B (3:41)

How long does it normally take if one's on a list? From the time they're on the list until the time they may get a new lung.

A (3:48)

So it depends. Lungs are allocated not by time on a list, but by severity of illness. And we've made some adjustments in the last couple of years to how that process works. It depends on a lot of variables. The sicker patients get the highest priority because they have the biggest risk of dying, waiting. So it depends on your lung disease, depends on your score, something called the CAS score. It depends on your blood type. And so we still have inequities in this country depending on blood type, but we've made a lot of improvements with the current listing process and the way the computer does the math. And so the median waiting time today appears to be about a month and a half. That can vary widely. The sickest patients, patients who are in the hospital on machines, sometimes their waiting time is a matter of days to a week. On the other hand, more stable patients sitting at home on oxygen may wait months. Even those patients, it becomes a glass half full or glass half empty, right? They're not as sick, they're stable, they're not going to die, but they're slowly drowning over time. And that can also be a very anxiety provoking and frustrating process.

B (4:57)

Brandi, I know you've been with lung bioengineering for what, about a dozen years or so. Why is this work so important to you personally?

C (5:04)

When lung bioengineering was created by United Therapeutics, it was founded to find a cure for pulmonary arterial hypertension patients. So historically, United Therapeutics has focused on these medicines to help this patient population. After our founder's daughter was diagnosed at a very young age, she developed United Therapeutics and the next phase of her efforts was around increasing and influencing more patients getting a lung transplant, because eventually this patient population will need a lung transplant. And that is where she decided to start lung bioengineering, optimizing ways to reevaluate lungs that currently aren't being used today.

B (5:55)

I'm wondering, Dr. Haney, let me ask you a little bit about the supply and demand situation. There is a mismatch right now for lung transplantation in this country.

A (6:05)

So lungs are a little bit different than some of the other organs. Kidney, heart, liver. There's not nearly the huge discrepancy in terms of people listed for transplant and people and organs available. Currently There are about 3,300 lung transplants done per year in this country. And each year about 3,600 people get added to the list. So there is a relative balance compared to something like kidney, for example, or heart transplant, where truly there are lots of people who, for whom an organ is inaccessible. Now, that doesn't mean there's not a discrepancy and a disparity between supply and demand. One of the reasons that number could be higher is if there were more lungs available. And right now, lungs remain the hardest organ to place from a donor. Part of that is physiologic. Lungs are very sensitive. They're this tissue paper thin membrane that's very sensitive to factors and can be disrupted by infection, by fluid overload, by lots of things. Right. But the bottom line is lungs have probably the lowest recovery rate from available donors in 13 to 15% from a donor. In this country, 13% of donors recover and donate lungs. And that is far lower than liver, kidney or heart transplant. So the discrepancy really exists in that if we can improve those numbers, get quality lungs, not only will the outcomes continue to get better for those patients listed, but we will be able to then continually list more patients and offer lung transplant to more patients.

B (7:42)

Quality lungs. Brandi, what does that mean to you?

C (7:45)

Lungs are really difficult because there's so much subjectivity involved in the evaluation. When your brain sends out a signal that it's time to die as a result of this injury that the organ donor has sustained. The lungs being that very delicate tissue can really be impacted. And even the process of being on a ventilator can allow for additional infections in those types of patient population. So when the transplant team is trying to evaluate whether or not this lung might work for their recipient, they've got a lot of challenges ahead of them. Like Dr. Haney mentioned, fluid imbalance and other multi system organ issues can be masking the way that the lung actually could perform if you would take it outside of that environment. When a transplant physician is trying to evaluate all of these factors, that is where lung bioengineering can help with our ex vivo lung perfusion technology to be able to take a lung out of the organ donor, put it on a device, gather data without all of those confounding factors, and give the transplant physician the information that they need to make a better decision on whether or not that lung should, should be used for their particular recipient.

B (9:15)

What happens exactly when you get an organ and it goes on the machine? Right. What kind of tests do you have to run? How do you talk to the transplant team and then deliver the organ?

