William Lewis: I’m sorry, I’m having a hard time understanding the question. It sounds like your line is a little broken up. Could I just ask you to repeat it, please?
Nicole Germino: Sure. [Technical Difficulty] going back to the TPIP and PAH [Technical Difficulty] how does the drop in oxygen levels compared to [Technical Difficulty]–
William Lewis: Gene, did you hear that question? It sounded like how does it compare to Tyvaso?
Eugene Sullivan: How does — which aspect?
William Lewis: TPIP on the PH-ILD side. Is that right — did I get that right?
Nicole Germino: Yeah, that’s right [Technical Difficulty] how does the drop in oxygen levels compares to the [Technical Difficulty] —
William Lewis: Well, I’m really having a hard time hearing there. I think it was the oxygenation levels in the PH-ILD. How does it compare to Tyvaso.
Eugene Sullivan: She’s asking if the oxygen — the drop in oxygen levels, how do they compare to Tyvaso? We didn’t do a direct comparison because, again, this is a small study and we’re not trying to make claims against today. So I think what we were looking for here was just to see that it didn’t harm patients. So I think the one point I want to make is that patients with interstitial lung disease. They saturate when they walk that, that is a function of the disease. And we wanted to make sure that one, there was no negative impact of the drug on their oxygenation at rest or have a no negative impact on their desaturation during the course of exercise. And we think that’s what we saw. The reason we were even looking for that — the reason we are even considering that as a safety finding of interest, is that when you deliver a vasodilator to the lung where there is underlying lung disease.
And there is a potential danger of diluting the vasculature in an area that’s not ventilated and you get what’s called shunt blood going past the lung, which is not getting oxygenated because the area of lung that’s has delivered a blood to is not getting ventilated. And there have been problems when systemically administered vasodilators have been used to treat PH-ILD and in fact have led to some contraindications in the product labels for Rio SigmaQuad and for Amber Santana. The general understanding is that’s not a good idea to deliver a vasodilator systemically orally or IV in these patients. But as the increase trial showed, the INCREASE trial is the trial. And for everyone’s benefit of the time, though, in this population was that that wasn’t a problem.
And the theory behind that is that we’re delivering the vasodilator primarily just to the regions that are actually being ventilated because you’re delivering it by inhalation. So we just wanted to we they apparently did not see it in and with ide-cel, and we just wanted to monitor that in our trial as well. And again, we were we were pleased to see that come on at baseline three tests. There was no change in tack patients on placebo required a little bit more oxygen that patients on active drug had no change in their option supplementation. And then with exertion on there was really no significant decline compared to placebo.
Operator: Your next question comes from Graig Suvannavejh from Mizuho Securities.
Unidentified Analyst: Hi. This is Jerry on for Greg. Has taken our questions. Congrats on the TPIP data. I guess, first, the LNTPODTPIP, based on what you know now, what a Phase 3 study in PH-ILD look like? And then I do have a follow-up on brenso well after.
William Lewis: Yes, I’ll take that quickly. We haven’t really put any thoughts in the public domain about what that Phase 3 study will look like. We obviously want to have some interaction with the FDA and other regulatory authorities to ensure that what we produce from that trial will be adequate for full approval. I think today’s data certainly suggests that there’s going to be a clear path to being able to create such a trial. We’ll rely on very likely on what has worked in the past, but it’s difficult to commit anything further than that in the design centers because we’re just obviously, the data is fresh and we’re digesting it. And then we’re going to want to have dialogue with regulatory authorities. But as soon as that is accomplished, we’ll get that design out to everyone so that they can understand what is going to look like.
Sorry, I can’t be more specific. So if I had That’s helpful on. And then for I guess, the upcoming ASPEN readout, since you know, you mentioned kind of the old patient that we have reached out to be two weeks of all the adults that time period. I’m wondering if I could gain more granular timing on the timing of data release. Well, I’d tell you that is the question of the day. I wish I could be more specific. We tried to narrow it down to the mid May end of June timeframe, which is 45 days that’s pretty specific for a biotech company on. Let me just perhaps give a little bit more color on what is the sequence of events when you when you get to this point on a large trial. It’s not simply the production of the top line results, as is often the case for something like a Phase 2 study.
