All right. All right, everyone, thanks. Been a long and busy day, a fun day, a lot of learnings, and I know we're all getting a little tired, but this is going to be an exciting one, I promise. Dr. Berger just laid out the clinical reality of IPF. Approved antifibrotics slow decline, but don't stop it, and tolerability limits how many patients can stay on therapy. The landscape is shifting fast with new oral agents and an FDA decision expected next April on nebulized treprostinil and IPF. We have two CEOs attacking this from different angles. Mike Castagna of MannKind, which brings inhaled delivery expertise and a stake in the treprostinil story, and Ahmed Mousa of Vicore, which is testing a first-in-class AT2 receptor agonist. Why don't we do a two minutes each introduction? Yeah, Ahmed, maybe you want to go first?
Great. Yeah. Thank you, Andreas, and thank you all for being here. My name's Ahmed Mousa. I'm CEO of Vicore Pharma. As Andreas mentioned, Vicore is working on advancing a program called buloxibutid for idiopathic pulmonary fibrosis. We have a mechanism that's unique in the landscape. We go after epithelial repair. Damage to the epithelium is, in our view, the first step of the disease, and attacking the disease from that perspective we think can be very fruitful, both independently in terms of a therapeutic approach, as well as then combining with other types of approaches. We're currently running a large phase II-B trial.
It's almost 400 patients, and actually, we're looking at the impact of our drug on lung function over 52 weeks, so same setup as a phase III trial in combination with available standard of care, as well as for patients who decide for different reasons not to take the standard of care, or who've tried the standard of care and couldn't tolerate it and discontinued therapy. Our large phase II-B trial follows a really nice phase II-A signal, where over 36 weeks, we actually showed that buloxibutid was able to improve lung function. A small open label trial, but nonetheless a really nice initial signal of clinical efficacy.
And we think that's a nice precedent to then our ongoing phase II-B trial, which should hopefully be a great reflection that we can have a good drug with good safety and tolerability, as well as something that can be really impactful from a therapeutic perspective in the landscape.
And just remind us when do we get that readout?
Mid-next year. The trial completed enrollment in late April, and we're looking forward to reporting results—
Okay.
Yeah, in the summer.
Around the corner.
Yes.
Mike, how about you?
Thank you for having us.
Yeah.
My name is Mike Castagna. I am CEO of MannKind. We are an inhalation platform company. We have been around 35 years. We have several FDA-approved products, inhaled insulin. We have inhaled TYVASO DPI, and one of the reasons we are here today is our inhaled nintedanib that we are working on. That is just going into phase II. We expect that to be about 140 patients testing two doses, and that will be in about 12 or 13 countries, depending on the U.S. FDA, and looking forward to today.
Yeah, great. We will just segue into a one. Nintedanib dry powder inhaler showed safety and tolerability in the phase I-B INFLO-1 study, and the global phase II INFLO-2 is enrolling. Oral nintedanib's GI side effects limit use. How much of the efficacy can you preserve while avoiding the safety, and when does INFLO-2 read out? Thank you. Yeah.
So far, I think we've dosed 60, 70 patients between healthy volunteers and IPF patients. We've seen no inclination of diarrhea. We've seen no discontinuations for cough, nothing for tolerability. That's over multiple doses over seven days in single day studies. But so far, things look pretty good, which gave us the confidence to go in here into phase II. That's fair. So I think feel pretty good about the tolerability side effect profile. I think the question is going to be efficacy, and I think with the TYVASO TETON readouts plus pirfenidone, we've now shown two times we can deliver drugs into the lungs and get an effect size. So we're pretty excited that hopefully this will be the trifecta here showing that lung-targeted therapies can make a difference in these patients.
I know we don't want to harp too much on DPI as we're diversifying away from that.
It's still important to us.
It's still important. So I'm just going to ask one question on the nebulized TYVASO and IPF. MannKind earns royalties on DPI. What has to happen for the DPI to get an IPF label, and how should investors model the potential upside from that?
Yeah, I think when you met the FDA, I think you mentioned about the mechanism of action. I think the FDA is still conservative when it comes to PAH versus IPF because we really don't know how these drugs work. We don't know the depositions, right? We don't know what happens in a fibrotic lung over time. My guess is just like they told us, you're going to have to do a phase III. You couldn't just do a PK/PD study or early phase II. My guess is there'll be some efficacy type trial required, and that's what we expect. Now, the question I have is, if we get good efficacy like in IPF, could you extrapolate to PPF, or do you really have to waste your time doing two trials?
I think the good news is where the FDA is probably getting away with one trial is better than two. I think that's good. Now the question is, what's the effect size you're building this trial for, and what does that look like?
