Company Panel: Idiopathic Pulmonary Fibrosis & Chronic Respiratory Disease: Antifibrotics, Bronchiectasis & COPD Innovation - MANNKIND CORP

all right um all right everyone thanks uh we're you know been a long and busy day a fun day a lot of learnings and i know we're all getting a little tired but uh this is going to be an exciting one i i promise um so dr dr berger just laid out the clinic the clinical reality of ipf approved anti-fibroids slow decline but don't stop it uh intolerability 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 trypanosomal and IPF. We have two CEOs attacking this from different angles. Mike Castagna of Mankind, which brings inhaled delivery expertise and a stake in the trypanostomal story. And Ahmed Moussa of Vicor, which is testing a first-in-class AT2 receptor agonist. Why don't we do kind of like a two minutes each introduction. Yeah, Ahmed, do you want to go first? Great, yeah. Thank you, Andreas, and thank you all for being here. My name is Ahmed Moussam, CEO of Vicor Pharma. As Andreas mentioned, Vicor is working on advancing a program called Bloxybutad for idiopathic pulmonary fibrosis. We have a mechanism that's unique in the landscape. We go after epithelial repair. Damage to the epitheliom is, in our view, the first step of the disease. And so attacking the disease from that perspective, we think, can be very fruitful, both independently in terms of, you know, a therapeutic approach, as well as then combining with other types of approaches. We're currently running a large phase two 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 kind of phase three 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 two B trial follows a really nice phase two A signal, where over 36 weeks we actually showed that biloxibutid 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 2b 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 we get that readout. Mid-next year. So the trial's completed enrollment in late April, and we're looking forward to reporting results yeah in the summer around the corner yes Mike thank you for having us my name is Mike Castagna I'm CEO mankind we are an inhalation platform company we've been around 35 years we have several FDA approved products inhaled insulin we have inhaled Taveso DPI and one reason you're here today is our inhaled the tetanus that we're working on that's just going into phase two we expect that to be about 140 patients testing two doses and that'll be in about 12 or 13 countries depending on the U.S. FDA and I look forward to today. Yeah, great. So we'll just segue into 201. So nantetinib dry powder inhaler showed safety and tolerability in the phase 1B inflow 1 study. In the global phase 2, inflow 2 is enrolling. Oral nantetinib's GI side effects limit use. How much of the efficacy can you preserve while avoiding the safety? And when does inflow to readout 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 see no discontinuations for cough no nothing for tolerability so that's over multiple doses over seven days and single day studies but so far things look pretty good which gave us the confidence to go in here in the phase 2 so that that's right so I think feel pretty good about the tolerability side side-effect profile. I think the question is going to be efficacy, and I think with the Iveso-Teton readouts plus rofenadone, 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 BPI as we're diversifying away from that. It's still important to us. It's a little important. So I'm just going to ask one question on the nebulized Tybeso and IPF. Mankind 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 don't – I think you mentioned about 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. And so my guess is, just like they told us, you know, you're going to have to do a phase three. You couldn't just do a PK, PD study or a phase two. So my guess would be some efficacy-type trial required, and that's what we expect. Now, the question I have is, if we get good efficacy, like an IPF, could you extrapolate the PPF? Would 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. So I think that's good. Now the question is, what's the effect size you're building this trial for? What does that look like? Yeah, I mean, we can bring Chris into that. The IPF to PPF translation data, how do you feel? Do you necessarily need to see PPF studies? Well, I would never say no to another study. Now that being said, you know, 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. And 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. And you guys, feel free if you have any questions. We'll keep the dialogue flowing here. So Amit, so Aspire completed enrollment ahead of schedule in April. Yeah. You talked about this. More than 360 patients across 14 countries testing biloxibuted. 50 mg and 100 mg twice daily versus placebo over 52 weeks with top line resetted in mid-27. What FVC effect would you consider a win, and how do you interpret results in patients on background and tetanib and random alas versus monotherapy? Yeah, absolutely. So in terms of what we believe this landscape needs, and I think this is really consistent with a number of the clinicians in KOL's landscape, and that's where we take our cues from along with the patients, is really better tolerated therapy. So I think that's the starting point, right? Perfinadone, nintetinib, and even narendemolast pose tolerability challenges, GI side effects, as Michael mentioned, associated with nintentinib that we're trying to clear from the landscape. So 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 near-endemolast-like, 65, 70 mils 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. So that's kind of what we see as the starting points from a win and going kind of up from there. Dr. Berger, what do you think? is