Speaker: [00:00:00] You're listening to the ATS Breathe Easy podcast, brought to you by the American Thoracic Society.
Patti: Life-threatening disease such as fibrosis affects millions. New promising treatments are on the horizon that could target the condition before fibrosis sets in. I'm Patti Tripathi, your host of Breathe Easy for the American Thoracic Society. Joining me is a world-renowned expert, Dr. Steven Nathan, who is the medical director of advanced lung disease and transplantation at Inova Fairfax Hospital in Virginia.
Dr. Nathan has authored three books, and on IPF, and also served on [00:01:00] multiple FDA panels. Dr. Nathan, my mother was diagnosed around the age of 51 and passed away at age 56 in late 2004. There were absolutely nothing except the steroids and prednisone at the time. A decade later, two drugs were approved by the FDA in 2014, and third last year.
Did they improve quality of life and survival? What are the shortcomings, such as side effects?
Dr. Nathan: Hi, Patti. First of all, thank you for, for having me on, on the show, and I'm sorry to hear that you lost your mom at such a young age. That's quite correct that we have two drugs approved in 2014, that was pirfenidone and nintedanib, which were shown to slow the rate of progression in patients with idiopathic pulmonary fibrosis.
And, you know, that was quite a breakthrough at the time because up until that time [00:02:00] we had nothing. Both drugs unfortunately come with side effects, and sometimes the side effects are intolerable to the point that pa- patients cannot continue on, on the, on these drugs. You know, nintedanib specifically can cause diarrhea, and sometimes that can be quite severe in terms of going to the bathroom five or six times a day in some cases.
Pirfenidone comes with its own set of side effects in terms of also GI upset and other gastrointestinal complaints, photosensitivity. And what we see from real world data is that somewhere in the range of around 75% of patients might not be on anti-fibrotic therapy one year after their initial prescription.
Mm. I think at the specialized centers it's a little bit better because we do, we do have a lot of experience with this. We do a lot of hand-holding with the patients. And obviously a drug can only be as effective as, as patients taking it. [00:03:00] And so that's where we were historically from 2014. But as I'm sure you're probably aware and we'll get into, times have changed recently.
Patti: Yes. And there was a third drug approved last year, but there are also a lot of complications, like affects your liver, kidney. Explain the unmet needs and gaps in care that contribute to delayed diagnosis or worsening in patients. It starts out as dry cough, as it did in my mom's case, and it's often misdiagnosed.
Dr. Nathan: Yeah. So the third drug that was approved, just to talk about all the drugs that have been approved, is nirumadomolast, and that was approved, as you said, last year. And one cannot say one drug is more effective than the other, but it does appear in my personal experience so far is that nirumadomolast is much better tolerated than either pirfenidone or nintedanib.
There's clearly an unmet [00:04:00] need in multiple different domains of the disease. Early diagnosis remains an issue, although I think over time, as we have these approved therapies, we are getting better at this. As you mentioned, the, the disease can present with a dry cough, but most of the time it actually presents with shortness of breath.
And, um, how early it presents depends on how robust the patient is. If you have someone who, for example, is a marathon runner, then they're gonna present earlier because they're gonna notice their symptoms earlier, versus someone who's more of a couch potato who might present later on because they're not moving around to stress their lungs and, and develop symptoms.
A lot of times now we're finding it incidentally. Patients are getting CAT scans of the chest for multiple different reasons. Mm-hmm. Be it screening for lung cancer or if they go to the emergency room with chest pain or something like that. So we are picking up patients who are asymptomatic, but we still see those patients who slip through the cracks who are only diagnosed later on in their disease [00:05:00] course.
Now, even though we have three medications approved, all of these medications work to slow disease progression, and none of them are cures, and they don't generally reverse what the damage that has been done already. So clearly there's ongoing need for earlier diagnosis as well as additional therapies to come to the fore.
Patti: Yeah. So tell us about the clinical trial that United Therapeutics is doing, the data, and how these findings might influence future therapeutic strategies.
Dr. Nathan: So the trials that you're referring to done by United Therapeutics are called the TETON studies. And just to give a little bit of historical background, it's a...
These are studies looking at inhaled treprostinil for its anti-fibrotic effects. Inhaled treprostinil has been around and approved for the treatment of pulmonary arterial hypertension since about 2010. So there's a very good track record in terms of safety and familiarity with [00:06:00] use of the drug. It was then studied in patients with interstitial lung disease, and that clues pat- includes patients with IPF if they had associated pulmonary hypertension, and that was the increased study that was published in The New England Journal of Medicine in 2021.
