasma concentrations, the darker blue line with closed circles represents epinephrine plasma concentrations and the hatch blue line represents systolic blood pressure over time. Considering the peak concentrations and time to peak, it appears that the systolic blood pressure response is largely driven by Dipivefrin plasma concentrations, at least early in the time course following dosing. The figure in the middle suggests, following dosing with 0.3 milligrams of intramuscular epinephrine, that changes in systolic blood pressure are correlated with plasma drug concentrations. Finally, the figure on the right side compares a representative PD response following dosing with both AQST-108 sublingual film and 0.3 milligrams of intramuscular epinephrine. In this plot, the area under the systolic blood pressure curve was used to represent the observed PD responses. As you can see, the PD responses observed following dosing with AQST-108 were comparable to those observed following injected epinephrine. These data suggest that AQST-108 treatment can elicit PD responses that are medically important during an anaphylactic event. In this slide, we have the PK results from the 203 trial. On the right side, I have detailed the PK parameters for Cmax, AUC and Tmax. The comparison is between our AQST-108 and subcutaneous and intramuscular injections containing 0.3 milligrams of epinephrine. For both Cmax and AUC, the average of the observed values is numerically smaller for our film when compared to those values obtained following the injections. For Tmax, the median of the observed values across subjects was larger for our film, indicating that more time was required to reach maximal plasma concentrations. On the left side, you see the concentration time plot. Like my previous slide, the vertical axis represents the plasma concentration and the horizontal axis represents time, in this case from dosing out to 2 hours. The dark gray line is the average plot of concentration over time for the 0.3 milligram intramuscular epinephrine injection. The light gray line is the average concentration time plot for the 0.3 milligram subcutaneous injection, and the light blue line is the average concentration time plot for our film product. For perspective, I have included the average concentration time plot for our film product from the previous 299 study, represented by the dark blue line. These data suggest that while our AQST-108 prodrug is converted to active epinephrine systemically, this rate of conversion may not be ideal in the context of anaphylaxis treatment. These lessons provide valuable information, which is allowing us to advance our aspirations in anaphylaxis. Now as an important reminder to you, and as many of the presenters have said, there simply has to be a better option than the epinephrine auto-injectors. As you know, Aquestive started on this journey to make better therapeutic options for anaphylaxis by studying epinephrine delivered using our sublingual film technology. That work led to a better understanding of the limitations of sublingual absorption for epinephrine and the development program for AQST-108. The 2 studies completed for AQST-108 have given us confidence on 2 counts: first, that our prodrug technology can be rapidly absorbed through the sublingual mucosa; and second, the conversion to active epinephrine in the systemic circulation needs to be rapid, and this is where the science gets fun. These lessons have led to the development of AQST-109, as was introduced by Steve. This prodrug was selected to overcome the conversion limitations observed with AQST-108 in humans. In preclinical models, this prodrug converts very rapidly. And as such, we anticipate better PK performance in the clinic. This prodrug will be shortly studied in a first-in-human clinical trial. This first-in-human trial will be conducted in 2 parts. In the first part, we will be following a single ascending dose approach to examine the safety, tolerability, PK and PD across a range of doses. The dosing will start with sublingual drops to help ensure a sufficient safety margin for human dosing. Thereafter, the subjects will be exposed to escalating doses of sublingual film from 3 to 4 milligrams. In part two, we plan to conduct a 5-period crossover study in healthy volunteers, which will include a reference comparator arm as well as 4 arms with different optimized formulations, doses and administration conditions. I'm really excited to be kicking off this work and look forward to updating you on our progress in the future. I believe you came here today to learn, to hear, to assess and to be able to take that knowledge with you in order to better predict for your stakeholders how to assess anaphylaxis treatments. And you heard some of the complexities and complications of advancing a solution as critical as saving lives and treating patients with serious allergies. Let me summarize our discussions today. You can see on the slide what Aquestive's AQST-108 has demonstrated, the ability of Aquestive's film technology to deliver epinephrine prodrugs, that these prodrugs absorb quickly and convert into epinephrine systemically, that the treatments yield comparable and meaningful changes in relevant PD parameters versus intramuscular epinephrine injection. We also learned that AQST-108 exhibits a lower Cmax and higher Tmax related to the rate of systemic conversion. Therefore, our plan is to advance another prodrug, AQST-109, which is expected to convert quicker in the human trials. At the same time, we are exploring adjacent indications where we feel AQST-108 could offer the opportunity to address other unmet medical needs. We see all this as hugely beneficial to you as our friends in the analyst community, to your families, children, physicians and stakeholders. Thanks for listening. I would now like to turn things back over to Dan Barber.