that fair fair assessment on what you would i think consider a win in a phase two i 100 agree anything that's going to be more tolerable from a side effect profile is um not going to have that added issue with the gastrointestinal side effect burden is going to be really helpful so um even with the narendra molasses that's better tolerated but we're not 100 there so i think anything that a different class action would be very helpful yeah Great. And Ahmed, you describe Aspire as a registrational quality data set. Could it support filing, or is a Phase III required regardless? No, we think a Phase 3 would be required thereafter, certainly in the base case, yeah. And then just one more follow-up for you here. So ERS data linked AT2 activation to MP13 and fibrosis resolution. Yes. Is biloxibutid potentially regenerative rather than just showing a slowing decline? Yeah, I think that there are a few mechanistic 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 epithelia type 2 cells. and 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, re-proliferation of that cell type, and we think that can have a big impact on the disease. So that's certainly one thing we've seen preclinically evidence of, and 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. And in that, we see upregulation of enzymes called collagenase matrix metalloproteinases, including, as you referenced, Andreas, MMP13. And essentially, these matrix metallproteinase are designed to digest existing fibrotic matrix, i.e., a response system to that pro-fibrotic drive that comes beforehand. And what's really nice to see is actually we see that signal in our clinical phase 2A trial with an upregulated level of MMP 13, that collagenase metrics metalloprotonase. And what's also nice to see is there are other MMPs that are not collagenases that are more associated with disease progression, like MMP7, and we don't see upregulated levels of those MMP. So I think we have some interesting signals on both kind of the preclinical and clinical side, and will have to see how it bears out in the larger clinical trial next year. Great. Okay. We'll turn to some controversies here. From Mike here, so roughly 60% of Q2 revenue came from United Therapeutics royalties and manufacturing. AFRISA sales fell 7% year-over-year despite years of investment. Now that the pediatric label is approved, what does success look like for AFRISE and how do you reduce dependence on a single partner? How do I reduce what? Dependence on the single partner. Yeah. I think last year we purchased SC Pharma 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. So I think as you get to Q4, you'll see an inflection for Fero6 and the ReadyFlow. So that's really exciting. I think one of the things we did this year is we took away half the Salesforce effort on adult and put it on nephrology to help boost the FeroX trajectory. And that definitely took away some of the momentum we saw in adults. But the PEDS side is doing very well in terms of we've already surpassed our adult market share in 90 days after 10 years in the market in adults and so. And then 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. So I think overall the companies on the growth trajectory, that it will continue to diversify its revenue streams. But the good news is, with this United Therapeutic Settlement last week, Tybasu DPI is probably going to return back to accelerated growth. So they're both going to be growing next year, so it should be a pretty exciting time for mankind, and that's going to fund our pipeline here on the Tetanib. The stock should be up. I don't know what people are doing. I mean, they're sleeping on this thing. Well, everyone here at the conference knows that, so that's good. When they freaked out about the Tresme situation, situation and now whatever it takes time to there's some rational thinking I guess but maybe just elaborate quickly on for o6 because I think that ready flow is a meaningful differentiator and you know that just became approved late September so how do you see the back half of the year going or for o six and what insights can you provide in the conversion from the on-body theater yeah So I tell you, in the first three weeks of launch, 90% of new prescriptions come in already for the auto-injector. So that converted way faster than we expected, which has a tremendous benefit to the patient, to the provider. And so we're excited about that. That means the on-body infuser will be there for another year. But it seems like the market has voted what they prefer, which is an auto-enjector in 10 seconds. So convenience usually wins in markets, and it's good to see that here. We will look to, you know, figure out how we can accelerate growth going into 27. I think Q4 should be a pretty strong quarter for P06. All right, fantastic. Ahmed, the phase 2 air data, phase 2A air data that underpin Aspire came from a single arm open label study, and investors have learned to be cautious about uncontrolled FEC data in IPF. I've heard this probably millions of times. Why should we believe that signal is real? And with, how do we say this one? Neurandamilast? Neuradamilatst, thank you. Inhaled tryprosinol 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's 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, right? Like, I think some of these more poorly tolerated therapies actually might sunset if we can, you know, bring subsequent to them better tolerated, better tolerative therapies based on, you now, KOL and patient feedback that we've, we've heard. Now, on your question of kind of this phase 2A signal that we observed, I'd actually say, you kno, right, there should be, of course, always caution around interpreting open label data sets, but I would say that's 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 FBC 