Yeah, maybe we can bring Kristin to that, the IPF to PPF translation and data.
How do you feel? Do you necessarily need to see PPF studies?
Well, I would never say no to another study, though, that being said. If we have to go based on our working data, I think we can. I wouldn't want to withhold treatment and obviously get people started as soon as possible on things that we think would work. I think, in terms of inhaled vasodilator therapy, again, for the PPF, especially those patients with the autoimmune diseases that put them at risk of the pulmonary hypertension, I think it's reasonable to presume that it would have a good benefit in those individuals as well.
Great. You guys, too, feel free if you have any questions. We'll keep the dialogue flowing here. Ahmed, ASPIRE completed enrollment ahead of schedule in April.
Yeah.
You talked about this, more than 360 patients across 14 countries. Testing buloxibutid. Is it buloxibutid?
Buloxibutid.
Buloxibutid. 50 mg and 100 mg twice daily versus placebo over 52 weeks with top line results in mid 2027. What FVC effect would you consider a win, and how do you interpret results in patients on background nintedanib and pirfenidone versus monotherapy?
Yeah, absolutely. In terms of what we believe this landscape needs, and I think this is really consistent with a number of the clinicians and KOLs in the landscape, and that's where we take our cues from, along with the patients, is really better tolerated therapy. I think that's the starting point, right? Pirfenidone, nintedanib, and even nerandomilast pose tolerability challenges, GI side effects, as Michael mentioned, associated with nintedanib that we're trying to clear from the landscape. I think that with a well-tolerated therapy, the actually bar from an efficacy perspective is relatively low, unfortunately. We think that the starting point for efficacy is probably something that's nerandomilast-like, 65 mg, 70 mg difference in lung function from placebo. And of course, as you're able to show effect building from there, that becomes all the more attractive within the landscape.
That's what we see as the starting point from a win and going up from there.
Dr. Berger, what do you think? Is that fair assessment on what you would think consider a win in a phase II?
I 100% agree. Anything that's going to be more tolerable from a side effect profile is not going to have that added issue with the gastrointestinal side effect burden is going to be really helpful. Even with the nerandomilast, that's better tolerated, but we're not 100% there. I think anything that is a different class action would be very helpful, yeah.
Ahmed, you describe ASPIRE as a registrational quality data set. Could it support filing or is a phase III required regardless?
No, we think phase III would be required thereafter, certainly in the base case, yeah.
Just one more follow-up for you here. ERS data linked AT2 activation to MMP-13 and fibrosis resolution.
Yes.
Is buloxibutid, I've got to get this one, potentially regenerative rather than just slowing decline?
Yeah, I think that there are a few m echanistic pieces of the puzzle that really support that this could be a very interesting mechanism of action. As I'd mentioned, this disease starts really with injury to the epithelial compartment, the kind of lining in the air sacs, and in particular, the stem cell that highly expresses the receptor that we're activating, the alveolar epithelial type II cells. These cells essentially come into a senescent or an injured state, and we believe we bring them out of that state and drive a replenishment, repopulation of that cell type. We think that can have a big impact on the disease. That's certainly one thing we've seen preclinically evidence of. Now, of course, we'll have to see how that bears out over time in the clinic. In addition to that, this is a mechanism that we believe can drive resolution of fibrosis.
It's what this process is designed to do. In that, we see upregulation of enzymes called collagenase matrix metalloproteinases, including, as you referenced, Andreas, MMP-13. Essentially, these matrix metalloproteinases are designed to digest existing fibrotic matrix, i.e., a response system to that pro-fibrotic drive that comes beforehand. What's really nice to see is actually we see that signal in our clinical phase II-A trial with an upregulated level of MMP-13, that collagenase matrix metalloproteinase. What's also nice to see is there are other MMPs that are not collagenases that are more associated with disease progression, like MMP-7, and we don't see upregulated levels of those MMPs. I think we have some interesting signals on both the preclinical and clinical side, and we'll have to see how it bears out in the larger clinical trial next year.
Great. Okay. We'll turn to some controversies here for Mike here. Roughly 60% of Q2 revenue came from United Therapeutics royalties and manufacturing. Afrezza sales fell 7% year-over-year despite years of investment. Now that the pediatric label's approved, what does success look like for Afrezza, and how do you reduce dependence on a single partner?
How do we reduce what?
Dependence on the single partner.
Yeah. Last year we purchased scPharmaceuticals to diversify into heart failure. I think that's been a great acquisition. It's delivered on all the expectations and cost savings. That product just launched at the end of the quarter, so we only had a week of sales, roughly. I think as you get to Q4, you'll see an inflection for FUROSCIX ReadyFlow. So that's really exciting.
