Insmed Incorporated (INSM) Earnings Call Transcript & Summary

Great. Good afternoon, everyone. My name is Jess Fye. I'm a senior biotech analyst at JPMorgan, and we're continuing the 40th Healthcare Conference this year with Insmed. I'm joined by the company's CEO, Will Lewis, who's going to give a presentation. It's going to be followed by some Q&A. [Operator Instructions] So let me turn it over to Will.

Thank you, Jessica. Before I begin, please let me draw your attention to our forward-looking statement slide which highlights the uncertainties inherent in making forward-looking statements and also references our public filings, which I encourage you to read for further context. If you can please turn to Slide 4, titled building a leading global biotech company. If I can leave you with 1 thought at the end of this session, it's this. The company you hear about today is not yesterday's Insmed. The Insmed of just 2 years ago has dramatically evolved and it is now a company at the perfect moment for investor attention. Why is this? 3 reasons, really. The first is commercial. We now have our lead program, ARIKAYCE, approved, successfully launched, using our own commercial infrastructure in the U.S., Europe and Japan. This year, investors are going to enjoy the benefit of the international revenue contribution to what we believe will be a return to growth in the United States. The second reason is clinical. 2 years ago, we were running a single clinical trial. Today, we have 7 Phase II or Phase III clinical trials running in parallel. And we believe these represent $1 billion plus market opportunities in the form of ARIKAYCE, brensocatib and TPIP or treprostinil palmitil inhalation powder. Now each of these is an impactful compound potentially that is addressing a large and expanding market opportunity. And one of them, bronchiectasis, is a market opportunity we believe could be in the multiple billions of dollars. The third reason I would encourage you to pay attention is our early clinical engine. ARIKAYCE and TPIP for Insmed established our strong capability in research. Both of those products came from our labs. We have augmented this in the past year with some of the most disruptive and exciting science through a series of acquisitions. We call this our fourth pillar. And I'm pleased today to share with you what makes up what I consider to be a very impressive engine for drug development. This includes artificial intelligence capability, protein engineering, deimmunization technologies, gene therapy, gene editing and breakthrough manufacturing to further enable these technologies. Now I know as investors, you can choose right now from about 700 public companies and maybe your interests are in early signs betting on the newest technologies or mid-stage clinical programs that could produce positive data and finally, perhaps commercial growth opportunities few and far between where a product is about to inflect and really grow. Insmed gives you all 3 of these. And I want to take each of them in turn with the first of these being ARIKAYCE, what we refer to as our first pillar. If you turn to Slide 7, that's entitled first-in-disease therapy. This highlights ARIKAYCE, our first approved product, which is a novel inhaled once-daily formulation of liposomal encapsulated amikacin, which is taken with a specialized nebulizer, to treat refractory MAC lung disease. This is a rare pulmonary condition that is chronic and can cause severe and permanent damage to the lungs. The problem with this condition is that it is brought on by bacteria that are everywhere in the environment. And so even in circumstances where you're able to treat patients who have this condition, they are likely to experience it the second time. Our product was a material advance for these folks. And we've taken this product now globally from the U.S. where we had success with what was a top 10 launch in history in the non-oncology rare disease space. To that, we have added Japan and Europe, as I mentioned. This is the only product that is included in the international guidelines with a strong recommendation for use for the treatment of this condition. So this year, we are looking forward to the international contributions and the hard work to put us in this place. What does that opportunity look like? If you turn to Slide 9, what we believe we can do with this program is take it from the hardest-to-treat patient, the refractory, into the frontline patient setting. And as you can see on this slide, what we've highlighted is the difference in base addressable market in the U.S., Europe and Japan. And focusing just on the U.S. and Japan for a moment, 12,000 to 17,000 refractory MAC patients in the U.S., 15,000 to 18,000 in Japan. But the diagnosed NTM patient populations are 95,000 to 115,000 and 125,000 to 145,000 respectively. These are material increases in addressable patient populations. Europe is about a tenfold increase with 1,400 refractory MAC patients, leading to 14,000 frontline. We think that market is understated and it's going to grow, but each of these represents a significant step-up from where we are today. The question, of course, is how are we going to get there? And the way we enable this approval into frontline is the trials that are outlined on Page 10. We have these 2 trials ongoing right now. And for those who are not familiar, this really highlights 1 of the key strategic approaches Insmed takes to drug development. The first program called the ARISE trial is designed to test the patient reported outcome we are using as the primary end point for the second trial, the ENCORE study. ENCORE is the study that will secure, we believe, approval for frontline use of ARIKAYCE in the treatment of NTM. So we want to ensure that, that PRO is responsive. We've heard tales of others that have not gone well. We wanted to give it a