C (9:28)

So typically the way the process starts is that the transplant center has received an offer for their patient from the organ procurement organization and they have questions that or they've got a couple of red flags. And so they are going to have that organ recovered and sent to one of our two facilities. And when the organ arrives, our clinical team of our clinical specialists are on site and ready to receive that organ. And it is cannulated on the back table. So they take two cannulas and sew them into the vessels. So one is going into the left atrial cuff and the other one into the pulmonary artery. And then they're going to put an endotracheal tube into the airway and flush that organ. And then they put it on the device and they're going to connect those cannulas into the tubing for the perfusion to start. So now the lung is cold and it's got cold solution that's going to be flowing through it. And every 10 minutes the temperature is increased and the flow rate is increased. And until the lung warms up to a certain temperature, then it starts to ventilate. And every hour after it goes on evlp, we're gathering data from the ventilator and from the blood gases. So we're I say blood gases, but it's actually an acellular perfusate. So we're actually drawing solution out of the lung and evaluating how well the lung is performing and putting oxygen into the solution just like it would in your body. And then we do bronchoscopies of the lungs. So we take a little tiny camera and put it down into the airways and look around and evaluate and make sure everything is dry and intact. And we also are capturing x ray images of the lungs throughout the procedure. We have live feeds into our operating suite, so our specialists are able to communicate directly with the transplant physician, but they're also able to see everything through that same system as if they were there. Everything short of physically touching the lungs themselves. That becomes a historical repository for the transplant team as well, with pictures and videos that we're capturing that will aid in their decision making and maybe a tool for them downstream if they ever have any issues and need to look back at that organ. Every hour, the team is checking in and looking at the data and communicating with the team. We have ex vivo lung perfusion consultants available to dial in and assist in any decision making or evaluation that may be of concern from that particular organ. And then at a certain point in time, the transplant team decides that they have or have not received enough data. And if they're happy, they tell us to cool down. So we kind of do the reverse where now that warm lung is going to be rapidly cooled down and taken off of the circuit and packaged up to be transported back to the transplant hospital.

B (12:51)

Hi, it's Kathy. If tomorrow's cure has opened your mind to the innovations and technology shaping the future of medicine, we'd love your help in spreading the word. Please take a moment to rate and review tomorrow's cure.

A (13:03)

Cure.

B (13:03)

Whether you're listening on Apple podcasts, Spotify or your favorite app, your feedback helps others find these discussions and discover how breakthroughs in healthcare are becoming reality. Tell us which episodes or ideas resonated most with you? What surprised you or what you're hoping to hear more of? Thanks for listening and for being a part of tomorrow's cure. Can you then, with EV lp, recondition the lung? In a sense, if there has been, say, an injury to it, can it be healed before it's used in a patient?

C (13:41)

What we are doing today is actually just reevaluating a lung. One of my colleagues coined a phrase turning a no into a maybe and taking these lungs that maybe you wouldn't take direct to transplant, putting them on the device and Then using that data to reevaluate whether or not you should use that organ.

B (14:02)

What does this device look like? You have to describe it to me.

C (14:05)

It is made up of several components that you would see in a traditional hospital setting. One of those is a ventilator. So the lungs are actually breathing, for a lack of better words, on. On the system. And then they're attached to a circuit that is actually perfusing solution through the organ. So we're able to see how the lung acts as the actual oxygenator of that solution. So it's a combination of a lot of different components that make up these different types of EVLP devices.

B (14:40)

Dr. Haney, you've seen this. What do you think?

A (14:42)

It's basically a lung that's ventilating in a plastic dome that you can see moving and ventilating. And it's pretty neat. So it's. It's like the heart lung machine, but without blood. And it takes that organ out of the confounding factors and isolates it to say, hey, is this. This organ working the way we expect it to work? To your question about rehabilitating organs, I think to a degree that happens. We treat that organ with antibiotics, we can sometimes get fluid out of the lung, et cetera. And certainly the promise of the machine is as a platform for doing more things to that organ over time. To date, though, I would say at this point in late 2025, it is still primarily viewed as a longitudinal information source. Right. How does this lung work over a period of, you know, two to four hours? Does it work as I would expect? And does it work in a way that I think is compatible with what I need for my patient?

