Hello everyone and a warm welcome to our World Pulmonary Hypertension Day webinar, 'A Bridge to a Bridge,' with keynote speaker Dr. Martine Rothblatt, founder and CEO of United Therapeutics. Also on the call today are Professor Vera Seager and Sir Magdi Yacoub, who will be moderating the talk and guiding the discussion after Martine's presentation. Before we begin, I'm just quickly going to go over some housekeeping. Throughout the talk, we encourage you to use the Q&A function which you can find in the toolbar at the bottom of your screen. Please make sure you use the Q&A box for the questions and not the chat box as we don't want to miss your question. The moderators will be going through the questions and we'll answer as many as possible after the event. A recording will be made available on our website and discussion forum and will be sent by email. I hope you all enjoy the webinar and I shall now hand over to Magdi.
Hello everybody. I am Magdi Yacoub. I am truly humbled by being given the task to present Dr. Rothblatt for a variety of reasons. However, it is both an honor and a privilege to do that. The reason is that I have known Martine for several decades and I have found her a source of inspiration not only to me but to a vast number of people for a variety of reasons. One is her sharp intellect, her vision, her deep understanding of science, business, philosophy, ethics and a few other things but most importantly humanity and friendship, and that is what I personally have enjoyed. I don't want to stand between you and having the treat of listening to Martine and therefore it gives me incredible pleasure to present to you, Martine Rothblatt.
Thank you so much Sir Magdi and thank you for the organizers of the PVRI World PH Day for giving me an opportunity to share a personal journey with you. Next slide please. I'm especially honored on this day to share my personal journey with my co-panelist Sir Magdi Yacoub and Professor Vera Seager. As Sir Magdi just mentioned, we have gone together on this journey for several decades. And there's no two people I would rather be joined with than Professor Seager and Sir Magdi. So this is a great pleasure and a huge kudos to the PVRI for their organization of this. The title of my talk is 'A Bridge to a Bridge to Longevity.' Next slide please. This T.S. Eliot phrase really summarizes the personal journey we've been on. I'll read it for everybody because it's I think so succinct and in a way succulent in its description of life and this journey in particular. 'We shall not cease from exploration and the end of all our exploring will be to arrive where we started and know the place for the first time.' So for me the place and I'm sure for many of us the place is pulmonary arterial hypertension, primarily also for me the place is prostacyclin and prostacyclin analogs. So this quote sums up the whole presentation very well. Next slide please.
Where we began our journey in the 1990s, the mean survival with pulmonary hypertension was extremely grim, about three years. Now some decades later things are definitely better but still about one-third of the patients die within five years. Next slide please. The goal of my journey is really very much summarized in this photograph of two extraordinary individuals. Sir Magdi Yacoub who provided me the generous introduction and Dame Julia Pollock who is unfortunately has passed away. Dame Julia was a histopathologist often working at the side of Sir Magdi as he undertook his very large number of thoracic transplants saving patients' lives. Unfortunately, in the middle of her life, in the middle of her career, Dame Julia was stricken with pulmonary hypertension and notwithstanding the efforts to try different medications to slow the progression and save her life, her course of pulmonary hypertension progressed quite rapidly. And in the end it was necessary for her to receive an en bloc heart-lung transplant from Sir Magdi. This transplant worked so well that she lived a further 15 years after the transplant, far longer than the statistics I showed on the previous slide. In fact, I believe she would have lived many more years but for the unfortunate tragedy of having to witness her only and quite brilliant daughter run over and killed by a motorcyclist in downtown London. Nevertheless, the point was really burned into my head from those days that we are fighting a two-front war, a two-front war in pulmonary hypertension. On one front, we need to develop better and better therapeutic treatments. And on the other front, we need to expand the supply and the quality of organ transplants so that everybody can have the excellent type of therapeutic outcomes that Dame Julia was able to experience. Next slide, please.
