Alright, thanks for joining today. My name is François Brisebois. I'm one of the biotech analysts here at Oppenheimer. Our first company presenting here is Savara. Savara is working on a rare lung disease called APAP. We'll go into a lot of details about it. In terms of the format, we're going to do a fireside chat, and we're lucky enough to have from the company. We have Matt Pauls, CEO, Braden Parker, Chief Commercial Officer, newly joined, sort of kind of recently joined here, and then Brian Robinson on the medical affairs side. So with that, apologize if the voice is a little funky today, but thanks for joining, Matt, and we'll jump right into it. So maybe if you can help us with that little overview of the company.
Yeah, great. Thanks, Frank, and thanks, Oppenheimer, for the opportunity to have a fireside chat today. Again, joined by my colleagues, Braden Parker, Chief Commercial Officer, and Dr. Brian Robinson, EVP of Global Medical Affairs. And, you know, standard forward-looking statement, disclaimer, you know, regarding commentary today and risk assessment based on those comments. So Savara is, François, as you mentioned, is a company focused squarely on rare respiratory diseases, with the primary focus, actually the singular focus right now, on Molbreevi, or molgramostim inhalation solution, which is a novel biologic that we have a soon-to-be-filed BLA here in the U.S. by the end of the first quarter. So we're in the home stretch. Molbreevi for a rare respiratory lung disease called APAP, or autoimmune pulmonary alveolar proteinosis, but we'll refer to it as APAP for the rest of the fireside chat. The company is well funded.
At the end of the third quarter last report, we had $219 million in cash, and have guided to having runway through 2027. Before I turn it back over to you, Frank, I'll just highlight the fact that APAP in the United States and Europe currently does not have any approved therapeutic. It's an ultra-rare disease, which we think is currently underdiagnosed and therefore, by definition, undertreated. We are in the process right now of helping to identify patients in the US and prepare the US market for the potential approval of Molbreevi, hopefully in the not-too-distant future, and we've also guided to filing the MAA in Europe by the end of this year. So a lot happening at the company, and it's a group of passionate, caring people here at the company who really are dedicated to the APAP community and ecosystem around the world.
Oh, that's great. And then maybe if we, you know, for those, this is ultra-rare, and oftentimes people might have heard APAP. They probably haven't, but can you help us understand what it is?
Sure, absolutely. I'll ask Dr. Robinson to provide an overview of APAP.
Yeah, thanks, Matt. And thanks, Frank. So autoimmune PAP, or APAP, falls under the category of a syndrome called PAP syndrome, which is basically a bunch of different diseases that are disorders of surfactant metabolism, of which APAP is one of them. And APAP constitutes about 90% of all patients who have PAP or PAP syndrome. And it's a, as Matt said, it's a rare pulmonary disease that is found in every region in the globe, affecting both men and women, all ages, but typically presents in patients between 30 and 50 years old. And these patients typically present with shortness of breath, a cough, and fatigue. So it's sort of this triad, if you will, of presentation, which is kind of typical for pretty much any pulmonary disease. But with autoimmune PAP, these patients also have a telltale CT scan that has crazy paving and ground-glass opacification.
These sort of things that you see on the CT scan are indicative of the buildup of surfactant, which causes the, as I said, the triad of symptoms that I just described. Because the presentation is typical of pretty much any pulmonary disease, these patients frequently get tossed around the healthcare system for an average of 18 months before they actually get a diagnosis. And once diagnosed, pretty much the only available care right now is a whole lung lavage. I'll get into that in a second, but just taking a quick step back and to tell you a little bit about the pathophysiology of the disease. What's actually happening is that these patients have an autoantibody to GM-CSF, and GM-CSF is an important protein or cytokine that's produced ubiquitously in the body, but specifically in the lung. It's produced in the air sacs of the lung called alveoli.
