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Hello, everyone. Today, I will be speaking to you about emerging therapies in pulmonary fibrosis care for 2025. Um, these are my disclosures available to you. And this is our assignment today, our learning objectives, and I'll leave those up for just a second. So, we move on to the next part of our discussion with Mr. Rice. Um, after we have discussed all of the FDA approved options to treat IPF, including the possible side effects and expected outcomes, Mr. Weis, Mr. Rice is overwhelmed by all of this. We will discuss side effects here in more detail as part of the talk, but let's assume we've already discussed those with Mr. Rice. He's really overwhelmed. He asked, is there anything else we can do? What about research trials available to me? Well, In 2025, this is a very exciting time um to be an ILD specific pulmonologist. Um. Because we have a really good understanding of all the possible mechanisms, um, that fibrosis both occurs and progresses that offers the opportunity for multiple therapeutic targets. This is just some examples here. We have, um, targeting the epithelial signal that starts the fibrosis cascade. We have macrophage signals that are potentiators of the fibrosis. We have these mesenchymal signal targets. Um, that help with the fibrosis, of the, uh, fibroblast to myofibroblast transformation that's more later or distal in the fibrotic cascade. This affords multiple opportunities for research and future clinical trials. Some of the medicines that I have lines crossed out there, these are medicines that have been studied already and did not progress past the phase 2 or phase 3 to approval because they were a negative study. So I'm gonna talk about some of these emerging therapies today. So the first one focuses on the lysophosphatidic acid pathway. Lysophosphatidic acid mediates the fibroblast migration into the alveolar space in patients with IPF. Um, if you take mice that have a knockout of, um, the, uh, lysophosphatidic acid receptor. Um, that was protective of having uh bleomycin lung injury in a mouse knockout model. So if we could somehow antagonize these lysophoshaidic acid receptors, this, um, uh, affords an opportunity to slow the fibrosis pathway. So indeed, There is one of those available for research right now that is um admilparin. Admilparin is an LPA1 receptor antagonist and in a phase two study, as you can see here on the right, it slowed the progression of vital capacity loss in a cohort of IPF as well as a separate cohort of progressive polyno fibrosis. This will be a recurring theme because The, the progression is parallel to patients with IPF. The mechanism is also theoretically, probably very similar also, as I showed in one of my earlier slides of the mechanism. Therefore, most of these, um, Emerging therapies both have trials for IPF as well as progressive pulmonary fibrosis. Because of this, uh, improvement in the rate of progression of FEC loss, um, Admilparin moved on to a phase 3 study. That phase 3 trial is ongoing for both cohorts right now, drawing to a close. So we should have results for, um, the Admilparent study probably in the next 12 months or so. So stay tuned for that. Hopefully, we'll have, uh, good news coming from the album of parent study when it closes. Um, inhale, uh, reprostinil. Traprostinil is a prostacyclin analog. Trostinil is a well-known medication to those of us who manage pulmonary hypertension because it's uh, a pulmonary artery vasodilator. It has used both systemically, uh, from an IV or subcutaneous form to treat pulmonary hypertension. There is an oral form of terrosinil and there is an inhaled form of traprosinil. Um, in a trial called Increase, there was, um, this increase was a study of patients with, uh, lung disease associated pulmonary hypertension. This is a real source of trouble for many of us who take care of these patients because most of the medications to treat pulmonary hypertension exclude patients who have lung disease because there's some contraindications with vasodilation, the pulmonary artery side that could actually result in paradoxical worsening of hypoxemia. So it's difficult to use these systemic therapies to treat pulmonary hypertension when it's due to lung disease. You could actually make the patient worse. Inhaled therapies have have been of interest because then you're not delivering the medicine systemically. You're giving it at the alveter level. So perhaps this is, this could just help patients where they're ventilating and help their pulmonary hypertension without worsening their hypoxemia. So this was a trial to do that. Um, and indeed it turned out that it was a positive trial. Patients with PH from, um, lung disease, they had improved systemic walk time. So we now have another option to, we have actually the first option to treat pulmonary hypertension. associated with lung disease. But there's some unusual features of these process cyclin analogs. They actually have distinct antifibrotic properties, um, via inhibition of the TGF, uh, TGF beta pathway that stimulates collagen production from these fibroblasts. There's also some extracellular remodeling, um, that's done that reduces fibrocytes entering these sites of vascular remodeling. So, in addition to its vasodilator effects, perhaps it could also help fibrosis and in a A subset analysis published in 2021. We actually showed that patients who had ILD had an improvement in their vital capacity in this pulmonary hypertension trial. So this was, this was huge news when this happened, and because of that, There has been a dedicated trial to use inhaled tprosinil to treat the fibrosis itself. So this is the Titon study. So Titon is enrolling patients who have a force body capacity of greater than 45%. If they were, they were, uh, they're allowed to be on background therapy as most of these trials will. And, um, you know, you know, appropriate diagnosis of IPF and a recent HRCT. Um, there are two trials ongoing for TO. There's TO 1 and TO 2 for IPF, and the TO 2 study, which were all the patients outside of the United States and Canada. This data was presented at the European Respiratory Society meeting in September of 2025, and it was a positive study. So it showed that patients that were randomized to inhale traprostinil versus placebo had a slowing of their, um, their body capacity loss at 52 weeks. This was very, very exciting. The Ton one study is also drawing to a close, so we should have those results soon. As I said before, there's actually a Ton PPF arm to treat patients who have progressive pulmonary fibrosis with inhaled traprosinil. So stay tuned for that. We should have those results soon. But right now, we're sort of getting a signal that we may have another medication coming for us soon, that being inhaled traprosinil to treat um idiopathic pulmonary fibrosis if the Teton 1 bears out the way Teton 2 did. Um, what else is coming? Well, there are multiple things in phase two trials going on right here. I'm not going to read this list, but this is just an example. These are 8 phase two trials that are either ongoing or drawn to a close and maybe moving to phase 3, but all of these were positive studies. So, um, either ongoing or the ones that were completed were positive studies. So, as I said before, this is a very exciting time to be involved in taking care of patients with fibrosing lung diseases because The research is moving so quickly. There are many therapeutic targets as we saw earlier and some very smart people in the industry are working on the research to find appropriate targets to try to slow down the fibrosis process. So hopefully there'll be even more options available to patients um down the road as research continues.