So, one of the first things that I did within our company was to try to increase the supply of transplantable organs so that more patients could live longer as did Julia. Don't start the video yet. The key to that was that about 80% of donor organs are in fact thrown away. It's a terrible tragedy and it's even worse than that because it's 80% of donor organs from brain-dead, heart-beating donors which are the organs which is the most least likely way for somebody to die and therefore the greatest possible supply of organs. Nevertheless, even in this least likely way for people to die, 80% of the donor lungs, I said organs before, I mean lungs are thrown away. And the reason for that is the lung is a very fragile organ and by the time the explant surgeons get to it, it's usually not usable. So all of the miracle of heart and lung transplants occurs with just 20% of the most accessible supply. So the first thing I thought of is if I could just expand this supply of transplantable organs then right away we could save the lives of many more pulmonary hypertension patients. And the way we've done this is building upon a technological innovation from Dr. Shaf Keshavjee at Toronto General Hospital which many of you may know is also the hospital that achieved the first single lung transplant, the first double lung transplant, development of insulin, a wonderful medical center. And Dr. Keshavjee developed a technique which we then expanded and increased quite a bit by creating the only concentrated centers of restoring lungs that no transplant surgeon wants until they're transplantable. So what happens in the United States at our centers in Silver Spring, Maryland and our second center at the Mayo Clinic is that lungs that go an hour without any transplant surgeon accepting them, they all reject them. We then ask them to fly the lungs to us. These are unusable lungs destined for bio-waste. And then within a course of several hours, we restore them to transplantability. And currently about 60% of the time the lungs are successfully restored to transplantability, flown yet another leg, a second leg out to a transplant center and in 100% of those instances the patients have successfully had their lung transplant whereas otherwise many of them would have died on the transplant list. This video shows how it's done. Sophie can you please show the video?
Through our lung restoration model, United Therapeutics currently receives lungs from transplant centers east of the Mississippi River. Our LB1 facility in Silver Spring, Maryland, is the first full-service XVIVO lung perfusion center in the US, housing six EVLP procedure rooms. Once the lungs arrive at our facility, our CMX system automatically sends a notification to the participating centers including the OPO, the transplant center, the LB1 clinical staff and the medical advisory team. The UNOS number and blood type are verified in CMX and a backtable evaluation commences noting organ condition. Perfusion takes place over a three to six hour period during which the donated lungs are placed into a sterile plastic dome and attached to a ventilator pump and filters. The lungs are maintained at normal body temperature and treated with a bloodless solution that contains nutrients, proteins and oxygen. Throughout this process, ongoing CMX documentation and assessment steps take place. These include bronchoscopy, X-rays, and blood gas analysis. During this period, our IT specialists facilitate visual and data communication with the transplant centers through our EVLP process. We are working to reduce the devastating effects of end-stage lung disease.
I'd like to put a face on this technology of increasing the supply of transplantable lungs, which we are continuing to roll out. And personally, we won't stop our efforts until we're achieving a large percentage of the currently discarded lungs both from brain dead as well as dead from cardiac death donors. So here on the stage, I'm in my white suit and with me is a remarkable young woman whose name is Heather Leighton. Heather was a college track and field coach who developed a rapid onset of pulmonary hypertension just a few years ago. And the disease progressed so rapidly that despite there being a number of medicines approved, she progressed through all of those medicines and was rapidly facing a situation where she was going to die if she did not receive a lung transplant. There was no other lung transplant readily available for her. So she accepted a pair of lungs from the very center lung restoration center that you saw in the video. The lungs that she accepted by the way had previously been not wanted by any transplant center in the US. So we accepted them, we restored them afterwards. Her transplant team accepted the lungs and went ahead to do the double lung transplant. Only a year after her double lung transplant, she had recovered so robustly that she won the gold medal in the US transplant games in the shot put. And then a further two years after that, just last year, during the time soon after the onset of the COVID pandemic, she successfully gave birth to a beautiful new baby. And this was something that she had been wanting to do with her husband for so many years. But as many of you know, pregnancy is kind of strongly contraindicated for people with pulmonary hypertension. But the lung transplant cured her of the pulmonary hypertension. She was able to safely carry and deliver the baby. And that just puts a face on why we're fighting this two-front battle, expanding the supply of transplantable organs, making them more tolerable, and developing ever better therapeutics. Now the next personal face in the story you see the young lady whose back is to the camera wearing the red dress is my daughter Genesis. Next slide please.
