for joining us this morning for the Insmed fireside chat at the JP Morgan Healthcare Conference. Thanks to everyone for joining us again this year. Nice and bright and early. We have the CEO of Insmed, William Lewis, with us this morning as my co-host.
Thank you for the opportunity to say congratulations on your.
Oh, thank you. Thank you then. And I appreciate you all. As long as you bring it up, I'd like to thank all the clients here for their ability to talk to you and look forward to continued excellent leadership. That was Will's way of avoiding me asking how the FDA review is going. It's a nice way to try to distract me. So how is the FDA review going? I think there's probably sort of less concern among investors on the data and maybe more concern around the process and internal FDA flow and capacity and how you guys think about going to your office.
Yeah. So the purposes of this conference, and for anyone who's listening, the one message I would leave you with is that the FDA review process is going extremely well. Everything is going as expected or ahead of schedule, which is remarkable given the backdrop you were just describing. And I think it's worth spending an extra moment on that backdrop. Everybody has a concern about whether or not different regulations that they have to be cut or what have you. Remind everybody of a couple of things. First is that the dues and fees that we pay cover the cost and the salaries of those who are doing the NDA review process. To the degree anyone in any part of any of these agencies is insulated, we are to the greatest degree possible.
The second thing I'd observe is that the staffers themselves, we haven't seen a big turnover in our area, and these are very dedicated people. What's really interesting to them as employees, we can step into their mind for a moment, is to be a part of novel medicines that are going to make a big difference where we're here to report how things are happening, and that describes to a tee what is going on in the brensocatib in the potential approval process for bronchiectasis. There is nothing approved to treat this condition, and this is a novel mechanism of action with an entirely new approach to inhibiting the inflammatory cascade that brings upon these patients their pulmonary exacerbations. Those are essentially like a small heart attack for the lung. They do permanent damage.
And the ability to reduce the numbers of those, to prevent the onset of those, to delay the first of all of those, as we have shown statistically significantly in our ASPEN study, is all an extremely exciting turn of events for this area. When the WILLOW study came out, the phase II data at the American Thoracic Society, this was during the COVID era, so this was done over a webcast, but there was a physician who described this as the holy grail of pulmonary medicine. And today we sit in a very enviable position, I think, with the view of that data post the ASPEN pivotal trial, and have worked very, very at a very appropriate pace. Very excited about what we're seeing. The PDUFA date has been set for August 12th. No AdCom, priority review. All those things have fallen into place, so we're pretty excited.
How should we be thinking of the label language from a perspective of easing insurance?
Yeah. So I think.
Especially on whether exacerbations, frequent exacerbations would be needed.
Our expectation, although we obviously don't know at this point, is that the label will not include a reference to prior exacerbations or exacerbations as the hurdle, if you will, for who's in or who's out. This is for the treatment of bronchiectasis. We'll see whether that reads through. But in any event, what we also want people to understand is we fully expect the medical community to limit the use of this drug to patients who have met the entry criteria for the phase three study, who are those who had experienced two or more exacerbations in the last 12 months.
As a consequence, a lot of our effort over the last two years through our medical science liaisons and our interactions with physicians in these academic settings has been to emphasize the importance of looking for exacerbations in your patients, documenting those events in medical records, and also approaching the patient community and encouraging them to speak up if they experience exacerbations to their physician. A lot of this hasn't really happened to the greatest degree it could have over the last decade or so because there's nothing approved to treat the condition. So the ability to document that you're having these exacerbations or that they're increasing or decreasing is really irrelevant in a world where the physician has nothing they can do about it. What brensocatib promises if it's approved is the first-ever medicine that would have an impact here.
So documenting that, speaking up about that, those are really important activities that we've been trying to encourage for both the patients and the physicians.
To that end, to the employees of yours, I will not stop.
By the way, you have a lot.
Going back to that conversation, to the flip side of it, how do payers perceive the value proposition of brensocatib? How would they engage cost savings around managing exacerbations?
