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Jeffrey J. Swigris, DO: Welcome to Medscape InDiscussion on the topic of idiopathic pulmonary fibrosis, or IPF. I'm Dr Jeff Swigris, and today in our final first-season episode, we'll be discussing what the future of medical care for patients with IPF will look like in terms of prevention, earlier detection of disease, and the diagnostic tests and therapies that will make it all possible. We've invited a person whose impressive portfolio of clinical and translational research includes among other things, studies of novel compounds for IPF and other interstitial lung diseases (ILDs). He is director of the Interstitial Lung Disease Program at the University of Southern California in Los Angeles, and professor of interstitial lung disease at Imperial College London. Toby Maher, welcome, and thank you for making the time for this conversation.
Toby M. Maher, MD, PhD: Jeff, thank you. It's always a pleasure to be catching up, especially when other people can listen.
Swigris: Toby, let's talk first about how you became interested in the field of ILD. What was the initial thing that piqued your interest in this field?
Maher: It's been a while now, so more than 20 years ago, when I started working at the Royal Brompton Hospital in London as a resident — to put it in American terms. About 2 weeks before I was due to start, the director of the program called and told me he was changing my job assignment. I'd wanted the sleep and ventilation job so I could learn more about how to use ventilators properly, but instead I ended up being assigned to work with Ron du Bois as his ILD resident. Six months later, he'd convinced me that ILD was the most fascinating problem in respiratory medicine. I think that's true because ILD has the beauty of imaging with CT scans to diagnose patients. It's a condition with a lot of complexity, and even now, 21 years later, there are a lot of unknowns. So from a research perspective, there were a lot of questions to try and answer, and it captured my interest. I'm still enjoying it.
Swigris: What a great first mentor. Ron du Bois is a gentleman and a scholar, and one of the pioneers in the field of interstitial lung disease, and you're so lucky to have that influence. Let's move on now to the topic at hand and talk first about early detection. Speak to us about why you think it's so important for us to make the diagnosis of fibrosing interstitial lung disease early. First, why is it important, and second, how do we do it?
Maher: The first question's a little bit easier than the second. So, why is it important? Fibrotic lung disease is a disease that travels in one direction only. Once patients have developed fibrosis, they have irreversibly lost functioning lung tissue, and as it stands, none of the therapies available to us will reverse that fibrosis or physiological loss.
The earlier we can identify our patients, the earlier we can think about starting treatment, and the better our chances are of preserving what normal lung tissue they still have. Early diagnosis is crucial from that perspective. How we do it is the harder part. We've had treatments for the last decade, so we've spent a lot of time raising awareness about the diagnosis of fibrotic ILD among our other pulmonology colleagues but also in primary care and with cardiology and radiology, so that we get referrals as early as possible. All of us having a high index of suspicion and doing the CT scan as early as possible are keys to making the diagnosis. Then, once that patient has come to see an ILD expert, there are still issues around streamlining the diagnosis.
You've been involved in a lot of the discussions about classification. One of the challenges we have within ILD is that diagnosis and giving patients a label can still be difficult even when they're coming to centers like yours and mine. The development of the concept of progressive pulmonary fibrosis has helped us to a certain extent. If we're at a loss to give the patient a precise label — whether it's IPF or nonspecific interstitial pneumonitis or hypersensitivity pneumonitis — we at least now know that if they've got fibrosis that's getting worse, we can come up with treatment options for them.
Swigris: Right. And the term progressive pulmonary fibrosis reminds practitioners exactly what you said — that generally pulmonary fibrosis moves in one direction and that the variability in the course of the disease is tough to figure out. In general, the fear is that fibrosis worsens. There is physiological decline and irreversible loss of lung function. I'm sure you get asked this quite a bit, and it's an almost impossible question to answer, but what do you say to a patient who's newly diagnosed with IPF who says, "Dr Maher, you've told me this is a bad disease and that fibrosis progresses in general, so how long do you think I have to live?"
Maher: That's always a challenging question. We're treading a tightrope, and we don't want to terrify the individual and strip them of hope. We need to acknowledge that as doctors, we are not very good at giving precise estimates for an individual. We're pretty good at population-based estimates. So I always explain to patients that of 100 patients like them, if they are untreated, in 3 years' time, half of those people will be dead. But I have no way of predicting which half they will fall into. My take on the current treatment is that it probably does extend life expectancy by as much as 18 months to 2 years. I communicate to patients that a lot of the information on the internet is now out of date in terms of the improvements in life expectancy with therapy. I try and balance a realistic impression of how the disease behaves and why it's important to treat it whilst at the same time trying to maintain hope for the patient that their disease will be treatment responsive. And that their prognosis might not be as bad as they fear based on what they read about IPF on the internet.
Swigris: So true. It seems like for half of those patients who have been on the internet and are terrified, their interpretation of outdated information is, "Oh, I'm dead in 2 years. I have this diagnosis. There's no hope." And there are other patients who are uninformed or have been told by another practitioner, "Oh, it's a little fibrosis. Don't worry. You're going to live with this for another 30 years." So, our job is to strike that balance and be realistic but not take away hope. We've been lucky enough to live through seeing successful therapies. Many doctors before us tried and tried repeatedly and never saw success with their therapies. Can you talk to us about the general direction you think the field is heading in terms of what therapies are emerging and what those therapies might have in store for the treatment of our patients with pulmonary fibrosis?