Thanks, Mark. Now let's talk about the upcoming milestones for our epinephrine development products. As Mark mentioned, we are excited about the results from AQST-108. We have now completed 2 studies in man, obtained fast track designation, held a pre-IND meeting with the FDA and opened our IND. We believe AQST-108 remains a valuable development opportunity, and we are excited to share our results with the FDA and discuss the potential next steps in development. Given the complexity around the prodrug peaks, the conversion to epinephrine, subsequent epinephrine peaks and corresponding PD data, we are going to refrain from outlining the next development steps for AQST-108 until we have discussed this with the FDA. We are currently conducting additional modeling work on the data from our 2 completed studies. Once that modeling is completed, we will schedule a meeting with the FDA. As of today, we are guiding this will be a second half 2021 meeting. As Mark outlined, we have submitted our dossier to Health Canada for AQST-109. We will commence our study for AQST-109 as soon as our dossier is cleared by Health Canada. We have taken all of our learnings about absorption and conversion and applied them to AQST-109. A we are very excited to see how AQST-109 performs in the clinic. We anticipate a top line data readout during the second half of 2021. The exact timing for this readout will depend on the timing of Health Canada's clearance and the subsequent dosing schedule with our CRL. If the data from AQST-109 is as promising or even more promising than AQST-108, we will rapidly seek to meet with the FDA in a pre-IND form and subsequently open our IND. If we reach agreement with the FDA on either AQST-108 or AQST-109 in 2021, then we will seek to follow the traditional 505(b)(2) comparability pathway. At this time, we are guiding that this will include a pilot PK study, pivotal PK study, as well as a human factor study. We would seek to conduct a pre-NDA meeting with the FDA as soon as these steps are completed. We believe it is possible to complete all of these activities in 2022 based on reaching agreement with the FDA in 2021. As we conclude the presentation portion of today's meeting, we would ask you to take a few minutes and think of the compelling benefits associated with our AQST-108 and AQST-109 programs. There is a large and unmet need and a growing patient population in this area. Aquestive is the first and only company that has successfully demonstrated a repeatable and predictable capability for orally administering epinephrine. And we have a pathway to approval and bringing our product to the market. With that, we will open up the line to Q&A.

[Operator Instructions] Your first question comes from Gary Nachman with BMO Capital Markets.

So first on AQST-109. Is this using the same prodrug as 108 that was modified or a different one altogether? I wasn't completely clear on that. And then what are the theoretical safety issues you might see with these prodrugs that you have to manage through? And do you think you need to get to the same Cmax and Tmax as EpiPen? Or can it ultimately be below that? What do you think the FDA will be looking for when it evaluates these drugs?

Right. Thanks, Gary. And let's take those one by one. First, on the prodrug platform. The -- and I'll hand it over to Steve in a minute here. The prodrug platform is designed to key on 2 particular things: The absorption of the molecule and then the conversion into epinephrine. And so each prodrug in that platform does have a different structure. And Steve, if you could elaborate on the differences between 108 and 109.

Yes. Happy to. Thanks, Dan. And so Gary, to your question, they are structurally similar, but there is a change in the molecule that actually creates the prodrug. There is the same linkage connection to the molecule -- to the epinephrine backbone, but the molecule is slightly different. And that difference allows for that faster conversion.

I think the second part of your question was, well -- and Gary, I'll interpret it. While you talked about safety, it's really about regulatory, right? What are the regulatory complications that could come out from using a prodrug. From our perspective, the prodrug platform absolutely is still a 505(b)(2) pathway platform. And in fact, in our pre-IND meeting for AQST-108, we confirmed that. And there is actually guidance around using prodrugs with the 505(b)(2) platform. And Steve, if you could elaborate on that a little bit for Gary as well.

