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CHEST 2023 On Demand Pass
Future Directions in Pulmonary Fibrosis
Future Directions in Pulmonary Fibrosis
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Okay, good afternoon everyone. I'm Jeff Horowitz from the Ohio State University and it's a pleasure to be here today for our session entitled Future Directions in Pulmonary Fibrosis. Before we get started, I want to acknowledge somebody who's not here, Dr. Sidney Montese from Harvard helped me put together the lineup for the session today, but unfortunately she wasn't able to travel and so we had to change some things at the last minute. I'm also very happy to have Dr. Deji Adegosonye from University of Chicago up here as faculty and Dr. Teja Kulkarni from University of Alabama Birmingham will be coming in here at any moment now. She's in another session. So the title today is Future Directions in Pulmonary Fibrosis and I wanted to launch the talk today by giving an overview of where we've been with pulmonary fibrosis and set the stage for where we are now and where we're going to be going with our understanding of pulmonary fibrosis. I have nothing to disclose and my objectives are really to take a dive into history and provide a historical overview of interstitial lung disease and how our conceptual framework in the disease has evolved over time. Along the way I'll discuss some evolving theories on pathogenesis with an emphasis on idiopathic pulmonary fibrosis and highlight the iterative scientific process as it pertains to lung fibrosis. So to get started I'm going to take us all the way back to the initial report from Heyman and Rich. This is from 1935 and in this report they presented four patients with high confidence on the overall pathogenic mechanisms of what was a new process that had not previously been described. They presented four patients who ranged in age from 27 to 47 years old, all presented with a subacute onset of dyspnea that had been present for about two to four weeks. They had cough, fever, and 100% in-hospital mortality. From autopsy specimens they described widespread inflammation of what they have referred to as an unusual type because they were comparing it to bacterial pneumonia. They described epithelial cells that were enlarged and desquamated, a progressive proliferation of fibroblasts, which is language that has persisted in the lexicon even though it's not accurate all the way through today. They also described marked variation in spatial organization and pulmonary hypertension. They noted that the etiology was obscure. So in that first report from four cases there was an unknown cause of an unusual pattern that would later become usual, overwhelming inflammation, fibroblast proliferation, spatial heterogeneity, and pulmonary hypertension. Many of the features that we would still attribute to idiopathic pulmonary fibrosis in 2023. About a decade later they published another case. And this was an older patient, it was 68 years old, who had about four months of symptoms before presentation. But in this report they noted that the patient was thought to have heart failure. Again that sounds very similar to a lot of the patients that we see in clinic now. They described fine crepitant rows over both lower lobes, diffuse septal thickening, wandering cells, I'm not entirely sure what that was, but I suspect it might be alveolar macrophages, the accumulation of fibroblasts and collagen, neovascularization and angiogenesis, and hyaline membranes. About another 10 or 12 years later there was a publication, and this was extraordinary because it was a 67 page manuscript in which Rubin reviewed sequentially 39 previously published and 15 new cases of interstitial lung disease. Here they noted that there was a lot of variability in the pathology and that a lot of it differed from that that had been described in the Hayman and Rich report. The majority of cases had lesions that appeared to have been present for a number of years. They found a significant number of siblings who had the same disease. They described an unpredictable response to steroids and shrunken, cirrhotic looking lungs which gave the lung a honeycomb appearance. They speculated that there may be more than one cause, and this is just an image from that paper showing the honeycomb lung. We move forward another 12 years into sort of the first of the modern classification of interstitial lung disease from Lebo and Carrington. Here they described usual interstitial pneumonia because it was the most common pathology encountered of patients with interstitial diseases. And they relegated Hayman and Rich to an acute form of this usual interstitial pneumonia. In this manuscript they outline the importance of clinical radiographic and pathologic correlations that were found even at this point in patients. And I think they might have been a little optimistic when they cited that clues to the etiology and pathogenesis which are currently scanty will be forthcoming. Again, I think a little optimistic. That was 1969. In 1970, this was a case report in the Journal of the American Medical Association, and yes, let's think about that for a minute, JAMA presenting a single case report. But it was entitled Corticosteroid Treatment of Diffuse Interstitial Pulmonary Fibrosis, and in the introduction they described idiopathic interstitial pulmonary fibrosis as Hayman-Rich syndrome. And again, you can see that these different entities are continuing to be conflated. They went on to write that massive doses of corticosteroids may be useful in this disease if the initial response to treatment is disappointing. Now, here's the problem. That was a 24-year-old who was admitted to the hospital with one month of symptoms. So we can see that this is not the entity that we consider idiopathic pulmonary fibrosis, that it's all getting lumped together and conflated with each other. And I'll show the x-rays. These would not be the standard of care today, but the one on your left does not look like IPF. It looks more confluent and peripheral in manifestations, and certainly it did look better after getting steroids a year later. The pathology also is not what we would call UIP here, but it also improved. We move forward into 1975, and at this point there was an NIH conference or an NIH workshop led by Ron Kristol. The publication from that really focused on the role of inflammation in interstitial lung disease. But at this point, we start to really see the evolution into that thing that we recognize as idiopathic pulmonary fibrosis today. The average age or the average duration was 2.9 years between the onset of symptoms and diagnosis, or at least presentation for evaluation. And the mean survival was four years. So we still see numbers such as this associated with idiopathic pulmonary fibrosis. They also noted that there was no histologic difference between groups with IPF and IPF associated with collagen vascular disorders. But they also wrote that the evidence strongly suggests that therapeutic intervention should be directed towards stopping the inflammatory and immune responses rather than stopping the fibrotic process. I'm going to jump forward 25 years to 2000, the first