Maher: Yes. From a trial perspective, it's been an exciting time. Recently, at the American Thoracic Society conference, we saw the announcement of data from Bristol-Myers Squibb with their LPA1 antagonist showing positive data at 6 months. We also saw Pliant's alpha-V-beta-6 integrin inhibitor with positive data at 3 months. The year before, we saw the data on Boehringer's PDE4 inhibitor, and before that, there were the data on treprostinil. Treprostinil was originally in their pulmonary hypertension–ILD study but interestingly seemed to show that it was an effective drug for forced vital capacity (FVC) change. So, we have a whole series of drugs that look to be entering phase 3.
Maher: And if you look at the industry success rate at phase 3, it's about 50%-80% success across all diseases at phase 3, but one would hope that with four good shots on target, we will see at least one of those, if not two, successfully reach approval. And it was transformative to have the first two drugs, pirfenidone and nintedanib approved in 2014. Hopefully if we can get one or two of these new drugs, that's going to be another step change into the future for what we can offer our patients in terms of therapy.
Swigris: And do you think that step change is going to be additive, meaning that if one or more of these drugs you mentioned are successful that are in phase 3 or entered phase 3, are we adding those to nintedanib and pirfenidone, or are those going to be standalone therapies? What would that look like in terms of effectiveness if it's combination therapy?
Maher: The short answer is that I expect combination therapy to be the standard for most patients. If we look at the current situation, there is a proportion of patients, so maybe a fifth of our patients, who do seem to see true long-term stability on the current available therapies, but about 80% continue to progress and deteriorate. Obviously based on the trial evidence, our expectation is that progression is slower than it would've been without therapy, so for those patients who are continuing to deteriorate despite treatment, my suspicion is that combination therapy is what is going to work best.
And certainly if you look at the phase 2 trial data for all those studies I've mentioned, none of those is arresting disease progression in all patients. So until we reach that nirvana of having one drug that arrests and ideally reverses fibrosis, we're going to be looking at combination treatment. There's precedent in the pulmonary hypertension field where multiple drugs target different mechanisms in the disease pathway, and they've got clear evidence that combining those drugs offers greater efficacy than each one on its own.
Swigris: When we talk about combinations or any mode of delivery, does one seem better to you than another in terms of oral vs inhaled vs intravenous? When you think about what we know about the pathophysiology of lung fibrosis, does any one of those strike you as being potentially more effective?
Maher: For ease of use, a daily tablet is probably the optimum choice, but obviously as pulmonologists, we're very used to administering inhaled therapy to our patients, albeit the ones with asthma and chronic obstructive pulmonary disease. So as pulmonologists, we're comfortable with inhaled treatments. The virtue of inhaled treatment is that you can potentially get the drug to the lung at much higher concentration with less systemic absorption, which in turn will cause fewer side effects. So, there is a lot of attraction to using the inhaled route — if we can find the right drug with the right physiochemical characteristics. Potentially, the ideal combination is a once-daily tablet, and if necessary, a once-daily inhaled therapy.
With intravenous treatments, they're obviously less convenient for our patients if they need to come up to the healthcare facility every 3-4 weeks. The subcutaneous route is certainly a "halfway house." And again, with asthma, we've seen the success of a lot of subcutaneous treatments, so we know it's feasible in patients with pulmonary disease, and one would imagine, equally so for our patients with pulmonary fibrosis.
Swigris: Right. You mentioned several drugs that are in the pipeline. How can we shorten the time from drug discovery to being able to prescribe these to our patients?
Maher: That's the million-dollar question. There are a few things to think about. There's obviously the developmental pathway that drugs must follow — the phase 1 through phase 3 stages — and one of the things that can be done to shorten that timeline is finding better clinical trial endpoints that give us a readout at an earlier stage.
Now, I think for phase 3, our hands are tied. The US Food and Drug Administration has certain expectations that trials are going to be at least 12 months long, and that's not just to demonstrate durable efficacy. It's also to provide reassurance that drugs are safe for longer term use. I think we're stuck with the phase 3 trial duration, but where we've been trying to make a difference, particularly with work-around biomarkers, is how we can shorten the phase 2 study. Can we find simple markers that are potentially blood measures? Things we've looked at with success have been CA125 and the neoepitopes of collagen turnover.
Can we perhaps develop a panel of biomarkers that will tell us within maybe 4 weeks or 12 weeks with a reasonable degree of confidence that we have an effective drug? And if we can shorten and shrink the phase 2 trials, it should help accelerate the studies. The other thing that can be done is around drug delivery mechanism.