And this GM-CSF that's produced binds to macrophages, which are another cell that lines the inside of the alveoli. And these macrophages are responsible for metabolizing surfactant, which is an important substance that lines the inside of an alveoli that keeps it patent so that gas exchange can occur, because the alveoli is a site where gas exchange actually occurs. So the epithelial cells that line the inside of the alveoli are responsible for producing the GM-CSF, and a different type of epithelial cells produces the surfactant. So there is this balance between the production of GM-CSF, the binding of GM-CSF to macrophages, and the metabolism of surfactant. The problem comes along, as I said, that the body of the patients who have autoimmune PAP produce an autoantibody to GM-CSF that binds to the GM-CSF, preventing it from binding to the macrophages.
So the macrophages can't do their job to clear the surfactant, and this is what leads to the buildup of surfactant and the problems with gas transfer leading to the shortness of breath and the cough.
Now, super helpful. And then, you know, you mentioned this, so right now there's nothing in the U.S. and Europe. You talked about whole lung lavage. That sounds just kind of like cleansing. Can you help us understand how brutal a lung lavage is?
Yeah, before I turn it over to Dr. Robinson on that, let me just, if I could, comment on whole lung lavage, and I'll let Brian walk us through what I think we can all agree is a barbaric procedure. You know, whole lung lavage is really, we believe, should be reserved as a rescue therapy or procedure. It's, you know, it's a non-standardized procedure that when patients, you know, progress with APAP, often to a, you know, kind of to an advanced stage, it's effectively a power washing of the lungs. And so, Brian, do you want to walk through that?
Yeah, sure. You know, as Matt said, this is a pretty involved procedure. And as you said as well, Frank, this requires patients being admitted to the hospital. They have to, it's an operating room procedure where they have to be taken to the OR for sometimes as long as six or seven hours. They have an endotracheal tube placed into their mouth, and they respirate one lung and they wash the other lung. And basically, it's just exactly as it sounds. Saline is infused into the lung, and once it's there, patients typically get their chest banged on to emulsify the surfactant, and then they drain it out. And they do this repeatedly until it gets clear. The challenge with this is, as Matt said, this is a rescue procedure. This is, as you said, not standardized.
It's done in pretty much specialized centers, so it's not done in every institution, and it's done by experts. And as I said, it also requires OR time, and that includes OR staff, you know, as many as six or seven people, and ICU time afterwards. The challenge with, you know, among the challenges with the whole lung lavage is that, as Matt said, it's not standardized, and also it's only a temporary relief. Patients reaccumulate their surfactant over time, and most of them require repeat procedures. And that is a challenge.
Yeah, and I think one other thing, just to thank for that, Brian. You know, we believe that there is a lengthy, potentially lengthy kind of pre-whole lung lavage journey that APAP patients, you know, are on or will be on or could be on, where potentially Molbreevi could step in. And given the data from IMPALA-2 and the support of data from IMPALA shows that there might be the potential for Molbreevi, you know, to play an important role. And that could be, you know, prior to a whole lung lavage, but, you know, it would be patient dependent. I think what's important to note is that the great news for patients is that whole lung lavage will always be an available rescue procedure. And that's a great thing for patients.
You know, we're hopeful that Molbreevi is going to, you know, again, be able to help address some of the, you know, the pathophysiology and help, you know, increase or improve the gas exchange and, you know, really try to address the biology of the issue.
Great. And I think to help people understand where it can fit in the treatment paradigm, going through the data would be helpful. Just before Braden, I won't let you go. The commercial is what a lot of people are asking about, so maybe a five minutes on the data today.
Yeah, so Brian, over to you.
Yeah, sure, thanks. Before I get into the data, I think it's important to sort of briefly describe the mechanism of action of Molbreevi. This is a recombinant GM-CSF that is made in E. coli, and it's paired with a nebulizer that is bespoke that's made specifically for the inhalation of Molbreevi. These patients take 300 micrograms of Molbreevi daily. Because this is an inhaled recombinant GM-CSF, the thought is that this overwhelms the existing autoantibodies within the alveoli such that some of the antibodies bind to the inhaled GM-CSF, but the residual GM-CSF binds to the macrophages, allowing them to do their job and maintain surfactant homeostasis. That's essentially the mechanism of action of Molbreevi.