ATS-ERS consensus statement on the diagnosis and treatment of idiopathic pulmonary fibrosis. They state that the treatment of IPF has been based on the concept that inflammation leads to injuring and fibrosis. And in the underlying and highlighted sections, they make the argument in their recommendations, there is no evidence of any effective treatment. But many experts recommend treating everyone. If therapy is to be offered, as many experts think it should be, it should be offered early in the course. And if you're going to offer therapy early in the course as recommended by many experts, those experts recommend combined therapy with steroids and other immunosuppression. What was the data that was based on? A number of very small trials that lacked placebos. They included mixed populations of ILD that were based on evolving classification syndromes. And in general, if you looked at the data from that time as summarized by Hal Collard and Talmadge King in 2002, there was about a 10% response to immunosuppressive therapy for patients with IPF. So there was a we-might-as-well-try attitude. And a lot of patients got immunosuppression and steroids. Well, 12 years later, we learned that we-might-as-well-try is maybe not the best way to go about treating patients. Because the PANTHER trial showed that patients treated with prednisone, azathioprine, and anacetylcysteine did worse and had increased risk of death and hospitalization than patients who got placebo. I remember Talmadge King making the statement that the more trials we do, the better placebo looks. But it wasn't all inflammation. If we go back between the 1970s, 1990s, into 2000s, there was an explosion of our understanding of cell and molecular biology as it pertained to a number of diseases, including fibrosis. Among them, growth factors were identified that could promote fibroblast proliferation. TGF-beta was identified as a critical contributor to lung fibrosis and fibrosis in other organs. And there was a shifting paradigm in which, instead of inflammation, fibrosis was thought to represent abnormal wound repair, mediated by growth factors and fibroblast. And so this was from 1998. It was a pathologic classification scheme proposed by Katzenstein and Myers. And we see here there's UIP, acute interstitial pneumonia is now what the original reports of Heyman-Rich syndrome were classified as. But the paradigm was that there was recurrent injury, followed by fibroblast proliferation, fibroblast activation, and collagen deposition. And then that cycle would continue until the patient died. This paradigm had no mention of inflammation. So then in the 2000s, we get into what is commonly thought of as the epithelial mesenchymal hypothesis. By this point, we were viewing interstitial lung diseases as a continuum of varying amounts of inflammation and fibrosis. We were also recognizing that there were a number of factors that went into the pathogenesis, including environmental factors, including genetics. Age was identified as a major risk factor for IPF, and with the still unknown etiologic agents. But the idea here is that there was a vicious cycle of injury and repair that was set up, wherein there would be epithelial injury, epithelial cell death. The damaged epithelium would secrete growth factors that caused fibroblasts to be activated, and the fibroblasts would not die, they were apoptosis resistant. And those fibroblasts that persisted in the lung would then secrete a bunch of things that would go back and increase the injury and death of the epithelial cells in a vicious cycle that would then perpetuate and account for the progression. At the same time, and for about the last 15 years and now, is what I'll call the matrix revolution. Because we learned that it wasn't just epithelial mesenchymal cells, but that the matrix served a purpose that was far more than serving as a scaffold on which all the other stuff happened. But the matrix itself was a primary driver of the epithelial and fibroblast phenotypes. We learned that it wasn't just the biomechanical or the biochemical composition of the matrix, but the actual biomechanics of the matrix could feed back and perpetuate fibroblast survival and epithelial cell damage. But what was also emerging is the idea of senescence and aging as a driver in lung fibrosis. And so in some beautiful papers from 2013 and recently updated in 2022, there was the description of what are considered the hallmarks of cellular aging. And I'm not going to go through them all, but the asterisks will show those that have been found in IPF fibroblasts and in IPF epithelial cells. So what we have now is a building level of complexity in how we conceptualize idiopathic pulmonary fibrosis. There's still epithelial injury, there's still fibroblast persistence, aberrant communications, all existing on a stiff, dynamic, and biologically active matrix. But aging of the cells, aging and senescence, seems to be the link between all of these phenotypes. So where are we now? I'd say it's complicated. I will call this the aging genetic epithelial mesenchymal inflammatory growth factor matrix hypothesis. We know there are risk factors. These risk factors tend to involve epithelial cell biology and aging biology, including telomerase mutations. Epithelial cells still demonstrate injury, apoptosis, but now we know that there's abnormal mucociliary clearance. We also have discovered that the alveolar type 2 cells get stuck in a transition to alveolar type 1 cells as part of the repair process. And the epithelial cells are senescent. The fibroblasts are still important and they're also senescent, but they demonstrate what's called a senescence-associated secretory phenotype, in which they will elaborate soluble mediators that can induce senescence in nearby cells. They're resistant to apoptosis, which is part of a senescence phenotype. They have impaired autophagy and proteostasis, so they don't turn over proteins appropriately. They deposit and remodel a biomechanically stiff extracellular matrix, and then there's impaired turnover, so the matrix, when it's synthesized, doesn't degrade the way that it should. Now that's happening in the context of many, many different growth factors, and one of our two approved antifibrotic drugs is not just a triple kinase inhibitor, as it's frequently billed as, but it inhibits an awful lot more kinases that are involved in growth factor signaling. But now inflammation is back in the picture, and we're finding abnormal macrophage and recruited monocyte phenotypes, abnormal T cells, abnormal B cells. Endothelium has never gotten a lot of attention, but it's never gone away, and there's kind of been a resurgence recently of hypotheses in biology related to endothelial cell dysfunction. And we're in the era of omics and big data and bioinformatics. We have transcriptomics, proteomics, metabolomics. That's right, the Krebs cycle is actually important in biology. Don't tell the med students. And to bring it full circle, I came across this letter in the Blue Journal a couple of weeks ago, spatial decoding of immune cell contribution to fibroblastic foci. And I'm not going to go into detail, but within the same pathologic sections, they find