Yeah. So we know that exacerbations vary in their severity. Some result in, in every case, in the modification of medication and intervention by the physician. They can result in hospitalization. We saw a trend toward improvement in that in the WILLOW study and the ASPEN study. That was very encouraging. But I think the right way to think about this is not as a swap out of value. You're not going to get dollar-for-dollar improvement by treating this condition versus leaving it alone. But it is the first-ever approved medicine. The vast majority of these patients are Medicare, so they have an order of 60%. So this will have to be covered by Medicare. We'll get a little bit more medicine to treat this condition.
But what was really exciting about the ASPEN data from our point of view is not just the percent reduction in exacerbations, which was a clinically relevant level, nor was it a delay in the onset of the first exacerbation or the percentage of patients who went exacerbation-free for a year. All of those were statistically significant. But the surprising data at the 25 mg dose was the preservation of lung function. That was not expected. And both from the market access point of view and the physician perspective, particularly among the experts, the payers are picking up on that as a very important aspect. And so we think that's a pretty exciting thing to be able to show at a statistically significant level.
So pulling that together, what is that going to be for expectations for prior authorizations? Are chest CTs going to be required for diagnosis? Just because they can be required.
We framed out the interest of the market. Roughly half of those with basically our data and analysis have had two or more exacerbations. All of those patients are definitively diagnosed with bronchiectasis, which includes a CT scan.
They're sitting there.
They're sitting there with a paperwork ready to go. So what we have to do at this point is to go and find the additional patients who may also be bronchiectatic but have not yet had that CT scan or that definitive diagnosis for the pulmonologist. We think that population could be much larger than the existing prevalence population that is already diagnosed and ready to go today. To be clear, our estimates contemplate only the diagnosed population of patients in the U.S., Europe, and Japan.
Do you think there'll be prior authorization for that CT diagnosis?
So I think there will be a prior authorization that will require a definitive diagnosis of bronchiectasis, which doesn't need a CT scan. But we are working right now with the market access world to try to ensure that the attestation or check the box, if you will, that the patient has bronchiectasis and meets the entry criteria in the study for moderate exacerbation. That can be done by the physician quickly without providing all the documentation.
Oh, like an exacerbation documentation.
If the physician can attest to the exacerbation, that's the ideal prior authorization. We're very comfortable with that. We think it's entirely appropriate. It's consistent with what we've seen in the previous study. It serves the patient's best interest, which is a North Sta r. As we progress beyond that, we think how can the market access world work to preserve its own financial margins? One of the ways they do that is that they're going to begin to bring resistance potentially to reauthorization of medicines across the board.
That was my next question.
So what we're going to do there is ensure that as a part of our contracting process out of the gate, that there's a clear path for reauthorization. There's a clear path for initial use. And the combination of those two things are something that we're going to be able to ensure that both the authorization and the reauthorization are smooth. We want, as our objective, the phrase we use is a frictionless launch. So the ability to access the medicine with the appropriate patient and for that patient to continue to see benefit over time.
Do you think that reauthorization or the ability to pay for full therapy is a requirement for improved something like less exacerbations or steady lung function or stability of disease or whatever? What will the reauthorization likely need to test?
So our experience to date is that none of that will be part of the reauthorization. The reauthorization is simply going to be a physician attesting to the fact that the patient should continue to receive the medicine because of their judgment of the patient's medication.
As you speak to payers, you're going in with that price point that you have discussed with the physician.
Absolutely.
Or Ofev versus ASPEN.
We've actually narrowed it down quite a bit to the point where we're able to go in and discuss the target product profile with the data from ASPEN and indicate what our intentions are. We are, I would represent today, very confident in the outlook that we want. This is an exciting medicine. Even for the market access world, there's nothing approved to treat this condition. And to have a low-burden medicine with a safety profile comparable to placebo means that from a market access point of view, yes, you're preserving lung function at the 25 mg dose according to the data, but you also have a low treatment burden with a low AE profile. The worst thing that happens in the market access world is that they pay for a medicine that the patient stops using because either of an adverse event or it's too burdensome.