dry run. That's what this program design allows us to do. Indeed, if we find something in ARISE that we think is slightly off in the actual design of the PRO or the statistical analysis plan, we can adjust it in ENCORE because it will still be blinded when ARISE reads out. So ARISE can be thought of as a way to ensure the success of ENCORE. In addition to the primary endpoint of patient reported outcomes, we are also looking at culture conversion. This is important because that's what the international regulatory authorities are focused on. It is also what market access is focused on. And there, we feel like we have a high probability of success as well. So there's a lot of opportunity that's unlocked using this trial design, and it should increase our probability for success. Our second pillar is called brensocatib, and while ARIKAYCE, and you'll hear TPIP came from our labs, ARIKAYCE -- rather brensocatib came from our business development efforts. This is something that we in-licensed from a large pharmaceutical company initially to address the condition of bronchiectasis. Bronchiectasis is a pulmonary condition that currently has nothing approved to treat it. It is a cyclical process, whereby bacteria colonizes in the lungs and leads to or is the origin of abnormal mucociliary clearance, that results in airway destruction and through exacerbations, permanent damage to the lungs, that results in inflammation, which then can lead to bacterial colonization and so on and so forth through the cycle. Historically, people have chosen to focus on bacterial colonization and treat with inhaled antibiotics, and those trials have proven to be unsuccessful. What we have done is bring forward DPP1 inhibition, brensocatib, as a way to target the inflammatory side of this cascade. And what you see on the next slide is the mechanism of action for the DPP1 inhibition. What this does is it prevents the activation of 3 or 4 neutrophil serine proteases that are then released when the neutrophils are recruited to sites of inflammation throughout the body. By inactivating these NSPs, we tamp down the inflammatory response and hopefully break that cycle that you saw in the bronchiectasis disease state a moment ago. The proof for this was in the Phase II WILLOW study, where we ran a very sizable program to explore whether or not brensocatib could in fact accomplish this. And this was a wildly successful study. It exceeded all of our expectations with both doses hitting statistical significance on the primary endpoint. The trial was published in the New England Journal of Medicine, the first time in almost 20 years that the New England Journal had published on a successful bronchiectasis study, and this really forms the background for our Phase III ASPEN study, which is currently underway. Unlocking this market is the key to the largest portion of value creation within Insmed. So we are very focused on the ASPEN study as we are, the other parts of the company, but this one in particular, is really -- can't be overstated in terms of what it might represent. So what we've done in the ASPEN study is take exactly what we did in WILLOW, but with more conservative assumptions. So we've gone from a sample size of 256 patients to over 1,600 patients. We are now powered 90% for a 30% reduction in events, and we have assumed a low exacerbation rate in the study. The primary endpoint of this study is rate of pulmonary exacerbation, not time to first exacerbation, that's at the request of the FDA. They made a broad policy decision to focus on rate of pulmonary exacerbation while the WILLOW study was underway. So we've had a switch to rate. That's not problematic because we studied it in WILLOW and at the 10-milligram dose, we were actually statistically significant on that endpoint as well, with a strong trend at 25. So overall, we have a high confidence rate that this design should bring about success. The actual design of the study is on Slide 16, and it spells out the 2 doses versus placebo. What I really want to emphasize here is that we are resourcing this study with more than 450 sites around the world. And it's important for people to understand that if either the 10- or 25-milligram dose works, then this is a winner. How big a winner could it be? If we look at Slide 17, right now, the total diagnosed bronchiectatic patient market is in excess of 1 million patients between the U.S., Europe and Asia Pacific. To that, we add some incremental amount, how much is still to be determined, but the literature suggests between 4% and 54% of COPD patients may also have bronchiectasis. That would add hundreds of thousands, if not millions, of additional patients to the addressable market opportunity. I cannot emphasize enough, as we further discern what the true addressable market is here. By any measure, this is a very substantial addressable market. And our ability to bring forward a first in disease, first in mechanism drug that is a once-a-day small molecule pill will fundamentally change the nature of this company. When people hear me talk about aspiring to be the next Vertex or Alexion, this is how we're going to do it with the approval of this product in the treatment of bronchiectasis. It will be augmented by our frontline approval of ARIKAYCE, and the same sales force that brought you the success of ARIKAYCE will be marketing this product around the world. But that's not where it will end. If we look at Slide 18, we've talked about how we've not only unlocked the treatment for bronchiectasis, but truly a mechanism of action. We are looking to treat neutrophil-mediated diseases, and we have spent time in the last several years building up real expertise in this area. So we have announced that we will also be bringing this program forward in cystic fibrosis, and there's a PK/PD study underway right now, but we'll read out this year