that there are cold fibroblastic foci that don't have evidence of inflammatory cells, and there are hot fibroblastic foci that have a lot of T cells around them. And when they do spatial transcriptomics, they find the cold spots look like fibrotic signatures, the hot spots look like inflammatory signatures, and I love their conclusions. The immune response may contribute to transition of normal repair processes to a fibrotic phenotype. Therefore, a more effective approach could utilize a combination of anti-fibrotic and anti-inflammatory agents. So we're back in the world of anti-inflammatory hypotheses in IPF. So what do I take home from all this? First of all, clinical observations can motivate important questions. And important questions can be difficult to answer. Knowledge builds, and our understanding evolves. That's a scientific process, and science is iterative and self-correcting. Complex disease is not a one-size-fits-all, and I don't think a single approach is going to be the answer to this complex disease. The next breakthroughs are probably just around the corner. When we think we know what the right answer is, we're frequently wrong, or at least only partially right. And because of that, we need to continue to support a diverse portfolio of ideas. Equipoise is essential. We can't be married to a hypothesis. And finally, crazy ideas can shift paradigms, and you may win a Nobel Prize for something that everybody thought was crazy. Finally, we need to keep moving forward. Our patience needed. We need to get better. And we are getting better. I love this figure from Onamora. He's six years old now. But it shows that the approved antifibrotic therapies are really just the tip of the iceberg. We have a very rich pipeline that's continuing to grow. And if nothing else, we've learned that we can do studies. We can do them well, and we can demonstrate changes and modification in the natural history of diseases that are killing our patients. I'll stop there. I want to thank you all very much. And I'm out of time, so we can take questions now, and then we can take some questions at the end. Thank you, Dr. Horvitz, for that lovely talk. It feels like I just got off a flight. That was a time capsule of the last 100 years. I'm D. Jerry Gunturi from the University of Chicago. I want to thank you all first for being here. I know it's Hawaii, so you should probably be out there in the beachside, in the cabana, in the Pina Coladas, but you're here, stuck with us, so thank you. I'll be talking briefly about genetic testing for diagnostics and therapeutics in pulmonary fibrosis. And my goal by the next 15 minutes is to present you with sort of a forward-looking perspective on where we think genetics is going to take us over the next few years. These are my disclosures, none of which are particularly relevant to the talk today. I'll start by reiterating what we understand fibrotic lung diseases to be. These are mostly parenchymal lung disorders that have architectural distortion, and oftentimes result in gas exchange impairments, which, as we might imagine, can also impair quality of life and life expectancy. The issue with the way it's currently categorized is the fact that many of these have overlying phenotypes, overlapping disease causes, overlapping outcomes, and that makes it incredibly difficult for us to tease apart disease diagnosis, but also when it comes to prognosis, to be accurate in what we tell our patients. Increasingly we are relying on biomarkers, specifically genomic markers or genetic biomarkers, to help us refine the accuracy of diagnosis, of prognosis, and more importantly in recent times, even pharmacotherapeutics. Why do we care, though? Well, it looks like there might be a surge, an increase in the rate at which allergies are being diagnosed, but more importantly in the outcomes from these ILDs. On the left-hand side is a nice study out of the University of Washington, Seattle, where they showed that the rates of mortality deaths from ILDs have increased over the last three decades. This is county-level data obtained from national databases. On the right-hand side you can see that these rates have actually increased, doubled, and in some cases tripled over the last 30 years. And so, can we do better using genetics? Well, it appears that using genetic markers we can identify those who are at risk of having pulmonary fibrosis and even the non-fibrotic forms of ILDs. On the left-hand side of your screen is a table, a short list of patients who have various forms of ILDs, but they have familial forms, so we call them familial pulmonary fibrosis, either one or more family members who have pulmonary fibrosis. The top part refers to those who have been identified to have telomere-related genes, so you see TERT and TERT polymorphisms there, and in total, these TERT or TERT or telomere-related gene variants account for about 25 percent of these familial kindred to pulmonary fibrosis. But beyond the telomere-related ones, we also have those that play a role in surfactants, so surfactant-related genes, which, as we know, help to preserve the alveolar integrity and preserve the function of the alveolar themselves. I'm not going to go into detail on the figure on the right, which you had from Dr. Horowitz earlier on, but again, we think that a lot of this culminates eventually in apoptosis and early cell semitens, particularly the type 2 alveolar cells, in addition to the fibroblasts which you heard about earlier on. But beyond these initial TERT-related genes and surfactant-related genes, there's a wide array of different genes and rare variants that can impact disease susceptibility, the risk for having pulmonary fibrosis, or even having detrimental outcomes from pulmonary fibrosis. It's a long list, which I wouldn't go through in detail, but this just goes to show that beyond idiopathic pulmonary fibrosis, the poster child for the fibroidic lung diseases, in HP, hypersensitive meningitis, connective tissue diseases like rheumatoid arthritis, you have gene variants that can increase the risk for developing ILD and even getting detrimental outcomes from this. But it's split by several factors, one of which is the low enrollment of minorities in many of the studies. All the GWAS studies I just showed you in the last couple of slides really had very low enrollment of minorities. So how then do we import the data that we get from these studies to apply that across board for the entire population? It becomes really hard to do that without enrolling minorities and other populations into the studies. So then, why should we do this? What are the benefits of testing early for genetic testing, either for diagnostic purposes or for prognostic or therapeutic purposes? Well, I'll start with the MUC5B, and again, I'm looking at this from the lens of biomarkers that matter, biomarkers that we can apply in practice eventually. So MUC5B is a gene that typically codes for the mucin 5B protein, which is very important for innate immunity and also helps with airway clearance. For those who have a single nucleotide polymorphism, the 5950 variant in the promoter region of the MUC5B gene, they have impaired airway clearance, they have impaired innate