In this case, we not only need to produce the top line results, but we need, by the time we lock the database for every detail and quality issue to be resolved because this is a submission database. And what I mean by that is this is a database that’s going to the FDA and the other regulatory authorities around the world. So if you will, there’s an additional level of quality control and scrutiny to ensure that the database is submission quality, we would hate to snatched defeat from the jaws of victory by having good top line results and then a database that got rejected for some quality issues. So we’re taking the necessary time to ensure that both goals are accomplished, that we can produce the data and that the database is in is in good shape, and I’m happy to report every aspect of that effort at the Company has gone incredibly well, and I’m incredibly proud of our clinical team for what they’ve been able to accomplish in that regard.
But it will be within that 45-day window. We’re confident of that. And that’s as specific as we can get but those are the reasons that are sort of pacing when that database will be ready for review.
Operator: Your next question comes from Jason Zemansky from Bank of America.
Jason Zemansky: Good morning. Congrats on the data and thanks for taking our questions. I was hoping you could provide some color on the discontinuation rates for TPIP. I’m appreciating these are small numbers, but about it 14%, it’s twice what was observed for the Tyvaso BREEZE study. That said, the rate of treatment emergent AEs looks to be in line and it doesn’t look like cough was the source of this. Was there something about the four patients who discontinued whether it was, I don’t know, underlying disease severity or dose received or I don’t know, was it early in the study, especially as you noted, the titration schedule was a little more aggressive? And then a follow-up, if I may.
William Lewis: Gene, do you want to take that?
Eugene Sullivan: Yes, sure. I think when we use the Tyvaso as the benchmark we don’t so much look at the BREEZE study as we do the INCREASE study. And I think the discontinuation of treatment in our study actually compares favorably to the graph that you’ll see in the publication that shows the discontinuations of treatment and the active arm with Tyvaso. So I guess I tried to point you to the INCREASE study as the better comparator than the BREEZE study. And then the second question was, but the second part of it was –?
Jason Zemansky: Was there something specific about these four patients? And like you said the titration schedule is a little bit more aggressive than what you normally see with Tyvaso. Is that when they dropped out or again, was there something about the dose that they received. I’m just curious if there was something consistent amongst the patients?
Eugene Sullivan: Oh, the actual dropouts from the study were not drug-related and nothing — no signal of a ability to titrate the drug or anything like that in the PH-ILD study.
Jason Zemansky: Got it. Okay. And then just kind of thinking more broadly, when thinking about TPIP’s potential in your guidance. How important is it that patients get to the 640 milligram or microgram dose or higher is the assumption that the drug will provide more benefit given the higher dose? Or is its value really in moving from four times daily to once-daily administration?
William Lewis: So I’ll just jump in on that one and then ask Gene to comment. I think what you hear from treating physicians is the higher they can go the better from their point of view. Indeed, when we first developed the drug and we’re working on the target product profile. We spent a lot of time with KOLs and asked them would they prefer a drug that had lower side effects and at a dose consistent with what’s already being used or a drug that had perhaps some side effects but could go up in quantity of drug administered and the universal response I quite enthusiastic was go as high as you can because that’s what we do with patients. We pushed them to max tolerated dose in practice. So we picked 640 micrograms for this study, which is 60% greater than what treprostinil is the equivalent of treprostinil.
It’s administered over four times and already. So it’s quite a substantial step up. The physicians are very encouraged by that. They’ve now encouraged us in the PAH setting to double that yet again, based on the safety profile that they’ve seen, and we consider that to be a ringing endorsement, not only of what we’ve been able to accomplish so far, but what the future may hold given some of the improvements we’ve seen in PVR just getting patients to 640. So I think there’s a lot of promise here for the clinical result that we expect to see from PAH as patients move from 640 to even higher levels. And that is a wonderful clinical objective that we have set for ourselves. And it’s a very high bar, but being able to get to higher doses should produce that result to be able to do it with a once-a-day administration is the benefit of convenience as well as the clinical side I just mentioned.