B (15:48)

And if that lung is not doing what you want it to do, then, Brandi, what happens after that?

C (15:55)

So the transplant team can decline the organ, and they may be declining because it's not the right lung for their particular recipient. So, for example, perhaps one of the lungs is potentially usable, but his. Dr. Haney's recipient needs a double lung. In those situations, we work with the organ procurement organizations to identify other potential recipients. If the lung is not usable, then that lung would go back to the organ procurement organization for direction on being discarded.

B (16:29)

Getting back to you personally here, Dr. Haney, as the surgeon, if indeed you run across a lung that you have to say no to, what's that like to tell a patient that this isn't going to work?

A (16:40)

At this point, I think it's all about the expectations. We are interested in looking at organs, right? Taking risks on going to look right, as Michael Jordan said, you miss 100% of the shots you don't take.

B (16:53)

I always have loved that shots taken Quote Dr. But as a hockey fan, because I am from Minnesota, I think that was Wayne Gretzky who first made that wonderful quote, who first said that.

A (17:04)

And that may be true and I do love the great one. But as a born and bred North Carolinian, I think it certainly sums up Michael Jordan's attitude.

B (17:14)

Point taken.

A (17:16)

So if we decline even to go to look at an organ, we're obviously not going to use that. We have the lowest fidelity of information about an organ, a lung donor, than we do any other solid organs. Basically, right. We have an X ray that's kind of hazy. We have a mechanical ventilator that works exactly the opposite way in which you naturally breathe and we have a blood gas. And so it's very difficult to assess an organ from afar before the time of donation. In addition, 50% of organ donors in this country today, for a lot of reasons, are donations after circulatory death or dcd. For those donors, there is not a beating heart, period, where we are able to assess the lung, inflate it, fully, feel it, look at it, test it at the time of donation. And so there is a tremendous amount of uncertainty about that organization. That's where EVLP really provides, in my opinion, a huge advantage because we can take that organ out, put it on the machine and test it for a few hours and make a decision as opposed to having to make a decision with very limited data beforehand when I'm talking to a patient. First of all, I want to set the expectation that when we are going to look at an organ that nothing is guaranteed. Right? Don't count your chickens before they hatch. We're going to look at these organs because we're to going if we don't look, we know we're not going to get them, but with the expectation that sometimes those organs are not good. And then I also tell the patient, look, if this is not a good organ, you don't want it. The last thing we want to do is set you up for an early, very rocky course. And that's where some of it depends on the patient. How much do I need this specific organ? Is it the exact right size? And this is a very difficult size match. Are there lots of antibody issues? And this is the one immunologic match? Right. How much can this patient tolerate? Some early struggles coming out of the case? Is this a young, robust patient that could tolerate a lung That I think is fundamentally good, but might struggle for a little bit. Or is this someone who. I really need an organ to work well right away because they're a little more frail, they need to have something that's really good. And by the way, are they stable and can wait? Right. So those are all parts of the equation going in. And that's why sometimes a program may turn down an organ for a specific patient that still may be usable and may be reallocated to a different patient, a different site. And EVLP really helps facilitate figuring all that out and assessing the organ independently.

B (19:56)

So it sounds as if this is really changing how the number and type of lungs can be used in your particular program at Mayo.

A (20:05)

Yeah, it really has. So in the last several years, we've really leveraged EVLP to do exactly what you just described to increase the number of organs available. And a lot of that, again, comes down to confidence in the organ and finding the right organ for the right person. Where do we want to take our risks if we're not comfortable putting the patient at risk of having a rough start and being set up for complications? EVLP allows us to be reassured that this is going to be a good organization. So over the last several years, close to, you know, 40 to 50% of our transplants have gone through EVLP. There's a number more organs that we sent for EVLP that we've declined. Right. That we've said, you know what, for various reasons, they're not good.