immunity, and they have an increased risk for developing pulmonary fibrosis. We saw this figure earlier on by Dr. Horowitz, where it suggests that the current conceptualization of how we think pulmonary fibrosis comes about is you have a trigger, either an autoimmune antibody or you have an inhaled antigen, that results in epithelial dysfunction and early senescence of the types of alveolar cells. That triggers a downstream process with cytokines that get released in the interstitial fibroblast proliferation, a term which Dr. Horowitz doesn't like, but we still use up to now, fibroblast to fibroblast transformation, and then matrix deposition in that interstitial space. All of these culminate in thickening of that single cell layer, the barrier between the alveoli and the capillary space, and of course, gas exchange impairment ensues, leading to hypoxia and downstream detrimental effects. But beyond MOC5B, which has been linked to diverse forms of pulmonary fibrosis, and IPF, and rheumatoid arthritis, and different forms of pulmonary fibrosis, there are other common and rare gene variants that play a role as well in disease susceptibility. The figure on the right shows the overlap between the different phenotypes of ILD, the different subtypes of pulmonary fibrosis, and how MOC5B, which plays a key role, is also accompanied by several other variants, many of them telomere-related gene variants that can increase susceptibility to pulmonary fibrosis. We talked about the surfactant-related genes earlier on, SPA through D, where SPA and D are responsible for alveolar cell function, and B and C help with integrity. But when you have mutations of variants in these genes, it leads to abnormal surfactant function. But I didn't mention TOLIP, which again seems to be very close on the genome to the MOC5B gene that we talked about. TOLIP codes for the TOL-like inflammatory protein, which again is very important for innate immunity. We now know that when patients have variants in the TOLIP gene, they can have not just impaired immunity, but also worse prognosis. On the right-hand side is data that shows that lung function decline and disease progression occurs more predominantly in those with the gene variant, the CT variants, the heterogeneous form, while those who have the TT variants have better outcomes, longer life expectancy, and are less likely to progress when it comes to disease progression. So how about the telomere-related genes? Well, telomeres, as we know, are the caps on the ends of our DNA that tend to protect chromosomal integrity. I think of them like the shoelaces that we have in our shoes, right? The caps on those shoelaces protect the shoelaces from defraying, from degrading. And the same thing with telomeres as well. They protect chromosomal ends from early degradation. When these genes mutate and we have variants in the genes or mutation occurs in them, well, we have problems with the enzyme, the telomeres complex, that really helps to protect the telomeres themselves. And there are eight different genes there, which I won't go into their function in detail, but these genes tend to protect the integrity of telomeres and the telomeres complex as well as the sheltering complex as well. So are there ways that we can identify those who are at risk of telomere shortening? What can we tell in a clinic? Who is more likely to have shorter telomeres or who is more likely to have telomere-related genes? Apparently, we can. So when we see patients in clinics, those who have early-onset gray hair, a shock of gray hair, before typically the age of 18 or 21, those who have unexplained liver cirrhosis, cryptogenic cirrhosis, unexplained bone marrow fibrosis or aplastic anemia, or even idiopathic fromocytopenia, skin cancers like basal cell or scremal cell cancer. These individuals are more likely to have telomere-related mutations or short telomeres, and we should be paying attention to them because it can make a difference, like I'll show you in the next couple of slides. So we now know that telomere length, based on data from the last eight to 10 years, can help refine the accuracy of diagnosis. Those with really short telomeres typically tend to have either a predisposition to familial interstitial pneumonias, idiopathic pulmonary fibrosis, or even the unclassifiable variety of pulmonary fibrosis. For those who have connective tissue disease or the HP variant, hypersensitive pneumonitis, they tend to have longer telomeres, not like the idiopathic variants or flavors of the pulmonary fibrosis subtypes. There's also data that tells us now, based on transcriptomic evidence, that we can also improve the way we diagnose patients based on lung tissue. The gene signatures in patients who have UIP variants have been studied extensively, such that we now have an approved intervention, a diagnostic tool, that can help us define those who have a UIP variant of pulmonary fibrosis, and after MDDs can result in an IPF or idiopathic pulmonary fibrosis form of ILDs. The NVSIA tool is now in common use. It's FDA-approved and reimbursed by CMMS, and we use it in practice to help improve that diagnosis of patients who we suspect have a UIP variant of pulmonary fibrosis, but do not know because the CT scan is suboptimal in determining that. How about using this transcriptomic data that we now know? Are there other ways we can refine that knowledge to improve our diagnosis or understanding of disease pathogenesis? In the last few years, we also have discovered the IPF cell atlas, which helps with discovery of novel cell types, the basaloid cell types, epithelial cells that are around the fibroblastic foci, which help to inform us about the pathogenesis of pulmonary fibrosis, how the disease develops, what cell types are more likely to be susceptible to novel therapies. So these really helps to outline the layout of, on a cell-by-cell basis, the layout of cells involved in disease pathogenesis, and helps us also identify potential therapeutic targets that we can leverage to improve outcomes in the disease. Going back again to TALiP, which I mentioned a moment ago, this is a study that was published a few years ago now where patients who had IPF, idiopathic pulmonary fibrosis, were genotyped for the TALiP gene. And the older Mitthal looked at this group of patients and performed genotype stratified Cox models. They stratified patients based on whether they had the TT genotype, the CT genotype, or the CC genotype for TALiP. For those who had the CC genotype, they had way worse outcomes when they were given N-acetylcysteine, prednisone, and isothioprene. For those with the heterogeneous CT genotype, there was no difference in their outcomes. And for those who had the TT genotype, they actually did better when they received N-acetylcysteine compared to placebo. Now, this data actually informs a national randomized clinical trial, the largest precision-based clinical trial in the field today. It's called the Precisions Trial, funded by the NIH, where patients can, based on the results of the trial, we can determine who's likely to benefit from N-acetylcysteine in the setting of IPF based on their genotype specifically. Chad Newton from UT Southwestern in Dallas