BIO from the BAYOU: Build Your Biotech Network with Key Opinion Leaders and Investors
28 May 2024 · 23 min
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In this episode of Bio from the Bayou, host Dr. Elaine Hamm interviews Dr. Victor Thannickal, the Harry B. Greenberg Chair at Tulane University, about idiopathic pulmonary fibrosis (IPF). Dr. Thannickal explains that IPF is an age‑related disease characterized by progressive scarring of lung tissue, presenting with subtle symptoms such as non‑productive cough, exertional dyspnea, and fatigue, often mistaken for normal aging. Diagnosis relies on high‑resolution CT imaging, multidisciplinary discussion (MDD) of clinical, radiologic, and pathologic data, and occasionally surgical lung biopsy; biomarkers are still under investigation. The treatment landscape has shifted from decades of immunosuppressive regimens (prednisone, azathioprine, N‑acetylcysteine) to two FDA‑approved antifibrotic drugs (pirfenidone and nintedanib), which slow disease progression but have notable side effects and do not cure IPF. Dr. Thannickal highlights molecular drivers—TGF‑β signaling, NOX4‑generated reactive oxygen species, and fibroblast activation—as central to fibrosis. He describes ongoing therapeutic efforts: a phase‑2 trial of a NOX4 inhibitor (nearly complete enrollment of 60 patients), repurposing metformin to target metabolic and mitochondrial pathways, and exploring pharmacogenomic subsets for N‑acetylcysteine. The discussion expands to inter‑organ fibrosis, noting common pathways across lung, heart, liver, and brain, and the importance of aging biology. Dr. Thannickal outlines extensive collaborations within Tulane (immunology, nephrology, bioengineering, aging center) and external partnerships with industry, the Pulmonary Fibrosis Foundation, and the Innovation Institute to protect IP and advance commercialization. The episode concludes with an invitation to meet at BIO International and promotes the Bio from the Bayou platform and Gulf Coast biotech community.
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I'm James Zanewicz, the Chief Business Officer for the Tulane School of Medicine.
And I'm Dr. Elaine Hamm, the Executive in Residence for the Tulane School And this is Bio from the Bayou. Hi, and welcome back to Bio from the Bayou. I'm your host, Dr. Yelaine Ham, the executive in residence at the Tulane School of Medicine. And today's guest is Dr. Victor Thanakul. He is the Harry B. Greenberg Chair of the John W. Deming Department of Medicine and a professor at Tulane University School of Medicine. His research is focused on cellular and molecular mechanisms of lung repair and regeneration. He's here to talk with us today about his research on idiopathic pulmonary fibrosis, or much easier to say, IPF, a disease that causes intense breathing difficulties and where the cause is yet to be clear. But his research aims to help provide those answers that could one day develop solutions to this devastating disease. So, welcome to the show, Victor.
Thank you very much, Elaine. It's great to be with you, and I'm always happy to talk about IPF and our research and where we are going.
Well, great. Well, before we dive into that, help me understand pulmonary fibrosis. So pulmonary fibrosis is marked by progressive damage leading to permanent scarring of the lung tissue, which obviously can result in death. But before we jump into your research, can you talk a little bit about idiopathic pulmonary fibrosis or IPF in general? What is it?
Yeah, so happy to do that. IPF is a disease first and foremost of aging. So as our population in the United States and worldwide advances in age, the prevalence and incidence of this disease will also increase. That's an important point to keep in mind. In terms of the clinical presentation, most of these patients present in their mid-60s. The symptoms are somewhat subtle. They're usually nonproductive cough, progressive dyspnea on exertion, or what we refer to as shortness of breath with exertion. So if you've taken a walk or— Going to the mall and you can walk several hundred feet without shortness of breath, and then all of a sudden you find that's getting a little harder to do. That's one of the presenting symptoms. And just generalized fatigue. A lot of people don't get diagnosed with this because they attribute a lot of the symptoms to just aging. And so we miss a lot of these cases of IPF because— A lot of patients just disregard it and don't go seeking medical attention for it.
Are there— I mean, because there are a lot of symptoms that correlate with typical signs of aging as well as cardiopulmonary issues, how do doctors distinguish between normal progression of aging versus something more serious of IPF?
