Good morning, and welcome to the Insmed's R and D Day Conference Call. All participants will be in listen only mode. After today's presentation, there will be an opportunity to ask questions. Those listening through the webcast may submit questions through the event by clicking the word Questions on your screen. Please note this event is being recorded.
I would now like to turn the conference over to Sarah Bohnstein. Please go ahead.
Good morning and thank you for joining us for Insmed's R and D Day, where we will share exciting updates across our pipeline. The slides from today's presentation will be made available on our website shortly after the presentation is concluded. During today's presentation, you will be hearing from various members of the Insmed leadership team around some meaningful corporate advances. Importantly, we believe we have funding to cover our current planned programs over the next 3 years, which you will hear about today. You will first hear from Will Lewis, Chair and Chief Executive Officer of Insmed.
Following his comments, we will turn to Doctor. Eugene Sullivan, Chief Product Strategy Officer at Insmed as well as Doctor. Ronald O'Deeze, an internationally recognized expert in pulmonary arterial hypertension or PAH for a discussion of recent developments as well as the opportunity present in treprostinil palmitil inhalation powder or TPIP. I will then turn to our brenso capsid program where Doctor. Kevin Manje, Senior Vice President, Head of Clinical Development and Colleen Silk, General Manager for Bensokaptive, will provide development program updates and the opportunity that Bensokaptive represents for Insmed.
Next, I will pivot we will pivot to an update for ARIKAYCE, Insmed's first commercial product, where Doctor. Manj Neil Hughes, General Manager, Head of Europe, the Middle East and Africa or EMEA and Roger Assett, Chief Operating Officer, will provide a discussion around our label expansion efforts and anticipated ex U. S. Launch plans for ARIKAYCE. I will then conclude with the financial update and closing remarks.
Following the prepared remarks, we will open up the call for questions. For the Q and A portion of the call, you will be able to submit questions through the teleconference as well as the webcast portal. Before we begin, let me remind you that today's presentation will include forward looking statements based on our management's current expectations and beliefs. Such statements represent our judgment as of today and involve substantial risk and uncertainties that may cause actual results to differ materially from the results discussed in the forward looking statements. Please refer to our filings with the SEC, which are available through the SEC's website at www.sec.gov or from our website for information concerning the risks and uncertainties that could affect the company.
And please note, this event is being recorded. With that, I would now like to turn the call over to Will.
Thank you, Sarah. I would like to start off by discussing what it means to build one of the next great biotech companies, one grounded in science with a purpose to tackle multiple therapeutic challenges and transform how patients across the globe with difficult diseases are treated. At some point along that journey, a company needs to make the leap from being a single product company. It needs to build on its initial success by developing a portfolio of medicines that has the potential to profoundly impact the lives of patients. I am thinking of a handful of biotech companies that have made that leap, companies such as Vertex, Alexion and Gilead.
Our ambition at Insmed is to join this group. And today, we will outline the cornerstones of our strategy to achieve this vision. 3 years ago, when we hosted our last R and D Day, we stood before you on the cusp of a turning point for our company, the readout of the Phase 3 clinical trial for ARIKAYCE. We predicted that the success of that trial would lead to ARIKAYCE becoming our first approved product in the United States, followed by our first commercial launch. At the time that was viewed as an especially bold goal.
Since then, we commercialized ARIKAYCE ourselves in the U. S, a step that many biotech companies failed to make. We drove exceptionally strong growth in our 1st year of launch. The launch of ARIKAYCE exceeded expectations, especially for a rare disease for which no product had previously been approved. Looking back, we can now say that we successfully met the challenge.
But today's meeting is about much more than that achievement. Today, Insmed is a fundamentally different company. We have a demonstrated track record of success in research, development, regulatory engagement, commercialization and business development. We can now see before us the pathway to a company with 3 overlapping pulmonary programs, each of which has the potential to profoundly rewrite the way patients are treated in their target diseases. We are ready for our exciting future and our purpose driven to repeat and build upon our recent accomplishments.
And importantly, we are well capitalized as we execute against our high ambitions in the next chapter of Insmed's growth. Our presentations today will highlight these capabilities from lab to market and the development expertise that bridges the 2. But first, I wish to share how we view each of these 3 product candidates within our overall growth strategy. The first program we will discuss today is treprostinopalmatil inhalation powder or TPIP, which was formerly known as INS-one thousand and nine. Developed in our labs, this potentially highly differentiated prostanoid may provide a disease modifying effect in a less frequent, better tolerated therapy.
Essentially, we are trying to unlock the full potential of prostanoid therapy and thereby create what we hope will be a leading choice for physicians treating PAH patients. We are honored to have Doctor. Ronald O'Dea's, one of the most well respected thought leaders in PAH here today to provide his perspective on how this product could fit into the PAH treatment landscape. He will be introduced by our own Doctor. Eugene Sullivan, also an expert in this field with a distinguished background having served as the Deputy Director of the FDA's Division of Pulmonary and Allergy Products and as the former Chief Medical Officer for United Therapeutics.
Gene will provide a detailed look at the preclinical data we are sharing today for the first time. Following this opportunity, we will turn to brincicatib, our DPP-one inhibitor. There is much to discuss about this compound as we approach the start of our planned Phase 3 Aspen trial for the treatment of bronchiectasis. We are very optimistic in the potential success of this trial because it is intentionally designed to closely track and repeat the success of our Phase 2 WILLOW study. Please note that all references to bronchiectasis in this presentation refer to non cystic fibrosis bronchiectasis, consistent with the patient population seen in the WILLOW study and planned for in the Phase 3 Aspen trial.
The impact of the WILLOW study cannot be overstated. It is a game changer for Insmed. This is because it is not just a drug to treat bronchiectasis. The WILLOW study revealed a new potential pathway for treating inflammatory diseases that are impacted by neutrophil recruitment. We believe it is a pathway potentially as robust as complement was for Alexion.
This broad mechanism was recognized with the publication in the New England Journal of Medicine just a few weeks ago, the first time in nearly 20 years that the journal has published on the topic of bronchiectasis. One of the most important takeaways from today's research day is that the DPP-one pathway represents the possibility of an entirely new platform technology for the treatment of neutrophil mediated diseases. In the hands of our research department, we now have a platform for development to fuel future growth. Our initial focus for this platform is in bronchiectasis, where we believe the opportunity is significant. You will learn today, bronchiectasis stands as one of the more globally prevalent pulmonary conditions with no approved treatment options.
We believe we are on the cusp of achieving through our Phase 3 Aspen program what one physician at the American Thoracic Society late breaker session described as the Holy Grail of pulmonary medicine. From a strategic standpoint, NTM and bronchiectasis are well aligned. The call point is the same, giving us perfect access to global thought leadership and allowing us to leverage synergies in our commercial organization. However, the bronchiectasis market is many, many times larger than even the frontline NTM opportunity. Our research suggests this number may be far greater than currently appreciated with significant overlap with COPD and asthma patients who today are undiagnosed.
But we intend to go much farther than just bronchiectasis. We plan to extend this platform and become a leader in the neutrophil mediated disease space, leveraging both our expertise and intellectual property. We have devised a stepwise strategy to expand development into new diseases using this pathway where early data and established animal models already indicate promising results. Today, we will discuss the first of those expansion opportunities. Coming back full circle, we intend to build upon the successful backbone of our company, the ARIKAYCE franchise.
Having honed our commercialization skills by the successful U. S. Launch, we are now prepared to replicate that success for refractory MAC lung disease globally. This begins with the commercial launch of ARIKAYCE in Europe this year, having recently received CHMP positive opinion and anticipating to receive EU marketing authorization next month. If ARIKAYCE is approved in Japan on our anticipated timeline, we plan to further expand access to ARIKAYCE for patients in Japan by the middle of next year.
Our goal is to extend the ARIKAYCE franchise to become the standard of care for NTM disease worldwide. To accomplish this in the near term, we will be launching our ENCORE and ARISE trials to support full approval of ARIKAYCE in the U. S. And potential expansion into the larger frontline opportunity in MAC lung disease in the U. S, Europe and Japan.
If successful, this would represent a more than 5 fold increase in the addressable market for ARIKAYCE. Taken together, we have several overlapping programs addressing clear unmet medical needs for patients around the world. Let me put the series of opportunities we are discussing today in a perspective that this audience will appreciate. Successful approval and launch of these therapies could translate into several $1,000,000,000 of revenues annually in the not too distant future. We have the proven development and commercialization capabilities, global infrastructure and the right expertise in place to execute our strategy and transform Insmed into one of the great biotech companies.
Indeed, one of the most important elements to bring this all about is talented people with the right motivation and mindset. If you were to look deep inside our company, you would find a cadre of extremely capable and motivated people who are in this for the patients. Within the company, we often speak about how much of a difference we are making for patients. By helping patients with meaningful life altering therapies, we will continue to build a great company and drive shareholder value. I would draw your particular attention to the people on this slide who are leaders within Insmed.
These people and their teams are the ones who have led the company to the position it enjoys today. Whatever this team has set its mind to, it has accomplished. I want to thank you for joining us today and giving us your attention. I invite you to join us on the next leg of our journey as we set our sights on becoming one of the next great biotech companies. If we are successful with the programs we are describing today, we will be that much closer to accomplishing this goal.
Now let me turn the call over to Gene Sullivan, our Chief Product Strategy Officer to unveil in detail our newest program from our research labs, TPIP.
Thanks, Will, and good morning, everyone. Starting with Slide 8, as many of you know, I've had a longstanding interest in pulmonary arterial hypertension or PAH, having cared for patients with the disease during my clinical academic career and having participated in the development of various drugs to treat PAH over the years. PAH has been an area of significant interest over the past 2 decades and we have seen meaningful innovation in the space over that time. Prostinoids in particular have provided notable clinical benefits for patients, but there remains a substantial need for more effective and better tolerated therapies. So I'm particularly excited to provide an update on our work with treprostinilpalmatil.
When we originally started working with this drug several years ago, we were primarily focused on the opportunity for the prodrug formulation to provide improved tolerability and convenience relative to the existing carcinoid options. However, our perspective has evolved over time as we've gained more experience and have seen the preclinical data emerging from this program. We now believe that the lung connects we are seeing may not only result in less frequent dosing and an improved tolerability, but also could allow us to increase the therapeutic window and drive improved efficacy. It is well known that in vitro, prostenoids exert an anti proliferative effect, but it isn't clear that the existing prostenoid therapies have been able to exert this effect in the clinic. Based in part on some of the data that I'm going to show you today, we believe that the potential improved tolerability and ability to maintain sustained high local concentrations of the drug in the lung may lead to a disease modification or remodeling effect.
With lung kinetics that we have achieved with this novel formulation, we may be able to harness the maximum benefit of this important class of drugs. And this compound may prove to be a differentiated prostenoid and an important new therapeutic option for patients with PAH. Today, I'm joined by Doctor. Ron Uddis. Doctor.
Uddis is a professor of medicine at the UCLA David Geffen School of Medicine and the Director of the Pulmonary Hypertension Center and Acting Chief of the Division of Cardiology at Harbor UCLA Medical Center. Doctor. Rudiz is an internationally recognized expert in PAH and is the past editor in chief of the scientific publication Advances in Pulmonary Hypertension. He is also the lead investigator for our planned Phase 2a trial for treprostinilpalmatil inhalation powder or TPIP. We are pleased to have him here today to provide some perspective on the PAH treatment landscape and the potential role for a differentiated prostenoid in the treatment of PAH.
Turning to Slide 9. Here's an outline of this morning's presentation. Doctor. Uddis will begin by providing a brief overview of PAH, addressing the nature of the disease, the currently available therapies and the remaining unmet medical need. I will then detail our work with TPIP and review highlights of some of the preclinical work that we've done with an eye toward how the preclinical findings suggest that TPIP may prove to be an important new product.
Finally, we will discuss our path forward. And with that, let me turn it over to Doctor. Udi.