also looked at their cohort, again, looking at this same panther cohort of patients who received prednisone, isothioprine, N-acetylcysteine. And they found in their retrospective analysis of patients at UT Southwestern that those who had IPF, who received N-acetylcysteine, appeared to do worse when they had telomeres below the 10th percentile. So specifically, critically shortened telomeres. Not just short telomeres, but those that were critically shortened. They then went ahead and looked retrospectively at the 2012 panther IPF cohort and found exactly the same thing. So it appeared that the high mortality rates seen in those who received triple therapy in the panther IPF trial was driven predominantly by the presence of critically short telomeres in that cohort. And so again, this begins to inform us how we can think about leveraging genetic or genomic markers in patients with idiopathic pulmonary fibrosis to impact their outcomes, impact the decision to start therapy, or impact prognostic decisions as well. But beyond IPF, looking at HP, hypersensitive telomeres, can we find exactly the same thing? Brett Lay out of UCSF looked at a large cohort of patients with fibrotic HP, and they genotyped them finding a high prevalence of telomere-related gene variants in these individuals. And of course, with telomere-related gene variants, they also found a high prevalence of shortened telomeres. We looked at this in a relatively larger cohort of patients, about 282 patients with fibrotic HP, and found that when you stratified the telomere length into quartiles, those who lay in the shortest quartile did not seem to get any benefit from institution of mycophenolate therapy. Now, I'll back up a little bit here to point out that in HP, we often leverage steroids or steroid-sparing agents to help reduce the detrimental outcomes that these patients have, right? I think about HP as a disease that, as lung doctors, we thoroughly hate, right? It's linked to all the good things of life. It's linked to birds, you love birds, you get bird-francias disease, you love music, bad piper's lungs, you like eating cheese, you love wine, winemaker's disease, hot tubs, spas, saunas, all the good things of life can lead to this disease. And so it's really sad that when we have patients that have this disease, we don't have great therapies for them, it's like those in a randomized clinical trial fashion, but can we decide who will benefit from steroids or steroid-sparing agents? Apparently, we might be able to do that using this knowledge that we just showed. In fact, in this much more recently published study just a few months ago, now in ARJ, we found that for those who had critically short in telomeres, below the 10th percentile, when they received immunosuppression with mycophenolate, they had a six-fold increase in mortality. So perhaps we should be thinking very carefully about instituting immunosuppressive therapy or immunomodulatory therapy to patients before we get more genomic markers that can be very specific. Can this also inform pre- and post-transplantation outcomes? Apparently, it can. So the time-to-CLAR, development of chronic lung allograft dysfunction, appears to be much more rapid in those with short telomeres as well. And this is data actually published in ISHLT, the JHLT as well, that shows that for those with short telomeres, they were more likely to be on multiple immunomodulatory therapies compared to those without. And it's not unusual, anecdotally in clinic, we typically see patients cycle through a variety of immunosuppressive therapies in the post-transplant setting before they find one that works really well for them. Are there other avenues that we can leverage this data? Apparently, yes. Telomere length shortening can predict early-onset bone marrow failure. It can predict immunodeficiency, neurologic disorders, early-onset liver cirrhosis, hepatocellular carcinoma, and a variety of other features. It's also helpful when we start to counsel patients in terms of what medications they can or cannot take. It helps us with prognostication for these libidos and also evaluating potential therapies in clinical trial settings. It has implications for progeny as well, the offspring of affected patients. They often want to know, are they at risk or not? And having these data at hand at the point of care can help us refine the counseling for patients affected. I put this up there to talk about it really briefly. This is recent data out of the European Restorative Society where a task force was given the responsibility of coming up with recommendations for those with familial interstitial pneumonia. So which patients should get genetic sequencing and which ones should not? Apparently, those who have familial ILD, like I mentioned earlier, with one or more family members with the disease, and those who have suspected telomere length shortening should probably be discussed within a shared decision-making fashion about the possibility of undergoing genetic sequencing, both for them and for their offspring as well. It also discussed the natural history of familial pulmonary fibrosis. We know that those who have this gene variant are more likely to have progression. But even without the presence of gene variants, for those with familial pulmonary fibrosis, they are more likely to have disease progression compared to others. What genes should we be testing? Now, that's a really big question because we don't know the full spectrum of gene variants that influence the disease. But in practice, based on whole exome sequencing, targeted sequencing of data, the GWAS studies we have, it appears that the telomere-related gene variants and surfactant-related genes are the most predominantly affected, the ones that have the higher minor audiofrequency or penetrance, in this case, that would impact susceptibility to the disease. Is there any evidence for this? Well, telomere length can support that diagnosis, can support the data obtained from telomere-related gene variant sequencing, as well as surfactant genotyping as well. And in pending the association in studies that show that common genetic variants like the MOG5B are really important to developing the disease and progression of the disease, there isn't any recommendation at this point in time to include them in genetic panels. These are really highly prevalent gene variants with very low penetrance. So in patients who are of European ancestry, typically the MOG5B is about 32 to 34% prevalent, even though in Asian and African populations, it's almost absent, rare to absent in those populations. And then what are the optimal treatments for patients who have familial interstitial pneumonia? It doesn't matter what they have. The subtype that they have is what should drive the disease. So if they have a diagnosis of IPF, we should be treating them like IPF in that case. If they have a diagnosis of progressive pulmonary fibrosis, they should be regarded as progressive pulmonary fibrosis and treated accordingly as well. And then which family members should we be sequencing for this disease? So those who have proven monogenic disease in whom they have telomere-related gene variants identified or other specific gene