C (20:46)

I think it's also changed even how you and your team look at organs. Right. I think you're actually probably, as a result of working with us, we've seen organs that in the early days may have come in for evlp, but now you're taking direct to transplant because your team is going and actually looking at more organs. So it's actually a kind of a cultural change as a result that we've. That we've noticed in working with your program, and we see that transcend across a lot of programs.

A (21:17)

This is in a lot of ways, just as much art as it is science interpreting data, figuring out what organs are usable, what are good, what are not good, what's going to happen with a DCD donor. All of these things you learn. And my. My use of EVLP has changed over time. And it also has a lot to do with where you're willing to, at different programs or with different patients where you're willing to take risk. And I think EVLP fundamentally allows you to take less risk, to bear less Risk as a program and as a physician for a patient because you have more reassurances that an organ is going to perform well. And so it really has dramatically improved our ability to not only use more organs, but also, I think, find the right organ for the right patient.

B (22:05)

The one year mark in a transplant is key. It's incredibly important. And I'm wondering what are you seeing in terms of the early outcomes and the one year results for patients who receive lungs through evlp?

A (22:19)

This is a technology that as we said, has been around for over a decade. It also has evolved. The early studies showing EVLP was safe basically were non inferiority studies to say, hey, listen, we think a lung from EVLP has the same level of short, intermediate and longer term outcomes as a lung that didn't come from evlp. What continues to happen as we test these is we move the goalposts right, we send different organs, we gain more confidence with it, we send sometimes, quite frankly, lungs that we were less sure about. I think we have a reasonable amount of data and certainly anecdotal experience and my personal experience, having done a ton of transplants, that an organ coming off EVLP has the same short and intermediate term outcomes as a lung that was not on evlp. There's not really a price to be had in the short to intermediate term for that organ. Now, long term, obviously that takes years and years to determine, but we don't have any evidence that says that there's any long term implications. And we think that if a patient's early and intermediate results, meaning, you know, days, weeks, months, year, predicts their long term success. What I tell patients is a lung from EVLP that works is going to be just as good and you're going to have just as good a chance of doing well long term as a lung that doesn't come from it. And if it means getting you an organ like we went back to the beginning, the reducing the waiting time, getting you out of harm's way, out of that high oxygen in demand, where you're worried if tomorrow's going to be your last day, right? If we get you transmitted safely and set you up for success, there's no difference long term between a lung that spent a few hours on a machine and one that came directly from a donor. The other thing about lung transplant, quite frankly, is that the difficulty of lung transplant long term, beyond EVLP is still the immunosuppression, the medicines. Lung transplant is a tough business and the median survival for lung transplant is about six years, which is about half the survival of heart transplant or liver transplant. I like to describe it to patients as the best of some bad options. And lung transplant can be fantastic. And I have patients texting me and families texting me all the time. Patients out living their lives, doing things that they could never do. And EVLP is a part of that. I have a lot of patients transplanted who got lungs because of EVLP that they might not have gotten. There are a tremendous number of success stories that we certainly in the business have to hold on to because it doesn't always work well. But EVLP certainly has been a huge part of our ability to expand and offer lung transplant safely. The future is great and the future is really bright. EVLP is a part of that future. It's a platform for organs to be out of a body between donor and recipient for several hours. People have tried a variety of different therapeutic interventions on those organs and to date, we haven't hit on the one. Right. And whether it's going to be a gene therapy, whether it's going to be a drug therapy that makes the organ work better, makes it more tolerable to the immune system, et cetera, someone is going to hit upon something that makes a dramatic difference in the organ performance. In my opinion, it's most likely immunologic. Right. Because that's the biggest long term problem is that these are not your lungs and they didn't come from a box on the shelf. Right. They're from another person. Person. And so when we have an ability to make that organ look more like you or look less threatening to your body, that's when we're going to have a big benefit. And there are a number of strategies with lung transplants, some of which United Therapeutics is very heavily involved in. Right. Whether it's xenotransplant and modifying pig organs to use in people, or whether it's rescaffolding pig lungs with human cells to basically grow a human lung in the lab or 3D print a human lung. Right. United Therapeutics has companies and subsidiaries doing all of that work. But certainly EVLP as a technology offers a lot of promise to say, hey, we can make better lungs to put into more patients.