to address that. Beyond that, we are looking at other indications, 2 of which we will identify at our February end-of-year call and 1 of which will go into the clinic this year. So lots going on with brensocatib as well. Now we turn to our third pillar, TPIP, treprostinil palmitil inhalation powder. What TPIP represents is fulfilling the promise of prostanoid therapy. Prostanoids vasodilate the vasculature and help alleviate the constriction that patients with PAH face and the downstream effects from that are well established. What we're trying to do is change the way that this drug's PK/PD profile results in benefit to the patient. And what we saw quite dramatically in animal models suggest that this can lead to not only hemodynamic but histologic or disease-modifying changes. So Slide 22 spells these out. When we ran these models, we didn't just look at our drug, we compared it to other approved treatments for PAH, inhaled treprostinil, IV treprostinil, selexipag and 2 doses of our drug. And this spider graph here, the closer you are to the red dot in the center, the closer you are to normalcy. And that dark green line that is closest on all measures is our drug. And the ones that surround it are the others that are approved, and you see they have mixed benefits in different measures. But what we saw was hemodynamic benefit that resulted in disease modification, and that's why we're excited to bring it forward. What does this look like in Phase I.? This is a quick snapshot. The dotted black line on the right-hand side shows what happens when treprostinil is inhaled, it spikes to a very high level and collapses almost immediately. The measure along the x-axis is time. And so within a matter of hours, it's gone. What we show with our formulation is the ability to go to a lower peak and a much, much longer trough out 24 hours or more. And if you look at the doses in the dose guide or box up above, the Tyvaso dose you see indicated here is 54 micrograms. That's the max dose permitted in the label. Our drug in Phase I, we took to 675 micrograms. So we have what we believe will be a more efficacious once-a-day delivery of a drug that could produce histologic change. We're super excited to bring that forward, and we're pursuing a number of different trials. We have a Phase IIa study, which is a 24-hour examination of this drug in a PAH patient. We have 2 Phase II studies that are also underway. Now we have a single site initiation that was completed at the end of last year for the Phase IIb program that will ramp up now and the Phase II study for PH-ILD, which will be running in parallel. So a full program there. Now I want to turn to our fourth pillar quickly and just talk about translational medicine and what this means for Insmed. This is the underpinning of the future of the company. This is a combination of all of the most exciting technologies that we believe we can bring to bear for the benefit of patients with rare disease. When we talk about protein deimmunization, what does that mean? It means, as an example, taking the AAV viral capsids that are naturally occurring and making them so that they do not provoke an immune reaction. This is delivering on the promise of gene therapy by providing the opportunity for repeat dosing. And we are very excited about where that technology already is. It's just an example of what we're doing in the protein deimmunization space. We are also bringing forward therapeutic proteins that we are deimmunizing for repeat dosing. Some of these are already well established, but are limited in their ability because they provoke an immune reaction. We intend to work around that. In the field of gene therapy, we have identified our first candidate. We intend to bring it forward and file the IND by the end of this year. We'll have more to say about that. While we're not talking about therapeutic area today at the moment, I can tell you that across the spectrum of what we have here, these move very far afield of pulmonary medicine, and that is because we are a rare disease company. These technologies unlock the potential to turn back the clock on some of these patients' conditions, and that's what we're excited to pursue. So we'll be saying a lot more about this throughout the year. I'd just draw your final attention to the far right side. It's not perhaps an area talked about as much as others, but breakthrough manufacturing technologies can be the key to really unlocking value. As we all know, 50% of CMC -- a 50% of complete response letters are CMC-related. So focusing early on manufacturing and overcoming the hurdles of things in areas like gene therapy where manufacturing is a constant problem and a hurdle and a cost, we think we can unravel with some of these technologies that will enable us to produce not only the viral capsid and the transgene at lower cost, but as we mature the deimmunization technology, do it in a way where we could eventually pursue repeat dosing. So we're targeting one IND a year at the moment. We think we can move this up to a much higher pace in the future. We're not going to do that right now because we think the prudent deployment of capital demands that we validate the first 3 pillars, which we're extremely excited about, and then augment that with this research engine producing regular and promising therapeutic opportunities. I'll just close by saying we have all the capital at the moment that we need to support all of these broad ambitions. But as I said at the outset in this final Slide 29, we are sitting here today a very different company than the 1 you knew even 1 or 2 years ago. And so as we come out into the endemic phase of COVID, we believe across our 4 pillars, we have something that's really going to be making a difference for patients and consequently for our investors. And so I'll stop there, Jessica, and turn it over to you.