variants should be getting genetic sequencing. This is an algorithm that has been proposed in recent times as well, which we can adopt in practice here in the US, where we obtain very carefully a family history of fibrosis in all patients who have the disease. And then consider based on what I just told you, offering genetic testing to those who meet criteria. And this genetic testing should not go by itself. It should be accompanied by counseling as well because of the downstream ramifications of genetic testing in these individuals. I'll end with saying that all of this is not without careful thoughts. There are ethical ramifications that can impact widespread gene sequencing in patients with pulmonary fibrosis. And all of this should be carefully considered as we make that decision to genotype patients. There are concerns about privacy and de-identification of data, patient data. What patients are consenting to should be done in an informed fashion so they know the implications downstream. And then there is an emotional and psychological impact that also brings to bear on these patients as well. When we genotype patients, we often discover other variants that have other implications outside of the pulmonary fibrosis. And how this should be handled is actually a cause for debate as well. The data sharing in the context of collaborative studies, potential for misinterpreting these data, and an equitable access across board for all individuals is still not yet accessible here in the US. So in summary, I'll say that genetic testing can play a crucial role in predicting disease progression for patients with pulmonary fibrosis, and potentially can help us tailor treatment strategies for those with pulmonary fibrosis as well. The clinical adoption of not just telomere length measurement but also telomere related gene sequencing is on the rise, and it can help us inform treatment from a genetic perspective. And while genetic testing does have profound benefits, both therapeutic and diagnostic, it also presents us with several ethical challenges that should be addressed as well. Thank you, and we'll take questions. Thank you. I'm Teja Kulkarni, the director of the ILD program at the University of Alabama at Birmingham. And thank you again for being here for this exciting session. So following all the discussions on the understanding that we have now of pathogenesis, the role of genetic testing, I'm going to talk a little bit on the current and future treatments for pulmonary fibrosis and where things are right now. These are my disclosures. So idiopathic pulmonary fibrosis is what we talk about most often when it comes to pulmonary fibrosis, right? So it's a specific form of chronic progressive interstitial pneumonia that is of unknown cause. It primarily affects the older individual. It is characterized by a progressive worsening of this, and this is a figure from 2011, but it's still very applicable where we see that majority of our patients do have, it's a progressive disease and majority of their patients have declined in their lung function over time. Now what have we done for IPF? Now this is the chart, right? These are so many studies that we've done over years to look at therapeutic options for idiopathic pulmonary fibrosis, which has been the focus of discovery of therapeutic strategies. But what do we have? We have two drugs, two medications that have shown that they can slow down disease progression. They were still not there. They slowed down disease progression. And these were forfenadone and intradanib that were published in 2014. But since then, there were three other medications or therapeutic drugs that were evaluated and had positive phase two data, but unfortunately the phase three studies were terminated early due to futility. So what have we learned over time? There are several questions that come up. Why are we not able to discover drugs as our other fields? Why is it so difficult for idiopathic pulmonary fibrosis? Now some of the questions have been around our primary endpoint. Historically, if you look at the earlier studies, the primary endpoint was mortality and we soon realized that that would require a very large sample size to see the effect size that we would require to see if the drug actually works or not. And then over time, we have now settled down to look at the forced vital capacity and so change in forced vital capacity is the key primary endpoint that we look at. So what do we have currently for idiopathic pulmonary fibrosis? The two medications, intradanib and forfenadone, which were approved in 2014, both of them showed that it can slow down disease progression in patients with idiopathic pulmonary fibrosis by about half. It's about a 48% risk reduction that you can see with intradanib here compared to the placebo arm and with forfenadone, there was a decreased reduction in the proportion of patients who had a decline in FEC or death at 52 weeks. But now these medications do come with a lot of their side effects. A lot of our patients are older. They have several comorbidities and these medications, in addition, causing side effects make it intolerable. As we can see in practice, we have to either dose reduce, think about switching anti-fibrotic therapy, and in a small proportion of patients with IPF, they don't tolerate either of these medications. So with that in mind, what are we doing for that? Well, why do we have these challenges to drug development? One is therapeutic targets. There are many questions around what targets do we choose? And then therapeutic modalities, whether this is oral medication, do we look at subcutaneous or IV? And then combination therapies with the presence of, with having nitsdanibenforfinidone as therapeutic options, how do we combine them in treatments? Trial endpoints that we talked about, patient-related factors, acute exacerbations and biomarkers. So with therapeutic modalities, now oral medications oftentimes are what patients prefer, but then they also have, they're older, have reflux symptoms, and may have difficulties in taking tablets, which are bigger. When it comes to IV therapeutic options, some patients may not be able to come to the center, to a care center or an ILD center to be able to get these medications. And then with inhalational, there's always the question of, can our patients actually optimally utilize inhalational medications? What is the drug delivery? Can we achieve the PK we need with inhalational drugs? And then finally, the frequency of administration of these drugs. When it comes to combination, again with the approval of nitsdanibenforfinidone, this makes it challenging to design clinical trials. But we do have to incorporate these medications into our clinical trials. So then the other question is, can we combine these with the newer therapeutic options? Is it safe? What pathways should we combine? Is it just one pathway? I mean, and Dr. Horowitz went over this. We talked about the multiple different pathways that are involved in pulmonary fibrosis pathogenesis. So which of these pathways do we combine? Or what is the synergy between the different medications that we are evaluating? And then finally, drug-drug interactions and looking at