Good morning, everybody. Thank you, Gene, and thank you, Will, for inviting me to speak today. If we can go to slide 11, this cartoon is what I use to help orient people and I apologize if this is review for some of you. But the concepts here are important and the understanding of what pulmonary hypertension, specifically pulmonary arterial hypertension is extremely important. So the hemodynamic definition of pulmonary hypertension is one that says that the pulmonary artery pressure is higher than it should be.
We have been using a mean of 25 millimeters of mercury. It's been recently revised to be about 20. Most of us sitting around today probably have means in the teens at the highest. So the problem is, if we go to the next slide, that we have some perturbations in the system that involves the pulmonary circulation. And so on your left is the blue blood that is venous blood that returns from our veins into the right side of the heart and is pumped into the lungs where the alveolar capillary membrane exchanges gas, specifically oxygen coming in, turning the blue blood red.
And then in the pulmonary veins, the red blood returns to the left side of the heart, where it pumps to the rest of the body and the circulation continues. So as you see here on the bottom right, left side of heart disease is something that raises the pulmonary venous pressure, because downstream from the pulmonary veins, there's a problem in the heart. It could be valvular heart disease, it could be after a heart attack and the pump is not pumping well, something results in a backup and the pressure increases because the right ventricle on the left side of your screen has to pump that blue blood through the lungs and force the blood into the left side where the backup is. So that's where the pulmonary hypertension comes from in left sided heart disease. On the top right, we see lung disease hypoxemia.
The alveolar capillary membrane where gas exchange occurs is affected with conditions like interstitial lung disease, where that gas exchange is no longer occurring normally. The reflex in the body is to vasoconstrict, it's to reduce the diameter of the blue blood coming in the pulmonary arteries on the left side. And the idea there is that, let's say, you have an ammonia where there is not good gas exchange occurring and the body natural response is to shunt blood or to constrict blood to that area. So that blood goes to places where there is gas exchange occurring. So when you have diffuse interstitial lung disease, there is diffuse phase of constriction and the arteries narrow and the right ventricle fin has to generate a higher pressure to overcome that resistance.
If we go to the next slide, thromboembolic disease is not uncommon in patients who have had a pulmonary embolus. And so what happens in some of these patients is over time they develop chronic emboli that essentially mechanically plug up the pulmonary circulation. And then again, the resistance goes up, the right ventricle has to pump a higher pressure to get the blood to go forward and continue the circulation. So if we go to the next slide, what you end up with when you excluded left sided heart disease and interstitial lung disease and thromboembolic disease, then you're left with what we call pulmonary arterial hypertension, several forms, idiopathic and those associated with certain conditions. If we go to the next slide, this is an outline of those conditions.
We call it group 1 pulmonary hypertension, which is essentially saying that it's not group 2, not group 3, not group 4. Group 5 is a grab bag of conditions that are known to be associated with pulmonary hypertension, but either the mechanism is unclear or multifactorial. So the proper diagnostic workup involves patients that have a suspicion or proven pulmonary hypertension and ruling out the other kinds of pulmonary hypertension. Next slide, you'll see that I've stamped no approved therapy for groups 2, 35. There is one medical therapy and there are surgical options for group 4, but really there is no other indication for PAH or PH drugs in these other groups.
Most of the drugs we're going to be talking about today, all of the drugs we're going to be talking about today, have indications specifically for pulmonary arterial hypertension. There are different kinds of PAH. In other words, the idiopathic one is where there is no apparent underlying associated condition known to be associated with pulmonary hypertension. There is a heritable form that is associated with certain genes that have been discovered and other familial forms where the gene yet has not been discovered. And then probably most commonly that we see in our clinic is 1.4.1 connective tissue diseases.
This in effect is also idiopathic in the sense that if you have a disease, an autoimmune disease like scleroderma and you develop pulmonary hypertension, in your lifetime, the expectation is that you might have a 10% lifetime risk of developing PAH. In the idiopathic form, it's 1 to 2 per 1000000 per year. So there's something about the scleroderma patients that predisposes them, but we don't know what it is. So in that case, it's still idiopathic and it's still deadly and progressive. Next slide describes what I mean by progressive.
So we think that there is some kind of timeline, whether this is minutes, hours, days, months or years, we don't really know. But if you start on the left side where PVR, pulmonary vascular resistance, PA pressure, PAP and cardiac output, CO, are normal. And then you start to get the disease that I showed you in that cartoon of the blue pulmonary artery circulation narrowing. Over time, the resistance goes up and the body has a pretty good way to compensate the right ventricle continues to pump under higher pressure, but it continues to maintain cardiac outlet for a certain amount of time. And during that time, we are unfortunately asymptomatic or we call this pre symptomatic.
And I say unfortunately, because if we were able to detect that there was a problem at this point, we might be able to intervene much, much sooner. By the time we get to point B, and unfortunately, most of the time where we're at point X, cardiac output has started to fall as PVR continues to rise and we get decompensated heart failure. The black box there is a small picture of an echocardiogram in the short axis On the bottom right at about 5 o'clock, if you tilt your head to the right a little bit, it forms the letter D. That ventricle, the left ventricle has been smashed, if you will, or pushed aside by the right ventricle, which is up at 11 o'clock, the larger black circle that is now a dilated and flabby right ventricle that is no longer able to continue to pump when the demand is there. As you see here, the overall 2 year mortality untreated from a database many years back before we had treatments and all we could do is record what happens to these patients is about 50%.
If you were a functional class 4 patient at the time in that registry, you had a 6 month 50% survival. So it's a very progressive and very devastating disease. The cartoon at the bottom describes what we think aligns with this timeline, where we have the intima, the median, the adventitia that are all affected and over time produce this narrowing of the blood vessel. It's a very proliferative, very inflammatory, even in situ thrombosis, thrombotic kind of a hotbed or a cauldron of disease. At the very end on the bottom right, you see that there is neovascularization, what we call the plexiform lesion, where there is blood vessels that are trying to be formed.
And unfortunately, that results in further encroachment of the lumen and increase in resistance. We go to the next slide, we'll see this depiction of what I was talking about with the D shape, the very bottom on the left, the left ventricle forms the letter D. It is not a nice round structure that is able to normally pump. It is generally starved for blood because the blood can't get through the pulmonary circulation to get back to the left ventricle for pumping to the rest of the body. The right ventricle, as you see, is dilated and becomes flabby and thin.
And on the right, you can see that the pulmonary arteries are normal on top and then progress to very, very narrow on the bottom. Next slide. There is an algorithm for diagnosing pulmonary hypertension, as I alluded to. There is a sequence of things that one must do to exclude other causes of pulmonary hypertension. But the first sign that there might be pulmonary hypertension is usually either symptoms or an echocardiogram that non invasively detects pulmonary hypertension.
And you go down this list, you get to the bottom, you refer to a PH expert center, hopefully, if you've been reading the literature and you understand. Next slide, again, this is just highlighting the idea that the echo is the first window into opportunity. And next slide, it continues the algorithm at the expert center. Next slide will show that central to this algorithm is the right heart catheterization. You in fact cannot be considered having pulmonary arterial hypertension until you have the right heart catheterization and the date you're diagnosed is the date of that first right heart catheterization that number 1, confirm pulmonary hypertension exists and number 2, excluded left sided heart disease, which really can't be done effectively and reliably without the catheterization.
Next slide. So now that we have that background, we can talk about the pathways affecting PAH treatments. There are 1,000, if not tens of 1,000 or more pathways that have been identified that mediate or propagate or are a marker of pulmonary hypertension. We're focusing on these 3 in this slide and later on we're focusing on just one. The first one briefly is endothelin pathway and is targeted by endothelin receptor antagonists.
Endothelin is one of the most potent vasoconstrictors known to man, and it is found in high levels. Endothelin receptors are upregulated in pulmonary hypertension. So it was genius to develop a drug that blocked endothelin and in fact had clinical improvements in patients when you use these endothelin blockers. The nitrous oxide pathway as the prostacyclin pathway is a pathway that involves vasodilatation and bathing the circulation in substances that are not only antiplatelet, but anti proliferative and vasodilatory, thereby facilitating improved pulmonary blood flow. In patients who have pulmonary arterial hypertension, nitric oxide levels and prostacyclin levels are low.
So again, genius to replace that and augment the effect of these drugs to improve pulmonary blood flow. So we're talking about the prostacyclin pathway then on the far right mediated by arachidonic acid. And as I alluded to before, there are things like antiplatelet and anti proliferative properties of prostacyclin that we as experts consider as the sort of gold standard, most potent, most effective, but unfortunately most toxic drugs around for pulmonary arterial hypertension. Next slide. This box here is really to remind me to mention that these patients who have pulmonary arterial hypertension for the most part are given prostacyclin as either a second line therapy or when they are very sick.
It sometimes doesn't make sense when you think about giving the most potent and the best drug out there only for the very sick patients, why not give it to them early? And that's actually a really valid question and we will speak to that later when it comes to the opportunity to use an inhaled drug that is targeted to the lungs themselves. Next slide. So the 3 different pathways here are again outlined prostacyclin endothelin PD5 focusing on the left, the prostacyclin analogs come in IV forms, they come in inhaled forms, they come in subcutaneous forms and also oral forms. And next slide.
Part of the problem with these drugs and with prostacyclins in general is not just the toxicities or the tolerability issues, but it's also the dosing and the pharmacokinetics. So if we look at the top, the oral has a very obvious advantage of being oral. The problem is that when you take prostacyclins in oral form, they can be very dose limiting, usually because of GI, but sometimes more systemic side effects, things like headaches and muscle aches and things like that. The parenteral therapies, as I said, are probably not probably, they're definitely the most effective and the most potent, but they also have the most toxicity. There are systemic toxicities such as hypotension.
It is common for patients to have some nausea or anorexia. Diarrhea is common. Some patients are on anti diarrheals, several pills a day in some cases. Headache and the phase of illatory flushing and the peculiar jaw pain are also associated with these, especially at the higher doses. Now the inhaled dose, the inhaled prostacyclins were given or developed as a way to target prostacyclin therapy to the lungs.
One of the limitations with the inhaled therapies is that we don't seem to be able to get doses high enough or consistent enough to mimic the parenteral therapy. So the parenteral therapies are the most potent because number 1, we can get them in high doses. Unfortunately, that means they're systemically administered and systemic side effects, but we can also get a constant delivery. And the levels in the body are not only high, but constant. So with the inhaled therapies currently, we have intermittent dosing, we have generally QID dosing and this sort of up and down, as you see here, sawtoed PKPD profile that we would like to smooth out and we would like to get a higher dose for.
Next slide. So the goal for this new process of proximally therapy, for example, TPIP, is to provide a more convenient administration. Clearly, a dry powder administration is much easier to use than a nebulizer with a device that's battery operated and uses a liquid and needs to be cleaned and prepped every time you do your QID inhalation. But we want a sustained effect, a long lasting effect without the ups and downs, and we want to target high doses. And specifically, if we can do that without systemically exposing the body to systemic prostacyclin, there is that potential that we could get all 3 desired effects in our patients with 1 or 2 doses, let's say, of an inhaled dry powder.
So with that, I'll send it back to Gene for a continuation of the discussion.
Thank you very much, Doctor. Adees. Let me now move to Insmed's investigational product, treprostinilpalmatil inhalation powder or TPIP for short. As noted on Slide 30, TPIP is a dry powder formulation of treprostinilpalmateal. Treprostinilpalmateal is a pro drug consisting of treprostinil linked by an ester bond to a 16 carbon chain.
The pro drug is itself inactive. In vivo, esterases cleave off the 16 carbon chain, resulting in the active moiety treprostinil. The dry powder is formulated for use in a simple capsule based inhalation device. Of note, our treprostinil palmitile drug substance was previously formulated as an inhalation suspension for administration using a nebulizer. This older formulation was evaluated in a Phase 1 study, which included a cohort of subjects who also received Tyvaso.