And the drug got the additional indication for PHILD in t- in March of 2021. What we saw from the increased study, though, was a somewhat unexpected signal that FVC appeared to be preserved, and in fact was increased over the course of the 16-week study in comparison to the placebo arm. In other words, the patients who got the active drug, inhaled treprostinil, had better, significantly better FVCs at the end of 16 weeks compared to the placebo arm.
FVC is a, a, a marker of fibrosis and is c- commonly used clinical trial endpoint for all these studies in inter- interstitial lung disease. At that [00:07:00] point, the Teton program was undertaken. Teton 1 was limited to the USA and Canada and looked at patients with IPF, and was a typical IPF study in that it was 52 weeks, patients randomized either to active drug or an inhaled placebo, with the FVC being the primary endpoint at 52 weeks.
Soon after that, Teton 2 was undertaken. Same study, but instea- in 14 countries outside of North America. TETON 2 recruited quicker and therefore resulted earlier. And I had the privilege of presenting this data at the European Respiratory Society meeting in Amsterdam in September last year. And this was a decidedly positive study with a placebo-corrected difference in the forced vital capacity at 52 weeks of around 96 cc or mLs.
TETON 1, which was once again North America, resulted [00:08:00] in March of this year, and once again, this was a positive study with a placebo-corrected difference of around 130 mLs in favor of inhaled treprostinil versus placebo. Now, many of the secondary endpoints were also positive in, in both of these studies, and the cumulative data was positive in all the secondary endpoints except one.
So it hit ... The study hit on its primary and five secondary endpoints. The sixth one that it didn't quite meet was mortality, but there was a trend in favor of inhaled treprostinil. So the cumulative evidence from both clinical trials seems to be very positive, and the hope is certainly that this will get an approval by the FDA.
I'm not sure what the timing will be around that, but we have two very positive phase three clinical trials that hopefully this will be the fourth approved drug to treat IPF.
Patti: Okay. So this is at the first stage, or are there other stages after these clinical trials?
Dr. Nathan: No, these [00:09:00] are both phase three clinical trials, so these are registrational studies, and generally the FDA wants to see two registra- phase three studies in order to go on an approval.
So I think things are teed up quite nicely for this to be approved, and, you know, the drug is available as it is for these other indications. It's just the question of whether or not, and it should get the added indication to treat IPF.
Speaker 4: Founded by our CEO Martine Rothblatt, United Therapeutics transforms the treatment of rare diseases and pioneers alternatives to expand the supply of transplantable organs.
We are bold and unconventional, moving quickly from scientific theory to practical technologies. As a public benefit corporation, we serve patients, act with integrity, create long-term shareholder value, and operate sustainably.
Patti: What are the priority areas for future research [00:10:00] and innovation, such as novel targets, biomarkers, and approaches to personalized treatment for patients with this terrible progressive disease?
Like watching your loved one choke to death, and I hate to put it that way, but that, that's what it felt like going, you know, through my mom's disease. And so what are the priority areas?
Dr. Nathan: I think there are multiple priorities. You know, even though we have three, and hopefully soon to be four drugs to treat the disease with, I think there's still room for other drugs to come to market.
There's still patients who are gonna progress, patients who are still gonna progress to succumb to the disease or need a transplant. So much like any other disease state, there's a room for, for many other drugs to come to market, and I think the good news is that there's a lot of interest in the space, and a lot of drugs that are in various stages of development.
I think what was particularly novel and [00:11:00] interesting about inhaled triprolidine is that it's the first inhaled drug that's been- Mm-hmm ... shown to be useful for IPF. The others are all given via the oral route. So I think it represents a new avenue to target the disease, and to me it makes a lot of sense to give something systemically via the oral route.
But it may be perhaps w- where we're evolving is to give something at the same time via the inhaled route, and therefore you are better assured of drug getting to the actionable areas by attacking the disease from the front and the back, so to speak. So I think that's perhaps what the future will, will hold in terms of multimodality therapy.
I think all the diseases that we've made inroads i- in have not been single therapies, but multimodality therapy. I think you bring up a good point in terms of personalized medicine and how are we gonna get to decide which of these drugs is best suited to individual patients. And I think there's a lot of activity in that area in terms of [00:12:00] genomic profiling and looking at markers that might suggest that one kind of treatment is better than another.
So I think certainly there's room for further research and development in that area.
Patti: Okay. So this is a spray in the mouth. That's what makes it different?