the side effects. I mean, if you have already medications which cause a lot of side effects, then what is the new medication going to add on to this? So these are all questions that we have to think about. And then finally, how do we measure the efficacy when we already have two medications which are slowing down disease progression? What is the effect size that we would need to see for a newer medication to be approved? The other important factor that we don't often talk about or are difficult to measure are patient-related factors. The severity of clinical status. Now, often, if you look at any of the protocols for the clinical trials, majority of them only allow patients who have an FEC of greater than 40 to 45% or DLCO, which used to be much more, but now more. So we have finally settled down on accepting patients over DLCO more than 30%. But what about those patients who present to you with a much more severe disease state? Only one trial, really, the INSTAGE trial, had focused on enrolling these patients with severe impairment, but we have to take that into consideration. And then even after approval of the medication, if they do work, then what? If you've only included patients who have mild to moderate disease, what about the patients who present with severe disease? So can we expand eligibility criteria? How do we take into consideration the impact of comorbidities when we design our clinical trials? And then again, focusing on the side effects and the tolerability. We talked a little bit about the trial endpoints. Now, a desirable clinical endpoint for IPF, it needs to be reliable and valid, but also responsive to changes in the clinical or disease status. And we've settled on decline in FEC, and that's mainly because over time, we've observed from the placebo groups of the different clinical trials that these have provided insight into what is the decline of FEC in an IPF patient who is untreated compared to a healthy subject, and how much can we utilize? So typically, most of these patients who are not on therapy will have a decline of about 150 to 200 cc of FEC annually. And so incorporating that and thinking about the current antibiotic therapies to now make that into half, so we're now looking at about 80 to 100 cc decline in FEC. So how do we design the trial to show that effect size is something that we need to consider? And then quality of life questionnaires. That's another area that we have sort of overlooked. There's a lot of subjectivity to how these questionnaires are answered and how we can interpret that into our clinical trials and interpretation of the data. So thinking about how the patients feel and function rather than just looking at the physiology is another area that needs a lot more work when it comes to challenges of designing trials in IPF. And finally, the impact of acute exacerbations. There's a variable incidence rates of acute exacerbations that have been reported, but mostly it's in the five to 10% range if you look at a composite of several trials. But the risk of death increases tenfold with an acute exacerbation. So how do we utilize that within our trial endpoints is another area that needs work. And then finally, biomarkers. Now that's always a hot topic of discussion. The most realistic hope of decreasing the size of our phase two, phase three studies, reducing the timeframe on how long we're doing these trials is to develop a biomarker that is relevant to not just the mechanism of that novel agent, but to the disease process itself. But unfortunately, there's been a lack of any validated short-term tools. We can look at some circulating blood and molecular biomarkers. We've talked about genetic markers here that can be utilized. Some other markers like MMP7 have been looked at, but not validated enough to utilize these as trial endpoints at this stage. The other area that's really up and coming is to look at imaging biomarkers. Can we use HRCT scans? Can we calculate fibrotic scores? Is that enough? Or then, thinking about molecular imaging, there are, that can actually give you real-time data on the pathogenesis or the molecular level pathogenesis that can show a difference in either therapeutic treatment or drug engagement, as well as early therapeutic response, giving an early readout for trials. So, I think this is our favorite figure. All of us have really utilized this, and this is from a very elegantly written review article from 2018. But what you can see here is that since 2018 already, I've struck out some medications, some drugs that were in trial at that time, which have since, have shown futility, and we're now back to the drawing board on which medications to look at. I'm not gonna go into the details of pathogenesis since we've already discussed that, but what I wanna highlight is, yes, there are some that I've struck out, but also some that I've added on to this figure. So, it's a moving field. There's, yes, we've had several challenges that have come up, but also, we have learned from these challenges and are now looking at other therapeutic strategies that might be applicable for pulmonary fibrosis. So, what do we have in IPF and what's coming up in progressive fibrosing, ILD, as well? There are three, I'm gonna only focus on the three trials that are in the phase three currently. So, the first one is looking at inhaled troposinil. This was based on data from the INCREASE trial, which was a 16-week, randomized, double-blind placebo-controlled trial looking at, which included any patients with ILD and associated pulmonary hypertension. The intervention was inhaled troposinil, and 326 patients were included in the study. What I'm gonna talk about is more the post-hoc analysis. Now, the primary outcome was to look at the six-minute walk test, which improved, and improved exercise capacity was reported. But also, the main thing that led to the next phases of discovery with this medication is that the analysis of patients who had idiopathic pulmonary fibrosis showed that there were stabilization or a little bit improvement in the FEC, as we can see from this figure here. And that led to the design of the TETON trial, which is a randomized, double-blind placebo-controlled trial, which is a phase three. It's a 52-week study, which is currently enrolling. And then, also, will be looked at for patients who have progressive pulmonary fibrosis. The next trial that I wanna talk about is the preferential phosphodiesterase-4B inhibitor for idiopathic pulmonary fibrosis. Again, this is data from the phase two study, which was a 12-week randomized, double-blind placebo-controlled trial with patients who had IPF. Now, this was done a little bit differently, where they utilized a Bayesian approach according to the background therapy utilization or not, with anti-fibrotic therapy, which allowed them to do a smaller trial, 12 weeks, and also utilize data from the placebo arms from the previous trial. This was 147 patients that were enrolled in this study. And, as you can see, the primary outcome was changed from baseline in the FEC. And in both patients who were on background therapy and were not on background therapy, there was a probability that this medication, I'm not gonna read out the