Yeah, it's a great question. So most of the current approach to diagnosis is really based on imaging of the chest. Obviously, Getting a good history from the patient as to any type of exposures that might contribute to the risk of developing the scarring condition in the lung, which is really what fibrosis is. There are certain connective tissue diseases, systemic collagen vascular disease is another term for it, that can also cause scarring in the lung. And so all of those types of questions in terms of exposures to Drugs, organic, inorganic dust in the workplace, and any other concomitant diseases, rheumatological diseases in particular, like scleroderma or rheumatoid arthritis. You need to elicit that from the history, and then on physical examination, you can pick up what are these distinct lung sounds on auscultation of the lung, which are referred to as rales or Velcro-like rales. And that allows us to clue into more advanced imaging. And the gold standard nowadays is the high-resolution CT scan that'll give us a characteristic pattern on the CT that will allow us to more definitively look for patterns that we refer to in the medical field as usual interstitial pneumonia, UIP.
Right.
And that sometimes, if it's not very clear, you may need to go on to a biopsy. A surgical lung biopsy is often used, but less used now since we've gotten better with imaging technology.
So currently, imaging is the more definitive way to diagnose, but are there any biomarkers on the horizon that are being investigated to perhaps better determine before having to get to something as Definitely complicated as biopsy, but as expensive as CT, or are we just not there yet?
Yeah, it's a great question. And just to be clear on my point about imaging, I want to make patients and providers, make them aware of the latest and best way to diagnose this condition, which requires a multidisciplinary discussion, or what we call an MDD, between clinicians, pathologists, radiologists, to look at all of the available data that history, the physical exam, the laboratory findings, the pathology, if they'll eventually go into biopsy, and the high-resolution CT scanning findings. And together, this discussion among the experts will allow us to get a more accurate diagnosis. So there really isn't a gold standard per se.
Sure.
It really is an iterative discussion That allows us to make the most accurate diagnosis.
Makes sense. Well, so how has the treatment of the disease progressed, and are there really a lot of shortcomings in terms of our current knowledge and, and the ability to treat it?
Yeah, so this is where I think we've made some great strides over the last decade or so. It was almost exactly a decade ago, in 2014, that there were 2 drugs approved by the FDA for IPF, perphenadone and nintedanib. And before that, for decades, particularly in the late 1990s, early 2000s, where across the world, the standard treatment for IPF was immunosuppressive agents, prednisone and other immunosuppressive agents.
Sure.
And I think where we have made tremendous progress is actually an effort through the NIH where we were part at Tulane and other institutions around the country participated in the Idiopathic Pulmonary Fibrosis Network, where we recruited patients and performed the very first placebo-controlled randomized study of immunosuppressive agents versus placebo, which had not been done before. And surprisingly, in the patients that were treated with standard of care at that time, which was this 3-drug regimen of prednisone, azathioprine, and N-acetylcysteine, those patients actually did worse. So they had higher rates of hospitalization and death in the treated arm. So that was a real paradigm shift in the field of IPF because for the first time we realized that this wasn't a steroid or immunosuppressive regimen-responsive disease process that it required something more specific to target fibrosis. And that's where we are today. We need to do better, I think, than the current FDA-approved drugs, which do slow down the rate of progression of this disease, but it doesn't cure the disease. And there are some significant side effects from both of these drugs and a high discontinuation rate, anywhere from 20 to 30% of patients just can't tolerate the drugs because of the side effects.
Wow.
And that's where we and others around the country, where we're studying the disease at a much deeper level and with changing concepts of understanding the pathogenesis of this disease as an age-related process. And that's what I'm most excited about here at Tulane, where we are looking at the aging biology in IPF.
And I think we can make some strides To be fair, I've only really heard about IPF in probably the last 5 years, and primarily through my work in the drug development industry. IPF is a common area of interest for a number of different pharmaceutical companies, but I don't think I appreciated the aging factor as playing a role in IPF. That's just such an interesting point. But thinking about fibrosis, I mean, it seems like many diseases, we're very good at treating symptoms, but not necessarily treating the causes. And so fibrosis is such a huge challenge, but your group is working on that. Your group has identified a molecule that seems to be a primary driver of this fibrosis. Can you talk a little bit about that?