Great. Thanks for that presentation, Will. [Operator Instructions] So we have one in the portal so far, which I'll ask before going on to my own questions. When can we expect readouts for the frontline NTM studies in Phase III brensocatib study?

Yes. So we are going to give an update at our February end-of-year call, where we will go into some depth about our clinical trial enrollment status and when we think the readouts will be. We'll also provide a perspective on what we think commercially we're going to accomplish in the next year. So end-of-year call in the middle of February, plus or minus, is when you can expect those updates in real clarity.

Okay. Maybe starting with ARIKAYCE, just in the context of the most recent COVID surge, can you talk about how that's affected ARIKAYCE sales, if at all? Have you seen any surges in ICU occupancy that could hinder the ability of doctors or pulmonologists to take care of those more chronic patients?

Yes. I think what we've always said historically is that as surges come and go, we see regional variability throughout our commercial engagement. And now, of course, that touches the U.S., Europe and Japan. And I think that continues to be the case. Having said that, we also see very promising areas for return to growth. And that's why I have some confidence today that the U.S. on a stand-alone basis, mirrored by Japan and Europe, will all be contributing to our growth as we enter 2022. Omicron, I think, is going to burn out as fast as it came. And it is -- not to take anything away from those who are suffering from it, but it does appear to be more mild than the Delta variant. And for that, we're all very grateful because Delta really hit us hard. But what it also was doing back in the sort of third quarter time frame is it really stopped what we saw was the beginning of momentum returning to the ARIKAYCE brand in the U.S. So we're happy to be on the other side of Delta. We're excited by what we're seeing. It's early. Omicron is definitely tamping down things in a couple of places. But I think it will be behind us quick, and I expect that 2022 will be the year of return to growth for Insmed.

You mentioned Japan. How is the launch coming along in Japan? Is it still on a similar ramp as the U.S. was, albeit with lower absolute patient numbers? And are the majority of patients still initiating therapy in the hospital?

Yes. So Japan is going well. I would say it's facing some of the same headwinds in other regions of the world of COVID and some idiosyncrasies that related to launch in Japan. For example, you can only get a prescription for 2 weeks at a time. And yes, they do bring patients into the hospital, the majority of the time, that is a common practice in Japan. It actually, we think, could end up helping and training the patient to understand what the therapy is going to be like and how to mitigate side effects, et cetera. But setting that aside for the moment, that has resulted in a couple of places where they're reserving beds for COVID patients being unable to bring in additional ARIKAYCE patients. But notwithstanding that backdrop, the Japan launch, I would characterize is going well. And I would say that we expect it to be a meaningful contributor to our top line this year.

Okay. And what about the ARISE and ENCORE trials as it relates to enrollment progress? Not the time line for data, I know you're going to give that in, I guess, a month or 2 here, but how do you feel about how the enrollment is going?