I'll show you some data from that study in a few minutes. But first, I'm going to describe a series of preclinical experiments that together demonstrate a number of key differentiating attributes of inhaled treprostinil palmateal as shown on Slide 32. These include improved pharmacokinetics compared to treprostinil, prolonged duration of pharmacodynamic activity compared to treprostinil, the ability to exert a local pharmacodynamic effect after delivery by inhalation, an impact on the hallmark histopathologic features in the SUJAN Hypoxia Model of PAH, And finally, a reduced instance of cough in a commonly used guinea pig model. The potential implications of these preclinical findings, if borne out in the clinical development program, are quite compelling. First, the prolonged lung residence time, prolonged half life and prolonged duration of pharmacodynamic activity suggests that the product could be dosed once or twice daily.
The prolonged lung residence time and the local pharmacodynamic effect suggests that the high systemic exposures that are achieved with other forms of treprostinil may not be necessary in order to achieve clinically relevant vasodilation. Comparable effects may be achieved with lower systemic exposures. The effect on the histology in the SUGEN Hypoxia Model suggests that the achievement of sustained local concentrations in the lung may allow treprostinopalmatyal to exert disease modifying activity. Finally, the lower Cmax and reduced incidence of cough may translate into improved tolerability to both the systemic and the local effects of inhaled treprostinil. Today, we will walk through the data supporting this potential product profile.
I will start with the preclinical data that demonstrate the improved pharmacokinetics achieved with treprostinil palmateal in both rat and dog. Turning to Slide 39. On the left, in the right, the top panel shows that while inhaled treprostinil, shown in blue, rapidly passes through the lung, Inhaled treprostinil palmateal remains in the lung for many hours. This results in a much lower plasma Cmax and a prolonged plasma half life as shown in the bottom left panel. In the dog shown on the right, the comparative PK is quite similar.
The Cmax of inhaled treprostinil was 10 fold higher than for inhaled treprostinil palmatil. And treprostinilpalmateal demonstrates a much longer plasma half life. Turning to the next slide. The next question is whether the prolonged residence time in the lung is associated with prolonged pharmacodynamic activity. Can treprostinilpalmatil exert prolonged vasodilatory activity?
As you can see on Slide 41, the answer is yes. Here in an experiment where the animal is subjected to a hypoxic challenge, we show that the vasodilatory activity of TPIP extended for many hours, in fact, out to 24 hours at the 2 higher doses. This is far longer than the duration of activity of inhaled treprostinil, which typically lasts for only about 2 hours in this type of model. As seen on the next slide, we ran the same type of experiment in the dog and showed very similar effects. In this case, we use dogs who had indwelling right ventricular catheters to allow for serial measurements during hypoxic challenges.
As was seen in the rat, inhaled treprostinil palmitile resulted in very prolonged vasodilatory activity out to 24 hours at all, but the very lowest dose. So these two figures demonstrate that the prolonged retention of the drug in the lung may result in significant prolongation of the pharmacodynamic effect of vasodilation. Next slide. The next preclinical finding I'd like to highlight is a phenomenon that we refer to as a local pharmacodynamic effect. To me, this is one of the most exciting findings that we've seen.
A persistent question, which until now has been rather difficult to address, is whether or not treprostinil is truly a locally acting drug when administered by inhalation. That is, is inhalation simply another means of getting the drug into the circulation where it can then exert its effect? Or does treprostinil exert its effect at least in part locally in the lung parenchyma prior to reaching the circulation? This experiment in the rat was conducted to address this question and the results shown on Slide 44 indicate this phenomenon of a local effect may have very important clinical implications. So in this study, we challenged rats with a thromboxane mimetic, which results in pulmonary vasoconstriction.
As a pulmonary vasodilator, treprostinil will reduce the degree of vasoconstriction resulting from this challenge. We then plotted the exposure response curves for infused treprostenil and for inhaled treprostinil palmateal using plasma treprostinil concentrations as the measure of exposure. The top figure is the exposure response curve when treprostinil is administered intravenously. You can see moving left to right that at a certain plasma treprostinil concentration, IV treprostinil begins to demonstrate vasodilation in this model. The bottom figure shows the exposure response when treprostinil palmateal is administered by inhalation.
What you can see is that the entire exposure response curve is shifted to the left. Remember that in these figures, the exposure is expressed as plasma treprostinil concentrations. So this means that you can achieve pulmonary vasodilation at significantly lower systemic concentrations when you deliver treprostinil to the drug to the lung by inhalation in the form of treprostinil palmitile. Therefore, these data indicate that treprostinil exerts a local pharmacodynamic effect beyond the effect that can be attributed to the plasma concentrations. We conducted the same type of experiment in dogs, this time using a hypoxia challenge.
I won't walk you through this figure on Slide 45. It's available with additional detail in the cited manuscript. But in short, we saw the same phenomenon in dogs that we had seen in rats. At any given plasma treprostinil concentration, the vasodilator effect was markedly greater with inhaled treprostinil palmitile than with IV treprostinil. In fact, the difference between IV and inhaled was even more dramatic in dogs with the EC50 being 5.50 times lower with inhaled treprostinopalmateal compared to IV treprostinil.
Our findings aren't entirely new. This 2,005 publication in the Journal of Applied Physiology noted a similar phenomenon in a sheet model using inhaled versus intravenous treprostinil. The problem was that because of the rapid transit of treprostinil out of the lung, the only way to demonstrate it was to continuously nebulize the treprostinil. That's not a feasible approach clinically. Because it leaves the lungs so rapidly, intermittently dosed inhaled treprostinil can't take advantage of this local effect phenomenon.
We believe that due to its prolonged residence time in the lung, treprostinil palmitile may be able to capitalize on the local effect as suggested by the results in the rat and dog models. This would mean that effective vasodilation may be able to be achieved at much lower systemic concentrations. The next finding I'd like to highlight are the results of experiments that we conducted using the rat sugen hypoxia model of PAH. As many of you know, the sugen hypoxia model is favored because in addition to resulting in pulmonary hypertension, this model also results in histopathologic features that are reminiscent of the proliferative plexigenic vasculopathy that is seen in the lungs of patients with PAH. Slide 48 shows the results of our first experiments using the SUGEN Hypoxia Model.
What we saw was that in addition to the expected effects on pulmonary arterial pressure and biferentricular hypertrophy shown in the left, We also saw dose dependent effects on the histopathologic features such as arterial wall thickening and vascular muscularization shown on the right. These findings really intrigued us. Until we saw these data, we primarily looked at treprostinopalmatil as a means of delivering treprostinopal more conveniently and with fewer adverse events. But these data suggested that because of the local effect and improved tolerability, we might be able to really harness the anti proliferative activities of this class of drug and achieve a remodeling effect. So we went back and repeated the rat sujin hypoxia study, this time adding in comparator groups representing other prostenoid therapies.
Specifically, in addition to inhaled treprostinil palmitile, we included comparators of inhaled treprostinil, IV treprostinil and orally administered selexipag. We wanted to explore whether the improved pharmacokinetics that we saw with TP might translate into improved signs of efficacy in the SUGEN Hypoxia Model. These are the results of the rat SUGEN Hypoxia Comparator Study. In these figures, the values for the healthy, unchallenged animals appear on the left in purple, followed by the 4 treatment groups, each with its own vehicle control. First of all, in terms of the hemodynamics and resulting right ventricular hypertrophy, what you can see is that all of the drugs showed some degree of benefit on the elevation in pulmonary arterial pressure on the left and the development of right ventricular hypertrophy on the right, which are induced by the SUGEN Hypoxia Challenge.
However, the magnitude of the effect was generally most pronounced with TPIP shown in green, particularly at the higher of the 2 doses. Now, in terms of the effect on the histology, on Slide 50, we show 2 of the histologic readouts from the model, vascular wall thickness on the left and vascular muscularization on the right. Again, we see that each of the prostenoid drugs showed some degree of effect on these parameters, but the effect was generally most prominent with TPIP, particularly at the higher of the 2 doses. The next slide is a spider graph intended to visually depict the degree of treatment effect of each of the compounds used in the comparator rat sugeonhypoxia study in 6 different domains, representing both the hemodynamic effects and the remodeling effects. The individual parameters are represented on separate axes radiating out from the center of the figure.
Each parameter is normalized between the normal healthy state, a score of 0 at the center of the figure, and the vehicle control sujin hypoxia injury, a score of 1 at the periphery of the figure. The findings for each compound are depicted in various colors. In this type of figure, the closer that the lines are to the center, the more efficacy they demonstrate. Here you can see that the high dose TPIP in dark green demonstrated a superior overall profile. We believe that the high dose TPIP represents a clinically relevant dose level.
As we move into early clinical development, we will learn more about whether we may be able to exceed that dose level with chronic dosing in patients in PAH. Finally, I'll share some of the results of a study that we did using a commonly employed cough model in the guinea pig. The data that I showed you earlier speak to the potential to achieve greater efficacy with an improved systemic safety profile. As many of you know, one of the bothersome side effects of inhaled treprostinil is cough. With our product, the compound that is being inhaled is the pro drug treprostinilpalmatil rather than the active moiety treprostinil.
To the extent that the cough may to the extent that the cough may be attributed to upper
airway deposition of the active moiety,
we wondered whether treprostinilpalmateal might be less likely to induce cough than treprostinil. Slide 53 shows the dose response data for inhaled treprostinil on the left and for inhaled TPIP on the right. What you can see is that the threshold concentration for causing cough was 7 times higher with TPIP than with treprostinil. The data that I just reviewed is part of the basis for our belief that TPIP may prove to be a differentiated product and one that may be an important addition to the therapeutic arsenal for the treatment of patients with PAH. The preclinical data are certainly very encouraging, but of course, we'll need to explore whether the features that we've seen in rats, dogs, sheep and guinea pigs will also manifest in humans.
We do have a first look at one aspect in man, the pharmacokinetics from our previous Phase 1 clinical study of treprostinopomatil inhalation suspension. These data were presented at the 20 16 European Respiratory Society meeting and are shown on Slide 55. In that study, we saw pharmacokinetics in man that were very reminiscent of the animal PK. Similar to what was seen in animals, we saw a 10 fold lower Cmax as compared to the molar equivalent dose of Tyvaso, and we also saw a very prolonged systemic half life. In addition to the obvious convenience of a portable dry powder inhaler, the existing preclinical data suggests that TPIP may allow for once or twice daily administration due to the prolonged lung residence time, prolonged half life and prolonged duration of pharmacodynamic activity.
It may also result in improved systemic and local tolerability related to the lower Cmax and the reduced incidence of cough. In addition, we have the potential to achieve greater pharmacodynamic vasodilatory effects at significantly lower systemic exposures due to the combination of the prolonged lung residence time and the local pharmacodynamic effect that has been seen in 3 different animal models. As we move into the clinic, we will be exploring how this may translate into an ultimate product profile. That is how high can we go on the dose in order to maximize efficacy while still maintaining tolerability. We hope to learn more about these trade offs in our Phase 1 and early Phase 2 experience.
And finally, these characteristics may allow treprostinopalmatyal inhalation powder to more fully realize the therapeutic anti proliferative potential of the prostenoid class with resulting disease modifying activity as suggested by the findings in the rat sugen hypoxia model. So where do we go from here? As noted on Slide 58, we recently initiated a Phase 1 study in the U. S. And I'm happy to report that the first subjects have been dosed.
This is a single ascending dose and multiple ascending dose in healthy volunteers with a key goal to understand the PK and tolerability profile. We expect to announce top line results in the Q1 of 2021. The next study, which will be conducted by Doctor. O'Deese at UCLA, will be the first use of treprostinilpalmatil in patients with PAH. This will be an open label exploratory Phase 2a study in a small number of patients to establish the time course of the hemodynamic response and to better understand the relationship between the pharmacokinetics and the pharmacodynamics of the drug and to assess the tolerability of the drug.
The patients will be continuously monitored in the clinic over a 24 hour period. We expect to get some very rich information out of this study, which will help us to quantify the local effect that I mentioned earlier. We expect data from this study to be available in 2021. Finally, I'll just note without much detail that we are tentatively planning to initiate a Phase 2b study in the second half of twenty twenty one. Planning is underway for that study and the goal there will be to establish the evidence that will be needed to move into a pivotal registration program.