Sure. Yes, again, thank you. So this really, from a regulatory perspective, this is about the guidance that establishes it. The precedence, and as I mentioned in the presentation, the prodrugs are becoming quite common. So there is strong precedence for the utilization of that pathway. And then it is the confirmation that we received during our pre-IND interactions with AQST-108, that provides confidence that AQSD-109 will follow a similar path. And again, just the molecules that, from a safety perspective with that -- the molecules that come off of the epinephrine, the prodrug also has that established safety.

And I think, Gary, the third part of your question was around matching on Cmax and Tmax. We absolutely continue to believe, and I think that FDA continues to guide to us and other companies that Cmax and Tmax will be primary indicators of the ability to use the 505(b)(2) pathway. And so for us, we look to people like Dr. Oppenheimer and Dr. Fleischer to help guide us, which as Dr. Oppenheimer showed you a little while ago, that high variability with injected epinephrine are the 2 -- I believe the numbers were 280 to 520 on Cmax and under 20 minutes on Tmax. In our minds, that's the target. That's what we're looking to achieve, and that's where we will put our position forward with the FDA. Dr. Oppenheimer, I'll just ask quickly, does that align with your thinking as well?

I think so, as pointed out by several of the speakers, it's unethical to do research in anaphylaxis itself, comparing one product to another without known safety. So I think the Tmax and Cmax represent the ultimate surrogate to prove equivalence, because we don't have any other model.

Right. Gary, did I -- did we answer all of your questions?

Yes. Yes. That was great. And then I just have a follow-up for Dr. Fleischer and Oppenheimer more from, I guess, a market standpoint. In your experience, when you talk to patients and caregivers about the risk of anaphylaxis, what percent just say no because of the needle phobia? And are there any other alternatives that you can recommend to them at this time? And then is there an issue if someone ultimately swallows the film rather than getting the correct sublingual delivery? Maybe that's more a question for the company, just if you think that there could be administration issues potentially with the film, that we could answer.

Yes. Gary, we'll take the swallowing question in a minute, but definitely want Dr. Fleischer and Dr. Oppenheimer to give their view. And maybe Dr. Fleischer, if you could start on the first part of the question.

Yes. So I'll put it in context. I mean, we prescribe epinephrine auto-injectors to every patient that has a risk of anaphylaxis. So it's not that they're going to deny taking that prescription. They may not fill it, but pretty much most of the patients, at least in pediatrics that I work with, and I only work in pediatrics, and John can talk to you more about the adult side, we prescribe for everyone. I think the fear is given your child an injection is not something that you really want to have to do. So there is significant fear -- and of patients, to give an example, we have patients that have had anaphylaxis and gotten injections, and they're afraid to get another one. And we worked with a psychologist, we're fortunate to have one, at our center that tries to get over some of that needle phobia because you don't want the patient running around and avoiding epinephrine, which may increase the risk of more severe anaphylaxis. So I think there is significant needle phobia, not so much in getting the prescription, but actually using it unfortunately and especially in kids. But I think John may have something more with adults, too.

Yes. I want to go back. David, you showed some slides on the KAPLAN study, which was a California HMO. And again, remember the numbers, 46% filled once, 25% filled more than once and only 11% filled yearly. So that's pretty scary. It means that about 90% of people aren't filling it yearly. Let me turn it around another way. There's a study by Warren published 2 years ago -- I'm sorry, 4 years ago in the Annals of Allergy, that looked at a group of people that had anaphylaxis and followed what they did. And this is the scary part. 52% of people having significant anaphylaxis did not use their EpiPen or auto injectable epinephrine. And there were lots of reasons why: Needle phobia, I wanted to see if it was going to go away. But in truth, think about it, do you really want to give yourself a needle? Many people just don't want to do it. So I think with all that said, yes, an alternative is something that we're all searching for. As a matter of fact, in that study, they found that 60% of people point blank said, I would love an alternative. So there is really a need for one.