And the once-a-day piece was enough to get enthusiasm from treating physicians in and of its own right, even if the clinical profile is the same, the fact that we’re able to suggest we may be able to get even better clinical outcomes and have the once a day is really sort of the Holy Grail. We’re after why we think this will be on as some have said the potential go to a prostanoid of choice for the treatment of these patients. I don’t know, Gene, if you have other reflections.
Eugene Sullivan: Yeah, I mean, I just the only thing to add to that, Tom, first of all, the basic assumption with prostanoid in PAH is that the more you can get in the better and generally patients and doctors tolerate a little bit of prostanoid related side effects to kind of match the efficacy. I will say that there tends to be a spectrum of tolerability like some patients tend to get just get who are more sensitive to the prostanoid-related side effects and others. So if you look at a population of patients on Remodulin, for instance, there will be patients had lower or higher doses depending on their individual sensitivity to the prostanoid-related side effects. So I don’t necessarily think we need to get everyone up to the top dose.
It’s more a matter that there’s the ability to keep going up. If the patient is tolerating it, the ability to keep increasing the dose. And you have that ability with Remodulin to just to keep increasing the dose. With Tyvaso, because of the peak systemic exposure immediately after dosing, you kind of don’t you get up to the you titrate up to the target dose and then you stay there and you and label does not include continuing to dose escalate. I think that’s probably related to that, you know, the pharmacokinetic pattern. So because of our lung kinetics, we hope to be able to dose TPIP in a mannermore similar to the way IV treprostinil is dosed. In other words, you can continue to increase the dose according to the patient’s tolerability. We think that in addition to the once daily versus four times a day, that’s a great distinction.
But this is another distinction, you get the benefit of delivering the lung, the drug directly to the lung, but also the ability to titrate it in a manner that they do with the parenteral product interesting.
Operator: Your next question comes from Ritu Baral from TD Cowen.
Ritu Baral: Hi, guys, and thanks for squeezing me in and I apologize in advance. I still swear I hate biostatistics more than any of you, but often we did the analysis on WILLOW and ASPEN for brenso. Our statistical consultants basically said that it was the distribution of the data that mattered far more almost than the event rate. And then so looking back to the distribution constant between the arms and historical studies, we noted that WILLOW obviously had very low variance of 0.04 to 0.1 and historicals work in the 0.4 to 0.5 range have you been able to look at all at the ASPEN data and what distribution of data that has been seen either on time or at the very end because it does seem to make an important difference in power. And this is a quick follow-up.
William Lewis: Yeah, I hate to disappoint, Ritu, because I know the work that you’ve put into this and I appreciate the the I’m focused on this particular aspect of the dataset, but that’s not something we’ve talked about publicly other than to say, generally looking at everything in this study, we continue to feel very positive about what we’re seeing on it. No one variable controls, but you note there really is nothing in this study that has given us pause or alarm with regard to what the expected results will be. We’ll know it shortly enough, but I think we’ve seen remarkable consistency with WILLOW across many parameters, and that’s about as far as unfortunately, I can go.
Ritu Baral: Fair enough. Just on discontinuation rates and ASPEN can — have you tallied the final discontinuation rate, whether it stayed within expected parameters as per the last update?
William Lewis: Yeah, what we can say is that while we haven’t given any update with the final data, the with the vast majority of data already in, we’ve been indicating that the safety is as good or potentially even a little better than WILLOW. We’ll obviously see once we unblind by by various arms, et cetera. But the blended blinded data continues to look very favorable with regard to safety and just getting a lot of it.
Ritu Baral: Got it. And just one last in on the TPIP-ILD study, Eugene, I think you mentioned that cough was the main reasons to stop the titration upwards. Were there any other unusual symptoms that could be unique to TPIP that emerged either to impact titration or discontinuation?
William Lewis: Gene, you want to take the hit.