We know that from ARIKAYCE. Our approval for the treatment of NTM is an inhaled antibiotic. It creates cough. It has a possibility of losing your voice. It will challenge it. We've had to work through those complications very successfully. It's still growing at double digits after seven years of launch. So that's something we've learned. It's the same pain point. This is a totally different experience. This is a once-a-day pill that they take with an adverse event profile and data that shows a comparable medicine. That's actually a medicine the market access world would accept.
Let's talk about the logistics of the launch that you mentioned about the CTs. How are you focusing on adjusting that by composing or will there be, say, a more limited sales effort and marketing effort for driving these quarter-term doses in brensocatib?
So the short answer to that is yes, there's some effort in that regard at the pulmonologist. And this comes in various forms. One is what I referred to earlier. We're going to be coming up on the American Thoracic Society for the last two years. We have been educating physicians and patients about the importance of identifying their exacerbations, documenting them. And that includes patients who are in the pulmonologist's office who are experiencing exacerbations but may not have a definitive diagnosis of bronchiectasis. Some insight on how many of these patients there are can be gleaned from the success of the WILLOW launch, where they are targeting the top two deciles of pulmonologists that had a pretty successful launch because the exacerbation patients with COPD are already resident in the pulmonologist's office.
That means that these patients we're describing, if we think about the funnel and step back for a minute, there are 20 million people in the U.S. that have COPD. Of that, it's estimated somewhere between 20%-40% of those patients probably also have bronchiectasis. We know today from the real world that there are medical claims forms that there are 500,000 patients definitively diagnosed with bronchiectasis. Somewhere between that 500,000 number and that implied number of 4 million-8 million patients is a group of patients who may be comorbid with COPD or asthma and bronchiectasis are experiencing exacerbations. And with a definitive CT scan and a diagnosis by a pulmonologist, they would be on-label and eligible for treatment. So we've looked at the conservative numbers. It's just the beginning. We don't know how much bigger it is.
Certainly, the background data here is extremely encouraging with that.
Let's talk about the number of sales force. Caller, please. We're not hearing the pulmonologist. What's the variables? Amongst pulmonologists, is it going to be a set or an excellence-driven initial launch or a good start?
Here's where I'm going to take a moment to brag on the special team at Insmed. If we rewind the clock to the ARIKAYCE launch, which was for brensocatib and MAC, the street estimated that we were going to do about $40-$60 million in our first year of launch. We did $100 million. That was a strategy to target NTM centers of excellence as well as newly-elected physicians. To do that, in that market, we had about 70 therapeutic specialists. We have since added an additional 120 in the U.S., so we've come close to 200 therapeutic specialists. Let me describe the caliber of these people. Many of them are the ones that participated in the launch of ARIKAYCE, and we know how successful that was.
That was a top 10 rare disease and non-oncology launch in the history for an inhaled antibiotic with a 30% dropout rate. These people are exceptional. The 120 we added, we had over 7,000 resumes applying for those 120 jobs. So we have brought together, I consider to be, the best in the business in targeting this launch. In parallel to this, out of recognition of the importance of this launch in this disease state, the COPD Foundation has launched a campaign to identify centers of excellence in treating NTM and bronchiectasis, and they intend to identify roughly 200 of these centers over the coming years that would be specialized in the treatment of these conditions. That is going to help bring standards of care for the best treatment for these patients.
As the only approved medicines for those two conditions, it doesn't get any better than that for us in terms of laying the groundwork. Our strategy with these roughly 200 therapeutic specialists is to be able to call on every single pulmonologist in the United States. And that is how we're going to go about this. We certainly will tier. We haven't defined what that would be in terms of who's going to get what kind of effort. But it's fair to say the centers of excellence will certainly get plenty of attention, but so too will community-level physicians. And that, in our judgment, is key to a sustained and successful launch.
Among the COPD pulmonologists, are there codes or proxy RXs that you can use to identify those potential high-risk treaters that you can go after their use of some treatment or geography? I know we're just preparing to call this, but how do you think about that?