Now, as far as the data is concerned, the IMPALA-2 trial was a large, in fact, the largest clinical trial that's ever been done for an autoimmune PAP that enrolled 164 patients in 13 countries, including 43 different centers. I'm sorry, 16 countries and 43 centers. This was a 48-week trial. The double-blind period of the trial was 48 weeks. The actual open label extension of the trial is currently ongoing. In this 48-week trial, patients were randomized either to receive placebo or 300 micrograms daily of GM-CSF. The primary endpoint was the change in the DLCO, the difference in DLCO between placebo and control. I'm sorry, between placebo and the Molbreevi group at 24 weeks. There were also secondary endpoints of the change in DLCO at 48 weeks, the SGRQ, or St. George's Respiratory Questionnaire, which is a respiratory PRO at both 24 and 48 weeks, the total score, and then the activity score at both 24 and 48 weeks, and then finally exercise tolerance at 24 and 48 weeks. So just quickly about DLCO, this is a surrogate measure of gas transfer, and it stands for the diffusing capacity of the lung for carbon monoxide and just measures how well gas is transferred from the alveoli into the arterial space. From a data perspective, we met the primary endpoint of the change in DLCO at 24 weeks. We also met one of the key secondary endpoints in the change of DLCO at 48 weeks, which was amazing because it actually showed the durability of the effect of Molbreevi over the 48-week period.
Regarding SGRQ, total score, activity score, and the exercise tolerance, which was the measure of exercise capacity, these endpoints were either statistically significant, nominally significant, or there was a numerical difference in all of these. So overall, this was a positive study, a resoundingly positive study, and everything trended in the right direction if it was not statistically significant. So we're truly pleased with the outcome of this trial.
Great. And can you use in the filing here, Matt, can you use IMPALA-1 for the submission? Is this, you know?
Yeah. So as you refer to, we refer to IMPALA- 2, which is what Brian just described, our recent phase three, largest study in, you know, really the history of APAP for Molbreevi. And there was IMPALA-1 , and that is a supportive study that clearly there are some important data there and the body of evidence, you know, when you take IMPALA-1 , while technically it didn't meet the primary endpoint, very valuable data to be supportive of IMPALA-2 . So the long answer is yes, it's supportive data that can and will be used in the submission.
Okay, that's great. And if we were to do the quick back of the envelope, so you said you're on track for the filing of the BLA by the end of this quarter. And then how do we walk through the timing until potential PDUFA?
Sure. So I'm tracked to complete the BLA submission by the end of the first quarter. So we're, again, as I mentioned earlier, in the home stretch, so to speak. And there will then be a 60-day review by the agency, assuming that they then accept the filing and file it. And also assuming that Molbreevi is assigned priority review, that would then, on a roll-forward basis, would be a six-month review and put PDUFA probably at the end of November, beginning of December of this year.
Okay. All right. Big year. With that, I think with this ultra rare, this is where a lot of people have questions for Braden, and I know the company has done a lot of work so far. So could we just better understand? I think, you know, sometimes you speak to physicians, and whether it's 3,000 or 5,000 or 7,000 might not be a big deal for them, but for the market potential, it is a big deal. So how do we think about the U.S. TAM here?
Sure, so like many rare diseases, when you look at the epidemiology and the published literature, there's a wide range. It can range from six patients per million all the way up to 26 patients per million. With that latter being a study from Japan where there was mandatory testing, so we really see that as a true opportunity. In order to really understand the US market, we did some claims database work, and what we found leveraging ICD-10 codes is about 3,600 patients in the US diagnosed today, and then we applied machine learning to that same dataset to say, okay, which patients look like APAP patients, but just don't have the ICD-10 code in the system.
When you run that machine learning or artificial intelligence against it and score the different claims histories, you come up with another 3,700 patients that are either likely or highly likely to be APAP as well. The totality, around 7,300 patients, if you apply that to the U.S. population, skews to the upper end of the range. We think there is a very sizable opportunity in the U.S., both with known patients today as well as where it could go tomorrow with the ceiling of patients that are likely or highly likely to be APAP.