With that, I want to thank you for your time and attention. We look forward to addressing your questions during Q and A. For now, let me turn it over to Kevin Mann, Senior Vice President of Clinical Development, who will lead off our discussion of the brincocatib program.
Thank you, Gene, and good morning.
I'm here today with my colleague, Colleen Silk, General Manager of the brincicativ program. We're excited to share with you our clinical strategy and the commercial dynamics for branzakativ bronchiectasis as well as opportunities for further development in the near term. Turning to Slide 60. At a high level, we view brincicatib as a pipeline and a product and the cornerstone of our efforts to build a portfolio around neutrophil mediated diseases and the DPP1 pathway. This novel, oral, once a day reversible DPP1 inhibitor represents an entirely new way to address a broad array of diseases where high neutrophil activity in this pathway is a component of the disease process.
These include rare diseases like cystic fibrosis and granulomatosis as polyangiitis or GPA, which we'll discuss today. And beyond that, we see opportunities in inflammatory bowel disease, lupus nephritis, rheumatoid arthritis, COPD and asthma among others. We also plan to leverage our experience in neutrophil immunomodulation to bring forward additional programs to build a portfolio. Colleen will describe our portfolio strategy in more detail shortly, but I will start with what we consider our launch pad in this initiative, our clinical development program and bronchiectasis. To better appreciate the relevance of branzikatib in this setting, let's revisit a graphic that we have shared in the past to help visualize the vicious cycle of this disease.
It starts with abnormal mucociliary clearance on the right hand part of the slide, which leads to bacterial infection. This then drives chronic inflammation on the left that ultimately leads to airway destruction. Unlike prior bronchiectasis programs in the industry, we are addressing the neutrophil mediated inflammation associated with the disease process. Studies have shown that neutrophilic inflammation is related to frequent pulmonary exacerbations, which are a hallmark of this disease. In contrast, prior clinical drug development programs focused on the bacterial colonization process of the bronchiectasis cycle where they used intermittent exposure to inhaled antibiotics over predetermined time intervals or cycling.
Runcicativ instead focuses on the inflammatory component. Our Phase 2 WILLOW study validated our approach with positive data on the time to the first and the rate of exacerbations in patients with non CF bronchiectasis. Whereas the Phase 2 studies of these other earlier programs focused on reducing colony forming units of bacteria. As noted on Slide 63, these results were recently published online on September 7 in the New England Journal of Medicine. This was the first time in nearly 20 years that the New England Journal of Medicine had published on the topic of bronchiectasis, underscoring the importance of these data and raising the visibility of the program to the broader scientific and clinical community.
The importance of these results is further underlined by the infrequent publication of data in the New England from Phase 2 studies. We're very proud of the results and publication and encourage you to review the article if you haven't already. I won't be walking you through the full study results today, but I do want to briefly draw your attention to a few key highlights as we've carried over many of these elements into our Phase 3 ASPEN study, which I will describe in more detail in a moment. Slide 64 shows the WILLOW trial design, which evaluated 10 25 milligram doses once a day versus placebo and focused on exacerbation endpoints with the time to first exacerbation as the primary endpoint, which both doses achieved. In terms of efficacy, I want to highlight the consistency of these data from the WILLOW study and what is generally considered a heterogeneous patient population as shown in these forest plots.
For the rate of exacerbations, which will be the primary endpoint for our Phase 3 study, both doses in the WILLOW study showed numerical reductions in the rates versus placebo in almost every subgroup. The levels of sputum neutrophil elastase based on a single measurement at baseline were not predictive of branzakativ effects. Across the 2 doses study, there was only one outlier of a point estimate of an effect versus placebo that was seen in the 10 milligram forest plot. It's important to note that none of these subgroups based on sputum neutrophilelastase levels are statistically different from one another and they have wide confidence intervals. Based on these data, we conclude that patients benefited from treatment with bronzocastif regardless of sputum neutrophil assays baseline levels and there is no larger benefit in patients with levels less than lower limit of quantitation at baseline.
But what is important is the consistency of the effects of both doses on a clinical outcome with the overall impact for patients. Strength of these results is reflected by the acceptance of the study by the New England Journal of Medicine. On this slide, we see that via the mechanism of action of brincicatib, there were significant reductions of 3 sputum NSPs including neutrophil elastase, which are aligned with the beneficial effects of brincicatib and the statistically significant reduction of the clinically meaningful outcome of exacerbations. PPP1 is an enzyme that will lead to the activation of several proteases. The most studied is neutral elastase, but for individual patients, their disease is impacted potentially by the combination of this and other proteases as well, for example, kathepsin G.
We see here a consistent effect of brancakativ on the reduction of measurable sputum neutrophil serine proteases or NSPs with a reduction in neutrophil elastase, PR3 and cathepsin G. These data further demonstrate the mechanism of action for brincicatid and point to the potential in a range of neutrophil mediated diseases that involve the DPP-one pathway. Turning to Slide 67, we summarize the overall safety data from the WILLOW study. For the Brunswick Catholic groups, the safety data were acceptable as events were mild to moderate in severity.
Patients in
the placebo group had higher rates of serious treatment emergent adverse events and discontinuation of treatment due to adverse events as compared to the branzakativ groups. With that background, let's now discuss our Phase 3 study for brancic acid and bronchiectasis known as the ASPEN trial. As shown on Slide 69, the ASPEN study was developed integrating feedback from both the FDA and EMA. We aligned on the adequacy of 1 global study with a primary endpoint that is of clinical relevance to patients and a design that retains many key elements from the WILLOW study. This path forward for branzakativ and bronchiectasis is a recognition of both the significant unmet need and the strength of the Willow data, which led to breakthrough therapy study having shown statistically significant reductions in exacerbations for 2 dose groups and consistent data across patient subgroups.
Our discussions with the health authorities were very productive and we were pleased with the level of engagement around this program. So based on the FDA E and A feedback and if we achieve a positive trial outcome in the Aspen study, we would be able to file for approval for prinsic acid for the treatment of bronchiectasis in the United States and the European Union based on the single Phase 3 study. We have planned interactions with the Japanese Health Authority before the end of the year and look forward to their feedback. Single large study will avoid the challenge that confronted prior development programs across the industry of having to have 2 positive Phase 3 studies for approval. Additionally, the number of patients from our entire program with bremsakativ across all studies will support a safety database consistent with International Council For Harmonization General Guidance for drugs intended for long term use.
So let's now review the specifics of the trial design as noted on Slide 70. Similar to WILLOW, the ASPEN study will enroll patients with at least 2 documented bronchiectasis exacerbations treated in the past 12 months. For the single study, 540 patients will receive 10 milligrams or 25 milligrams of resikativ or placebo once a day for 52 weeks for a total of 16 20 patients. The primary endpoint will be the rate of pulmonary exacerbations over 52 weeks with an identical definition for pulmonary exacerbations as was used in the WILLOW study. The Aspen study is powered at 90% to show a 30% reduction in exacerbations with a p value of less than 0.01.
Key secondary endpoints include time to first exacerbation, which was in fact the primary endpoint in the WILLOW study, the proportion of subjects remain exacerbation free as well as change in FEV1. This trial will also include 2 sub studies, a CAT scan study of approximately 225 patients to evaluate their lungs and approximately 300 patient PKPD study to evaluate sputum and blood NSPs. Turning to Slide 71, we are on track to launch the study in the Q4 of this year. We plan to enroll patients across approximately 480 sites in 36 countries. In order to drive enrollment, we are fast tracking 6 countries and expect to have sites activated by year end.
We are also targeting sites that were involved in the WILLOW study, of course. We look forward to providing updates as this trial progresses. So let me now turn the call over to Colleen to discuss the commercial landscape for bronchiectasis as well as our strategy for the broader resikatib program.
Thank you, Kevin. As discussed earlier, the mechanism of brincicatib provides us with multiple opportunities across a broad range of neutrophil mediated disease areas. We plan to prioritize and capitalize on the potential inherent in this program and work toward building an industry leading portfolio around brathocatib. The first step will begin with brontheopsis, which we expect will serve as a foundation of our franchise. We are focused on executing the Phase 3 ASPEN trial and preparing for a launch of brincucativ and brachiectasis in the U.
S, EU and Japan, leveraging the relevant experience and infrastructure we have built in these markets for our ARIKAYCE franchise. To expand our portfolio in the near term, we plan to focus on advancing a development program in cystic fibrosis. At the same time, we will advance our research efforts to support expansion into other rare diseases like GPA and to broader indications like IBD, RA or lupus nephritis. As we've shared previously, we believe there is significant global opportunity in the bronchiectasis market. Today, there are no approved therapies specifically targeting the inflammation and exacerbations associated with this chronic and serious pulmonary disease in the U.
S, EU or Japan. Based on our market research, we believe that brincicatib, which has been shown to significantly delay the time to first exacerbation and reduce the frequency of exacerbation could address the needs of multiple stakeholders, healthcare providers, payers and most importantly patients.
For
patients living with bronchiectasis, the impact of this disease on quality of life is severe. Everyday symptoms of cough, dyspnea and fatigue interfere with daily activities and fear of exacerbations negatively impacts their emotional and social well-being. This quote from a 54 year old bronchiectasis patient is striking. She said, it's like waiting for a hurricane. There's a constant level of fear and anxiety of the unknown.
When will an exacerbation hit? Healthcare professionals call for more effective treatments specific to this disease, treatments that are supported by robust clinical trial data. And from the payer perspective, there is a need for approved drugs that provide greater efficacy and reduced pulmonary exacerbation. As Will and Kevin mentioned, New England Journal of Medicine publication was the 1st bronchiectasis study published in their journal in nearly 20 years, which underscores the broad desire for treatment that specifically target this disease, particularly given the number of patients affected. On Slide 75, we provide an overview of the global market opportunity.
In the U. S. Alone, an estimated 340,000 to 520,000 patients have bronchiectasis. Estimates suggest a similar per capita prevalence in the EU5 countries. And while the estimated prevalence of the disease in Asia lacks full consensus, reported rates, particularly in urban areas, support an estimated 1,000,000 to 5,000,000 patients in the region.
There are limited epidemiology reports specific to Japan, but with our Insmed GK team, we plan to refine our market expectations in the near term. We expect these global prevalence numbers will evolve as we sharpen our understanding of the global brachyectasis opportunity. And as shown on Slide 76, we believe prevalence may be substantially higher given the under diagnosis of bronchiectasis. As we've discussed previously, there is significant overlap between bronchiectasis and COPD and asthma. Estimates again vary with anywhere from 650,000 to 9,000,000 U.
S. COPD patients also having bronchiectasis. This represents an estimated range from as few as 4% to as many as 54% of COPD patients depending on the literature report. In asthma, the overlap of patients who also have bronchiectasis falls between approximately 450,000 and 675,000 patients in the U. S.
Or approximately 2% to 3% of asthma patients. Our early market research and analysis of U. S. Claims databases corroborates the suspected overlap in patients, giving us a high degree of confidence that there could be a meaningful number of COPD and asthma patients that are currently undiagnosed with bronchiectasis. We will continue to do more work to understand the extent of this overlap, but even at the low ranges, there is a possibility that the market in bronchiectasis could be multiple times higher than reported prevalence numbers suggest.
Now let's turn to our commercial focus for bracicatib and bronchiectasis shown on Slide 77. The INSMED team is uniquely positioned to commercialize bracikativib approved given the synergies that exist between bronchiectasis and NTM lung disease. Based on initial research and our ARIKAYCE experience, we know that bronchiectasis patients are typically seen by pulmonologists and that there is a meaningful overlap in patient population, allowing us to leverage our existing commercial infrastructure. In addition, the work we've done over the past several years to build a team to reach and support the NTM lung disease community can be rapidly mobilized to support the potential launch of brincicatib for brukiptosis in the U. S, EU and Japan.