Yeah. So the first thing we've done is put our therapeutic specialists in fully trained out of the field. So they were all trained and deployed as of October 1 of last year. What they've been doing during this time is disease state awareness about bronchiectasis, while in parallel, they're targeting promotion of ARIKAYCE appropriately for the brensocatib and MAC disease patients. So we have a long-standing dialogue already about potential demand for this drug from those interactions. In a highly compliant way, we are understanding what the physicians see on the landscape and how this medicine, in our minds, may be able to be helpful to the appropriate patients. That gives us a lot of insight. In addition, there are ICD-10 codes that are already in existence for the treatment of bronchiectasis. So we can look at those data and understand where patients might be.
The excitement and enthusiasm around this drug came out of the outset at the World Bronchiectasis Conference in Scotland last year. One of the key opinion leaders who stood up and joined the wave in the first week described it as a Vertex-like openness. This is the arrival of the first actual medicine known for the treatment of this disease that's been developed in the world. We know we've talked to 90% of physicians, and those physicians have told us, and we'll be very quick, we've talked to all the physicians. 90% of them have said they intend to treat their patients who have two or more exacerbations. In fact, they intend to call them into the office. We've talked to more than 90% of covered lives who know that the market access world is going to be supportive of this medicine.
We have more than 41,000 people who have gone to our website and downloaded information to ensure they've registered so that the day this medicine is approved, we can send out an email directing people to their physicians, 41,000 of them, to tell them to go and ask for their history, so the background for this is about as positive as we can.
I'm going to walk the presentation.
Yeah, so if you look at the history of drugs and revenue generation associated with the successful treatment of appropriate patients, what you see is typically about 80% of the revenue generated by the United States, and then also other sources outside. It varies to a degree, but our expectations are that probably somewhere in that neighborhood, the vast majority of that coming from the U.S. Having said that, we have certainly seen a significant demand in both Europe and Japan.
There are a lot of folks.
Yes, there are. As we all know, there's a lot of them, and we've seen our own experience with ARIKAYCE, so we're already in dialogue with these physicians, talking to them, and they see a landscape of bronchiectasis. I would say that we will be cautious about Europe. Europe is a region of the world that struggles more now than ever with securing approval and reimbursement of novel medicines, and so we want to be responsive to the patient demand, but also cautious about our spend and support it. Japan's a different story. We see more than 20% of our revenue right now coming from Japan, and so I think we're going to learn a lot from the U.S. launch, but we're also in dialogue with the physicians in both those regions now. Remind everybody, we already have a sales infrastructure in Europe and Japan. It is our own.
And so it would be our expectation we'll expand to meet the demand that we perceive in those regions in a proportionate way. Those launches will come next year. That's our expectation. And the approval path for those, I think, is going to be very good.
All right. We're going to turn now to the NTM, which is pretty important. Even at these levels, sort of pH and pH change. Is 25% placebo adjusted still the right number that defines success in the long run? Talk about what we'll get from.
Yeah. So to be really clear, 25% is not what I would consider success. 25% PVR reduction is what I would consider a home run. If you look at the range of PVR percent reductions across the prostacyclins as a class, the range from the low double digits to sort of just about 20%. So we've always said if we could get to the high end of that or above it, that would be a very solid goal. If we could get as high as 25% in that area, that would be a home run. And that would put us clearly the best-in-class prostacyclin out there. To remind everybody, treprostinil palmitil inhalation powder, or TPIP, is a dry powder formulation of treprostinil with a 16-carbon chain appended to it with an ester bond.
That dry powder, in a virtual form of the molecule, is then breathed in, and the ester bond is cleaved off by esterases in the lung. The practical result of that is we're getting a slow release of the active moiety of treprostinil directly delivered to the lung. We think that the inactive form of the drug reduces the side effects as you breathe it in. That's particularly relevant for PH-ILD, but it's also relevant for PAH. We put out a PH-ILD set last year that was very compelling. It was lost a little bit in the shadow of the brensocatib ASPEN data, which is okay. But this year, the PAH data will be at the front end of our next series of events. So TPIP will have PAH phase II data in 100 patients, randomized two-to-one treatment versus placebo.