Going back now almost, I hate to admit this, but over 2 decades now, where we've identified a cytokine called TGF-beta, which is a canonical profibrotic signaling cytokine that induces generation of reactive oxygen species that causes oxidative stress. So I think most of our Audiences and physicians and providers are familiar with oxidative stress in aging. This idea of how oxidative stress develops and whether you can target it or not has been a little bit unsettled. And what we showed that an enzyme that generates reactive oxygen species, we refer to it as NOX4, stands for NADPH oxidase. Isoform 4. And this particular enzyme generates hydrogen peroxide in cells that respond to TGF-beta, in particular the fibroblasts. And these fibroblasts are the effector cells in pulmonary fibrosis, and they cause a lot of the damage through elaboration of extracellular matrix and other cytokines that may result in this profound scarring condition that causes pulmonary fibrosis. We've worked with a company in Switzerland that they had seen our paper that was published originally in Nature Medicine in 2009. And based on that work, they developed a small molecule that targets NOX4. And we've started phase 2, which was actually going to be completed this month. We were recruiting 60 patients and we are right now around 59 or so. So I think we're excited about completing the study and hopefully it'll lead to bigger and better things down the road. Now, just for disclosure, I don't have any financial relationships with this company in Switzerland. So I, we are hoping to do our own drug discovery around some of these targets here at Tulane. And that's ongoing work that some of which obviously I can't talk about, but we are excited about what's out in the public domain. We've also worked on a drug called metformin, which is an anti-diabetic drug that does affect different pathways that relate to aging, including autophagy and mitochondrial health. So mitochondrial dysfunction. That's been associated with IPF. So that's another opportunity to target IPF. And so metabolism drugs targeting specific metabolic pathways that are aberrant in IPF is another approach that we are actively pursuing in the laboratory.
Very complicated disease, as you are describing it. As just out of curiosity, was the original use of N-acetylcysteine From an antimucolytic perspective, or was it for its role in oxidative stress, or both, or?
Yeah, great question.
I think it's an interesting old drug.
Yeah, no, I think that's a very good question because when the N-acetylcysteine is actually being looked at now actively in that original study that was published in 2011, actually the actual publication that came out in press was 2014. But the third arm of that study was N-acetylcysteine alone. And those patients actually, there may have been some signals suggesting some improvement in some of the endpoints. And I think that there are other studies and people around the country that are looking at N-acetylcysteine in specific subsets of patients that may have a particular genetic predisposition. So it's sort of the pharmacogenomics. area of determining which patients may respond to N-acetylcysteine or not. Your point, which is wonder— a great point about the antioxidant effects of N-acetylcysteine. The difference between using a general antioxidant that scavenges reactive oxygen species or upregulates glutathione is very different than targeting the source of reactive oxygen species, which is what we are doing.
Right.
So, it's a little bit We think it's more specific because as we have published many years ago, and a paradigm that has stood the test of time, if you will, is this idea that reactive oxygen species are also essential in cell signaling. So you just don't want to scavenge all of the reactive oxygen species. And you want to be able to target the source of the pathological enzyme that's generating the ROS rather than just nonspecifically inhibit. Right.
Right.
ROS production.
Well, and so thinking about that source, I mean, I can imagine that it's involved in a lot of different pathways and thinking through sort of age-related diseases like Alzheimer's disease, cardiovascular disease, and other forms of fibrosis. Is that something that you're exploring as possible sort of secondary indications for your drug that you're currently working on? Yeah.
So what gets me really excited, and one can come to work every day and go to the laboratory and work with our scientists, postdocs, and junior faculty members that are actively involved in this area really is this idea that fibrosis is the end result of impaired regeneration. So we know that the older we get, we just don't regenerate as well. You know, I think you've, we know, we have heard about Alzheimer's and cardiovascular disease where tissues don't repair and regenerate the way they used to. When you're younger.
Yeah.
And that leads to a lot of the pathologies that we deal with in an aging population, not only IPF, but cardiovascular disease, Alzheimer's, kidney disease, liver disease. It's a long list of diseases of aging. And if we can address how to repair and renew tissues targeting oxidative stress pathways, metabolic pathways, bioenergetic pathways, these are probably going to be more effective, not only for fibrosis, but also for other diseases of aging.
Yeah. Including something like NASH or non-alcoholic steatohepatitis. I mean, that one of the big challenges with NASH is the fibrosis piece. I mean, you can do a lot to deal with the other symptoms of, including metformin, ironically, but the fibrosis is ultimately the sort of holy grail as it relates to addressing that particular disease. I imagine IPF That fibrosis piece is key to disease resolution.