Can you just repeat the number of known kind of diagnosed and confirmed patients today?
Sure. 3,600 was what we found through our analysis of the claims dataset.
Okay, and you could basically double that up, so what is likely and highly likely? How do you break that down?
Yeah. So there's a scoring system that we applied to the other claims history, and so based on the number of procedures or types of procedures that you had, you could get a higher score. For example, those that are highly likely to be APAP either had a bronchoscopy or some type of lung lavage in the system as well, so they got a higher score and were deemed highly likely versus just likely.
Do people have whole lung lavages for a bunch of different things? Or is there a bunch of different reasons to get whole lung lavage?
To my knowledge, it's mostly around APAP, if I'm not mistaken, Brian, right?
Yeah, that's right. I think A PAP, people who have PAP syndrome are likely because of the whole accumulation of surfactant.
APAP is 90% of PAP.
That's right. Exactly.
Okay. Understood. And then you talked about the line of sight on previous calls of, so PDUFA, let's say you mentioned towards the end of the year. At that time, at time of launch, can you just talk about, you know, the 450, then you talked about going to 1,000. What is that?
Yeah. So as we talked about, there's a sizable opportunity here. We'll talk about the 3,600 diagnosed patients today. So now it's about how do you, practically speaking, prepare to exceed expectations on a launch trajectory. And the way you go about doing that is just doing the blocking and tackling of profiling accounts. Those 3,600 patients were found across about 1,100 accounts. We've segmented and prioritized those accounts, and we've begun knocking on doors, if you will, and profiling the accounts, understanding are those patients still being managed at that location? How big is the practice overall? How frequently do patients come in? Any other factors that we need to think about as we think about the launch trajectory?
So in doing that, we've set an internal goal of having line of sight or profiling and understanding where these patients are to about 1,000 patients by the end of the year or about the time of approval, knock on wood. Back in September, we reported that we had line of sight to about 300 patients. More recently, we've upped it to about 450 patients. So we're about halfway to our goal. And that's really just with a limited number of people doing the work, really, Brian as well as two MSLs that were recently joined the organization. We're looking to accelerate that since things are going very well. We're looking to accelerate the market development team that we are going to bring on board. In totality, it'll be about 25 people strong. This will eventually be a sales force, but obviously pre-approval, you can't promote.
So it's about profiling accounts. It's about disease education and awareness and testing education. So by bringing on the market development team early, we'll be able to not only target the accounts that we're targeting now, but expand that list and ensure that we well exceed the 1,000-patient line of sight goal that we have.
And so when someone, if you have these patients, you know they have APAP, in terms of, you know, when people start thinking about market penetration that would be successful, does that depend on the severity of the patient? You know, like, why would someone not want to take this, I guess, is my question. Or it's like, look, you know, we do whole lung lavage just a few times. I'm very mild. How do we think about that?
I think the first way to think about whole lung lavage, again, as a rescue therapy, and really patients are not keen to take it, as Brian described, the procedure is pretty barbaric and challenging, so there's a high degree of interest across stakeholders for Molbreevi, and certainly anecdotally, from what we've heard from KOLs, as well as what we've seen in market research with a broader population of pulmonologists, they are looking forward to Molbreevi and looking to offer it to all of their patients, so we think the whole 3,600 patient number is in play at launch, regardless of disease severity, again, because this is an autoimmune disease, it's not going away, and if we can reduce the surfactant burden now and avoid whole lung lavage, hopefully in the future, you know, people are really keen to do that.
Yeah. And I think it's very well said, Braden. I think also the way to think about this, Frank, is, you know, as Braden said, autoimmune disease, probably not going away. Patients are probably, most of them are going to have to grapple with this disease for most of their lives. And, you know, when you talk to KOLs, you talk to, you know, general pulmonologists, what they would love to do, if someone has mild, an APAP patient has mild symptomatology, they'd like them to maintain mild symptomatology, right? So address the pathophysiology. You know, the good news is based on the IMPALA-2 data, the risk-benefit of Molbreevi, we think is, you know, really looks positive over the long term.