B (26:25)

Brandi, I'm interested in the potential use of this for genetic modifications. If you can revitalize along on a cellular level with this, with oxygen and nutrients and that kind of thing, healing cells, I wonder, can those same cells possibly be genetically modified so they would function like the patient's own?

C (26:47)

I think it is very futuristic. I think this is something that we believe that ex vivo lung perfusion will be used for is to be able to be used as a platform for potential therapies like that. Right now, when organs are recovered, they're transported in a cold manner and it goes from donor to recipient and there's not a lot of time and being able to administer those types of therapies and those are going to take some time to be able to deliver. I do think that that is the promise of what we're doing today, is that hopefully someday someone out there will have a way to be able to do just that and be able to give patients on the downstream a much better, better organ than what we can give them today.

A (27:36)

I'm a realist. I like to think about what we're doing right now. But I also think that future is around the corner and I think that United Therapeutics has put a lot of different irons in the fire. Not knowing what the future of that is going to look like, I'm not sure. I couldn't tell you exactly what I think the, you know, future therapy is going to be that makes the biggest difference for those lungs. I certainly have guesses, but there's nothing so close around the corner that I could tell you, oh, this is going to be in clinical trial, you know, next year. That said, I think not only is evlp, you know, a useful technology right now, I really think it has tremendous promise as a tool, as a, as I said, as a platform for those interventions. And I think we are inevitably going to see significant progress probably from an immune standpoint to make that better.

B (28:28)

You know, I was wondering as we've been talking here, equity, of course, is a big focus in medicine and might this platform, brandi, be used to maybe make more organs available across the board and really do help when it comes to the questions of equity in organ transplantation.

C (28:47)

Yeah, I think that's the thing we're most proud of is that every organ that currently comes in for EVLP is an organ that wouldn't otherwise have been used. So being able to put more organs into the system will allow for more patients to be able to receive these life saving transplants. And getting back to, you know, Dr. Haney's comment earlier about patients with end stage lung disease and eventually being able to potentially expand those indications. I think that's what's going to be really helpful. And that's something that we've done today with having transplanted over 600 patients just out of our facilities.

B (29:28)

Might this also help the smaller Less resourced centers that can also benefit from this.

C (29:36)

Yeah, historically these devices and still today some transplant hospitals have these devices within their transplant hospital. But with that requires a very large resource with staffing, the capital investment, managing all of the consumables and very specialized products that go with this that have very short lifespans. And the way that lung bioengineering does it is that we kind of have centralized those resources. And so we actually serve right now 25 lung transplant programs in the United States out of our 2,000 facilities. So the organs can come from anywhere. We've brought lungs in from Alaska and from Puerto Rico and it goes out to one of those transplant programs that are qualified to to use this medical device. And that means that the smaller programs that would never have been able to invest in all of this equipment and expertise now can leverage a service provider to be able to do that. And so we do think that this is bringing more options to more patients and through being able to serve the large transplant programs as well as the small ones.

B (30:49)

Doctor, since you have been working with evlp, how will you think EVLP protocols will become routine rather than experimental in some places?

A (30:59)