Yes. I feel good about it. NTM is one of those sort of insidious diseases where the orchestration of running a clinical trial that has run well is pretty involved. We know that from our Phase II and our Phase III programs. And what you saw in those cases was about an 18-month enrollment rate from the time the last clinical site was open. So that's the best available public benchmark that's out there that people have been looking at. I think as we continue to move forward, I would just say, I think COVID has been a little bit of presence in all of our clinical trials, but not a break. And so I don't feel badly about where we are in terms of progress because of COVID. The only trial where I would make an exception is our Phase IIa TPIP trial, which we'll talk about in a minute. But ASPEN, the CF program, ARISE, ENCORE, all of these programs are running well.

Got it. And you mentioned how ARISE could help inform ENCORE. Can you just elaborate a little bit on how much insight the ARISE data set could really provide into what we're going to see in ENCORE? Is it basically a preview? Or is that not the right way to think of it?

No, we think it's like a dry run, call it a canary in the coal mine, right? This PRO tool, when it gets used by companies for the first time can sometimes be problematic because it unveils things that weren't expected. I think of other companies, I won't name, but where the PRO was expected to work and then it didn't and the drug eventually gets approved, but it becomes problematic at the approval moment, and probably more angst than it's worth. So what we did here was to design a dry run to examine whether or not the PRO is performing as we expect. The benefit of that is that we also dialogue with the FDA, and we believe we have secured an understanding with them, wherein if we discover from this PRO dry run that there's some aspect of its readout that informs us that a particular aspect of the PRO were more sensitive in measuring. We can adjust the statistical analysis plan of the ENCORE study so long as it is still blinded because it's no different than running this PRO dry run prior to launching the ENCORE study. We're just doing it in parallel to save time. So the FDA has endorsed this. And this is important because the only reason we're doing this PRO study is to satisfy the FDA. Most of the regulatory authorities in the world are focused on culture conversion exclusively. That will also be measured in this study, but the PRO is for the FDA so that they can satisfy the establishment that this product helps the patient feel, function or survive better, and that's their standard. So the PRO should accomplish that. And I think ARISE is going to give us all the data we need to know whether or not ENCORE is on the right track.

I guess if we think of your case as a product that can drive durable culture conversions, what gives you confidence in that link between culture conversion and meaningfully better scores on the PRO tool?

Yes. Well, first of all, we've seen it. We know patients when we see them through a complete cycle of treatment. Anecdotally, we've noticed and have heard reports of how they feel better and they're fundamentally different from where they -- what does that look like. If you're constantly coughing and hacking up sputum and then that goes away, that's a material change in your quality of life. And that is one of the byproducts that we have observed. Moreover, we have done a series of clinical trials historically where we've included things like the quality of life bronchiectasis questionnaire or the St. George's questionnaire in the refractory population. And that's given us some insights into where we think our drug is particularly effective in improving patient outcomes. So as a consequence of all that, we really have put a lot of time and thought into the design of this PRO, and we go into the study with a high conviction rate that this is going to work. What we bought with ARISE is some extra insurance to make sure that's the case.

Maybe switching to brensocatib. Can you remind us what led to kind of flipping the primary and secondary endpoints as you went from Phase II WILLOW to Phase III ASPEN? And talk about why you advanced 2 doses into Phase III?

Yes. So the first question is the FDA's guidance. They changed their perspective as a result of the Bayer/Nektar, Grifols/Aradigm studies. Those twin Phase III studies and the AdComs that surrounded them caused the FDA to go through all of their data and conclude that a better measure for anyone developing a drug for bronchiectasis is frequency of pulmonary exacerbations, not time to. So they requested that for Phase III, we switch them. In the middle of the WILLOW study, we were looking at both anyway. They were just ordered differently. And we said, would you like us to switch them? And they said, no, it's not necessary. You're going to collect the data, you'll know how to design Phase III. So that's the basis for why we changed it. And I'm sorry, your other question, there were 2 parts.

Why did you advance 2 doses in Phase III?

2 doses. So both 10 and 25 were statistically significant. Physicians always like to have a dose selection if it's possible to gain access to it. There was some observation by the community that the 25 dose was sort of a plateau response. It was -- they were each right around 40% reduction in efficacy, which is startlingly good, but because they were both roughly the same, the question was, is 25 really better. We think as we dug into the data that it really was and that a longer study, right, this ASPEN study is a year whereas the WILLOW study was only 6 months, and that's, again, from guidance from the FDA. We think that Kaplan-Meier curve is going to really be much more distinct with the larger patient numbers between placebo 10 and 25. I would reiterate, we only need 1 dose to work to win, but we're going to bring both forward and we think that, that will be useful to physicians and patients.