Our expectation is, with the primary endpoint of pulmonary vascular resistance % reduction, we should be best in class. We're also going to be able to offer it. That's an extremely exciting outcome if we can achieve it. Anything close to that will still be exciting because this will be the only once-a-day treatment that is available that gives 24 hours of coverage. Let me just make two observations about the data set you're going to see. The first is that pulmonary vascular resistance % reduction in our measurement is taken 24 hours after the drug is administered in the trial compared to our competitors who measure it right after administration. That's a very significant issue because they have to repeat the administration every other week to keep that coverage. The truth is that shortly after it's administered, it drops off dramatically. We're looking at it 24 hours later.
That's an extremely high hurdle and not a perfect apples-to-apples comparison for them. It puts us at a major disadvantage. But we think we're going to do well despite that. And I think that that's a very significant issue with this drug. The other is keep a close eye on what the actual percent reduction is because the max tolerated dose we've submitted in this phase II study is 640 mcg. Now, that's more than 60% greater than what you get with Tyvaso in any form. But what I will also tell you is that we have now, in our open-label extension study, gone to double that level, 1,280 mcg. That is unprecedented in terms of the amount of treprostinil we were able to administer. And the suggestion for that did not come from the company.
It came from the scientific advisory board that was viewing the data from phase II and said, "Keep going." So we now have data that will come out at 640, but we know we can go with some patients as high as 1,280. And that portends even greater efficacy, we believe, than what you're going to see with these phase II data today.
How should we be thinking about scleroderma? So six-minute walk. Do they need to go lockstep? Does PVR in six-minute walk need to go lockstep, which biologically should, in order to sort of have that cohesive ongoing activity? If you show a PVR of 20% or PAH of 20%, what's the six-minute walk that you want to see to be safe?
Yeah. So it's an interesting question. There's a lot of variability around six-minute walk test. We want to see that in these data sets across all kinds of pulmonology cases. And right now, there are roughly 12 of 14 or so approved medicines to treat PAH. That's why we think it's going to be so important for us to present this part of our profile to be only once-a-day treatment that will ensure a PVR reduction of roughly 20%. We'll see what it ends up being. We know that the approval criteria is your six-minute walk test. That's what the FDA looks for. Because the assumption is by reducing pulmonary vascular resistance, you may create your exercise tolerability as measured by six-minute walk test. So six-minute walk test is administered. It's notoriously variable.
What's interesting is that in our case in the Middle East and the last year, we saw a 15-m improvement, which is quite dramatic, compared to drugs that have been approved as low as 15%, a 15-m improvement. So what do we need to see? That precedent would suggest 15. I'll be disappointed if it's not 20, but it's highly variable. So it's something you have to be cautious about. If we see a pulmonary vascular resistance reduction of, let's just say, 20% and a 20-m improvement in six-minute walk, we are the only ones that have approved therapy that covers patients overnight, and we know we can go up 100% more in amount from there. That is a very winning product profile.
If you have a six-minute walk that suggests 100%, and of course, a higher PVR, let's fast forward phase III data based on six-minute walk. You have this clear win. In pulmonologists' minds, is that clear win?
Yes. And that's not just because of that. Just for this. And six-minute walk is an encouraging dream. People have a hard time interpreting what that really means to have a six-minute walk benefit. But you're a great example. We've seen in our study in blinded line of data, PVR reductions in excess of 60%-75%. Dramatic reductions. We've seen correlations between that and six-minute walk. I saw a piece of data the other day that showed me a dramatic PVR reduction, but six-minute walk went completely the wrong direction. And when we did the inquiry to find out what was going on, it turned out that things were negative for most people. So this is the kind of thing that can happen in a clinical study. You have to dig into the data to know what's really going on.