Dr. Nathan: It's not a spray. The study was done of... by a nebulizer, and patients had to take... be on the nebulizer or take the nebulizer four times a day. The goal was to get them up to 9 to 12 breaths of the nebulizer four times a day.
So a device that they stick in their mouth. Now, um, the medication inhaled triprolidine is also available through dry powder inhalation formulation, which is much more facile. The device is generally quite small and fits in a patient's pocket. So certainly my hope is that when the FDA does, hopefully, a lot of hope here, provide- approval that they'll approve not only the nebulizer but also the [00:13:00] DPI as well, and give patients and providers the option of using either one of these.
Patti: And DPI means?
Dr. Nathan: Dry powder inhalation.
Patti: Okay. Idiopathic means cause is unknown, but experts like you might say that it's ch- really genetic and, and environmental. Is that correct?
Dr. Nathan: That's correct. I think it's a, a trifecta of things that come together that set the disease in, in process. There's certainly a strong genetic component that makes patients predisposed.
We don't fully understand that. Familial IPF result, familial, which is heritable, is about 5 to 10% of the cases, but the other patients do have some kind of genetic predisposition, and that's one part of the tripod. Mm-hmm. Environmental exposures are also another part that can predispose patients to developing IPF.
And so there are many different things [00:14:00] that have been shown to increase the risk of IPF. For example, cigarette smoking being one of them, air pollution, and if you look at any type of occupation where there's exposure to outside noxious fumes or material, be it a hairdresser, a woodworker, a metalworker, they all have a higher incidence of developing IPF.
Dental workers being another example as well. And then the third component is aging. It is a disease of the elderly. And so when these things, three things come together, that sets the stage for IPF. And I think we see more of it now, not only because we are more aware, because we get more CTs, but because we also have an aging population as well.
Patti: Okay. A South Asian mom who is about 51 is probably a rarity, right, with this disease?
Dr. Nathan: That's young to get IPF, for sure. And anyone in their 50s to s- in their 50s, we always [00:15:00] think about could this be something else? Could this be a connective tissue disease, for example? Mm-hmm. Could they have had some kind of exposure that predisposed them to developing chronic hypersensitivity and pneumonitis?
So in terms of the diagnosis, the pulmonologist will do, do, do their due diligence to rule out these other entities. When we call something idiopathic pulmonary fibrosis, it's incumbent on us to rule out other things that we know can cause pulmonary fibrosis.
Patti: Okay. Dr. Nathan, and you do transplants at Fairfax Medical Center.
That's correct,
Dr. Nathan: yeah.
Patti: And at what stage do you decide that this is the last resort and that this has gotta be the only life-saving procedure?
Dr. Nathan: We try and exhaust all medical options first, and we talk about a window of opportunity for lung transplant. Here's our window. We don't want to do patients when they're too early, and we don't want to wait until they're too late in their disease course as well.[00:16:00]
Now, it's important to know that not everyone's a transplant candidate. There are certain strict criteria, age being one of them. Generally, we won't transplant patients more than 75 years old. And when we, when patients go through an evaluation, we try and exclude things that might preclude them as transplant candidates.
So we do a whole body check. We make sure their liver's in good shape, kidney's in good shape, they don't have any significant heart disease, that they have appropriate support. Um, uh, they need the finances, the insurance, the ability to pay for their co-pays. And so there are many different things. We, we look at nutrition.
We have our social worker see the patient. So the decision to whether or not someone's gonna be a candidate for transplant is really a multidisciplinary team and decision to be made. The time to think about transplant and put them on the list is when there's certain things that, you know, come to the fore.
If they're [00:17:00] progressing, if they need oxygen, if they develop a buildup of pressure in their lungs, pulmonary hypertension, these are all indications that their likelihood of living longer with a transplant is greater than their likelihood of living without getting a transplant. So if the likelihood is higher that they're gonna live longer with their primary disease, then they're not ready for transplant.
But there's an inflection point where the projected survival with transplant is greater than their projected survival without a transplant.
Patti: Dr. Nathan, thank you so much. In memory of those whose lives were cut significantly short, like my mom, and those who are currently suffering, we hope the work you're doing paves the way for a cure, and we appreciate you being here.
Dr. Nathan: I appreciate you having me on. Thank you very much, Patty.
Speaker: Thank you for joining us today. To learn more, visit our website at thoracic.org. [00:18:00] Find more ATS Breathe Easy podcasts on Transistor, YouTube, Apple Podcasts, and Spotify. Don't forget to like, comment, and subscribe so you never miss a show