So get to patients early in the course of their disease and see, you know, while we can't claim this right now, you know, the hope here is if you turn the signal on and you improve gas exchange, you know, can you help patients do better over the longer term? Still to be determined, but that's the hope. And we're going to drive towards that.
So it does seem like the mild could turn into moderate to severe sort of thing. Like there is a natural progression.
Good. You know, it's very patient-dependent, of course, and I want, you know, I need to be careful not to, you know, generalize over everyone, but it's common, you know, I think about myself, like if, you know, if someone told me I had an autoimmune lung disease like APAP and that I could inhale something five minutes a day and, you know, all in be 20 minutes and, you know, the side effect profile and tolerability profile looks like Molbreevi does, I'd think very, very seriously about jumping on board.
And five minutes a day, 20. So this is chronic, right? Molbreevi we see as a chronic treatment.
Absolutely.
Yep. Okay. Great. And you talked about the number of accounts. Is this like, you know, is there a top decile of accounts where you just got to hit these guys and you get 80% of the market sort of thing or?
Sure. So we've prioritized accounts really across three major segments. One is the centers of excellence, and there's probably 15 to 20 of those. ILD clinics, where you have potentially an enriched population of APAP patients, and you could say maybe 30 more of those. And then you have general pulmonology centers, and there's probably 150 or so of those. So those top 200 accounts, 200 accounts plus, well exceed the 1,000 patients that we need to get line of sight into. And then beyond that, of course, between the 200 or so to the 1,000, you know, you're going to have smaller volumes of people in general pulmonology centers across the country.
Okay. Great. And I think what's important here with the story is the IP or longevity of just being a BLA. Can you talk a little bit about your confidence there, Matt, in terms of this last thing?
Yes. So in the United States, of course, if the BLA for Molbreevi is approved, Molbreevi will be granted 12 years of regulatory exclusivity. In Europe with orphan drug designation, assuming MAA is approved for Molbreevi, that would be 10 years of regulatory exclusivity. You know, I think in addition to that, you know, given the fact that it's an inhaled biologic, we think that, and we have a proprietary long-term deal structure with PARI, our nebulizer manufacturer. We think there's a pretty large moat built around Molbreevi. And so very well could, you know, have, you know, kind of constructive, you know, exclusivity for much longer than 12 years.
Okay. And then maybe lastly, you guys had a recent press release about some open label data. If you guys could maybe touch on that. I think, you know, as you educate the community, I think this data could be important here. So just give you a chance.
Yeah. No, thanks for asking. I'll have Brian opine on those important data.
Yeah. Thanks for the question, Frank. So this is a study in five patients in Europe that included patients who were treated with Molbreevi via our compassionate use program. And it looked at patients who were on Molbreevi an average of four years. And what it captured is pretty much the natural history of disease after being treated with Molbreevi. And the important point is that all of these patients had improvements across all of the symptoms of autoimmune PAP, including pulmonary gas transfer. There were improvements, quality of life improvements, exercise capacity, and surfactant burden, which is emblematic in the change in the CT scans that were shown in the paper. So it gives you sort of a real-world sort of look into how Molbreevi can be helpful in terms of managing this disease.
Okay. Very helpful. Thank you. And then, Matt, maybe if anything I should have asked or anything we missed, just closing comments in our last 30 seconds here?
We covered a lot in 30 minutes, and I think you had, you know, spot-on pointed, you know, lines of inquiry. So I think we're in good shape. You noted earlier, and I'll just highlight, this is a real significant year for Savara and importantly, very importantly, most importantly for the APAP, you know, community around the world, whom really don't have many options right now. And we're looking forward to trying to bring Molbreevi and get it in the hands of physicians as fast as we can.
Excellent. Well, thank you for all the good work. Really appreciate it.
Thanks very much. Take care.