Beyond the Current Standard: Addressing Unmet Needs in Idiopathic Pulmonary Fibrosis (IPF) Treatment

In this video, Dr Elizabeth Volkmann shares her extensive knowledge of idiopathic pulmonary fibrosis (IPF), including epidemiology, pathogenesis, current treatment approaches, and therapies in development.

Overview: IPF is a chronic, progressive lung disease with a critical need for new pharmacologic interventions that can alter disease progression and improve both clinical outcomes and patient quality of life. In this webinar, Dr. Elizabeth Volkmann, MD, MS, will provide a comprehensive overview of the growing burden of IPF and the ongoing challenges that persist with current treatment options.

Learning Objectives:

• Understand the pathophysiology, prevalence, and key risk factors contributing to the growing burden of IPF.
• Identify barriers to early diagnosis and explore the challenges with overlapping comorbidities and delayed interventions.
• Evaluate the benefits, limitations, and gaps in current standard of care options, including access barriers, treatment discontinuation, and the need for novel therapeutic approaches.

Presenter:
Elizabeth Volkmann, MD, MS

Dr Elizabeth Volkmann is an associate professor in the Division of Rheumatology at the University of California, Los Angeles, where she serves as the director of the UCLA Scleroderma Program and the founder and co-director of the UCLA Connective Tissue Disease-Related Interstitial Lung Disease (CTD-ILD) Program. Her research focuses on the identification of novel biomarkers that predict response to ILD-targeted therapies. Dr Volkmann endeavors to develop personalized treatment algorithms for patients with ILD grounded in solid translational science. She also has an enduring interest in exploring how the gut microbiome contributes to the pathogenesis of ILD and systemic sclerosis.

Transcript:

Dr Volkmann: Hi everyone. I want to thank First Report for inviting me to speak with you today about Addressing the Unmet Needs in Idiopathic Pulmonary Fibrosis or IPF Treatment. My name is Elizabeth Volkmann, and I'm an associate professor in the Division of Rheumatology at the University of California Los Angeles, where I also direct the Scleroderma Program and co-direct the CTD-ILD program. The learning objectives for today are to, first of all, understand the pathophysiology, prevalence, and key risk factors contributing to the growing burden of IPF. Second, we'll identify barriers to early diagnosis and explore the challenges associated with overlapping comorbidities and delayed interventions. Finally, we'll evaluate the benefits and limitations in current standard of care options including treatment discontinuation and the need for novel therapeutic approaches. So, to begin, IPF is a chronic fibrosing lung disease with a poor prognosis. It's a challenging disease where we have no cure and there is a high need for new pharmacological interventions.  

The pathophysiology is quite complex and not fully understood, but it's thought to involve an interaction between both genetic and environmental factors. The prognosis is poor for most patients with an average of 3.8 year survival rate among those aged 65 years or older in the United States, and the symptoms can be nonspecific. So, many patients will have a persistent dry cough that can often be attributed to more common causes of cough like reflux disease or even asthma or COPD. Other symptoms include worsening shortness of breath, which again, in this population of patients sometimes gets misattributed to heart disease. And then, fatigue, which is very nonspecific. About a third of patients will have digital clubbing, and that can really clue you in that this patient has a severe underlying lung disease. The approximate number of individuals living with IPF today worldwide is 3 million, and in the United States specifically, it's 130 hundred thousand.  

The highest prevalence is in South Korea, and the adjusted prevalence estimates are 2.4 to 2.98 per 10,000 persons living in North America. So, it's still a relatively rare disease. By definition, the cause of IPF is unknown, but there's several identifiable risk factors. So, again, the mean age at diagnosis is 65 to 70 years. A diagnosis before the age of 50 is quite rare. So, this is a disease typically that happens in the elderly. It would be unusual for this to happen in a younger patient. There's also known occupational and environmental exposure risk factors, and these include things like exposure to silica, metal dust, wood dust, stone dust, pesticides, farming, or livestock. So, it's very important in your patients where you're considering a diagnosis of IPF to ascertain whether someone has had these exposures, and they could even have happened remotely. So, you may have a patient, let's say, who's already 65 years old, but maybe in their twenties they were working on a farm and this could still have an impact on their lungs.  