Thank you, Dr. Oppenheimer. And Gary, the other part of your question was around swallowing the product and what would happen or the proposed product. I would point you to the 2 analog in our company. First is Suboxone, and second is our drug candidate, Libervant, which is currently -- we're pursuing approval on. With Suboxone, we have 10 years of history in a sublingual use without any significant complaints around swallowing and lack of efficacy. And with Libervant, we have almost 2,000 uses in a safety study. That's a buccal film where we had almost no issues with swallowing and effectiveness of the product. So I think we've shown that our platform can be used in these rescue situations, and we believe that will hold true with AQST-108 and 109.

Okay. Great. And then just last one for Dan, and then I'll hop back in queue. What are other adjacent indications for 108 that you might consider pursuing? And as of now, if you get the green light from FDA, do you think you'll be pursuing both 108 and 109 in parallel? Or you might just focus on 109 and then 108 could come later down the road?

Sure. Thank you, Gary. So let me start with the second part of the question, and that's AQST-108 versus AQST-109. As Mark outlined before with AQST-108 we like the PK data, we think it's very strong, but we find the PD data very interesting. And I know Mark showed you the systolic blood pressure and talked about the fact that there are other markers as well. We are excited to go to the FDA, show them those results and see what it means for AQST-108. So we don't see this as a competition of prodrugs against each other, we see this as an evolution process of how we get to a product, which is the best product we can put onto the market. In terms of the other part of your question, around alternate indications, we definitely -- today is definitely about anaphylaxis. But you are absolutely right. We, of course -- especially with Mark and our other experts have thought about potential other uses. And Mark, maybe you could provide a little more insight into some of the thoughts you've had.

Thanks, Dan. Sure, just a few quick points. So we don't yet have a specific indication to share when it comes to alternative indications. But we can tell you that we've been looking at conditions which are adjacent to anaphylaxis and also involve the mast cell activation and mediator release.

So Gary, I think on that one, it's -- not to be too coy, but more to come.

And your next question comes from the line of Jason Butler with JPMorgan Securities.

I guess it's the first one. Is there data from intravenous administration of epinephrine that validates the biomarkers? And I guess there, do you see less variability on the PD markers that supports the -- it's actually the intramuscular injection that drives the variability versus inherently something with epinephrine?

Right. Thank you, Jason. In terms of the PD markers, maybe a good place to start with that question. And I would love to hear Dr. Oppenheimer's thoughts. But Mark, before we hear from Dr. Oppenheimer, could you just express the ways on how you think about PD markers?

Sure. Thanks, Dan. Happy to do that. Getting back to the PD markers that we've studied in our 2 trials, we've looked at heart rate, systolic blood pressure and diastolic blood pressure. And we looked at the magnitude of these changes. The magnitude of those changes we observed was on par with those following epinephrine injection. So we feel this is further evidence that our prodrug is absorbed, converted and active at the sites of action. In terms of IV administration of epinephrine and how that might differ from injected intramuscular epinephrine, and of course, we can get feedback from Dr. Oppenheimer and Dr. Fleischer. But keep in mind, these things haven't been studied extensively during anaphylaxis, in patients with anaphylaxis. So there are some challenges in bridging what's available in the literature to what needs to be done from a drug development point of view.

Dr. Oppenheimer, do you have any thoughts you'd like to add?

IV epinephrine is a real tricky thing. When you're doing it, you're really being very carefully monitored. There's a lot of issues with regard to heart, et cetera. So it's not something you do if you're faint of heart, no pun intended. Likewise, interosseous use of epinephrine can also be used. But again, these are not well studied. As a matter of fact, there's a recent study by Ruiz-Garcia just published in the Journal of Allergy looking at what happens in food-induced anaphylaxis. So this was people that were undergoing challenges, and they actually watched the cardiac effects. There are very few literature like this. David, maybe you want to comment, as far as it does a lot of food challenges. But there's a surprising positing of data with regard to what really happens in anaphylaxis. And as the Ruiz-Garcia study may be a wonderful starting point for us to better understand what really is going on. One of the things that was noted was that when people anaphylax, believe it or not, a lot of the swelling or edema, they mention vasodilatation during anaphylaxis actually occurs in the gut, and we didn't know this until the study, so clearly. David, do you have anything to add?