Yeah, absolutely. And the NIH actually had an RFA looking at interorgan fibrosis and comparing fibrosis mechanisms in different organs like the liver, as you mentioned, the lung, the heart. And I think what we've learned from that is that there are some common pathways, and I mentioned TGF-beta and NOX4. Which is something we've been interested in. That does seem to be a core pathway in fibrosis across different organs. I do think there are also differences between these organs that may make it a little bit more difficult to repurpose anti-fibrotic drugs unless they go through that rigorous testing. So, you know, I don't want to be presumptuous and say that any of the drugs that we discover that may be beneficial in IPF will turn out to be just as effective against cardiovascular disease or liver fibrosis or even Alzheimer's because they're, you know, the pathogenesis is complex, as you said. You know, I do think that we can target fibrosis. I think you heard about the SGLT2 inhibitors for diabetes that unexpectedly had a beneficial effect in heart failure.
Yeah.
That's an example, and we think that may have some effects on fibrosis. So that's an ongoing area of investigation.
Very cool. It's an interesting Venn diagram when you start layering these different types of diseases over each other and seeing the commonalities, and, but also, of course, the differences too. Well, one of my favorite things about your work is that your lab doesn't work in silos. And so do you have any collaborations that you can talk to us a little bit about?
We are fortunate here at Tulane to have a lot of great investigators that are down the hall from where I work. You know, I'm thinking about Dr. Jake Holes, who is a lung immunologist, but he and I have been discussing immune aspects of IPF. In a recent grant we just got funded from the NHLBI, collaborated with Dr. Samir Eldar, On looking at some of the epigenetic changes that are regulated through these metabolic pathways. So the environment here at Tulane to work with different groups, whether they're in your field or even in a completely different area, like Dr. Eldar is a pediatric nephrologist and Dr. Coles is a pediatric pulmonologist. And we've got a lot of great collaborators in microbiology and immunology. Dr. Chad Steele's group, Even beyond that, going to the Uptown campus with some of the bioengineering folks, and we have worked with some of them in terms of model development. The Center for Aging is another group that we have worked with. Now, they have focused mainly on neuroscience and dementia, but we think that there are some common themes that we could develop in collaborating with them. So it's a very rich environment, and we are excited about these collaborations that we hope will lead to a better understanding of diseases across organ systems and hopefully lead to new treatments.
Well, fantastic. So, what types of external partnerships are you looking for that you think that could help your research to the stage where we think that your drug or the things that you're working on can become medical interventions or treatments and, fingers crossed, hopefully a cure?
We've worked with industry obviously at multiple levels, including just conducting clinical trials here. So the person who I should not forget to mention there is Dr. Joe Lasky, who was director of the Pulmonary Fibrosis Foundation. He's also the head of our pulmonary and critical care section here at Tulane.
Wow.
And he's been a leader in ILD and IPF in particular. We've run a lot of industry clinical trials here, but even across the spectrum of just consulting with them and helping them run some of their proof-of-concept studies in animal models to exploring opportunities with certain companies that want to get into this space and doing sponsored research with some of the companies that are vested in this area. We are considering all of those options. Now, obviously, the other area that you've helped us with and others here at Tulane is to work with the Innovation Institute to try and not only protect the intellectual property, but also to commercialize and develop these down a pipeline that will lead to better, more effective, and better tolerated drugs. In patients with IPF.
Well, and on that note, we will be at BIO International in San Diego the first week of June and sharing the work that you've been working on in your lab as it relates to IPF. So if anyone would like to meet about that, we're happy to do that, even far beyond BIO. Well, thank you so much for sharing your expertise with us, Victor. This is such an important and challenging field, and we'll be sure to— Thank you.
Wonderful. And thank you for your support, and I appreciate you listening about my favorite topic.
Absolutely. Well, as always, we will have Dr. Theanickel's contact information and informational links posted in our show notes. Make sure you check them out to learn more. And thank you once again for joining us for Bio from the Bayou. Thanks for joining us for Bio from the Bayou, and we hope you'll join us again.
If you'd like to learn more about the emerging biotech scene in New Orleans and the Gulf Coast region, visit us at biofromthebayou.com, where we have more info on who we are, how to get involved and connected in biotech in New Orleans, and the industry events we'll be hosting where you can meet with us in person.
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