Notably, our experience in patient identification, execution of disease awareness campaigns and work with patient advocacy groups positions us well for a global launch if brincicativ is approved. Now let's discuss where we plan to go next with the brincicativ program. With bronchiectasis as our launch pad, our next near term focus will be initiating a development program in cystic fibrosis, a disease that despite recent advances in treatment options still represents an area of serious unmet need. At the same time, we'll continue to explore opportunities across the neutrophil mediated disease landscape, including GPA. As you can see on Slide 80, each of these opportunities is backed by clear scientific rationale, strong value proposition and roadmaps for clinical development and regulatory approval.
Starting with CF, the role of neutrophils and neutrophil elastase in CF is well understood. The inflammation associated with chronic bacterial infection is neutrophil mediated and patients generally present with very elevated neutrophil counts. We believe that brincicativ could fill the gap in the treatment landscape for a CF specific anti inflammatory therapy, a category currently not met by marketed products. For those CF patients who experience any pulmonary exacerbations, it could represent an important additive therapy on top of CFTR modulators. As many of you know, previously approved products in CF provide a roadmap for development and there is a well established research network in the U.
S. And EU. We anticipate finalizing our approach to clinical development, including Phase 2 protocol design in the first half of twenty twenty one and look forward to engaging the CF community, scientific advisors and regulatory agencies as we advance our plans. We are also excited about the scientific rationale that supports frintikativ and GPA. GPA is an autoimmune vasculitis characterized by systemic inflammation within tissue and small blood vessels, harmful inflammatory tissue masses or granulomas and organ damage.
In GPA, antibodies target proteinase 3 or PR3, which is expressed on the neutrophil surface, triggering a pro inflammatory response by the body. This autoimmune response affects multiple organ systems, but has a predisposition for the upper respiratory tract, lungs and kidneys. We believe brusicativ could play a role in this disease, working through 2 distinct MOAs. In addition to the inhibition of NSPs, bracicatib may also reduce the expression of membrane bound PR3. Review brezincatib as a potential additional treatment option for GPA patients across the disease spectrum, helping to get more patients with active disease into remission and helping to keep them in remission.
Finally, I want to touch on our ongoing investigator sponsored trial in hospitalized patients with COVID-nineteen, which is being conducted in the UK outlined on Slide 75. As it becomes increasingly clear that COVID-nineteen will be with us for an extended period of time, treatment options for infected patients will be needed and we are hopeful our drug will be a useful therapy. As part of this study, there will also be additional follow-up to assess how patients are faring in the post hospitalization phase since many of these patients have long term sequelae. The STOP COVID-nineteen trial is ongoing with a potential data readout in the first half of twenty twenty one. We look forward to updating you on our efforts across the brincicativ program as we move toward launching Aspen, expand into trials in CF and gain more insights about the global bronchiectasis market.
Our enthusiasm for the brincicata potential is based not just on the robust clinical data we've generated to date, but also on our experience in developing and successfully launching our lead product ARIKAYCE. The Insmed team has demonstrated that we can take a compound from concept to commercialization and at the same time continue to look for opportunities to expand the pool of potential addressable patients. We are excited to share our plans for expanding the ARIKAYCE label beyond refractory MAC lung disease and to discuss this program in more detail, I'm going to turn the call back to Kevin Manch.
Kevin? Thanks, Colleen. Good morning again everybody. I will start with Slide 84 and spend the next few minutes reviewing our registration program and strategy for seeking approval of ARIKAYCE as frontline therapy to treat MAC lung disease, which still represents significant unmet medical need. This program will use a PRO based primary endpoint for the FDA and durable culture conversion for Europe and Japan.
Currently, ARIKAYCE is the 1st and only medication approved by the FDA for the treatment of MAC lung disease as part of a combination antibacterial drug regimen for adult patients who have limited or no alternative treatment options in a refractory setting. MAC lung disease is a rare, progressive and chronic condition that if not successfully treated can lead to severe and permanent damage to the lungs. Patients often find that symptoms including cough, dyspnea, fatigue, fever and chest pain worsen over time. The disease is caused by mycobacteria in the environment and tends to affect those with underlying lung conditions such as bronchiectasis or COPD. ARIKAYCE is an inhaled once daily formulation of liposomal amikacin taken with a nebulizer and utilizes our PalmaVance technology to deliver the drug directly to the lungs.
This mode of administration allows for prolonged release of amikacin while limiting systemic exposure. Finally, as InMed's first commercial product, the lessons we've learned through the development of ARIKAYCE can inform development and commercialization across our portfolio given the overlap in patient populations. Specifically over 60% of bronchiectasis patients also will have a non tuberculous mycobacteria or NTM infection. Moving on to Slide 86, our registration program to pursue FDA approval of ARIKAYCE as a frontline therapy aims at the overarching goal to establish a new standard of care for patients suffering from NTM lung disease with a 3 drug regimen. Our efforts to improve the treatment paradigm for patients suffering from this disease involve a planned clinical program that includes 2 separate, but interrelated clinical trials that will be conducted in parallel, but have staggered ends.
The first trial is the ARRISE trial that is expected to enroll approximately 100 patients with newly diagnosed MAC lung disease. This will be an interventional study designed to validate longitudinal characteristics of the PRO tools that will be used in the second study, the ENCORE study. And the ENCORE study will be the pivotal trial designed to establish the clinical benefits of ARIKAYCE in this new patient population. We expect to enroll approximately 250 patients. Data from the ENCORE study is intended to fulfill the post marketing requirement to allow for full approval of ARIKAYCE in the United States and would support a supplemental new drug application for the use of ARIKAYCE as a frontline treatment for patients with MAC lung disease.
We plan to initiate both trials globally during the Q4 of 2020 with fast track countries including the United States. On the next slide 87, you can see the designs of these two trials. The study designs have been discussed extensively with global disease experts, including those who have developed the recently updated NTM guidelines and have integrated feedback from the FDA. The ARRISE study will be measuring and validating additional cross sectional and longitudinal characteristics of the PROs in our frontline setting. Other secondary endpoints will be measured as well including rates of culture conversion and time to culture conversion.
The primary endpoint for the ENCORE study will be changed from baseline to month 13, which is 1 month off treatment and respiratory symptom scores for the FDA with the endpoint of durable culture conversion at month 15 which is 3 months off all treatments as the primary endpoint for other health authorities. Other secondary endpoints will be evaluated including those related to sputum culture conversion, recurrence and fatigue symptoms. Moving to Slide 88. While we're developing a respiratory symptom score and potentially a fatigue score to support potential approval for a frontline indication, it is important to note that we are not starting from scratch and developing a de novo instrument. We're leveraging existing instruments and specifically the quality of life bronchiectasis tool and promise fatigue tool.
And evaluating a subset of these questions and responses from these instruments are appropriate for the frontline MAC population. We believe this strategy can save us at least 1.5 to 2 years' worth of time compared to traditional development of de novo instruments. This year alone we've completed the concept elicitation work needed for the FDA with these instruments among patients with newly diagnosed MAC pulmonary disease. As anticipated, questions and responses within these questionnaires do cover those respiratory and fatigue symptoms that are important and relevant to these patients. We are now moving on to the last part of the qualitative work cognitive interviews that is also needed for the FDA and will be completed later this year.
This work will finalize the subset of questions and responses that subject to FDA review we expect will be the basis of collecting data for calculating respiratory and potentially fatigue scores at the end of ARRISE and ENCORE studies along with the sputum culture data. Let me underscore, the PRO related work is being done specifically to address the FDA needs, but does not impact our efforts in Europe or Japan where durable culture conversion will be the basis of evaluation for ARIKAYCE in the frontline setting. Moving to Slide 89. When it comes to developing a PRO or symptom score for the frontline indication, we look to lessons learned from prior drug development programs in designing our approach. Not unique to our program, the FDA requires longitudinal data to support the validity of the PROs or scores in the patient population of interest.
We believe it is best to do that separate from the Phase 3 registrational study so that these data are available early enough to potentially adapt what may be done in the Phase 3 study. ARRISE is scheduled to complete while ENCORE is enrolling and this will give us the ability to adjust if needed the approach to computing symptom scores for the primary analysis for ENCORE while preserving the integrity of the ENCORE study. Given the concept that sputum culture conversion or reduction of bacillary load will drive symptom changes, We re examined data from the ARIKAYCE Phase 2 study in refractory MAC patients. Now the data are quite limited and for a short period of time of treatment, but there is the indication that patients who converted had numerically higher, meaning better respiratory scores from the QLLB instrument than the patients had not converted with the addition of ARIKAYCE to the background therapy. Although quite limited, these data give us confidence that by achieving higher rates of sputum conversion with the use of ARIKAYCE that a higher proportion of patients will have improved symptom scores in the ARRISE and ENCORE studies.
We have powered the ENCORE study at 90% for the primary endpoint and additionally the study is powered at over 90% for durable sputum culture conversion. However, we have built into the ENCORE study an interim blinded sample size reassessment so that we can be confident that that targeted number of patients still allows adequate powering for the potential treatment effect. Since ARISE ends earlier than ENCORE by design, the data from ARISE will give us earlier insights into what might be expected and inform on the final approach to computing symptom scores in the longer ENCORE study. In closing, we are excited about advancing ARIKAYCE as a potential frontline therapy to treat MAC lung disease. The InsuMed team continues to make great progress on our registration program and we look forward to providing updates at a future time.
So with that, let me now turn the call over to Neal Hughes, General Manager, Head of EMEA for an update on the planned European launch of ARIKAYCE.
Thanks, Kevin. Good morning, everyone. Starting with Slide 91, ARIKAYCE has been and continues to be a successful commercial product in the U. S, and we're excited about its global potential. It had one of the top 10 most successful non oncology rare disease launches following initial commercial efforts in the U.
S, and we're fully utilizing all we've learned from this success as we prepare to approach the European and Japanese markets. Our strong U. S. Launch was a direct result of our efforts to engage health care providers and educate the U. S.
Patient population, while working concurrently with payers in support of positive reimbursement trends. We plan to utilize the same efforts as we look to global expansion for ARIKAYCE. The EU market is quite different from the U. S, not only in terms of the reimbursement environment, but also as regards treatment pathways for NTM disease. And notably, unlike in the U.
S, ARIKAYCE is not a drug device combination product in the U. S. Or Japan. In other words, the Lameura nebulizer manufactured by PARI is a separately listed product. Despite these differences, there are critical earnings from the U.
S. That we can take and apply as we prepare for future launches. As one example, we will apply the U. S. Insights around optimal support for healthcare providers and patient education, which in many EU markets will be 3 third parties when initiating treatment with ARIKAYCE.
Turning to Slide 92. Our education efforts with healthcare providers will be of great importance given the updated international treatment guidelines for NTN Lung Disease published earlier this year, where ARIKAYCE received a strong recommendation for use as part of the treatment regimen for MAC Lung Disease. Specifically, the newly issued treatment guidelines strongly recommend the addition of ARIKAYCE for adult patients with MAC Lung Disease with limited or no alternative treatment options who failed to convert to a negative sputum culture after at least 6 months of standard treatment. The guidelines also recommend the treatment of MAC lung disease should be continued for 12 months after culture conversion. These guidelines are the globally recognized standard for the prevention, diagnosis and treatment of NTM Lung Disease with the goal of providing the latest evidence based guidance to improve patient care and outcomes.
This is the first update to the guidelines in more than a decade, marking a significant milestone in the management of NTM Lung Disease. The inclusion of ARIKAYCE in these clinical treatment guidelines underscores the critical role ARIKAYCE can play in the management of patients with refractory MAC lung disease. We view this as an important opportunity to reinforce the optimal treatment approach for refractory MAC patients, including the recommended duration of therapy and look forward to working with global NTM experts on educational efforts. A key focus in Europe to date has been to ensure that we have a strong team in place to execute on our goals, as shown on Slide 93. The EU team is highly experienced.
Team members have deep respiratory rare disease experience and our country leadership have impressive track records of successfully launching rare disease products in their market. This experienced and passionate team has and knowledge necessary to successfully educate treating physicians around the treatment benefits that ARIKAYCE can provide. We certainly have a clear vision to make ARIKAYCE available to patients on a global scale. Roger will walk you through our efforts in Japan shortly, but let me now focus specifically on our efforts in Europe. Turning to Slide 94.