We've seen huge changes in how, as an ILD community, we've gone about recruiting patients to clinical trials. I think people forget that the first multicenter trial in IPF was less than 20 years ago with the interferon gamma studies, and they took several years to recruit patients. More recently, we've seen a rapid acceleration in the recruitment of patients with IPF into phase 3 trials, and I think that's come about because as a community we've recognized the importance of studies. The Pulmonary Fibrosis Foundation and others are in communication with patients about studies and telling them where the opportunities are. We've got more trial nurses working in our centers, so all these things have gone into improving our ability to recruit for trials, which then speeds up the trials themselves. So, there are several things we can do, and have been doing, to speed up this process.
Swigris: Great answer. And that brought up a lot of points. During this first trial, which was the interferon gamma trial that you mentioned, I was a fellow at the time. I'm sure you recall the general sense and dogma in our field, which was, "You will never enroll 300 patients in a phase 3 trial. You're never going to be able to do that." And now we have a recent trial 5 months ahead of schedule and enrolling several hundred patients from around the world. It's incredible progress in terms of getting patients into trials. Patients come in and say, "Why can't I get on this drug? I don't want to go into the trial. Get me the drug." We must remind patients that it may be safe in humans, but we actually don't know this, and we've gotten burned. We have come to realize that these drugs are not like multivitamins. They do have potential downsides, and that's why we do the trials.
Maher: That's an important point. It's very easy to imagine that being on a new drug is a positive thing, and yet there are examples of trials we run in IPF and other diseases where it was actually better to be on the placebo because some of the drugs caused harm. So I fully agree. We must balance our thinking about these new drugs, and it's critically important that we do these placebo-controlled studies to prove that a drug is successful but also to prove that a drug isn't dangerous or potentially harmful to our patients.
Swigris: I have one last question. We know reversing fibrosis is not an option, but when you think pie in the sky, the number of different pathways that could be targeted, the potential genetic information we can obtain from patients, and the biomarkers, how would you see putting all of that together and packaging it up to figure out the best approach to therapy for an individual patient? How is that going to happen? When is that going to happen?
Maher: So, to challenge what you said at the start of the question that fibrosis isn't reversible, it probably comes down to when we identify fibrosis as to whether it's reversible or not. When we see a patient in our clinic who's now got an FVC of 60% predicted and a diffusing capacity of the lungs for carbon monoxide (DLCO) of 35% predicted and they've got lots of honeycomb changes on CT scan, I agree that their fibrosis is going to be entirely irreversible. The lung has been destroyed. We're just not going to be able to get rid of the fibrosis and restore normal lung architecture. But if we capture that patient 3 years earlier when they've got subtle subpleural reticulation, minimal disease, and well-preserved physiology and lung structure, maybe that sort of disease will be reversible.
There are several tools becoming available that will hopefully help us identify patients at risk for fibrosis. We already recognize from the lung cancer screening programs that there's this subset of patients with interstitial lung abnormalities, which in many cases seem to be the precursor to developing clinically overt IPF a few years down the line.
If we can use genetic risk scores and simple blood biomarkers, so if we could have the prostate-specific antigen equivalent for lung fibrosis so that we could add the lung to screening programs, that may be useful. Once we hit the age of 40 and onward, we're encouraged to go and see our primary care physician to be screened for prostate cancer, and women get screened for breast cancer and cervical cancer. So there's an opportunity there if we develop the right tools to be able to screen for pulmonary fibrosis. The real ideal would be to undertake primary or secondary prevention to stop these patients coming to our clinic with breathlessness and incipient respiratory failure and intercept the disease early on when we might genuinely reverse it and truly change outcomes and prevent mortality. I think we're at an exciting pivot point where we are beginning to develop the tools to both identify those patients and hopefully then intervene and prevent the development of IPF.
Swigris: I would add that when patients go to visit their primary doctor and they're talking about cancer screening and so forth, it would be helpful if the practitioner places the stethoscope at the base of the lung and listens for crackles because we know that can be incredibly informative. And if you hear Velcro, get a high-resolution CT scan.
Given all that we've covered here in this short time, Toby, give me one bullet point of information that you want the practitioners who are treating people with IPF to consider differently. What do you want to emphasize?
Maher: I think we need to keep our patients front and center. We need to remember that to make a difference, we need to listen to them, and we need to listen to them early in the disease course. We need to be their advocates and continue this struggle to develop new medications and new diagnostics because ultimately, by the time I get to the end of my career, I would love us to have stopped our patients dying from respiratory failure.
It's been great having new treatments, but my patients still sadly die, and I have maybe close to another 20 years to make a difference. I think as a community we've achieved a lot in the last decade. If we can do the same decade on decade for the next 20 years, then we may be coming close to making a genuine difference and hopefully getting away from this expectation that our patients are ultimately going to die from their IPF.
Swigris: Wonderfully said. Well, we've come to the end of our time, Toby. Thank you very much for being here. And to the audience, thanks for listening to this final conversation of our first season on IPF with our guest today, Dr Toby Maher. Be sure to check out the Medscape app for prior episodes and share, save, and subscribe if you enjoyed this episode. I'm Dr Jeff Swigris for Medscape InDiscussion.
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Cite this: Now Unfolding: The Future of Idiopathic Pulmonary Fibrosis - Medscape - Aug 02, 2023.