And I also think that the need for additional therapies to complement those that are already effective is going to continue to be the case. This will be a combination market, and this represents a very different approach than the ones you’re enumerating, which I have a lot of confidence in. I think they’re going to do very well. But I think some of the effect sometimes wanes. The opportunity to come in with a once a day pill that could be contributory and improve these patients would be a very meaningful impact on patient outcomes, and that’s why we’re pursuing it. This is a neutrophil driven disease, and from that point of view, inactivating DPP1 and preventing the release of that inflammatory cascade of NSPs we think is going to be directly on point and potentially result in patient benefit.
Andy Chen: Right. And a follow-up on your early stage assets, so I noticed on your slide, it’s IND filing. It’s singular. So it looks like it’s going to be one single asset coming forward in 2024, but like I’m just wondering if you can provide a bit more color on is it going to be a new technology, or is it going to be validated, existing technology on the market? And are you leaning towards a hot areas that everyone is going toward, or is it going to be like more blank spaces that’s less competitive?
Will Lewis: Yes. So let me just frame out that we sort of think of this in four different categories, right? We have our San Diego operation, we have our New Hampshire operation, our New Jersey operation, and our Cambridge, England operation. Cambridge, England is driven largely by synthetic rescue as the underlying modality. San Diego is driven by gene therapy. New Hampshire is de-immunization of therapeutic proteins and viral capsids. And New Jersey sort of sits as a connecting tissue, if you will to these others involved in additional compounds and some of our own original research. As we look at each of those, I am expecting progress and IND filings to come from all of them. The timing of that has not been specified to any great degree.
But what I will tell you is it is multiple INDs that we expect to have. Certainly in 2025, the timing is going to be very close, whether it’s 2024 or 2025 in terms of single and multiple. But right now things are looking very encouraging, and I have a lot of faith in the teams. I think you’re going to see, just by way of example, in 2024 and 2025 IND filings for Stargardt disease using gene therapy, ALS using gene therapy, DMD using gene therapy, to name just the first three that we expect to go forward. And the details around the IND filings are more about supplementing what has already been done. So if there’s one message I can leave you with, it’s that the preclinical work that provides encouragement as to therapeutic benefit is already done.
We already know what we think is going to happen when we put these into humans. And the effects we’re talking about here are, we believe going to be profound. And from that perspective, it is a very exciting new chapter of Insmed’s research and development operation. I expect the work that’s coming out of Cambridge, New Hampshire and New Jersey to be equally impressive and impactful. And I think 2025 and 2026 are going to be very exciting years where we’re talking about a range of products that are in the clinic, producing data, on some of the most intractable diseases that are out there. And Insmed is going to be there at the forefront with what we believe are going to be game changing therapies.
Andy Chen: Thank you.
Operator: Your next question comes from the line of Graig Suvannavejh from Mizuho Securities. Your line is open.
Unidentified Analyst: Hi, this is Jerry on for Graig. Thanks for taking our questions. Maybe starting first with brenso on the stat plan, if the p value in the ASPEN trial does come under the 0.05 mark, but the reduction in pulmonary exacerbations does not reach the level of what you expect, how would you view the data in that context? And I have one more follow-up.
Will Lewis: Yes. So we’ve talked about these different scenarios. It’s one of the reasons we tried to highlight today for people before the fact, what we consider to be the smoothest path to an approved product that will be well received by market access, the regulators, the physicians, the patients. And from through that lens, that’s where we focus on that 15% threshold. Because if you talk to FDA and other regulatory authorities and physicians, they really want to see a 15% treatment effect. And we should be adequately powered at the 0.05 level to achieve that. What happens if we’re below 15%, but statistically significant at the 0.05 level. At that level, I think going down to as low as perhaps 10%, it would still make sense to file, if the safety is very good.
Remember that this is not sort of a one and done medicine, this is a lifetime medicine. Every exacerbation is like a heart attack for the lung. It does permanent damage. The ability to reduce that even marginally, we think is clinically meaningful. I do think as we get below that 15% threshold, we start to talk about or contemplate a different target product profile where price would change and probably come down, so those kinds of adjustments would be made. But I would be in a position where I would say, hand on heart, that if I’m a patient who has exacerbations, right, not everybody has, let’s say it’s between 10% and 15% reduction. Not everybody would have that reduction, right? That would be the average. If you think about the range, there might be some patients who would benefit much more dramatically on the positive side.
And given the safety profile, it could make sense to file in that context. I do want to acknowledge that we are hoping for 15% or greater, and we’re hoping for, in a very clear way less than 0.01. But if we’re between 0.01 and 0.05, and we’re above 15%, we believe we have a product that’s going to make a difference. If we’re between 10% and 15%, we’re probably adjusting how we think about the business opportunity side of it. But for patient benefit, given there’s nothing approved, I think we would still have something that would warrant approval and appropriate use in patients that are responsive.
Unidentified Analyst: Got it. That’s very helpful. And then just on the gene therapy DMD program, any updates on timing or enrollment? Thanks.
Will Lewis: Yes. So we continue to make good progress there. And I think what we’ve guided to this year is that we will do our best. It’ll be somewhere near the end of this year or the early part of next year that we’ll file the IND. There’s some work that still needs to be done to sort of get all the ducks in a row, if you will, with the FDA. And we certainly have taken a lot of learnings from watching other programs. And consequently, I think we’re in a strong position as we enter the clinic and we’ll be able to produce data that while it isn’t designed for direct comparison, people will inevitably do that. What we’ve set for a threshold for success here is a clear, superior profile to what is already out there.