The literature suggests that there 14,000 total diagnosed NTM patients in the European five countries, with approximately 1400 refractory MAC patients. As we've looked into this more closely, we've seen some indications that the opportunity for ARIKAYCE may actually be larger, as I'll discuss shortly. Turning to Slide 95, we received a positive opinion from the European Committee for Medicinal Products for Human Use or CHMP in July of this year and anticipate receiving EU marketing authorization in October. Based on the CHMP positive opinion, the indication for ARIKAYCE in Europe will be for the treatment of NTM lung infections caused by MAC in adults with limited treatment options due to not cystic fibrosis. And so it's a bit wider than only refractory MAC patients.
Essentially, this indication would also allow physicians to prescribe ARIKAYCE to treat patients who can't tolerate first line treatment or those who are contraindicated. Since receiving the positive CHMP opinion, we've worked steadily on finalizing translations and packaging in preparation for commercial product availability in Europe before the end of the year. Our initial assessment of the European opportunity for our case was conducted a few years back. More recently, on Slide 96, new analyses suggest that the actual size of the NKM population and the percentage of those patients with MAC infections may actually be higher than previously thought. Data also suggests that a higher percentage of patients than previously believed are refractory to treatment.
It's quite typical when introducing a treatment for a rare disease, which previously had limited or no treatment options to see the true prevalence of the disease become more apparent as there's more scrutiny of natural situation. If, as these recent analyses suggest, there are in fact significantly more cases that are currently not being diagnosed and referred, then it will take some time and effort to bring them to light. But over time, we're optimistic that the size of the opportunity may indeed be larger than originally thought. Turning to Slide 97, let me walk you through our European launch strategy. In preparation for the launch, we first built a strong but lean infrastructure and have focused on 4 operational priorities.
These include supporting value pricing and access, identifying and improving the NTM lung disease ecosystems to identify appropriate patients, ensuring INZAMED's launch readiness and building support for both patients and healthcare providers. This last effort is critically important to ensure that patients and treating physicians have a positive experience when initiating ARIKAYCE. Our experience in the U. S. And with early access programs in Europe has clearly demonstrated that there's a significant difference in both satisfaction and treatment outcome when patients and health care providers receive adequate training and support, perhaps not surprising for a daily nebulizer therapy.
In particular, analysis from our French ATU program showed that with comprehensive patient and clinician support for treatment initiation in place, adherence was many times greater when compared to patients received minimal support. The final launch priority is to ensure that the team executes launch strategy in Europe. We've utilized launch minus 12 months and minus 6 months reviews and resourcing deep dives to ensure that all the pieces will be in place and operating smoothly to support a strong launch. Slide 98 outlines Insmed's footprint in Europe. As I mentioned earlier, we've built a targeted organization here.
Our country managers have been in place for several years and are expert in the management of NKM disease in the respective regions. Our model combines building our own commercial entities and field force in major markets, while utilizing distributor models where appropriate. We expect that by the end of this year, we will have 24 fuel based customer facing personnel, and we anticipate that to grow to a team of 50 by 2022. The timing and shape of this growth reflecting the anticipated phased reimbursement and actual demand across Europe. Reimbursement in the EU is a country level exercise typically initiated after receiving the PANELU marketing authorization.
The chart shown on Slide 99 shows our current estimates for timing of green burst launches in the various markets. These estimates are just that, a range of where we would expect launches to initiate, typically several quarters post approval, as reimbursement timing will be based on individual negotiations, not past historical data. I should also mention that we plan to keep any list price differential between the U. S. And Europe to a minimum and to have a relatively flat global pricing approach.
The model in Germany is of particular importance as this is a key market for us given its size and early launch. Drilling down a bit more here on Slide 100, we expect that Germany will represent the largest market for us in Europe. The interrelationship between regional expert centers and community pulmonologists, as well as the strong support when desired for both clinicians and patients will all be supported by a 3 up territory model shown here. In other words, the commercial field manager, medical science liaison and third party patient support program nurse all share a common geography. We believe this approach will allow for seamless customer experience.
Finally, turning to Slide 101, the corollary of having lean organization, of course, is that you need to ensure that you have the right resources in the right places. This slide illustrates how we've gone about this in Germany. Here we've mapped centers of excellence, high potential community pulmonology centers and centers who've had clinical experience with ARIKAYCE already. Based on this analysis, we can identify high potential areas in which to focus our resources. Once we've launched, we'll further validate these analysis and we anticipate adding additional commercial fuel staff in some of the higher potential areas by mid-twenty 21.
We're extremely pleased with our progress to date in preparing for European launch of ARIKAYCE, and I'm proud of the team's ability to make such impressive progress ahead of the anticipated approval, leaving us in a solid position to make ARIKAYCE available to patients by the end of the year. With that, let me turn over to Roger Adsett, our Chief Operating Officer, to walk you through our efforts to prepare for potential commercialization in Japan.
Thank you, Neil, and good morning, everyone. Insmed took the decision to register ARIKAYCE ourselves in Japan and, if approved, to commercialize ARIKAYCE ourselves, adding this market to our core geographies in the U. S. And Europe. We see Japan as an attractive market that we can access without a partner because of our corporate strategy focused on discrete patient populations with high unmet medical needs.
We believe that building a high quality team in Japan to bring ARIKAYCE, if approved, to Japanese patients in a refractory population first, followed by frontline therapy, is the right strategy that leverages our global infrastructure and can be accomplished with a modest local footprint. More broadly, given the overlap with bronchiectasis and NTM lung disease, the investments we are making now position us extremely well for potential future launch of brentocatib in Japan. We are extremely excited about the potential of the Japanese market and the progress we have made with our commercialization plans in Japan. As shown on Slide 103, the opportunity in Japan is significant with an estimated 15000 to 18000 refractory MAC lung disease patients. There are several factors that may explain this prevalence, including the fact that Japan is an island nation and proximity to water is a risk factor for NTM as the mycobacteria aerosolizes above bodies of water.
It's a large elderly population and underlying lung disease from smoking. In addition, Japanese annual physicals typically include chest imaging that could aid diagnosis. It could simply be that Japanese physicians are better at diagnosing NTM Lung Disease. Turning to Slide 104. We are on track for approval in the first half of twenty twenty one and an anticipated launch in Japan mid year 2021.
As we previously disclosed, we filed our JNDA for ARIKAYCE as planned in March of this year. We anticipate a 12 month review putting potential approval in the March time frame, if all goes according to plan. If ARIKAYCE is approved, we would anticipate a 3 month price negotiated, putting our potential launch in the middle of 2021. The Lomira nebulizer was approved by the Japanese Ministry of Health, Labor and Welfare or MHLW in June of this year, again, in line with our expectations. This is an important milestone as ARIKAYCE is not considered a drug device combination in Japan.
Turning to Slide 105 and pricing. The reimbursement process in Japan is different than what we see in the U. S. And Europe. A base price is calculated using a number of inputs and the government then looks to a basket of countries, specifically the UK, Germany and France for the list prices in those markets.
They then apply a foreign price adjustment. If the calculated price is lower than 75% of the foreign price basket, the government may adjust up to the 75% level. We anticipate that we will have supportive list prices in Germany and the UK to inform a favorable Japanese foreign price adjustment. We have a capable team working towards securing this reimbursement and we'll be constructively engaging with the government to negotiate a mutually acceptable price. The Lomira device is reimbursed separately.
Government reimbursement will support the base device plus disposables such as the handset and the mesh head and will also provide a medical fee to the physicians for training the patient on how to use the device. There are some key characteristics that are unique to the Japanese market shown on Slide 106. We want to highlight some of those nuances to better inform on the opportunity for ARIKAYCE.
First, for the 1st year that a drug is
on the market, prescriptions are limited to a 2 week supply for patients. This means that if ARIKAYCE is approved, patients would need to return to their pharmacy every 2 weeks to replenish their ARIKAYCE supply. 2nd, Japan is a copay market where all approved drugs are reimbursed at fixed rates and there are various programs to support elderly and lower income patients. And finally, unlike in the U. S.
And Europe, if ARIKAYCE is approved, the InSped team would not be permitted to directly train patients on the use of ARIKAYCE with the LUMIRA device. Rather, we would explain how to use the device to physicians and physician offices will conduct training for patients. This is why securing reimbursement for the device and medical fees to cover training is important. To support our anticipated launch if ARIKAYCE is approved, we've built a strong presence in Japan shown on Slide 107. Our infrastructure thus far currently includes 28 people under the leadership of Mr.
Yuji Orehara. Mr. Orehara joined us in 2018 and our success in recruiting talent in Japan has been due largely to his efforts and his reputation. Mr. Orihara has worked for many large biopharmaceutical companies, most recently Gilead, where he oversaw the launch of their hepatitis C franchise in Japan.
Under Mr. Orihara's leadership, we already have in place a very qualified and motivated team. Moving to Slide 108. So how will this team maximize the potential launch of ARIKAYCE in Japan and reach patients and healthcare providers? We have already had appropriate medical engagement with major medical associations in Japan, including the Japanese Association For Infectious Diseases, the Japanese Respiratory Society and the Japanese Society of Tuberculosis and NTM.
It is perhaps noteworthy that the Japanese Society of Tuberculosis added NTM to the society's name in January of this year, indicating strong interest in NTM Lung Disease. Japanese KOL interest in ARIKAYCE is very strong and we are gratified for the early support they have offered to Insmed in bringing ARIKAYCE to Japanese patients if it is approved. Let's discuss our sales force in Japan. Please turn to Slide 109. Our current sales force deployment plan is to deploy 15 sales representatives to call on physicians at 2 15 key hospitals.
They will call on over 5 50 physicians within these hospitals. Based on prescribing data, we estimate this covers approximately 80% of the refractory MAC lung disease market. One of the lessons we learned in the U. S. Launch involved the knowledge gap in NTM guidelines and the need to offer educational support to physicians on guideline recommendations for treating NTM lung disease.
To address this gap, by the Q4 of this year, we plan to have 15 sales representatives calling on doctors under collaboration with Japanese manufacturers of clarithromycin. This will allow us to educate healthcare providers on the treatment guidelines for MAC lung disease in a manner that complies with Japanese law. These efforts will include education around the utilization of a macrolide as recommended by NTM treatment guidelines. Additionally, to further support these medical education efforts, we intend to deploy 4 medical scientific liaisons or MSLs by year end. In summary, I'm thrilled with the progress of our launch plans in both Japan and Europe.
The Insmed team has worked hard to apply the knowledge gained through the U. S. Launch and we are putting into practice the expertise gained as we implement plans to launch ARIKAYCE in Europe and Japan. I want to thank those teams for their efforts and continued dedication. I am looking forward to seeing the fruits of their labor.
More broadly, as I take a step back and reflect on the ability of Insmed to operate as an international company, executing multiple launches across diverse geographies, handling regulatory filings and approvals with multiple government agencies, managing complex supply chains to ensure our drugs and devices are available to patients wherever they are, executing clinical trial programs across multiple products, disease states and phases of development, all the while bringing additional impactful differentiated products forward from our labs, I couldn't be more impressed by the people we have within Insmed working to make a difference in the lives of patients. I'd like to thank them for their efforts to date and encourage them to continue to strive to make a difference. I'd now like to turn the call over to Sarah Bohnstein, our CFO, for closing remarks.
Thank you, Roger. Today, the team is taking you on a tour from the test tube to global commercial markets for important treatment opportunities both realized and potential. I want to close with a high level view on the collective impact of these programs. The past 3 years have been a whirlwind for the company as we've advanced from a development stage operations to a commercial company with a global footprint and an enviable pipeline beyond. And we fully expect the next 3 years will prove to be even more exciting given the opportunities ahead of us.
As we hope you've seen through today's presentation, we are well on our way to building what we believe will be the leading pulmonary focused pipeline in the industry. In the short term, over the next few months, we expect to initiate a registrational program for ARIKAYCE as a frontline treatment for NTM. In tandem, we are well underway in our efforts to expand global access to ARIKAYCE for patients with NTM outside of the United States. We also plan to initiate a registrational trial for brensocapatib as a treatment for bronchiectasis. Finally, we expect to advance treprostinilpalmitil inhalation powder or TPIP into Phase 2 development in an effort to transform treatment for patients suffering from PAH.