Smoking is a huge risk factor for IPF and a risk factor for a myriad of other health conditions. But individuals with a history of smoking have a 60% increased risk of developing IPF. So, again, to summarize, risk factors include advancing age. Family history is also important as well. Many of your patients will tell you that maybe they had a grandfather that they heard of that died of lung disease and he died really quickly and they thought, oh, maybe it was from COPD from smoking. But it's quite possible that that grandfather who didn't get quite good care maybe had IPF. Again, the environmental and occupational exposures are important. Male sex is something also that's extremely important to consider, again, because if you have a younger woman who has interstitial lung disease, it's less likely to be due to IPF. More likely to be due, let's say, to an autoimmune disease and the smoking history. And then, we think that perhaps microbial pathogens play a role, but there's a lot more research to do on this.  

Misdiagnosis and diagnostic delays remain a large challenge in this area. We know that for most diseases, when you diagnose a patient early, you can intervene early. And this is especially important in this disease where we think that when patients have progressive fibrosis, it becomes irreversible lung damage. There are common reasons for these diagnostic delays, and they include issues like comorbidities. So, again, many of these patients are older men with a history of smoking. So, they’re also going to have diseases like COPD, coronary artery disease, and they may even have lung cancer. And so, you have a lot of other good explanations for a person having poor exercise tolerance or shortness of breath or fatigue on exertion that sometimes the IPF gets missed early on. There was a retrospective claims analysis that used administrative claims database of Medicare fee-for-service beneficiaries from a period of 2014 to 2019. And using these claims data, they determined that the average time to an index diagnosis of IPF was 2.7 years after the patient's other initial respiratory diagnosis. So, this is not even after their first symptoms. This is just after they got a misdiagnosis related to their respiratory symptoms. Half of those diagnosed with IPF had two or more respiratory-related hospitalizations prior to IPF. So, these were patients who went to the hospital, probably had some advanced CT imaging, and yet we're still misdiagnosed as not having IPF.  

There are guidelines that have been issued in terms of the management of patients with IPF. And this guideline was published in 2022. And it wasn't just an American guideline. But it involved a lot of other respiratory societies throughout the world, where experts convened using evidence and also their own experience caring for patients to determine that, in terms of pharmacological therapies, there are two approved therapies currently. Nintedanib, which is a small molecule tyrosine kinase inhibitor approved by the FDA in 2014. In the same year, pirfenidone, another oral antifibrotic drug, was also approved. There's also a number of other clinical trials that are ongoing for the treatment of this disease, and most of these trials allow patients to be on these background therapies. But nonpharmacological options are just as important for our patients. So, we know that lifestyle changes can have a huge impact on a patient's health and well-being.  

So, smoking cessation is an obvious first step for these patients, but then addressing other factors that might increase their risk of having poor health. So, weight loss is important in these patients. Ensuring that they get all of their regularly scheduled vaccines. Again, because these patients have abnormal lung architecture, they're more susceptible to respiratory infection. So, you're going to want to make sure that they get their flu vaccine and their pneumonia vaccine and even their COVID vaccine. Vitamins and supplements can be important. And this comes into play with patients who maybe have poor nutrition or malnutrition or may be suffering some GI side effects from their medications. And most patients with IPF will have esophageal reflux disease. And we think that patients who have worse reflux disease are more likely to have progression of their ILD over time. So, it's quite essential for you to make sure that you're optimizing the management of their reflux disease.  

And this can be done through medications, also dietary adjustments, sleeping with a wedge, and many other issues that can be helpful to recommend for patients. Pulmonary rehabilitation is also important. I will tell you that I've never met a patient who didn't love pulmonary rehabilitation. I've met many patients who don't like physical therapy. But there's something about pulmonary rehabilitation that can be very empowering for patients with lung disease, particularly those who consume supplemental oxygen. Because you can imagine when you have a disease that affects your ability to breathe and you become short of breath, that symptom can almost be paralyzing. You know, when you get short of breath, you automatically pause, you know, to regain your breath. And a lot of times, patients will just stop exercising because they're worried that they're going to cause more harm by pushing themselves. The great thing about pulmonary rehab is that when a patient does exercise, they are supervised.  

So, someone is monitoring their oxygen saturation. They're monitoring their heart rate. So, a patient learns what they can do safely, and this helps with their overall conditioning. And then, I mentioned supplemental oxygen can be important. And this is something that, you know, many patients are a little bit resistant to do early on. But once a patient who needs supplemental oxygen starts it, again, it can be very empowering because they're able to do more in their daily life. And then, finally, palliative care can be helpful for symptom control. As IPF progresses, patients can have a lot of other issues. They may have pain. They may have, again, difficulty with eating. And so, having palliative care specialists on board can really help address the extra pulmonary issues that arise over the course of caring for a patient with IPF. And it's always better to, you know, get palliative care on board earlier versus later. Some people confuse palliative care, let's say, with hospice care. And it's an entirely different thing. Hospice care is really end-of-life care. Palliative care is symptom control. And then, finally, lung transplantation is really the only effective cure that we have, but not all of our patients are eligible for this. It's quite a rigorous and difficult journey for a patient to undergo. And because IPF often happens in older individuals, many centers won't transplant patients who are beyond a certain age.  