I would just say the six-minute walk is a necessary measure to get. We'll power the study appropriately to ensure that we do. I also believe that the PVR measurements we're taking 24 hours after administration. If they get into 20%, that's a clear win. We'd be very excited to be able to show that because it would be entirely consistent with what we saw last year with PH-ILD. 39 patients with a 30-meter improvement in six-minute walk. We saw an improvement in time to worsening, which is about as good a measure as we hope for, with a benign safety profile, particularly important for PH-ILD patients. One of the things these patients do is they struggle if they have a cough. If they're bringing in the active moiety, that induces cough. We'll see what the data show.
I would say we're excited about the possibility that we could have a clear best-in-class profile of this compound. I think right now, it's fair to say that most of the street does not give us much of any credit for this program. If the data come out as we suggest, I think it's going to be approved. It is. We're getting a little more attention now. I think people are anticipating the readout. Let's remember that sotatercept, which showed a 33.9% PVR reduction after phase II, which is the best data they had. Right after that phase II data was produced, they were purchased for $11.5 billion. So the value creation surrounding these phase II data can't be overstated.
So how should we assume phase II success, right? Balancing strength and tolerability. Where's the blending that you need on that sort of on that sensitivity analysis based on what patients want, what doctors want? How do you see it?
Yeah, it's interesting. We went to the physicians when we were designing this molecule. We said, "Would you prefer to have a molecule that is more tolerated better or a molecule that pushes the dose despite adverse effects?" and they universally said no. They want to push the dose because this is a fatal disease, and their experience teaches them that the more treprostinil they can give them, the more effective it is for patients, the more benefit they'll receive, particularly when it's administered by a patient. So that sets us up that we want to push the dose as high as possible. We're going to be setting the max tolerated dose at phase III at a 1,280 mcg level because we've seen this last blinded line of data report, north of just about 80% of patients got to a max tolerated dose of 640 mcg in just five weeks.
In the real world, they'd have much longer to titrate up because of the study and the artificial need to show impact over a sustained period of time. We had to cut off titration for five weeks. But my expectation is we're going to 1,280. We'll give patients much longer to get there. As a consequence, we're going to see patients going much higher than 640.
We have one minute to talk about brensocatib for CRS. That data is coming out. Remind us about what that program is and how it is changing.
So CRS with nasal polyps is a target market, at least as big as polyposis. We are targeting patients who are not responsive to steroid therapy, only improved with medicine to treat this condition, and those who have undergone surgery. We are looking at a primary endpoint that's called STSS, or sinus total symptom score. And we are 80% powered to show a 0.97 point change on that score. Patients come in on that measurement between zero and nine, nine being the most severe. They have to be at least a five on stable background steroid therapy, which means they're highly symptomatic. If we can show that roughly one point improvement, that is clinically meaningful. We do know that the only other approved medicines that fail steroid showed a benefit of about 0.7 or 0.9 improvement on the STSS score.
We are 90% powered to show about a 1.14 point change, so the variability around that point measurement is not that great. We should be able to demonstrate clear benefit. I'm super excited about what that represents. It is a gigantic market. Nothing novel is going to be able to treat that really ever, and to put it in perspective, we think there are several hundred thousand patient incidents every year coming in that need surgery or have had surgery, and this is a medicine that will have impact here. It comes out. Let's just think about what this means. We have the TPIP PAH phase II data that we'll publish here. We have the launch of brensocatib roughly the third quarter of this year.
We have the CRS with nasal polyps readout, which is going to validate a market as big as bronchiectasis at the end of this year. At the beginning of next year, we have the ENCORE data, which is the expansion by about five-fold of the ARIKAYCE market. We have, after that, the readout in HS and Teva, first 100 patients looking at that indication. We have three different gene therapies targeting DMD, Myotonic Dystrophy, and Stargardt disease, all of which will be in the clinic and show the patient data we need at 12 to 18 months. This is an unbelievably busy time in the world today, and as dramatic as last year's impact was, we think the next 12 years will be much harder for this disease.
Great. With that, we are at time as well. Thank you, William. Thanks, everyone.
Thanks, everyone.