Importantly, from a financial perspective, we are well capitalized to execute on these planned studies as we advance our mission. We ended the Q2 of the year with a strong cash position of $641,900,000 which we believe will support our operations for over 3 years. This includes our global expansion efforts with ARIKAYCE, supporting both our planned ARIKAYCE confirmatory and frontline studies and our planned brentocaptive acid study for the treatment of bronchiectasis as well as the planned Phase 2 study of TPIP with PAH. Consistent with our commitment to focused investment, we will continue to closely align our expenses with our strategic priorities. Earlier, Will outlined the growth trajectory for Insmed and I want to take a moment to discuss how we expect the many opportunities we outlined today could translate into meaningful revenue growth for Insmed, leveraging our existing development and commercial infrastructure around the world.
For ARIKAYCE, on the heels of a successful U. S. Launch, we are well positioned to support global expansion efforts, if approved, into the EU and Japan. Neil and Roger outlined the strong teams we have on the ground and region specific strategies to support the launch in those markets. We believe successful outcomes in our planned ENCORE and ARISE trials could support full approval of ARIKAYCE in the frontline setting in the U.
S, Europe and Japan, which we believe could establish ARIKAYCE as the standard of care for any patient with NTM. We believe this in turn could represent a fivefold increase in the addressable market for ARIKAYCE, making ARIKAYCE a product capable of generating over $1,000,000,000 in annual revenue. We believe that the frontline setting could leverage our established commercial infrastructure from the refractory indication. For the brensocapoptip program, we fully intend to leverage the transformational potential in this once daily oral therapy starting with bronchiectasis. As Colleen outlined, we believe the market here is underappreciated as it is likely that many bronchiectasis patients are not accurately diagnosed.
The bronchiectasis indication alone could represent an addressable market opportunity 10 times to 20 times larger than ARIKAYCE. Even the low end of this range would yield substantial revenues potentially into the billions for InSpend. Notably, we believe we can accomplish the potential commercialization of bresocaptive with only modest investment in our commercial infrastructure. Given the overlap in the NTM and bronchiectasis patient populations and treating physicians in the U. S, we anticipate only a modest increase in our current sales force would allow us to reach the majority of the bronchiectasis community in the U.
S. We believe the strong alignment in geographies where these two diseases tend to be prevalent would also allow us to leverage our commercial footprint in both Europe and Japan. We view the ARIKAYCE expansion and bronchiectasis opportunity as only the beginning. We expect the next growth cycle beyond that will be fueled by our brenzocastin platform. Finally, with TPIP, we have a potentially highly differentiated proximoid that may provide improved benefit with a better tolerability profile and even the potential for a disease modifying effect.
Given the over 200,000 diagnosed PAH patients globally, we see the potential for significant value creation around TPIP in this initial indication. We are very excited about the many opportunities ahead for the incident portfolio. I would like to thank Doctor. Odies for taking the time today share his perspective on the PAH treatment landscape. In addition, I want to thank our shareholders for their continued commitment to Insmed and our shared vision to bring forward new treatments that can fundamentally change treatment paradigms in their target indication.
And I would like to thank the talented Insmed team for their efforts in transforming this organization. I truly believe that at Insmed, if we put our minds to it, we can achieve it. I'm extremely proud of this team and all that's been accomplished and the potential that lies ahead of us. We look forward to sharing our future successes with you. With that, let me open the call for questions.
Operator?
Our first question today comes from Ritu Baral with
Cowen. Hi, guys. Thanks for taking the question. I'll stick to 2. We'll start with the Aspen study.
You mentioned there was a 300 patient PKPD subgroup. Can you address the purpose of this subgroup and the, I think you said, biomarker data that it will be generating? And then my follow-up just has to do with some additional detail around the Aspen design, stratification, background treatment, and whether you are looking at any additional quality of life measures in that study?
Thanks for the question, Ritu. I'm going to ask Kevin to comment on the two questions. The first, the PKPD sub study within Aspen. And then answering the second one, we may also throw in there one of the questions that was written in, which is, what are the what's the hierarchy of the other secondary endpoints and what's the rationale for that hierarchy? Sure.
PKPD sub study and the Aspen study, that will focus on collecting data from both blood and sputum on the NSPs for which we've already measured in the WILLOW study. We'll do the same here in the Aspen study perhaps with additional NSPs as assays become available. So that will be the focus of the PD part, PK part, we'll be gathering additional information on the levels of remdesacativ in this population. Again, just to add to the wealth of data we already have here, so that's really the focus of that 300 patient PKPD sub study in asthma.
And is that data that will be used commercially potentially to manage these patients?
So, no, I don't think so at this present time. I think the data that we're going to collect are useful data for scientists and clinicians in this disease space to help further understand the effects we see with Brenza Cat to be its mechanism of action on exacerbations of the clinically relevant outcome.
Got it.
And then maybe Kevin you can comment on the hierarchy of the secondary endpoints in the study and thoughts behind that.
Sure. So just to be clear, the primary endpoint for Aspen is the rate of pulmonary exacerbations over 52 weeks. As we've shown in Slide 70, the secondary endpoints are listed according to the hierarchy that we've propose, so that the 1st secondary endpoint in that hierarchy is time to 1st pulmonary exacerbation over the 52 week period. The next is the proportion of subjects who are free of exacerbation. And the third is the percentage change in post bronchodilator SVP1 during that time.
Now in terms of some of that rationale, it gets us and the health authorities different aspects of exacerbations that we've already in fact shown favorable effects in Willow. So we've shown an impact on the time to first exacerbation. That gives you some additional information as opposed to the primary endpoint, which is rates of exacerbation, which is really more than one exacerbation. The other secondary endpoint, the proportion of free It will give us a total exactly as it says, a total number of patients at the end of the study who are free of any exacerbations, different information from the time to first exacerbation. And then the last one, not the last secondary we look at, but in that hierarchy, the change in post bronchodilator FAV1.
Interesting data from WILLOW that we shared at ATS Virtual as well as is described in the New England Journal, where placebo treated patients showed a numerically larger decline than the bremsakativ treated patients, although not statistically significantly different, intriguing enough, different enough that perhaps through 52 weeks, we might observe something in an area that would provide additional useful information to clinicians.
And Kevin, in that data that we saw where placebo declined in Phase 2, was the decline seen in the placebo patients consistent with expectations?
Yes, absolutely. I think our assumption here, the rate that we would see was almost virtually head on to what we had predicted for that. So yes.
Okay. And Ritu, I want to make sure we answered your second question adequately.
Yes. But also just what you're allowing for background treatment for Aspen and stratification?
Two questions. So, let me take the first one first in terms of background therapy. So, these patients, the patient population that we're enrolling virtually the same as the WIL population. These are people who have had a history of 2 or more exacerbations, as I said earlier, within the prior 12 months requiring treatment. And so, these patients, as you would expect, are on various inhalers that you know well.
So those will be allowed. What will be important though is they are unstable dose and stable types of medications for at least 4 weeks before actually getting randomized and that's really important here and that's what we did in the WILLOW study as well too. To the second question in terms of stratification factors for randomization, we're going to be using the use non use of macrolides at screening, whether they had 3 or more exacerbations or less, everyone has to have at least 2 or more. And then lastly, the presence or absence of Pseudomonas during screening in their sputum. So those are the stratification factors that we'll use.
And then did we look are we going to be looking at quality of life or any PRO sort of benefit?
Yes. So as for example, the quality of life bronchiectasis tool we'll be using, the bronchiectasis severity index as well is another example of something that will be useful information I think for clinicians.
And then finally, how are we going to handle background inhaled steroid usage? That was another question.
Sure. For the patient population who has 2 or more exacerbations, it's expected that pulmonologists in their present care of these patients today are using ICS inhaled corticosteroid. And we saw that in the WILLA study as well. I'll just come back to the point is they could use it, but they have to be on a stable dose for several weeks, 4 weeks before they actually get randomized into the Aspen study.
Terrific. Ritu, does that answer all your questions?
Yes, indeed. Thanks.
You bet.
Our next question comes from Matthew Harrison with Morgan Stanley.
Hi, all. Thanks for hosting the call and this is Connor Meehan on for Matthew. So this is a question on CPIP, maybe for Doctor. O'Dea, if he's still on.
Still here.
So
we're just wondering great. How does the rule out technique affect the addressable market for TPIP? Do you think certain subtypes of patients would benefit more? And if you are to target idiopathic disease, how do you think that will affect patient outcomes and enrollment?
I apologize if I made any points towards the use of this drug only in idiopathic pulmonary hypertension. My intent was to show that Group 1 is the rule out disease in Group 1 and it comes to all PAH. As it stands, all currently approved FDA approved drugs for PAH are approved for all subtypes of Group 1, and we don't usually make any specific subset distinctions, so that anything that you saw in that list of Group 1, which would include idiopathic, heritable, associated with connective tissue disease, portal hypertension, etcetera, would be candidates for inhaled prostacyclin as they are currently.
Got it. Thank you. And then so just one other. So on brincicatib, I guess whoever might be the best for this one. What do you expect in terms of the dose response given the relatively mixed efficacy across dose levels?
But in a prior call, you had mentioned that that was due to the trial just wasn't powered for that. So if you could just comment on what your expectations are for each dose level in Aspen?
So this goes to the heart of the question of dose response that was observed in the Phase 2 study. And for that, I'll ask Kevin to respond. Thank you. I think
as Will was alluding to in the WILO study, both doses were clearly effective. They showed statistically significant effects as you know on the time to first exacerbation here. And we said it may be that we did not see a dose response effect there on those endpoints and it may take us longer to show that interestingly through its mechanism of action on those sputum NSPs that we mentioned there was clear dose response to that you there that I showed today and it's also shown at European Respiratory Society. So clearly, the DPP-one mechanism has a significant role in the risk for exacerbations. And I think the Afrensacaftive as we've shown in Willow, we expect that we will one have an impact on rate of exacerbations and it remains to be determined perhaps through a longer trial whether we'll see those responsivity between the two exposures that we're studying.
Got it. Thank you.
And I'm just going to follow-up, Doctor. O'Dea as long as we have you, because there was another question that was written in that I might just ask you to comment on. And the question is this, if TPIP is able to show the desired target product profile, how would that impact the treatment of PAH, your patients with the there are a lot of products on the market. So can you help folks understand the potential impact of something like TPIB? How significant an innovation would it really be?
Highly significant potentially. The story with prostacyclins goes back to when Tyvaso was first introduced. And the idea was finally we're going to be able to get patients on prostacyclin therapy early and we're going to be able to do it without having to do an intravenous or subcutaneous infusion and the so called pump that everyone gets attached to. The reality with Tyvaso was that it works and in certain subsets, it's effective. However, it's not a replacement for the intravenous therapy for the reasons we described about pharmacokinetics, local delivery, efficacy and tolerability.
This drug, if it can give us once or twice daily dry powder inhalation that will give us sustained high local levels, could then be the equivalent of what we were looking for with a parenteral therapy and it could then be delivered earlier because of the ease of use and tolerability.
Thank you.
And our next question comes from Marty Auster with Credit Suisse.
Hey, everyone. Thanks for hosting this event. I had a couple of quick ones, I guess, both on TPIP. The first one would be, what do you expect the benefit from the Phase 1 study of TPIP versus the previous Phase 1 you run with a nebulized version, you referred to that as the inhalation solution of trebrosinol palmitile. Would there be tolerability benefits, ability to dose higher?
Are there PK differences you'd expect to see between the two formulations? And the second question might be for Doctor. Adi. What's your sense of the kind of the meaningfulness of what we can get out of the single dose Phase 2a data in PH patients? And how would you be able to kind of frame and compare the findings from single dose versus other therapies?
Is there any way to start to tease out the potential for differentiation in this product clinically from that study? Thanks.