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. So I would say one of the really nice features of the phase 2a trial that we ran, which is a 36-week trial, and it shows not only that you're able to kind of stabilize, but ultimately in the observed data set improve lung function, but also it shows that more sustained effect rather than kind of a quick shot anti-inflammatory effect, which is different than the mechanism that we have. So that's not something we'd expect, but it's nice to see that in the ultimate data set. I think that, you know, 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 2B trial. But what I would take from the phase 2A 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 um 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 maybe we talked about this but maybe for people who weren't attending you could just chime in on that yeah i think the future is definitely combination therapy And currently, if I'm wrong, the 2B allows for background JASCADE as well, right? Which I think moving forward, I think if our goal is to eventually get to a point where payers will pay for JAScade upfront as opposing to have to prove that you failed either of the other two, which is the kind of situation we're in right now when we're prescribing currently. But hopefully, we'll get to the point where we can do JAScade. And so I think having that as the initial startup for most people and having that as allowing for the background therapy and kind of demonstrating efficacy on top of that medication in particular would be really a boon to that study. I'm sure Mike and you guys agree as well, right? Yeah, I mean, we're excited. Even if you look at our trial, we're allowing GESCAID, we're allowed Tyveso nebulizer in the trial, profanadone, the only one you can't be honest with, you could have tried it and failed, but that's okay. But I think these are critical. Even the T-TOM1 and 2 data really showed you combination use was greater than monotherapy of Tyvesos. So I think we remain pretty excited. And we got three shots on goal here with IPF. We got the Relenopeg, we got Tybicidipi, and we got Natetnib. So we're excited that all three of those drugs hopefully work, but at least two out of three better. Hopefully one's Natetinib. 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 long AI model predicting a potential up to 150 ml delta in the line of peg in what she's predicting, which is twice as good as what we're seeing. For the inhale, right? Yeah, what she put in her long A model, yeah. So that could be a meaningful delta. What other color do we have on that program? The what? The real line of pig, DPI. RAL DPI, she's calling it? Yeah, yeah, yeah? She's got a new name for it, General D. So it's now called General D officially, is what Martin named it. So, we're excited about that program, and that should be in humans, hopefully, by the end of this year, and in phase two for IPF, late next year. So, that's some of what we heard on the chat. Lots of potential upside. It's an exciting time. Yeah, look, I mean, you know, certainly our phase 2b is a study where the majority of patients are coming in on background therapy, nintetinib, nirendamilast. We certainly think, you now, there's room for both oral and inhaled therapies. like our oral positioning at the same time you know you could certainly imagine for example many patients in our trial are on oral nintetinib if you know an inhaled nintatinib plays out that is ultimately able to be better tolerated it certainly make a lot of sense to combine our oral drug with it with an inhaler type of with an inhale type of approach as well so I think that makes a ton of sense okay So we're going back to the heart failure space, right? Just to be clear. So I think that one obviously will not be combination therapies, right, so we think that that's really single-use cases over five to seven days of work. I think what we're seeing play out in the real-life marketplace over the last year is that the nasal bubentonide just is not having the same efficacy as IV furosemide, And so several customers have used and tried that product, and they said the patient wound up in the hospital and wound up back on our product. And so 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. And so I think we're doing some market assessments right now before we start making the millions of dollars of investment on Bumet and Idenhale. But we got the FDA clearance to proceed. We have a clear pathway to market on it. And so, 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? Maybe a quick financial picture for each company. Mike, do you want to go ahead? Sure. We invested in two launches this year as well as a phase two trial for Natetnib. So 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 so we don't need to raise money. So we're in a good spot financially and a good spots in our pipeline diversification platform. So we feel pretty good about the optionality around the company, whether that's partnered with United Therapeutics, our own assets, or in-line assets that are growing. The company's in a major growth mode. It's never looked brighter, but the stock has slowed down. The stock's never been lower, and the future has never looked brighter, so go figure, guys. I don't know. Yeah, also quite happy with our financial position. We have sufficient capital to finish our impactful Phase 2 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. I was supposed to just do the KOL segment, but we appreciate you joining this. And with that, we'll conclude. And thanks, everyone. Hopefully, it's 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 three o'clock on the topic of AI and biotech, which I recommend everyone joining. There'll be a lot of learning there. So thanks, everyone. Appreciate it. Thank you. Thanks, Andre.