Latest / BioSpace / Fibrosis, IPF and the search for better therapies
Transcript
- speaker-0: Hi, my name is Jennifer Smith-Parker, Director of Insights at Myospace, and you're listening to The Nature. In this episode, I'm joined by Georg Boske, CEO of Tribune Therapeutics, and Jonas Hallen, co-founder and chief medical officer of Coluna Pharma. We dive into IPF and fibrosis challenges, unpacking treatment hurdles, emerging targets, unmet needs, and expansion paths beyond the long. Jonas and Hi York. Thank you so much for joining this episode of Denatured. If you can please introduce yourselves, that would be great. I'll start with Jonas. speaker-1: Hi Jennifer, my name is Ulner Solheim, I'm the CMO of Kaluna Pharma and we're developing biologic therapy for pharmoic diseases and we're currently running a phase two study in IPF. We just actually announced this week that we've completed the enrollment. speaker-0: Perfect. Congratulations. Your go ahead. speaker-1: Thank you. speaker-2: Hi Jennifer, I'm Georg Beiske, I'm the CEO of Tribune Therapeutics and we are also developing novel therapies for IPF and other fibrotic diseases. And Tribune is focused on protein family called CCM proteins. And we have a unique view on how these proteins function, which has enabled us to develop novel mechanisms and therapies for fibrotic disease. speaker-0: Perfect. Okay, that sounds very exciting. So let's go ahead and kick this off. So for our listeners who may not follow the space closely, how would you introduce fibrosis as a disease area? And why has it been so difficult to treat? speaker-1: So, great question. So, pulmonary fibrosis is a chronic scarring disease of the lung. Causes the lungs to become stiff ⁓ and makes it very difficult to breathe. And it's a progressive disease. So it gets worse over time. Now the scarring happens because the normal wound healing response doesn't switch off after injury. So you get this chronic activation of scar tissue producing cells called fibroblasts. The current treatments slow decline. modestly in terms of the decline in economy function, but they come with significant tolerability challenges and they don't really address the underlying drivers of scarring. And as a result, particularly of the tolerability challenges, many patients struggle to stay on therapy for the long term. speaker-2: And I think that that's also overlapping, you know, with, the second part of your question, why have so many things failed? Why has it been so difficult to develop novel treatments, effective and safe treatments for heart product diseases? ⁓ it's been really hard to find therapeutic windows with the pathways and approaches that earlier generations have taken. A lot has been focused around transforming growth factor beta. because that is a mother regulator of fibrosis. So obviously you want to go after it to treat fibrosis. However, while transforming growth factor beta is driving fibrosis, it's also resolving inflammation. So by inhibiting it, you can get local inflammation or secondary malignancies. And it's not been possible to find the therapeutic window ⁓ by going directly after that. And other strategies like broad-spectre, you multi-kinase inhibition are also riddled with tolerance issues. So this next generation of anti-fibrotic therapies that both Coluina and Tribune are part of are really focused on finding the safe and tolerable targets in fibrosis. speaker-0: So you've both quite well described the unmet need as well as the difficulty and the targets to be addressed. So on that aspect, what has changed now that makes the field more investable and scientifically tractable? speaker-1: Well, I'd like to say we have, as Gero also pointed out, I'd like to say we have a better understanding of the biology, the striving fibrosis, particularly the signals that sustain the phlebotomy process over time. But then also, you we have seen some success stories, there have been some positive clinical trials, and that's always important also for the conviction. And then lastly, I think there's a very large unmet need still. which gives confidence for new programs to launch because patients are so desperate for novel therapies. speaker-2: The to phase three translation has been an issue in IPF with many failures and a few recent successes help to show that it is actually possible to have positive phase three outcomes in IPF. ⁓ And I think that the odds are much better when starting with targets and mechanisms which are safe because that's where many of the failures have come from. speaker-0: So definitely good to hear that there is progress or that there is optimism for the future, especially for both of you developing therapies. So what would you say is the single biggest unmet need in fibroidic disease today? Would it be stopping progression, reversing established scar, or identifying the right patients early? speaker-2: From my perspective, it's stopping the progression. Unfortunately, patients are still progressing. Their lung function decline is only slowed by about 50 % of the approved therapies. So that's what we need to do first is to stop the decline in lung function and improve on the vulnerability issues. speaker-1: Yeah, I completely agree. Reversal, at least partial reversal, I think is an aspirational goal. It might be possible in the future, but