That’s a point I really want to emphasize. This is not an attempt to go out and do what others have done. This is an attempt to go out and beat clearly what is already on the market. And that is the threshold we’re setting for ourselves and we have some confidence we’ll be able to beat it based on the data we’ve seen pre clinically.
Unidentified Analyst: Got you. That’s very helpful. Thanks for taking our questions.
Operator: Your next question comes from the line of Jason Zemansky of Bank of America. Your line is open.
Jason Zemansky: Thank you. Good morning. Congratulations on the progress this quarter. We appreciate you fitting us in. Two, if I may, on brenso, mostly follow-ups on your previous comments. But the first, to what extent is your peak potential forecast dependent on this sort of base case 15% reduction in exacerbations. If the levels are well above this threshold, closer to, say, WILLOW’s 25% or 36%. How does that change your outlook, especially when it comes to something like penetration? I mean, what sort of upside do you think could conceivably be here?
Will Lewis: Yes, I think it’s a great question. I think the target product profile will certainly drive the confidence that we’ll have in terms of what that penetration will be, how rapid the uptake will be, what the price will be, all that sort of thing. What we use as our assumption set is something in the WILLOW like territory. So it’s Statsig below 0.01 and a treatment effect that I would say is comfortably in the 20s and if that is where we end up, then I think we feel comfortable with the guidance that we’ve given. Could it go higher if we’re higher? I guess we’ll have to revisit that. That’s certainly a big part of the reason why we’re going to have this commercial day within a week. We’re targeting of actually putting out top line results.
I would also say that what we’ve heard from physicians, and this is perhaps a significant point to emphasize, there is a general skepticism out there that we’ve encountered from people who say no one’s really been able to conquer the bronchiectasis market. So we’re cautious and optimistic based on the success of Phase 2, because no one had really ever produced data as strong as what we saw in Phase 2. That’s why it was published in the New England Journal of Medicine. In a world where ASPEN clears that hurdle and is statistically significant at either dose below 0.01, the physicians to a person have said this drug is going to fly off the shelf. They will proactively call their patients in. They will enthusiastically embrace the use of this drug.
I think you’re going to see a very rapid uptake in the use of this drug, not only because it’s the first ever approved medicine for this condition, but because the treatment burden of a once a day pill and the safety profile suggested by WILLOW and what we’ve seen in ASPEN so far is very positive. That backdrop and the sheer appetite that we’ve seen at the different conferences in terms of medical education and responsiveness to the potential for a drug arriving to treat this disease is very significant. We had standing room only at the last several sessions where we were doing teach-ins on the medical area of bronchiectasis, very appropriately, talking about this disease state and the challenges that patients who experience this sort of vortex of inflammation, what their life is like, and how impactful a treatment could be if it were ever to be accomplished.
I think it is referred to at the ATS as the holy grail of pulmonary medicine, the last large pulmonary indication without something approved to treat it. So if we can be that first entrant, that’s a very exciting opportunity for us. And one, I think that the treating community and the physician, the patient community is going to embrace.
Jason Zemansky: Got you. And then in terms of the other endpoints, beyond reductions in PE like QLB [ph] and FEV1, in terms of the commercial opportunity, how important are these to hit on, and what’s your confidence you can get there, given the longer duration of therapy?
Will Lewis: Those are real unknowns in my mind. I think they’re nice to haves. They’re not necessary. The thing that market access the physician, the patients, the regulators are all very focused on is this exacerbation rate, the ability to impact that, because each one of those is like a heart attack for the lung. It does permanent damage, and it is a major negative for the patient. And right now, there’s nothing that can be done about it. So if we can show up and say we’re going to reduce that on average by about, say, 20%-plus, that’s a big deal. And of course, it will help some patients more and some less, but to be able to have that kind of impact over time, this is a chronic medication these patients will be on for the rest of their life, would be a major breakthrough and accomplishment. And so far, it looks like we’re on track to be able to produce that kind of a result. We’ll know here shortly.
Jason Zemansky: Got it. Thank you so much for your color.
Operator: Your next question comes from the line of Vamil Divan from Guggenheim Securities. Your line is open.
Vamil Divan: Hi, great. Thanks for taking my follow-up here. Just got a few questions this morning or during the call around the filing the $500 million filing, the ATM with Leerink. Can you maybe just I know you talked to someone a little bit at the beginning, but I think we’re getting some questions just on why that’s being announced today. And so maybe if you can just kind of restate what you said before or a little more details on exactly the rationale for announcing the standing, you’re kind of pretty clear about not looking to do any sort of big raise or equity move before ASPEN, so any clarification might just be helpful.
Will Lewis: Yes. I appreciate the question. I’ll actually ask Sara to address that.
Sara Bonstein: Sure. I’m happy to address it. So I want to be clear on a couple of points. The filing of the ATM this morning is not a capital raise. We used our ATM last year for strategic purposes. Those intentions have been met and we do not plan on proactively utilizing the ATM in the near-term. The ATM is a broader — is a complement of the broader strategy of our multiple levers, on the other side of data, it’s housekeeping. I would not — I would encourage people to not over think it. And it’s something that all companies of our size have and in place. And it’s something that we put in place an ATM three years ago, and we hadn’t used it for quite some time, so people should think about it that way. Will, I don’t know if you have more you want to add.
Will Lewis: Nope, that covers it.
Vamil Divan: Okay. Thank you.
Operator: There are no further questions at this time. So I’d like to hand the call back to Will.
Will Lewis: Perfect. Thanks, everyone, for joining us this morning and look forward to talking to you in the not too distant future about the updates on our various programs.
Operator: That does conclude our conference for today. Thank you for participating. You may now all disconnect.