If these Phase III data are positive for brensocatib, can you talk about where it fits in the treatment paradigm? And maybe what severity of patients are likely to take the product?

Yes. I think initially, what we're targeting are moderate to severe patients, and that's largely because we're looking for an adequate number of events, right? What we want to make sure of is that there are enough events for us to show the benefit of our drug versus not taking it. So 2 or more events within the last 12 months is typically defined as a moderate to severe bronchiectasis patients. And so that's what's contemplated in the entry criteria for the study. However, we don't think the FDA will limit that as a usage criteria for the drug when it's approved. Nonetheless, the -- certainly, the market access world and the physician community will certainly start with the moderate to severe patients who will benefit the most from this medicine based on what we've seen to date, and that's where we'll go in at least initially.

Can you talk about the side effects you're going to be monitoring in Phase III and why?

Yes. So we had 2 adverse events of special interest that we tracked in Phase II related to the disease state, Papillon-Lefèvre syndrome, which is patients who suffer from a total inhibition of DPP1. We wanted to track that carefully to see if our more modest inhibition and our gradual administration was going to provoke those reactions. We didn't see that. We studied them very carefully, and so that was a very encouraging sign. As a consequence, we don't have to study those in any kind of specialized way in Phase III. But these are sort of hyperkeratosis and gum condition that we did quite detailed in Phase II. So those will certainly be included in adverse events generally. But what was most striking about WILLOW was the safety profile. There was a higher dropout rate in placebo than there was in either the treated arms. And that, to me, is just an incredibly powerful opportunity to bring an effective medicine with a pretty low treatment burden. Remembering that this is a once-a-day pill for a pulmonary condition. So it doesn't get any better than that really.

You talked about potentially taking this product into multiple indications. What should we think of those other indications as being?

Yes. So right out of the gate, it will be cystic fibrosis patients. So these can be patients who are successfully treated with Vertex' drug. They still suffer from lung damage and infection that leads to exacerbations. In this regard, we really think this drug represents the last mile for their betterment. And we know that because they still suffer from those exacerbations, they're effectively bronchiectatic patients once they've successfully been treated with this other set of drugs. So this should work just as effectively with them as it does in the non-CF bronchiectasis patients. And that's one of the things we're going to be exploring as we move through this development program. Beyond those 2 indications, which are almost overlapping and very logical, we're also going to be looking at 2 new additional indications, which we'll talk about in February, one of which will go into the clinic this year. Before the end of the year, the trial will start. Beyond that, we're doing a lot of preclinical work to defend the intellectual property around the use of DPP1 inhibition in this program, in particular, in areas like rheumatoid arthritis and lupus nephritis where we've seen very good response in gold standard models. So we don't anticipate bringing it forward in those indications. Those are too large. But in the more targeted indications where we think this drug can have impact and the competitive landscape invites it, we will certainly be seriously considering bringing it forward for treatment.

Maybe we can switch to TPIP. It's -- understanding that it's shown prolonged residence time in the lung, can you describe how it can actually result in a disease-modifying effect?

Sure. So our understanding at this stage is driven by the animal model work we've done and our -- the fairly thorough understanding of the impact of the hemodynamic changes with treprostinil in humans. So what we saw in the animal model was by reducing pulmonary vascular resistance, the downstream negative effects of the disease are alleviated. So think of it this way, the vasculature is constrained and constricted and so the right heart has to pump harder to move the blood. The body responds and revascularizes to try to get a way to perfuse more effectively. The cell wall thickness increases. All of those things were alleviated when you were able to reduce the pulmonary vascular resistance and keep it at that level over a long period of time. And that's what got us really excited about this opportunity in humans. Now we obviously won't be able to examine histologically in humans but we do know from this Phase IIa study, direct measurement of reduction in pulmonary vascular resistance should bring about the same histologic change in benefit. And that's why this Phase IIa study is so significant.