for now, stopping or arresting progression would be an amazing achievement. And then I'd also really like the point Gerd made about the tolerability of these agents, because if you have better tolerated agents, then... more patients can stay on therapy for longer. And I think that would make a really meaningful impact, both in terms of quality of life, but also in terms of their long-term prognosis. speaker-0: I just want to follow up question to what Giyog mentioned now about the 50 % reduction in the disease progression. Is that over a certain period of time or is that to at the lifespan of the patient? speaker-2: to clarify that's per year. speaker-0: That's per year. Okay, got that. So I think going forward here when we talk about what makes your particular targets biologically compelling as a broad fibrosis driver rather than just another pathway among many. speaker-1: Well, for Kaluna, we're targeting a protein called S104. So this is an analog signal that's released from stressed or injured tissue. It's very early in the process of fibrosis and it drives both the abnormal immune signaling as well as directly impacting the behavior of these fibroblasts that produce scar tissue. So what you get with targeting S104 is broad modulation of several downstream pathways. ⁓ much more disease or injury specific passion than with other agents. So rather than completely suppressing pathways, which may be harmful and cause side effects, you're modulating these pathways. And we think that matters both for the efficacy, but also importantly for the tolerability. speaker-2: And the CCN proteins, we are targeting at Tribune Therapeutics, they are specifically activated in inflamed and fibrotic tissues. They're very important in embryogenesis and early in growth, but in a healthy adult, they have a very limited role. So this specificity to the fibrotic tissue in terms of how they are activated, that's really key for us because it means that we can actually intervene with a safe and tolerable drug. And these proteins, they act in concert with the mother regulator of fibrosis, transforming growth factor beta. They act in synergy. So, and they have their own feed forward loop, which we are also stopping. So they are really driving fibrosis. And there's also clinical data from other compounds that have shown that CCN2 specifically, one of these family members ⁓ is a valid target, which is driving fibrosis in humans. speaker-0: So when it comes to tolerability, because you've both mentioned that a couple of times, what is problematic with the current therapies? But also what kind of safety profile do you think it's necessary for fibrosis drugs to become true chronic therapies? speaker-1: Right. So with the current agents, a lot of patients experience various gastrointestinal tolerability issues, which in some instances has a very meaningful impact on their lives in terms of their ability to do social activities, et cetera. And so it's a daily struggle for some of these patients with the gastrointestinal side effects of current agents. And we've also seen when you try to put them on top of each other. some of these issues become compounded and so it makes the problem worse actually. speaker-0: When you say compounded, I'm just curious. you talked about putting different agents together and that's where the speaker-1: Okay. Sorry. It's an additive. It's an additive. speaker-0: I say. So going forward when we're talking about having true chronic therapies, at least with your respective programs, are we talking about having no gastrointestinal issues or just minimizing those gastrointestinal issues that we're seeing right now? speaker-1: We would like to believe that it's possible to develop a therapy with no gastrointestinal side effects. as you said, mean, these are lifelong diseases. You want treatments to be predictable, to be well tolerated and also compatible with other drugs. Because I think that the future treating fibrosis in general, but IPF in particular, is to have several approaches at the same time. think there's not one, maybe one magic bullet that can. solve all issues, you need various approaches. And it's important that if you have a therapy that can be combined with several other agents, that's a major benefit. speaker-0: Georg, any comments from yourself about the tolerability aspect? speaker-2: Yeah, we don't have any reason to believe that our drug is going to have any of these, these GI tolerability issues. And of course, the first bar to meet for, for, for patients is that the trade off has to be worth it. Right. So you should see that the, the discontinuation goes down a lot. then you really know, achieved something. And at the same time, I think I also believe that it's very important to open up the possibility of combining therapies and different mechanisms to further. improve outcomes and also the opportunity that lies in personalizing treatment for the individual patients, understanding how the patients differ and which therapy is right for the specific patient and combination. speaker-0: So given FVC is still the strongest endpoint correlated to mortality in fibrosis trial, what are other endpoints are supportive or could shed light on this condition? speaker-1: So I can say in our ongoing Aurora study, you know, we see the primary function is the