Gene, I'll ask you to take the first question and then Doctor. Udiase, if you could please address the second one.
Sure. Thanks. And hi, Marty. Thanks for the question. Yes, I think as you pointed out, we've already got some experience with this drug substance in the inhalation solution study that was done.
And what we've seen in the animal, so we repeated a lot of the experiments and the initial stuff was done with the inhalation solution in animals and then we went back and often in the same model and looked at the TPIP formulation and we saw basically it behaves the same way. So we actually don't expect much difference in the PK. This is more to just be sure. We wanted to go into healthy volunteers with a new formulation going straight into patients. And we really just want to sort of verify that the PK is expected to be roughly the same, tolerability should be roughly the same.
We don't we're not expecting anything new. Now the other thing that we will get out of this study because it's got an MAD component is some multiple dose experience that we didn't have with the study that I referenced, which was just single dose.
So the second question really is a good one because there's a paper that we wrote in pulmonary circulation that involved transitioning between parenteral and inhaled therapies in a carefully selected subset. And in that paper, you can see that the hemodynamic responses are rather acute and they wane quite quickly. So with our early Phase II study, we will at least see the hemodynamic effects. We will also be measuring other certain acute effects physiologically in the ICU. So while it won't inform us completely as to the differentiation because we're not using any other kind of comparator.
It will still give us an idea based on what we already have seen acutely hemodynamically in the ICU with the catheter in place with other therapies, specifically with inhaled treprostinil.
And then if you could remind me for the Phase II, what sorts of patients would you be looking for? Will these be kind of naive to therapy or wash out or patients? Or would you be adding on top of kind of baseline oral therapies or who would you like to target for that study?
We're not looking for a lot of patients, so I'm being fairly strict with the enrollment criteria. So we're going to look for stable patients that are going to be who are going to have prostacyclins added. And one day before or a short time before that happens, if they volunteer to be part of the study as just a one time use sort of a thing, that will be the case. If we have difficulty, of course, in enrolling the few patients, I don't think we will. We can certainly open it up patients who aren't necessarily going to be placed on prostacyclin therapy, and have those that are just stable.
It's harder to find volunteers who are doing well and for no other reason want to just try something for 24 hours in an ICU.
Okay. Thanks a lot for your answers.
Our next question comes from Joseph Schwartz with SVB Leerink.
Hi, thanks for a very helpful set of presentations. I was wondering if you could talk about the makeup of your proposed PRO that you'll be validating for the frontline NTM indication. Which components do you feel strongest about? Which are more exploratory and are there any that the FDA has indicated that absolutely must be included? And do you have how much leeway do you have to contribute some components that you might particularly want to have in there?
Kevin, I'll ask you to address that.
Great. Thanks Will for the question. The work we're doing for the FDA is that around the PROs or symptom scores, we are doing and we've completed work this year and there is work ongoing that we will complete at the end of this year that will help inform really the answer to that question. So what we've accomplished this year is make sure what symptoms patients in frontline setting have in terms of symptoms that are prevalent, bothersome to them and impactful. And that information from the concept elicitation work that we've completed strongly supports that we're heading in the right directions with our focus being appropriately placed in the area of respiratory symptoms as well as in fatigue symptoms.
So that's where we're headed. The work we're doing now in the cognitive interviews is the last stage of what is the traditional approach and qualitative work. So I think we're heading the right direction of respiratory symptoms, as well as fatigue symptoms. That's where we want to head. The dialogue that we have with the FDA is clearly supportive of that.
It will be data driven. So there's nothing here that we're being necessarily forced to focus on per se. It will be data driven. Those are the 2 areas we're focusing on.
And Kevin, have we had an explicit discussion with the FDA about the use of the ARISE trial to inform the ENCORE study so that if when it reads out early, we can take the learnings from that quantitative analysis and adjust the ENCORE, PRO tool and how exactly first of all, have we had the discussion explicitly with FDA get their okay? And then how would that what would that look like? How would that work?
Yes. So at the end of the work that we'll complete year, we'll finalize the subset of questions or questions or responses that we'll use in both those trials. Now from ARRISE, the data we're generating in ARRISE is part of the data we have to give to the FDA around longitudinal psychometric data. And so based on those data that will inform what we will use ultimately at the end of ENCORE to compute the symptom score. So we've had that direct dialogue laid out those plans and it will be an ongoing sharing of information along the way.
So they're comfortable with the data that we're showing to support where we're headed throughout this entire program.
That's very helpful. Thank you.
Our next question comes from Stephen Willey with Stifel.
Steve, you may be on mute.
Hey, sorry about that, Will. Thanks for taking the question and thanks for the presentation. So can you just comment on the decision for Aspen to be 1 year in duration? I know there's been some regulatory discussion previously just regarding the ability to capture enough events within a year timeframe? And then maybe just second to that, I know some of the physicians that we've spoken to suggest that these patients don't really seem to exacerbate that much during the summer months.
There's kind of a seasonality trend there. So just given that this is a global trial, is there going to be any effort to try to geographically enrich for patients to compensate for that?
So I'm happy to ask Kevin to respond to that question. I think the good news is this is a prudent path in terms of what is the right way to approach the Phase 3 study design. But Kevin, maybe you can talk about the discussions you've had with FDA that have led us to a 1 year study and how we think about the issue of seasonality if there is any.
Sure. The 52 week timeframe is not unusual for this disease, Aerie for bronchiectasis and prior programs that actually have looked at exacerbation and COPD is another example of disease for 52 weeks is the timeframe of showing an effect. Part of that is help deal with that seasonality issue, right, where if we only do 6 months, we may be only cash burning the summertime in the northern hemisphere versus in trial enrollment plan is enrolling patients from North America as an example as well as from Australia, New Zealand and for the 52 weeks we think we'll capture the full cadre of a period of time that people are at risk for exacerbating here. I think in terms of the number of events that we would see throughout that year, I think as we saw in Willow, although it's 6 months, we saw enough events in 6 months to see clear separation of brincicatin versus placebo. I think as we go out to 52 weeks, we're really confident here that that's the right approach to allow one of the doses, if not both, to have a significant effect on exacerbation of that 52 weeks.
And I'll just add, Steve, that we have 2 or more exacerbations in the last year as the baseline entry criteria. And when we did that previously, we actually pinned down an estimate of what that would look like on an annualized basis in the patient population, the placebo population, and we got it exactly right. So I think our ability to understand based on prior experience and review of other trials as well as our own internal expertise in this gives us a lot of confidence that we know how these patients are likely to behave in this study and it will be powered to address that.
Understood. And then maybe just a quick follow-up on ENCORE as it pertains to clinical outcomes. Can you maybe just kind of speak to what your control arm assumption is regarding culture conversion on background placebo therapy? And can you also just speak as to whether or not the statistical plan for capturing culture conversion contemplates the same level of early discontinuations that were seen in the refractory setting? Thanks.
Kevin, do you want to address those?
Yes. Thanks, Steve. With respect to durable culture conversion, so this is 3 months off all treatment. The ENCORE study specifically is powered at 92.5 percent to show a 20% difference between the treatment group and placebo arm at that time point. We're roughly estimating some assumptions of around 40% to 50 percent placebo group here, but that's our basic assumption.
We're assuming well powered, show a significant effect for durable culture conversion. In terms of rate of discontinuation, so I'll have to get back to you on what that assumption was. We did consider that in the assumption for powering of the study. So if of interest, we'll get back to you on that one.
All right. Thanks for taking the questions.
And maybe I'll just bring up one question that's come in on Aspen on the statistical front here, get into the ARCANA a bit. What is the statistical analysis plan for Aspen? And specifically on the primary endpoint, are we running a hierarchy of testing by designating 1 or the other dose level and if so which 10 or 25 and testing in sequence or are you first testing for any differences at all in ANOVA modeling exercise?
Yes. Thanks for the question. The primary analysis to the primary endpoint of rate of exacerbations will be via a negative binomial model. We use that in Willow for the rate of exacerbations, where we showed significant reduction on the rate of exacerbations and this has been agreed to by the FDA and EMA. So against a negative binomial model, that does not presume hierarchy and allows for the possibility of either of those two doses to show a statistically significant effect on the rate of exacerbations.
Thanks.
Our next question will come from Gregg Suvannavejh with Goldman Sachs.
Greg, if you're on, you may be on mute.
Okay. So sorry about that. Thanks for the really thorough presentation. And I've got 2 questions, if I could. Maybe just a follow-up on the powering assumptions question.
Can you just review the powering assumptions in Aspen? The slide I think referenced a P value of 0 point 0 1. And I just wanted to clarify that that's not the hurdle that you need to hit in this study. So just a review of those powering assumptions. And then my second question actually is if you could with all these trials that are starting, could you just maybe provide a sense if you can, I know it's early, but just some sense of timelines into kind of how long you expect, whether it's enrollment completion timelines or even time to data around Aspen, ENCORE, NRIs?
And then maybe a last question for the doctor, if I could just ask him what his current use of Tyvaso is right now in terms of PAH patients? And is it fair to assume that if TPIP shows the target product profile that use of that product would be higher than what it is currently for Tyvaso? Thanks.
Sure.
Go ahead, Doctor. Go ahead, Doctor. Dan. I'm sorry,
second or first?
No, no, you go ahead.
Okay. I'm going to have to run-in a few minutes anyway. I've got some patients building up. The current use of Tyvasa for us is probably on the order of 10%. A good number of patients went into some clinical trials of other products with the dry powder inhalation.
The dry powder concept from a better mousetrap standpoint is already one that is making things better. But the QID dosing, as we discussed, is still a limiting factor. And the relative amount of drug that one can get in, even with the dry powders slated for FDA review soon, are still limiting. So absolutely, the use would go up if all of the things that we think will happen with
TPIP can happen.
Thank you, Doctor. Houdis. And if you have to step away, I want to make sure I get the opportunity to thank you for joining us today. On the other two questions, maybe the first one that relates to powering of Aspen, I'll turn that over to you, Kevin. Great.
Thank you.
Aspen, as I think we mentioned earlier, is powered at 90%, show a 30% reduction in exacerbations by 52 weeks. Part of that powering is to your question is related to Type 1 error rate or the p value. So let me just take just really a moment if I could explain why we think we're in an enviable position following the discussions with the FDA and EMA. The Type 1 error rate is the key value when you look at the prior programs in bronchiectasis, those entailed 2 studies and both of those individual studies initially had p values of 0.05. When for the Type 1 error rate that they had to preserve across the program, across those two studies, if you do the math, your P value is 0.00125.
When you look at our program, hopefully you can see that a P value of 0.01 versus what prior programs had, we're quite happy with the discussions that we've had with the health authorities. Now we've also had a direct conversation with the FDA that if our at the end of the Aspen, our P value is between 0.01 and 0.05, we would move ahead with the submission and that would be a review issue for them.
Hopefully that helps on the powering question. On the timeline question, we're not putting out any guidance at the moment on how long it will take. I think for the frontline ARIKAYCE study and certainly for the Brenza Cassa program, I think you can see based on the number of sites we're going to be using and the global nature of the studies, that we are bringing all resources to bear to get these done in a timely but quality way. And as those unfold and we begin to see in the COVID and post COVID world, what enrollment rates look like, then we'll be able to comment on the expected timeline for completion of the enrollment, and all the details that surround that. So look forward to getting some of that detail in the future, but as of now, it's too difficult to predict.
Okay. Thanks for that.
At this time, I'm showing no further questions from the phone line.
Terrific. So I'll take the call back operator and I just want to tell everyone how much we appreciate them joining today. We tried to accomplish was a detailed look at what is now well understood as the intimate pipeline. It's much broader than I think most people appreciate and its potential is enormous. And I really hope that that came through today.
Perhaps the undercurrent that sits underneath all of this is the further opportunity that the DPP-one pathway represents for us. And it's something you're going to be hearing a lot more about in the future. We've got the resources to do all this. I certainly can tell you we have the talent and hopefully you saw that today. So thank you all again for joining.
And if there are any questions, we'll be happy to follow-up offline. Have a good day.
The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.