Yes I think the IV administration and then interact, if you're doing that, those patients that are in an ICU are much higher monitored situation. When we do the food challenges, we have the patients on CR monitors and things. In kids it's like -- I think the difference what John stated sort of about the filling prescriptions. I'll just go back to that in a second. Our parents are the ones that are filling them for their kids, the rate of that -- filing higher. But as far as epinephrine, it really goes back for me, what set up the EpiPen or IM as the gold standard of what we need to compare things to? So I think you've got difficulty there. So I mean that's what I would add at this point.

Okay, great. And then just, I guess, a clinical adoption question for Dr. Oppenheimer and Dr. Fleischer. Can you maybe just give us some thoughts about how you would start to use a product like this? I mean, obviously the most -- do you start with the needle phobic patients? The pediatric patients? And how do you think about use by, for example, health care providers like EMTs and paramedics or use in the military?

David, why don't you start?

Yes. I mean, I think having an alternative is having a discussion with the family. I mean, it's just like we have shared decision-making things with whether we do a food challenge or whether we put patients off immunotherapy. I think we've got to have some presentation of the different advantages and possible disadvantages of the various products. Certainly, if there's no needle phobia, I think especially in our pediatric patient, again that I only see, there is a high consideration for -- confidence in the physician that's prescribing it, to reassure families that this is going to work just as well, and that's where the data has to show that. But I think there's a huge market for it. And not just as an alternative route. But just look at the carrying rates of EpiPens or other auto injectors. If you've got something that's really much smaller to use and you can have 2 doses -- because we try to get patients to carry at least 1, you recommend 2. But the reality of carrying larger devices, we're lucky if they carry one. So I think there are significant advantages when we talk to patients about the sublingual product that I think will get patients from families, especially parents of kids, that would be a huge advantage over other -- of the injector itself.

Yes. I would echo what David said, a couple of points. Number one is, part of my job is to be a good used car salesman. I can make the right diagnosis, put somebody on the right medicine. But if they don't take it, or in this case, carry the EpiPen, I failed because when they have a reaction, it's like I made the wrong diagnosis because they're not going to get better. I would also echo what David said that you got to get them to use it. I mean, there are data from Carlos Camargo, who's the Chief of ER at Mass General, showing that if you give the epi early you probably have better outcomes. When they looked at mortality, at least one of the signals appears to be delay in using auto injectable epinephrine. So people are scared to give themselves a needle. If they're more likely to use something that they see is less painful or invasive and use it earlier, we'll probably have better outcomes. Lastly, when you look at the money as a system, delaying use of epinephrine is one of the reasons people get hospitalized. So if I can get them to use it earlier, maybe that's going to reduce costs in the end. So these are things that need to be looked at, but I think bode well for a future-looking at alternative delivery.

And your next question comes from the line of Randall Stanicky with RBC Capital Markets.

This is Steve on for Randall. I've got 2, ask them both upfront. The first one is related to some of the market capture rates you guys had earlier in your presentation. I was wondering if you can give us some more color as what's giving you confidence that you're going to be able to hit those different market capture rates under the different scenarios? And if that includes any of some of the untapped market population pool that you guys suggested? And then my second question is related to -- you guys are in the process of gaining approval and launch of Libervant this year and into next year. Just kind of curious as how does that launch -- the success of that approval launch, does that impact your timing or approvals for 108, 109?

So why don't we take them backwards, and I'll deal with the second question, and I'll let Dan and his team deal with the first question. All of the costs associated with the program for epinephrine, for both 108 and 109, as anticipated for '21, are in the guidance that you've been given already. And that guidance has, if you recall, no expectations for Libervant, just because of the timing. So the answer to the question is we're moving in parallel with both. And the additional work in 108 and 109 is not dependent on an outcome at the very end of the year related to Libervant. And does that get to your question?

Yes, it does. I appreciate that.

Okay. Great. And do you want to deal with the market capture?

Sure. And on the market capture rate, I think the context that Michael gave around the EpiPen coverage at what's happened over the last few years is really important to understanding how we think about both market share and penetration. So with that, I'll hand it over to Michael, if you could expound upon that a bit.