Despite several recent phase two or three trials, no therapies have been approved in more than 10 years for this condition. So, again, there's been lots of interesting discovery going on in this area, but we haven't been able to find any therapies that really stop the disease from progression. So, for example, nintedanib and pirfenidone have been shown to slow the annual rate of decline of the forced vital capacity or FVC, prevent acute exacerbation. But, unfortunately, they don't lead to any kind of meaningful improvement in quality of life. In addition, the efficacy in slowing the decline in FVC is quite similar between the two drugs, despite having, you know, very different mechanisms of actions and even different safety profiles. There have been some, you know, real-world analyses. And this was an interesting meta-analysis of 74 studies involving patients taking either pirfenidone or nintedanib. So, it looked at over 23,000 patients. And the change from baseline in the percent predicted FVC was minus .75% for pirfenidone and minus 1.43% for nintedanib. So, not an improvement in FVC. The same for the DLCO. The average change, you know, went down in both groups. And then, in terms of acute exacerbations, the incidence in those treated with pirfenidone was 12.5% and 14.4% for nintedanib. And then, for the mortality rate, it also was not great, 13.4% for pirfenidone and 7.2% for nintedanib. So, I think we can do a lot better.  

Also, antifibrotic therapy uptake remains low since the approval in 2014. So, it's now been over 10 years. But, despite this, a retrospective cohort analysis—again, using claims data from privately insured and Medicare Advantage beneficiaries with IPF—demonstrated an adoption rate of only about 26.4% of either medication. And the adoption rate was lower among females compared with males. And this could be related to the fact that females might be diagnosed even later than male patients with this disease. And then, almost half of the patients discontinued treatment during the study period. There was another retrospective cohort study looking at data from the Pulmonary Fibrosis Foundation Patient Registry. And this is a large registry where there are centers throughout the country in the United States who contribute patients to this registry who have progressive pulmonary fibrosis. In this registry, 63% of newly diagnosed IPF patients were treated continuously with antifibrotics for 180 days, but 22% of newly diagnosed patients never received antifibrotic therapy during the study follow-up.  

And I'll mention that, you know, the registry here is mostly conducted at centers of excellence. So, these are really specialists in lung disease, and still these patients are not receiving antifibrotic therapies. And it may be for different reasons. Again, another real-world study looking at data from Optum’s de-identified Clinformatics Data Mart as well as the VA database, noted that the uptake was pretty dismal. So, it was 9.2% in the Optum database and 29.1% in the VA database. And the rate of discontinuation was quite high, again, 47% and 66%, respectively. And in these graphs here, you can see the proportion of patients on antifibrotic therapies during this time period. So, you know, as expected, when a drug gets approved, you see this kind of slow uptake. But what's interesting here is that it seems to really have plateaued around 2017, 2018. And again, this may be due to different reasons.  

It could be that, you know, the medication isn't very well tolerated, so people might not be apt to use it, or the prescribers may think, like, you know, this is not really benefiting patients too much, I'm going to prescribe it less. We don't know the reasons, but clearly there's been a plateau of the uptake of these medications. And then, again, another real-world study. This was a systematic review where 16.6 and 16.2% of patients taking pirfenidone and nintedanib, respectively, discontinued treatment due to adverse events. The incidence of adverse events was quite high. Over half of patients treated with either of these agents had adverse events. And the most common that we see with nintedanib is diarrhea. And for pirfenidone, it's anorexia. Patients use dose reductions and skin and GI adjuvant therapy to mitigate these adverse events. But the nutritional status of patients with IPF is closely related to prognosis.  