Yeah.
I think on Afrezza, one of the things we did this year is we took away half the sales force effort on adult and put it on nephrology to help boost the FUROSCIX trajectory. That definitely took away some of the momentum you saw in adults. The ped side is doing very well in terms of we've already surpassed our adult market share in 90 days after 10 years on the market in adults. I think when you look where peds is going, it does look like it's going to be far more accepted than the adult market, and we're excited about that. I think overall, the company's on the growth trajectory that it will continue to diversify its revenue streams.
The good news is with this United Therapeutics settlement last week, TYVASO DPI is probably going to return back to accelerated growth, and so they're both going to be growing next year, and so it should be a pretty exciting time for MannKind, and that's going to fund our pipeline here on the nintedanib as well.
The stock should be up. I don't know what people are doing. They're sleeping on this thing.
Well, everyone here at the conference knows that, so that's good.
When they freaked out about the TreSMI situation. Anyway, whatever. It takes time for some rational thinking, I guess. Maybe just elaborate quickly on FUROSCIX because I think that ReadyFlow is a meaningful differentiator and that just became approved late September. How do you see the back half of the year going for FUROSCIX, and what insights can you provide on the conversion from the on-body infuser?
Yeah. I would tell you in the first three weeks of launch, 90% of new prescriptions come in are already for the auto-injector. That converted way faster than we expected, which has tremendous benefit to the patient, to the provider. We are excited about that. That means the on-body infuser will be there for another year. It seems like the market has voted what they prefer, which is an auto-injector in 10 seconds. Convenience usually wins in markets and it is good to see that here. We will look to figure out how we can accelerate growth going into 2027, and I think Q4 should be a pretty strong quarter for FUROSCIX.
All right. Fantastic. Ahmed, the phase II-A AIR data that underpinned ASPIRE came from a single arm open label study, and investors have learned to be cautious about uncontrolled FVC data in IPF. Heard this probably millions of times. Why should we believe the signal is real? And with, how do we say this one? Nerandom?
Nerandomilast.
Nerandomilast.
Nerandomilast. Thank you. Inhaled treprostinil and other agents arriving, is there room for another oral add-on?
Yeah. So maybe the second part of your question first, I think there is still plenty of room in the market. This is a fatal disease, unfortunately, three to five-year survival, and we still have the need for better-tolerated therapies, as Dr. Berger mentioned, as well as more efficacious therapies. We still have this limited slowing of decline of lung function and also a desire to really deploy combination therapy. I think some of these more poorly tolerated therapies actually might sunset if we can bring subsequent to them better-tolerated therapies based on KOL and patient feedback that we have heard. Now, on your question of this phase II-A signal that we observed, I would actually say there should be, of course, always caution around interpreting open label data sets. But I would say that is actually not been the biggest challenge in IPF.
I think what we've seen is short-term small data sets have often not translated out in longer term studies, i.e., companies have shown, I have a 12-week impact on lung function, and then when you look at 24 or 52 weeks, it doesn't pan out. In many cases, that can be because inflammation and fibrosis are interrelated, and when you show an impact on FVC over 12 weeks, that might be an anti-inflammatory dominant mechanism, whereas that might not sustain as you come out to 24 and 52 weeks.
I would say one of the really nice features of the phase II-A trial that we ran, it was actually a 36-week trial, and it shows not only that you're able to stabilize, but ultimately in the observed data set, improve lung function, but also it shows that more sustained effect rather than a quick shot anti-inflammatory effect, which is different than the mechanism that we have. That's not something we'd expect, but it's nice to see that in the ultimate data set. I think that certainly the point that the study's open label is definitely noted, and we'll have to see what the exact effect size is in our ongoing phase II-B trial.
But what I would take from the phase II-A is that there's this really nice signal of clinical activity that's consistent with the mechanism of action, and it's nice to see it sustained over that longer period of time.
Okay, great. So back to this idea of inhaled versus oral. In a disease where patients are older and often on multiple drugs, which route wins long term and is the future combination therapy? I mean, we talked about this, Dr. Berger. Maybe for people who weren't attending, you could just chime in on that.
Yeah. No, I think the future is definitely combination therapy. Correct me if I'm wrong, the phase II-B allows for background JASCAYD as well, right?
Yes.
Which I think moving forward, I think if our goal is to eventually get to a point where payers will pay for JASCAYD upfront as opposing to have to prove that you've failed either of the other two, which is the kind of situation we're in right now when we're prescribing currently. Hopefully we'll get to a point where we can do JASCAYD, so I think having that as the initial startup for most people and having that as allowing for the background therapy and demonstrating efficacy on top of that medication in particular would be really a boon to that study, I think.