Yes. Steve, I think I'll just sort of recap if that's okay. And I'll point you to, first of all, what both of our KOLs have said in the last few minutes, which is they would appreciate and their patients would love a better car, if you will, and a better car to sell. So I think our KOLs will support that there's a real unmet need out there for patients. Also, please refer back to the market research I showed. As a reminder, we interviewed 150 patients and caregivers. We didn't tell those patients and caregivers who we were or what we were trying to get insights on. We just showed them devices and data and information and asked them to feedback to us what they liked. And recall that overwhelmingly, people wanted something new and we're really enthusiastic about the film product. And then what I'll leave you with on this question is -- I mentioned it at the top of my call, I've been in this market at the top of my talk. I've been in this market for 10 years now. I've talked to probably thousands of patients and hundreds of doctors over that time. And infallibly over those 10 years and consistently over those 10 years, people tell me they want a different delivery method. And so we're confident with the different and we think better delivery method, we'll be able to take a significant market share.

And your next question comes from Shveta Dighe with Wedbush Securities.

This is Shveta for Wedbush. So for AQST-109, can you anticipate a better PK profile and a conversions rate, do you think that the FDA would want to see the 109 data before they decide on a potential path forward for 108 in the second half of '21? And then I had a question for the KOLs. Given the profile of 108 that we saw today, especially the Cmax and Tmax, and if 108 was to be approved, do you think that would -- what are your thoughts on the potential prescription grade given the Cmax and Tmax data?

Shveta, let's start with the first part of your question, which was with the FDA. Will they wait on 108 before giving us guidance, or will they wait for 109 before giving us guidance on 108. From our perspective, they are 2 separate programs. And there are also separate programs from the FDA's perspective. So they'll have -- 108 already has an open IND. 109, we will eventually open a separate IND. So when we talk to the FDA, we will always talk in the context of each program independent of the other. And just as a reminder, on 108, the PD information, we think, is an important element. We'll see what we have from both PK and PD and 109, and then we'll make our decision on that program. The second part of your question, Shveta, I believe, was based on what we know about 108 today. If it was approved by the FDA, how would Dr. Fleischer and Dr. Oppenheimer view it? Did I capture that correctly?

Yes.

Okay. Dr. Oppenheimer, why don't we start with you for this question.

I would be a little cautious. I think that the data we saw from auto-injectable epinephrine IM, it had a better Tmax. And when somebody is anaphylaxing, I want quick onset of action. I would -- if I were king for a day, put all of my energies towards 109 because it looks like a much better Tmax scenario. And I think that's what Aquestive has done. I don't want to speak for them, but I would agree with their move forward to move -- directed towards 109 in anaphylaxis.

Dr. Fleischer?

I would only add that, how much delay is there to get patients to give epinephrine, whether it's to their child or to themselves. So if you potentially use 108 sooner, could you prevent more anaphylaxis or stop with regardless of what the Tmax is. But I would just keep that in mind. So I agree with John to some degree, that there's significant delay our patients have with hemming and hawing over giving it. If you had a sublingual film that there's no fear of giving it and possibly using it earlier, it could work.

So I thought about that. And I agree with you, David. I think that we know there's delay. 52% of people aren't even going to use it because they're fearful of using needles. I would ask Mark and the team, though, do you think the FDA would buy that as your argument?

Mark, do you want to expound upon that?

Yes. I think it's a great question. Obviously, when developing drugs like these, these are life-saving therapies, FDA is going to take everything into consideration. So while there is that lag in Tmax, we've seen from some of our early data with 108, we've also seen a very quick and robust PD response. The relevance of that PD response does need to be discussed with the agency, as Dan alluded to.

And what I would add, just before we move on to the next question, is given the 2 studies we've done and the predictability and repeatability of what we have, we're very excited about where we can take 108 and 109. So part of the development process is continuing to push the results we have and we're excited to do that.

Dan, I wonder if I can pull one other thing out. We didn't talk about this in great detail. But there is a whole literature that people that are large, and unfortunately, that's America as a whole, moving larger and larger each day. Giving epinephrine, remember, you want to get the vastus lateralis muscle. Because of large thighs, you may not be able to hit the muscle as well as you want. And some of the data we showed with regard to the tremendous variability, speaks to the fact that you may not be able to access that muscle. So while we're talking about ideal situations, if you were to look at a group of obese patients, it would be very interesting to do the same study, looking at injectable epinephrine. And then looking at sublingual epinephrine. That may be a real niche where actually sublingual epinephrine is going to be more consistent and a better choice.