So, we know that when patients with IPF develop malnutrition and have weight loss, it independently increases their risk of mortality. So, again, because these two drugs affect the GI system and affect a patient's weight, often, sometimes we're less apt to use them if we're concerned about malnutrition. There are also barriers to access that include high out-of-pocket costs, again, physician hesitancy, and then payer utilization management restrictions. So, in terms of physician hesitance, research has shown that patients treated with antifibrotics are generally younger. They have a lower rate of smoking. And this may suggest that physicians could be more hesitant to prescribe these drugs in older, less healthy patients. This may potentially be due to a fear of side effects or delay in prescription until other interventions like tobacco cessation are complete. In terms of the out-of-pocket costs, data from a retrospective study using claims data from private and public insurance plans found total costs to be quite, quite high.  

So, for pirfenidone, it's almost $9,000 per month with an out-of-pocket cost of the patient of almost $400. And with nintedanib, it's over $9,000 a month, again, with a similar out-of-pocket cost of about $400 per month. So, you can imagine in older patients who may be just relying on Social Security to live, this might be something that's just not even possible for them. Patients with commercial insurance typically have lower out-of-pocket costs than those with Medicare Advantage. And then, we do see some payer utilization management restrictions. So, antifibrotic brand coverage often requires prior authorization, and there are quantity limits. So, often placed on high tier and specialty tier with a higher patient copay. Also, there's required documentation of IPF to even be eligible for these therapies. And some even require that a patient undergo a multidisciplinary review or have a specialist weigh in before confirming the diagnosis of IPF.  

So, all of these are kind of barriers that can add up into a patient really not even having access to these drugs. There is still a high need for therapies that can alter the IPF disease course and improve quality of life. So, the symptoms of IPF can be quite debilitating and impact not only the patient quality of life, but even caregivers who are involved. And so, this is usually directly related to worsening symptoms like shortness of breath, cough, and fatigue. Declining lung function and substantial morbidity place a high burden on patients and their families. And then, if you start a patient on antifibrotics and they develop a side effect, this again can worsen their quality of life on top of their respiratory symptoms. And some of these patients, because they're not getting out so much, can develop depression, anxiety, even social isolation. And this be quite, quite challenging. And IPF is associated with a considerable reliance on healthcare resources resulting in a large economic burden. So, patients require routine monitoring. They're often in and out of the hospital. They typically use a well-resourced multidisciplinary team. So, they're not just seeing a pulmonologist, they're usually seeing a cardiologist, a gastroenterologist. They're probably seeing their pulmonary rehabilitation specialist, their primary care doctor, and again, other types of ancillary care. And again, in terms of this relationship with IPF and quality of life, you know, you can imagine that all of these factors here contribute to worsening quality of life.  

So, the key takeaways from the first part of this talk is that IPF is a chronic progressive lung disease with no effective cure and high unmet need for new pharmacological interventions that alter disease progression and improve clinical outcomes and patient quality of life. Despite the lack of treatment alternatives, real-world analyses suggest low uptake of current antifibrotic therapies with high rates of treatment discontinuations. And, again, we don't fully understand all the reasons, but there are these considerations. So, the medication side effects that I mentioned to you, the high out-of-pocket costs for the patient, the payer restrictions, and this physician hesitance that seems to be occurring to prescribe antifibrotics to older, less healthy patients. Due to the high symptom burden and substantial mortality rate, IPF places a considerable economic burden on healthcare symptoms. And we're going to talk a little bit more about this in the next webinar. So, we've—we’ve ended a little bit early today, so I wanted to take some time to go through the Q&A.  

Question and Answer Portion

Moderator: Thank you so much for joining us, Dr Volkmann, and for such an excellent presentation. So, at this time, we will now accept questions. Please feel free to enter any questions into the chat. We'll make sure we'll answer them for you. Let's get right to it. Dr Volkmann, given the poor prognosis for IPF patients, why might physicians choose to delay antifibrotic therapy for certain patients, especially those diagnosed when the disease is at an early stage?  

Dr Volkmann: So, I think that the studies have suggested that physicians are reluctant to prescribe these therapies typically to older patients who have more comorbidities when they may feel that the patient might not benefit to the same extent because they start to experience side effects that could also affect their quality of life and ability to thrive. So, I think the side effects are one factor there. But then, another thing that I've observed is that sometimes in the early phases of this disease, patients can be incidentally diagnosed with IPF, meaning that maybe they had a routine chest x-ray that showed some fibrosis. They were referred to a pulmonologist who did a CT scan, and they were found to have early IPF. And in these patients, they may not even have any symptoms. Their lung function tests may be fairly normal or just they may have a slight degree of restrictive physiology.  

