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Welcome to the Quick Consult podcast brought to you by Medall. Before starting this podcast, please review the faculty information, disclosure statements and learning objectives using the link in the episode description. To claim your CME credit, complete the evaluation using the link in the episode description. This podcast is a continuing education activity managed and accredited by Current Concepts Institute in collaboration with Metall. This activity is supported by independent medical education grant from Bristol-Myers Squibb. Welcome back to the Pulmonary fibrosis Pathways Forum podcast series. I am your host, Doctor Phil McIlnay, and in this 2nd episode, we shift our focus to the exciting landscape of novel and emerging therapies for pulmonary fibrosis, and we are once again honored to be joined by Doctor Corey Kershaw. Doctor Kershaw, thank you so much for joining us again. Thanks, thanks again for having me today. The future of treatment involves multi pathway targeting. Could you briefly delineate some of the key molecular pathways driving pulmonary fibrosis, such as the LPA, LPAR1, with antagonists like uh Mil parent, uh, the phosphodiesterase 4B inhibitors such as neurondommolast, and the prostacyclin pathway, which includes analogs like inhaled, uh, tremrostenol and explain their relevance as therapeutic targets. I, I, I think an important Consideration in the beginning is, is knowing that the process from lung injury. To fibrosis is, there are multiple pathways often feeding on each other that lead to fibrosis. And because of that, it, it makes treatment often challenging. And when we do have approved therapies that get it one mechanism, you know, you'll, you'll note that patients still progress and it's because there are more ways to get to the end than just the one pathway you're addressing. So, in what we know happens is, is the lung is injured by some perhaps unknown mechanism or by whatever their secondary causes for other types of fibrosing ILD besides IPF. The lungs heal aberrantly and that is often mediated by multiple fibrosis signaling cytokine mechanisms including IL-13, IL-4. The TGF beta pathway is very important, so a lot of the treatments that have either been studied or have been approved. Um, help with moderating TGF beta's activity and promoting fibroblast differentiation into myofibroblasts. We refer to this as mesenchymal transformation. So you'll hear this term quite a bit of fibroblasts having undergoing a synchymal transformation to myofibroblasts which lead to collagen production, laying down of new collagen. And that process begins to snowball, but there are many other factors that, for, for example, inform TGF beta activity, and it, because of that, we have to get, get at the disease by multiple different mechanisms and so As we get into this, I really believe the future is going to be multiple medications at the same time. We haven't cracked that code just yet, but just by knowing that there are multiple different signaling mechanisms that lead to this mesenchymal transformation and perpetuate it informs us that We have to consider multiple options besides just the one that we're using right now. It's, it's been a challenge in, in, in the research arena of how to do this. But as we, as more treatments become available and we start to see that patients are on background therapy, we'll understand this a little more as we go along. Let's look at some of the emerging evidence. What is the mechanism of action for the phosphodiesterase 4B inhibitor neurondommolast, and what did we learn from the phase 3 trial data regarding its impact on FEC decline in IPF patients? So, you know, part of this key mechanism is this differentiation from fibroblasts into myofibroblasts. And one thing about neuronomallast and this phosphodiesterase 4B mechanism is that by um Enhancing that pathway, we can interfere with that differentiation. It's actually, they use the term differentiate the myofibroblast back into fibroblast. Um, and this is modulated by module, this is done by modulating that TGF beta pathway, um, is, you know, that helps. Helps the fibroblasts turn back into fibroblasts after they're already mild fibroblasts. So we know that about the phosphodatrise 4B pathway. Um, and if we can reverse that, we may help stop that collagen deposition process I mentioned before, and we saw that in some sort of early. In vivo, in vitro type trials with the fibroblasts in human lungs with IPF that we saw this differentiation, the myofibroblasts back into fibroblast M. If you do that, you turn off the signal that perpetuates it. So, cause once you start having fibrosis, you get profibrotic markers there. If we can reduce the expression of those, you, you tend to turn the army back, so to speak. The, the, the call to arms is turned away. So we don't continue to perpetuate the process and that's how we think Neuronommalas might work. Another promising avenue is Inhaled chrostinol, what are its proposed anti-fibrotic mechanisms and what are the latest trials like Tetum 2 suggest about its role in IPF care? So an interesting thing about fiber fibroblasts is they also have prostenoid receptors much like the endothelial cells do. And we, we know that prostenoids such as traprosinil in its inhaled form can exert these, uh, can invert, um, antifibrotic effects on these lung fibroblasts. Um. Uh, you'll hear a lot about cyclic AMP, um, the intracellular levels of cyclic AMP, and if we can increase those levels, which is something that prostenoids do, this may inhibit fibroblast proliferation by binding to these prostennoid receptors. We slow down myofibroblast differentiation, see, same mechanism we talked about, but we're getting at it in different ways. That really is the goal of all therapies is to find all the different ways that I can Stop this mesenchymal transformation. Inhale traprostenol does that by this increasing intracellular cyclic AMP inhibiting fibroblast proliferation via these prostennoid receptors on fibroblasts slowing down collagen synthesis. We suppress TGF beta production which happens as the fibroblasts proliferate, which perpetuates the fibrosis process. We turn that down. We stop the mezeymal transformation. And hopefully stop the fibrosis from perpetuating as it goes along. We've discussed the current antifibrotic drugs and, and how they have limitations, particularly with tolerability and adherence. From a strategic clinical perspective, why is targeting a novel mechanism like the LPA1 receptor and developing therapies that might be used as foundational or combination treatments, so vital for the future patient care? It, it really, it really gets to this point about. It's a common end result that is fed into um Different from different pathways. I, when I think about this, uh, you know, I've, I've used analogies, but I, I remember when I was a kid, I had a, you know, a globe, and I remember thinking of that there was a, on the globe, there was the Nile River Delta, you know, and you know, it's all these different branches of the river, but they all flow into the same thing at the end. And I've always, I don't know why that picture pops in my head, but it does when I think about The fibrosis pathway is that, you know, we start off with one route and then it branches into multiple different ways, but it all ends up in the same place at the end, you know, the Mediterranean for the Nile. Fibrosis for this pathway here. So we can't just block off one branch of the river and expect that we're not gonna then fill up the end result there. It just, it just probably will not work that way. There, there's so many great analogies in other disease states for this, you know, management of You know, somebody's heart failure, you know, management of someone's pulmonary hypertension, you know, we have all these wonderful analogs in medicine where we have a disease state. But there is not, it's not a one in one mechanism. Cancer therapy, you know, not a one in one. I have lung cancer, so I'm gonna give you this one drug that will fix your lung cancer. It, it, you know, it's, it's complicated in the human body. Lung fibrosis is the same way and we're, we're just, you know, as we learn more about the, the fact that the pathway has multiple different branches to lead to the end result, it would stand to reason that I have to have multiple interventions. To stop each one of the branch points to stop the end result. We just We haven't figured that out yet. Um, but I, I'm optimistic that, that, you know, there's so many different things out there in the pipeline that get it, different mechanisms. A lot of this is clinical trials design, the science is sound, but it's just a question of getting the, the right combination of things and the right timing and the right recruitment of patients.