And your next question comes from the line of Thomas Flaten with Lake Street Capital.

Just a quick one. I just wanted to confirm on the 505(b)(2) prodrug discussion we've had. You would still need FDA to confirm a 505(b)(2) pathway for 109, correct? Or is that an assumption you're making? Or do you know that for a fact?

No. Great question, Thomas. So we have not held a pre-IND meeting with the FDA on AQST-109. And traditionally, as we develop drugs, we like to get our first-in-human data, and that have the pre-IND. So that's the study that we're about to do. We'll get that data, then we'll have the pre-IND meeting. And that is where we would talk about the prodrug in the context of the 505(b)(2) pathway. What I would say, and Steve, I'll look for your addition to this, is there's no reason -- there's no difference between the pathway of what we're doing on 109 versus 108. And Steve, did I say that correctly?

I think you did. Yes. The same as you have [ hypoconversion ] that makes this viable via the 505(b)(2) pathway, that was confirmed for when we -- is present in 109.

I was going to say, but the -- I guess, with 108, that was a known drug to the agency, right, whereas 109 is not a known drug to the agency. Is that correct?

Correct. But the pathway discussion is different than whether the safety and efficacy packages have been completed for approval under another indication.

Got it. And then switching over, I wanted to key off a comment that Dr. Oppenheimer made a couple of times around using anything quicker. Have you guys thought about constructing a pharmacoeconomic argument around how quickly you could theoretically have a patient administer epinephrine and the cost offsets downstream to perhaps support premium pricing or an advantageous managed care position?

Those are all things we're very interested in doing. We think they're farther down the line to really capture. At this point in time, what we have done is a very small market research study. I'll call it even just more of a survey around -- for people who've used an EpiPen, how much of a time delay is there when compared to thinking about the film. And we know that there is -- while we haven't published that data, we know there is a time delay. So you will hear us talk more about that. And I'm sure Michael and team will continue to do more work on that front.

And then just one quick one. On the 20,000 docs that were identified on one of the commercial slides. Can you just characterize that group of physicians? Is that all allergists? And then as a follow-on to that, for refill prescriptions, are those driven primarily by the original prescribing allergists, I would suppose? Or is that more pediatrics and PCPs that would prescribe those?

Michael, could you take that one?

Yes, I'd be happy to. To your point, the actual number of physicians that prescribe at least 1 epinephrine auto-injector per year is in the hundreds of thousands. So an OB/GYN might write one. Primary care would certainly write one. To your second question, a lot of those primary care docs are just doing refills. So when someone has a first severe reaction, they're more than likely going to see an allergist and/or a pediatrician. To your first question, yes, 20,000 to 30,000 is sort of the sweet spot for promotion. Those 20,000 to 30,000 physicians, and they all are mostly allergists and pediatricians, they're going to drive most of the business, especially the first prescriptions. So there isn't a lot of utility in promoting to a larger group than that because they will drive your prescriptions and then down the line, the primary care will refill.

Your next question comes from the line of [ Maz Selan ] with H.C. Wainwright.

This is [ Maz ] on behalf of Ram Selvaraju, H.C. Wainwright. So I wanted to get a perspective of payers and how they feel about the convenience of a product like AQST-108, in addition to your insights from patients and physicians?

Sure. And thank you for the question. At this point in the development process, we have not conducted significant payer work, as you would expect. Our current view and thinking, which we think is conservative, is that we would have the same coverage as EpiPen. As Thomas alluded to before with his questions, we do think that there are significant pharmacoeconomic considerations that could be brought into play as we get further down the development pathway. So for today, we -- our assumptions are the same as EpiPen. As we go forward, we'll continue to challenge that and provide more data to see if there's a better situation compared to EpiPen.

Okay. I have a follow-up, if I may. Do the KOLs think AQST-108 could be deployed more widely than existing epinephrine formulations? And specifically, in which populations do you think that might have added to use or greater acceptance?

Dr. Fleischer, do you mind taking that one first?