Making it more routine ultimately involves being comfortable with the procedure and not perceiving it as high risk. And so that's why you know, that thousand EVLP case experience has really been instrumental. The published data showing that these organs have similar outcomes. It really helps tremendously to alleviate that perception of this being an experimental or only for big programs that can bear risk process. Quite the opposite in fact. I view EVLP as the way for especially smaller programs to mitigate risk. I completely agree with Brandy's comments. Evlp, especially centralized EVLP allows organs to be accessible to lots more programs. Again, programs that don't have the resources to provide these services on their own, but also are smaller and may not have the denominator and the capacity to bear risk from things like DCD donors where there's uncertainty. EVLP allows you to be more reassured that this organ is going to perform well if it's a smaller program that again wants to be conservative. I no longer think of EVLP lungs as an aggressive, you know, forward thinking sort of experimental thing for big aggressive programs. I think of it as a fairly conservative things and in fact the riskier move is to say I know better, we don't need to use EVLP in these donors. And to your point about equity, I mean, listen, equity is a really critical thing. I mentioned before, there are discrepancies in waiting times. Blood type discrepancies Right. Even though O blood group is 50% of the population, people with blood type O, whether it's lungs or heart, because they can only take O, are at a disadvantage for getting organs. There's no question. And we've continued to try to adjust the modeling to try to reduce that discrepancy, but that discrepancy exists. Anything we can do to improve the number of available quality organs is going to improve equity. There's no question. And so I think EVLP certainly, as a platform, provides for more organs available to more places, to more programs, and thus to more patients in need.

B (33:17)

If you were to both look out five to 10 years from now, where do you think this lands? What are you most excited about when it comes to this particular platform?

C (33:26)

I'm most excited for the future of utilizing therapies on ex vivo lung perfusion. There's a broad spectrum of organs when it. When it comes to evaluation, there's the perfect ones that are going direct to transplant, and there's the ones that aren't even considered for ex vivo lung perfusion today because of those issues like infection or trauma, for example. So if we could shift the spectrum to being able to expand into even more indications will only help be able to serve more patients that are waiting.

A (34:00)

I'm most excited about seeing what therapeutic interventions we can perform using the EVLP platform again, whether it's a gene therapy, whether it's a drug delivery, something that makes the organs fundamentally perform better is going to be very exciting. And there's been a lot of changes, right? Improvements in cold static storage, understanding how tolerant lungs are of time and ischemia. So previously we had to put organs in, we thought between six and eight hours. Now we have organs out of the body, whether it's EVLP or not, for 24 hours. The entire landscape of transplant has changed, in which, as she mentioned, taking organs from Alaska, from Puerto Rico, all across the country, the timing of it, et cetera, has really changed. And I continue to look forward to seeing EVLP platforms be a big part of that landscape in which many more organs for which we have a lot of uncertainty are put on EVLP as our expertise and the quality of EVLP continues to rise. And then those organs can be allocated and sent all over the country to the appropriate waiting recipient to best match the organ with the recipient. I think it's an exciting time to watch that continue to unfold.

B (35:12)

I started our conversation by asking you about how you talk with your patients. And so it sounds as though the conversations you are having with your patients right now. Dr. And into the future are going to be different, are different because of this platform.

A (35:27)

There's a lot of different factors that go into assessing a donor organ. We talk about the fact that there's a lot of tools utilized and that EVLP is one of those tools. It has also changed the way in which we view time and we view a donor run. And oftentimes then it has taken a huge bit of the time pressure off of us, not just evlp, but our ability to kind of leave lungs in a cooler safely, et cetera. So now the conversation is it's not a fire drill. This isn't delivering a baby and have the suitcase ready by the door kind of thing. There's a conversation where the patients are at home. We're going to go look at an organ. It's a dcd. We're probably going to use evlp. The patient stays at home until we better assess. Right. So there's a conversation and a time pressure that's been alleviated by this. And it's an ongoing process of we're going to look at this organ. We'll let you know. But all of it involves using multiple tools, again, including evlp, to say we're fundamentally trying to make the best decision we can for you, the patient, to try to find you an organ. That's going to work well for you.

B (36:27)

Really interesting conversation, both of you. Thank you for your time. Dr. Jack Haney from Mayo Clinic in Florida and Brandy Zofke, associate vice president at Lung Bioengineering. We appreciate you. Thank you.

A (36:38)

Thanks so much, Kathy.

C (36:39)

Thanks for having me.

B (36:40)

Tomorrow's Cure is a production of Mayo Clinic with production help from the podglomerate. Be sure to find. Follow Tomorrow's Cure wherever you get your podcasts. I'm Kathy Werzer. Thank you so much for listening.