What would you consider a win in the Phase IIa study, I guess, as it relates to PVR lowering after just a single dose?

Yes, at this point, getting patients in, I think, would be the first part of the win. But once we get them in, and this is a big ask of these patients, right? These are sick pulmonary arterial hypertension patients who've been treated for a while, being asked to go in and have a right heart catheterization for 24 hours, which is done in an ICU bed, whether it's surrounded by COVID-infected patients who are on ventilators. So it is not an easy hurdle to clear. But we have identified patients, and we are incredibly grateful for the courage that they are showing in trusting us with this responsibility. What we think we will show in this with a single dose administration is PVR will drop, and it will remain down for a sustained period of time. Success, in my mind, is going out perhaps 6, 8, 12 hours with that reduction, recognizing that we're starting at our lowest dose. And in treating patients, we would titrate up to a much higher dose, which should extend that time line even further. But if we can even get to 6 hours, that's 3x the length that Tyvaso lasts in patients in terms of its vasodilatation.

Have any of the patients you've identified as candidates for the trial moved forward in the Phase IIa at this point?

So they're -- we're ready, they're ready. We almost had 1 or 2 in December and then Omicron showed up and the news cycle kicked up, and they got a little spooked about going into the ICU. So we're hopeful, and we've been saying, okay, in the first quarter, we're certainly hopeful we'll get a couple of patients. And we don't think it will take many patients in order to establish this PVR reduction and its implications. I know we're all anxious to see the data, but we've got to work with the patients and it's understandable.

So a question from the portal here. What are your expectations for the TPIP pivotal/regulatory path? Do you need to run a head-to-head study against Tyvaso to prove out the competitive profile?

So that's an interesting question that we continue to debate internally. Certainly, we don't need to. It's an interesting challenge we may wish to take on, but we'll give that some thought. Of course, the first goal of any clinical trial is to secure approval, then there is the competitive landscape that we'll be entering. And what's interesting about the profile of this drug right now is what we're hearing from KOLs is they're already there. If we can establish this PVR reduction and its durability with a once-a-day dose and a dry powder administration, they've already indicated that -- from their point of view, this would represent the new cornerstone of treatment for PAH patients in their mind. So we have a long way to go to prove all of that, but the earliest hint of it will come from the IIa data. And once we know that information and we know the results of the Phase IIb study in PAH and the Phase II study in PH-ILD, we will certainly engage with the regulatory authorities to ensure the fastest possible path to approval, and that may or may not include a comparator arm. I'm not particularly concerned about it, frankly, because a lot of that data for treprostinil and Tyvaso is already well established. So whatever we're able to produce while it won't be head-to-head, we'll certainly be able to place it in context in terms of benefit.

And before we wrap up, you had, I think, 1 slide at the end of your presentation talk for just a moment about protein deimmunization, gene therapy, gene editing. I guess what attracts you to those modalities? Why is Insmed going into those areas?

Yes. Well, the first and most important point is that we've been in them for a while, and this goes back to the earliest time when I was at the company and we were actually approached because of our liposomal encapsulation technology to see whether we could enhance some of the deliveries of other gene therapies and people who are really trying to break into the space. One way to think about gene therapy is the delivery is a hugely important part, matched by complex manufacturing processes. And I think in each of these areas, in important ways, Insmed has some real expertise. Having said that, it is far afield scientifically of the kind of delivery work we've been doing with inhaled antibiotics, Nonetheless, our ambition is to have medicines that are impactful to patients suffering from rare diseases regardless of what the technology is and regardless of the disease therapeutic area. And as you'll learn more about this, this is not a nascent effort that is coming from people who have not done this before. We have an extremely experienced group of people that we have brought on board with a track record of success, and we'll be talking more about that over the course of this year. And I think that is what will build additional confidence behind these efforts that we're making. I will just say they're measured, they're deliberately so. We're going to be stepping into this area, not full frontally shifting the entire focus of the company, they are a complement to the rare disease focus of the company. And in this way, I think entirely appropriate to answer the question for investors after these first 3 pillars, what's next? We now have the engine that can answer that for many years to come.

Great. Well, we will wrap it up here, and I guess, look forward to the updates with 4Q.

Thanks very much, Jessica.

Thank you.