primary endpoint. It's the best validated and established endpoint in the field. But at the same time, we see advances in things like imaging, particularly high resolution CT scans of the model combined with novel approaches to analyze those images. Those are becoming very powerful tools both to understand is activity or time, also to understand treatment effects. speaker-0: How should patients be selected to maximize the chance of seeing a positive signal, especially in a slow moving disease like IPF? speaker-1: So having looked at this very carefully, I would say you need to first, the formulas to show that the patients truly have IPF with new imaging, that's become much easier. So the diagnostic validation, I think is really the basic. And then good patient selection, know, reducing noise and potential confounders, making sure that if they are in background therapy, that they've been in stable background therapy for certain amount time, just reducing all sorts of sources of noise, I think is the most important thing. You know that there obviously is heterogeneous progression trajectories, but overall these patients unfortunately progress quite deterministically over time. And so as long as you have a confirmed diagnosis and you reduce the noise potential confounders, then you're in a good place. speaker-0: I'm when you said having a confirmed diagnosis of IPF from a lay audience perspective, is it difficult to diagnose IPF? It sounds from what you were saying, as if it is a problematic to even ensure that it is IPF from the very go. speaker-1: So that's a great question. So pulmonary fibrosis comprises a number of different underlying etiologies. so idiopathic pulmonary fibrosis is the largest subset of those patients, but you may have pulmonary fibrosis caused by other triggers as well, such as autoimmune diseases, et cetera. And traditionally those patients are not considered in these trials, but they are. rather in this diagnosis known as progressive pulmonary fibrosis, which comprises all of the non-IPF diseases. And so these patients have a more heterogeneous ⁓ demographics and also more heterogeneous progression of their disease. Well, it's important to sort of distinguish. speaker-0: I see, that's interesting. Are there any biomarkers as well that factor into this? Is there any sort of blood markers or anything along those lines that are also indications for IPF? speaker-1: There are no blood markers used to specifically diagnose IPS. So it's according to the guidelines and the imaging and the clinical presentation really are the cornerstones. speaker-2: And unfortunately today there are no biomarkers in IPF which can predict an effect on FVC. So there's limited value in ⁓ early development to look at that. speaker-0: Okay, yeah, that's interesting to understand that as well. So that's a gap that we have there. So I think to round it out, gentlemen, so if IPF, let's say, is the gateway indication, what would make you move confidently into other fibroidic diseases? And which one could be next on your list? speaker-1: hope you already have some pulse. speaker-2: Yeah, absolutely. So we've done a lot of work in the kidney as well. We see a tremendous unmet medical need there. ⁓ Most kidney diseases end in fibrosis in the kidney once the end stage kidney disease is very much associated with ⁓ fibrosis. And we have very encouraging data there as well. The clinical development path is not as clear as it is in lung, which makes my IPF fantastic. speaker-0: Interesting. speaker-2: proof of concept for a pan-fibrotic mechanism. But kidney is high on our list and so is liver is very interesting, especially with the new surrogate endpoints, liver stiffness potentially becoming an approvable endpoint makes the liver a very interesting organ for anti-fibrotic therapies as well. speaker-1: Yeah, absolutely. And I can just say, make a couple of points from our point of view is one is that S-104 as an alarm signal, really wherever there is injury and stress in the tissue, then S-104 is present and not regulated in that. And so just based off of that, there are a number of potential additional diseases we would like to pursue once we've proven. that the drug works in IPF. And then beyond that, just generally fibrosis is, regardless of the underlying triggers or the organ, channels into the same pathway so that drugs that work in one organ, they have a relatively high probability of also having an impact in other organs. And we've looked specifically a lot at systemic sclerosis, which is a multi organ systemic fibroinflammatory disease. where there's also a very large element. speaker-0: fascinating, especially hearing what Kyok was saying at the very start of kidney diseases and then, which I used to write about kidney diseases extensively in my past life as a journalist, but that being linked to IPF later on. So find out something new every day there. And also about systemic sclerosis. I remember writing about that ages ago as well. thank you so much, Yonass and thank you so much, Kyok, for joining this episode of Denatured. It's been a fascinating discussion to hear about fibrosis and fibroidic conditions as well as IPF. And good luck for both of you going forward for your programs. If you'd to listen to more episodes of The Natured, please turn to biospace.com. Thank you.