Sure. Mike and Ahmed, you guys agree as well, right?
Yeah. We're excited. Even if you look at our trial, we're allowing JASCAYD, we're allowing TYVASO nebulizer in the trial, pirfenidone, and only when you can't be on nintedanib because you tried it and failed, but that's okay.
But I think these are critical, and even the TETON-1 and 2 data really showed you combination use was greater than monotherapy of TYVASO. So I think we remain pretty excited, and we got three shots on goal here with IPF. We got the ralinepag, we got TYVASO DPI.
[inaudible]
And we got nintedanib. So we're excited that all three of those drugs hopefully work, but at least two out of three better. Hopefully one's nintedanib. But I think combination use and more tolerable therapies are definitely the bar. One interesting fact I heard Martine talk about at the grand opening of the factory the other day was her lung AI model predicting a potential up to 150 ml delta in ralinepag in what she's predicting, which is twice as good as what we're seeing.
For the inhaled version.
Yeah, what she put in her lung AI model. Yeah.
Yeah.
That could be a meaningful delta in our—
What other color do we have on that program?
With what?
With the ralinepag DPI.
RALDPI, she's calling it?
Yeah.
Yeah. She's got a new name for it, GenRALD. It's now called GenRALD officially, is what Martine named it. We're excited about that program, and that should be in humans hopefully by the end of this year, and in phase II for IPF late next year. That's some of what we heard on the chatter at.
Lots of potential upside.
It's an exciting time.
Yeah, look, certainly our phase II-B is a study where the majority of patients are coming in on background therapy, nintedanib, nerandomilast. We certainly think there's room for both oral and inhaled therapies. We like our oral positioning. At the same time, you could certainly imagine, for example, that many patients in our trial are on oral nintedanib. If an inhaled nintedanib plays out that is ultimately able to be better tolerated, it'd certainly make a lot of sense to combine our oral drug with an inhaled type of approach as well. I think that makes a ton of sense.
Okay. Yep.
The MNKD-701, just to give a little bit of background on the timeline for that. Are you worried about the to an IO or?
We're going back to the heart failure space, right? Just to be clear.
Yeah.
I think that one obviously will not be combination therapies. We think that that's really single use cases over five to seven days will work. I think what we're seeing play out in the real-life marketplace over last year is that the nasal bumetanide just is not having the same efficacy as IV furosemide. Several customers have used and tried that product, and they said the patient wound up in the hospital or wind up back on our product. We feel pretty good about the efficacy of the equivalent of IV Lasix at home, whether it's own body infuser or the auto-injector. We're doing some market assessments right now before we start making the millions of dollars of investment on bumetanide inhale. We got the FDA clearance to proceed.
We have a clear pathway to market on it, and I think it's just there waiting for us to make the decision, and we won't rush into it, but we'll be ready to start that trial if we find there's an unmet need we can solve. Right now, I'm having a hard time seeing the unmet need relative to what ReadyFlow gives us.
Any other questions from the audience? No. Maybe a quick financial picture for each company. Mike, you want to go ahead?
Sure. We invested in two launches this year, as well as a phase II trial for nintedanib. It's been a big year from an investment perspective, but overall, the company has cash to fund our innovation and fund our growth. We can become profitable next year if that's our goal, and we don't need to raise money. We're in a good spot financially and a good spot from a pipeline diversification platform. We feel pretty good about the optionality around the company, whether that's partnered with United Therapeutics, our own assets, or our in-line assets that are growing. The company's in major growth mode.
And it's never looked brighter, but the stock is still down.
Stock's never been lower and its future never looked brighter. So go figure, guys. I don't know.
Ahmed, yours?
Yeah. Also quite happy with our financial position. We have sufficient capital to finish our impactful phase II-B study, as well as a year of cash runway thereafter. Also recently, we're a legacy or historically European-listed company, also completed a dual listing over the summer as we kind of increasingly get more U.S. institutional investor audience in the stock as well.
Okay, great. Well, look, I appreciate you guys joining. Dr. Berger as well for attending this. I had you double-booked or whatever. You were supposed to just do the KOL segment, but we appreciate you joining this. With that, we will conclude and thanks, everyone. Hopefully, it has been a good conference so far, and we, I think, have two more sessions. One more, and then we have the big one, AI. A big one at 3:00 P.M. on the topic of AI and biotech, which I recommend everyone joining. There is going to be a lot of learning there. Thanks, everyone. Appreciate it.
Thank you.
Thanks, Andre.