number, was superior to placebo. So, with that, the five REMEAR trials are phase three studies, randomized, double-blind, placebo-controlled trial, both for IPF and patients with progressive pulmonary fibrosis that is currently ongoing. And then, the last one, the other phase three trial that is getting on board, is to look at the BMS drug, which, again, from the, it was a 26-week, the phase two study was a 26-week RCT, which looked at patients with IPF. There were two doses that were looked at compared to placebo. And, again, in this study, background therapy with instandible profinidone were allowed and the primary outcome was to look at the rate of change in percent predicted FEC and the paper is not published yet, but 54% reduction in the rate of change in FEC compared to the placebo arm with the 60 milligram arm was noted. And so, with that, the ILOF trial is another phase three study that we'll be looking at both patients with IPF and non-IPF. And then, finally, talk a little bit about what's going on, but the future is also in adaptive trials. As we've learned from COVID and everything that has changed over the last few years is that we need to look beyond the traditional trials that we do. Now, if you look at all the previous fibrotic ILD trials, we've shown that they're all conventional parallel RCTs. They just, you know, evaluate a single investigational product. There is a pre-specified treatment arm, pre-specified sample size, but there are several of the problems that we've encountered over time and we've seen that changes are needed to the way we approach clinical trials. And so, that really has prompted consideration of an alternative study design, which, you know, Remap is one of those. This has been applied to community-acquired pneumonia, COVID, and we've seen that an adaptive platform trial may help us accelerate bringing therapeutic options to patients in clinic. So, what is Remap? It's a randomized trial, embedded, which really means that it is embedded as much as possible into our clinical practice, so that reduces the number of patient visits. It also allows for several more centers who don't have a full ILD or full set up to do clinical trials that would allow these centers to participate. It's multifactorial, meaning multiple drugs will be looked at simultaneously to see if we can achieve efficacy for any of these medications earlier than later. It's adaptive. As the trial progresses, we learn from the data that we're getting and we adapt the trial design and the sample size to reflect that. And finally, it's a platform. It's a huge platform that would be, the goal of that platform would be that as some medications are evaluated and whether they work or not, they either get into clinical practice or they come out of the trial if there's futility, and then new medications can get added onto that same platform. So, you're not going through the whole startup process and identifying multiple clinical trial sites and getting it all set up multiple times to look at multiple different medications. It's a platform that will allow for rapid development of newer therapies. So, again, when it comes to study measurements, we're still thinking about pulmonary function tests. There are considerations with the statistical team to see if we could perhaps do a more composite endpoint, not just focusing on FEC, but also utilizing mortality within this and looking at patient-reported outcome measures as well as adverse effect monitoring. So, this is an example of what the study design would look like. So, all patients with fibrotic ILD, if they meet the platform criteria, can enter the trial, and then there are different domains, meaning there's antifibrotic domain or there's senolytic domain, anti-inflammatory domain, and patients that qualify for each of these domains can be randomized to multiple therapeutic arms. So, one patient may actually be doing two trials simultaneously there as well, and as the trial goes on, you look at the primary endpoint, see if they meet the secondary endpoints as well, either if it is superior, then it comes into clinical practice, and that would be up to us as clinicians on how we interpret that data and bring it into clinical practice. So, finally, with that, I want to say again, IPF is a complex disease that is driven by multiple pathways. Given that it is, you know, the effect of the approved drugs is, at best, modest, we need to think about how can we refine the preclinical models, even before bringing it into the clinical trial phase, but think about how we combine drug trials and redefine trial endpoints. And then, most importantly, I mean, a lot of other areas like cancer have done this, and precision medicine is the now and the future, so how can we apply that into our trials for fibrotic lung diseases is something we need to think about. So, development of biomarkers, looking at genotypes and phenotyping the disease process would be crucial, but nonetheless, I think we have data from several early phase trials which provide hope that there might be a new wave of antifibrotic therapy that will come to the clinic in the near future, and so, you know, the question is can we move beyond just slowing down the disease progression to actually saying, well, we can now reverse this disease. So, that's the future. With that, I'd like to thank you, and we'll take any questions. Thank you.
Video Summary
In this video, the presenters discuss the current understanding of pulmonary fibrosis and the future directions in treatment. They discuss the history and evolution of the understanding of the disease, highlighting key findings from past studies and clinical trials. They emphasize the challenges in drug development and discuss the two currently approved medications, intradermal and perfenidone, which have been shown to slow down disease progression. However, they acknowledge that these medications can have side effects and may not be well tolerated by all patients. They also discuss the potential for combination therapy and the need for further research in this area. The presenters then outline ongoing phase three clinical trials for new medications, including inhaled treprostinol, a phosphodiesterase-4 inhibitor, and a BMS drug. They also highlight the importance of patient-related factors in trial design, such as disease severity, comorbidities, and tolerability, and discuss the use of adaptive platform trials to accelerate the development of new therapies. Finally, they touch on the potential for biomarkers and genotyping to inform treatment decisions and personalize therapy for patients. Overall, the presenters stress the need for continued research and innovation in the field of pulmonary fibrosis to improve treatment options and outcomes for patients.
Meta Tag
Category
Diffuse Lung Disease
Session ID
1104
Speaker
Ayodeji Adegunsoye
Speaker
Jeffrey Horowitz
Speaker
Isabel Mira-Avendano
Speaker
Sydney Montesi
Track
Diffuse Lung Disease
Keywords
pulmonary fibrosis
future directions in treatment
clinical trials
approved medications
side effects
combination therapy
phase three clinical trials
patient-related factors
biomarkers
personalize therapy
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