And in these patients, the physicians may say, well, you know, considering the risk-benefit of using these drugs, you know, why would I start an antifibrotic now? This patient is feeling well. I don't know how rapidly they'll decline. But I do know that once I start them on one of these antifibrotics, they're going to have side effects. So, let me wait until their disease gets a little worse before starting it. And I don't know whether that's the right decision or not. You know, for most diseases, starting interventions earlier leads to better outcomes. But that, again, is something that I've observed with my pulmonary colleagues who manage patients with IPF.  

Moderator: Great, thank you. What may be the reasons behind the increasing prevalence of IPF in the United States?   

Dr Volkmann: I think there's several factors. I think the first thing to consider here is that IPF was probably underdiagnosed before. So, whenever new therapies get approved for a condition, there's a lot more visibility for the disease. And while we still have delays in diagnosis, we may be doing a better job overall of diagnosing our patients. That anecdote I gave you of a person coming in with this remote family history of, you know, older men in their family dying of lung disease very quickly, those patients might've had IPF that was not diagnosed. So, I think, first of all, we're doing a better job of diagnosing it, but there probably still is an increasing prevalence. And I think this might be attributed to environmental factors. Even though smoking rates in many parts of the world, like the United States, are lower, these other exposures, the known ones, like I mentioned, silica, et cetera, they could be increasing. And then, there's probably other environmental toxins that could be increasing the risks as well that we haven't even identified yet.  

Moderator: Great. Thank you. What is being done to address the lack of awareness of both patients and clinicians regarding the progression of IPF and its prognosis?  

Dr Volkmann: Yeah, this is where I think it's so important to attend programs like this. I think that, you know, at our big pulmonary meetings that happen, you know, on an annual basis, IPF usually got very little attention. You know, it was a very small part of the meeting, and most of the meeting was on COPD and asthma and airways disease and more common diseases. But now, I would say that at these meetings, IPF is something that's given a lot more attention. So, whenever you have more opportunities for continuing medical education in a disease area, it can certainly help raise awareness. I would also say that when drugs get approved, the pharmaceutical companies have their own interests in raising awareness about the disease to help with the uptake of their product. But that benefits our community in the sense that people now think more about the diagnosis of IPF. So, I would say that the drug discovery that's ongoing in this area is also helping to increase the visibility along with, you know, more continuing medical education that is available to practicing pulmonologists and even rheumatologists and primary care physicians.  

Moderator: So, on that same train of thought, what recent advancements have been made in understanding the molecular mechanisms underlying IPF, and how might these lead to new therapeutic targets?  

Dr Volkmann:

Well, I think what's really interesting is that we know that IPF, like most diseases can be heterogeneous. And there are some patients who have a relatively slow progression of the disease, and there are others that progress very rapidly. And then, I even care for a few patients that I've followed for 10 years and they've never had any significant progression. And so, now a lot of work is being done to understand the molecular phenotypes and endotypes of these patients. So, being able to do a blood test and measure a level of a circulating biomarker in the blood to determine, you know, what is that likelihood of a patient progressing. And then, that might help you make a treatment decision. So, if you measure a biomarker in the blood and it's very high and you know that this biomarker is a poor prognostic biomarker, you might start that patient on therapy right away, even if they don't have symptoms or even if their pulmonary function tests still look good because you know they're going to decline over time.  

There's also, in addition to prognostic biomarkers, there's discovery going on into predictive biomarkers. And predictive biomarkers are biomarkers that help predict a patient's responsiveness to a specific therapy. So, as our treatment armamentarium expands for IPF, we're going to have more options for treating our patients. And instead of just doing kind of trial and error, do this medicine, then next do this one, if we have predictive biomarkers that we can, again, measure in the blood of patients, we'll be able to say, oh, this patient has this biomarker, they're likely to have a better therapeutic response to this agent. So, we're going to choose that agent first. And I think that's really something that's on the horizon now for IPF and other interstitial lung diseases. It's quite exciting that even certain trials now are being designed to enrich for a population of patients more likely to respond to a specific therapy based on the underlying mechanism of action. So, I'm hopeful that not only will we have new therapies approved soon for IPF, but we'll also have the research to back up our treatment decisions and inform how we select these therapies for our patients.  

Moderator: Excellent. Thank you. Speaking of treatments, have you seen any benefits with using mullein?  

Dr Volkmann: I personally haven't used that before, but I am sure that others have and perhaps there are benefits.  

Moderator: Thank you. That does conclude all of the questions that we have. We so appreciate your time, Dr Volkmann for joining us. Thank you for attending today's webinar, and I hope you enjoy the rest of your day.