I don't mind. I think, obviously, in the patient population that I see at Children's, I think a huge unmet need, then parents would obviously use this. I think the way -- I don't know how many details the questioner wants me to go into. But we have talks with them about how we would use this potentially in our food challenge unit, where we do about 3,000 challenges a year. So I think there's potential application. I don't want to go into details if I'm allowed to. But I think we're very excited about the potential use of the 108 product in that setting.

Dr. Oppenheimer?

Yes. I think that you saw the numbers. People aren't refueling auto injectable epinephrine. Just think about the fact that 46% fill initially, and it's largely because there's probably needle phobia. And then as you look down to year two, we're down to 25%, just trying to get that 46% and keeping it year-by-year, think about what the growth would be on this product. I think the growth is endless. There are a lot of people out there that don't carry their EpiPen, that don't refill their EpiPen, and this would be a wonderful niche just to get people to buy into the product and carry it.

Yes. I think the carrying part is huge. I mean, until the smaller talking device came out, it's hard to argue with patients that have cellphones that they can't carry that device. But now I think it's much smaller device that they can carry. And again, have potentially 2 doses in a very small carrying is huge. So...

As David points out, when you think about this, imagine carrying an EpiPen, which is about this large -- my fingers, there you go, and you're carrying it everywhere. Or even the AUVI-Q, the talking injector, these are large. You're carrying them everywhere you go. When you go to the beach, when you go to the gym, you're carrying it everywhere you go. And I've heard arguments, it sounds sexist, it's easier for women because they have a purse, but do people really want to carry it in their purse all the time? And what I find, and David, I'm sure, is going to nod on this, is young boys and adolescents do not want to carry auto-injectable epinephrine. They have no where to carry it and they complain about it all the time.

We're certainly not going to put a lux pen in their pocket, let's put it that way. I think you can argue a little bit that AUVI-Q is smaller than the cell phone that they carry, but still it's something that -- wonder if you could swap around the back of the phone or whatever, like you have the credit card, things that magnetically stick now. So I mean, then you've got it stuck there, which is usually advantageous. So they don't even have to think about it because it's already there.

That's great. And just finally, I was wondering about any additional relevant evidence that might be required in addition to bioequivalence and PD data that might convince people to switch to 108. And do you think the FDA would ask for a real world usage study and what the parameters might be there?

So from our perspective, from the conversation we've had with the FDA to-date and where we believe the development process will go. In addition, as we talked before, in addition to a pivotal PK study, the traditional pivotal PK study, we do think a human factor study will be necessary, and we're happy and prepared to do that study. In terms of a real-world evidence study, at this point, we don't see that as a requirement. We'll continue to have the conversation with the FDA, and we'll continue to make sure we have a robust package for this product, whether it's required from a regulatory perspective or necessary for the market position.

Okay. And at this time, we'll turn the conference back to Dan Barber to take questions from the webinar.

Okay. And we do have a list of the questions from the webinar. We appreciate people putting those questions in. We will, in future segments, make sure we provide answers to those questions. And where we can, we'll provide them now. But we are at the top of the hour, and I want to be conscious of everyone's time. So with that, I'm going to turn it over to Keith Kendall.

Thanks, Dan. And thank you, everyone. As you can see, we have an exciting program centered around epinephrine. We've demonstrated we can consistently deliver meaningful amounts of systemic epinephrine. We have compelling PK and PD data we look forward to speaking to the agency about. And we have a number of additional prodrugs that we could use to manage a specific performance we're trying to get out of the product. We look forward to providing additional updates as appropriate throughout the year for all of you. But just to demonstrate how exciting and fast-moving this program is, we can now say we've gotten the necessary approvals from the Canadian health authorities to start the program or the trial for AQST-109, and we'll be moving to recruiting volunteers and administering the product to them as quickly as we possibly can. As we said, we look forward to talking about the results from that later in the year. I'd like to thank Dr. Fleischer and Dr. Oppenheimer for joining us today. We appreciate your time, your insights. They were invaluable to us. And of course, I'll -- kudos to Dan and his team for the work they've done to get us to this point. So thank you all to everyone for joining us today, for spending your time with us this morning, and we look forward to talking about this program again with you in the future. Have a great rest of the day.

And thank you.