Jeff Hung: And then can you talk about the brensocatib commercial readiness activities that you’ve undertaken so far? And what additional activities are still expected before the data readout next year?
William Lewis: Yes. So on the brenso front, the team has just done exceptional work. And this is medical education. It’s preparing the market access story so that we can educate the market access world. I mean, we’ve got a lot of lessons learned from a first in disease launch that we’re applying for bronchiectasis because again, this like NTM is a disease that has nothing approved to treat it. So there’s some upfront work we want to do. I think if you benchmark us against any best-in-class effort for drug launch, the efforts that we’re making now and the maturity of those efforts and the success of those efforts as seen at recent congresses by the interest level of the medical community are really just top shelf. And they’re very early.
We are getting underway with this work well over a year in advance of when we expect we’d be filing. So that is a pretty good timeline to be out in front of all this. So I’m really happy with what we’ve done so far. I expect that we will continue this effort, and you will continue to see, at the congresses, the significant interest in bronchiectasis and potential treatments.
Sara Bonstein: And I would just remind folks of the synergies between our commercial product ARIKAYCE and brensocatib as you think about the call and the relationships that we have already in the NTM community with the pulmonologists and ID docs. Many of those same prescribers would be assuming success on ASPEN. So just the synergies from an infrastructure perspective are tremendous.
William Lewis: And the efforts are underway and the hiring plan is already locked down. We know exactly what we’re going to do and trigger it off of data down to the day.
Operator: And your next question comes from the line of Jason Zemansky with Bank of America.
Jason Zemansky: Congrats on both the quarter and the data. In terms of TPIP, if I may, the response is, it sounds like there was a bit of a range here. Granted, it’s still early, but I was hoping you could speculate a little bit on what are some of the key drivers here? I mean is it dose exposure? Or do you think this is more patient-based in terms of, I don’t know, where they are in their disease progression or fundamental level of lung esterases. What I’m trying to get at is, to what extent do you think that moving to higher doses will collectively push responses up?
William Lewis: So I think the short answer to the question is that dose response curve is already well established for treprostinil. And so by going higher in dose, we would expect greater effect; simple as that. The challenge with that historically is the side effect profile. And if you look at the actual PK/PD profile of treprostinil in its earlier approved forms, there’s a very high peak and then it collapses very, very quickly, and that’s why it’s redosed over and over again. And that’s an attempt to stay above the therapeutic index and provide benefit to patients. There isn’t any nighttime coverage, and there are similar limitations as you try to go up, that peak gets higher and higher, and that’s really the origin of the side effect profile that is the most troublesome.
What is interesting about our drug is the peak is substantially lower even though you’re administering much more drug. And so the peak as it comes down, it’s a slow release formulation is the way to think about it. And as a result, you stay above the therapeutic index for up to 24 hours. So you’re getting, as I was describing earlier, a kind of constant infusion of the drug, I would think that will over time and with more patients actually reduce the variability. But these patients do have a lot of variants if you look at other studies and history. But the variance we really see is more around 6-minute walk, and I want to just point out an example. There’s one of the patients that we know. We don’t know whether they’re on drug or not that has a different medical condition that is going to impact their 6-minute walk test because it creates a hip problem for them.
And as a consequence, their 6-minute walk test is going to go down. Now I don’t know whether they’re on drug or not, but I do know that, that has nothing to do with the drug. And so that’s the kind of confounding factor for these patients who are very sick with a terminal disease that is going to make it very difficult to read through. And I think that’s historically why 6-minute walk has been such an intense debate for its benefit — predictive capability in these patients. What is not in question in my mind are things that are hemodynamic changes where you know what’s taking place there with higher confidence is a byproduct of the drug. And that’s why we’re seeing these dramatic reductions in PVR, which you would expect if you just extrapolate the dose impact from other forms of treprostinil.
You would assume that there would be better PVR reduction and indeed, that’s what we’re seeing. I mean if it turns out that the alignment between those who are showing a response is consistent with those who are on drug, that 47% reduction in PVR is without precedent. And that is what is really exciting, and I think it’s what’s got the KOLs and the steering committee so encouraged.
Jason Zemansky: And then maybe a quick one on ARIKAYCE. You highlighted that you’re in a growth phase certainly looks like it. But what are some of the remaining levers out there in terms of the refractory setting? And how sustainable do you think they are? Well, I think we continue to show growth. We think there are many more patients out there. So that’s not our concern. The thing that people have to remember is that there is a variable utilization of the drug in terms of duration of use. And so in a sense, after patients have had success with the drug, there will come a time when they’ll stop using it. And so you’re replenishing that patient population on a regular basis as patients come off. Now there’s a — we’ve noticed that there’s a decent percentage of those patients who are coming back on because they get reinfected.
But that’s really the dynamic that’s at play is that some of these patients are going to stop using the drug. And so it’s a kind of acute chronic therapy, if that makes sense.
Operator: And your next question comes from the line of Joseph Schwartz with Leerink Partners.
Joseph Schwartz: We’ve heard that seasonality can play a role in promoting some bronchitis exacerbations. And so given you’ve looked at and shared some of your blended blinded exacerbation data for ASPEN, I was wondering if you have any insight you can share on the seasonality patterns for patients before and after they entered the study? And do you have any sense whether patients who had exacerbations historically during a certain time of the year, have been able to live exacerbation-free during these difficult periods based on blinded data from ASPEN? And then I have a follow-up.
William Lewis: Yes. So the seasonality question is always a tricky one because it’s not a clear pattern that is going to apply to everybody. And remember that the trial is designed with both north and south geographies and across the globe so that you get different seasons, if you will, and that necessarily will mute any effect of any one particular area if, in fact, it’s on display. I think what gives us the greatest comfort and certainly, what we’ve heard from the KOLs is the fact that we require patients to have 2 or more exacerbations in order to get into the trial, documented in the last 12 months. And that means regardless of what seasonality they’re experiencing, this is a 12-month study, you’re going to see events, and that’s what we need in order for the drug to show its effect.