So Genesis was diagnosed about the same time in the 1990s as a movie that had come out called Lorenzo's Oil. I don't know if many of you have seen this movie, but I actually think it's one of Nick Nolte's greatest roles. And in this movie, which is based on a true story of a World Bank economist whose son developed a fatal illness, there were no treatments. The World Bank economist even though he knew nothing about pharmacology or health care tried to develop a type of nutraceutical-like treatment to halt the son's progression and he disguised it as a salad oil, salad dressing you might say, which was called Lorenzo's oil. So I watched this movie and I was very much inspired. I felt like if this economist who knew nothing about healthcare could develop a potential treatment for his son. Then myself as a satellite technologist, maybe there was a chance I could develop something for Genesis who similarly faced a fatal diagnosis with no approved treatments. So I did develop a heavily arginine-based treatment which this magazine ended up calling Jenny's oil. Unfortunately it tasted terrible and compliance was a serious challenge as we often face in the field of pediatric medicine in particular. Next slide please.
So at this time that my newest born nutraceutical efforts were floundering, Genesis was given just two to three years to live with her diagnosis at Children's National Medical Center by Dr. Roger Ruckman, the head of pediatric cardiology there. Her heart had expanded, her right heart had expanded to two times the normal size. I think helping to explain her continuous pain, her constant fainting episodes and cyanotic episodes, the cyanotic lips. She was referred for lung transplantation because no medicines had been approved at that time and she was prescribed off-label a normal dose of Procardia and aspirin. I described all of this several years later at the grand rounds at Children's National Medical Center. It was a terrible time. Being told that your seven-year-old daughter has a fatal illness, only has two to three years to live. No other children known had survived with it. There was a glimmer of hope that I didn't really appreciate and the doctor didn't appreciate either. He said that in the cath lab she showed herself to be an acute responder to vasodilation challenge and that meant that she would likely be a calcium channel blocker responder and hence the prescription of Procardia. I spent my time while she was sleeping in the intensive care ward down in the hospital's library. And down there in the library, night after night, week after week, I taught myself everything I could about pulmonary physiology, cardiopulmonary dynamics, pharmacology, and began finally knowing enough that I could read obscure peer-reviewed journals. In one of which I saw a report of a drug, an analog of prostacyclin that was being tested for congestive heart failure. It had failed in this report in congestive heart failure and I thank the authors for publishing a failed study. When scientists do that, it helps probably as much as publishing results from successful studies. So I thank the authors who did that but in that article there was a chart, there's a series of charts of graphs and it showed that this drug dramatically reduced pulmonary artery pressure but left systemic atrial pressure alone and this type of pulmonary selective vasodilator I knew by that time was exactly what I needed. So I saw a little glimmer of hope that there could be a pharmaceutical treatment for Genesis. Next slide please.
So at that time I sent out a request for proposals, a request for grant proposals to pharmaceutical companies working in this area and to physician scientists, physician investigators working in this area, saying that I would be willing to give them a grant of money if they could develop a treatment for pulmonary hypertension. Specifically calling their attention to this prostacyclin analog known as treprostinil. The reports I got back from the company Glaxo Wellcome which owned this molecule and had funded the failed study in congestive heart failure was that they were not able to develop the product because the drug had failed in congestive heart failure. Only 3,000 people in the whole US had pulmonary hypertension. That would not be enough people to support a drug development. And in any event, they had just been acquired by Glaxo. Burroughs Wellcome became Glaxo Wellcome. And Glaxo had a policy of only developing billion-dollar drugs. So they would not develop this drug. Another person that I contacted with this grant proposal was Dr. Robin Barst shown in the center pane. She was the head of pediatric pulmonary hypertension at Columbia Presbyterian Hospital. Unfortunately, she passed away by now and she sent me a proposal to do research which we funded. I communicated with her. She said that she would be happy to see my daughter as a patient. So, I moved Genesis, my daughter, from Children's National Medical Center over to Columbia Presbyterian Hospital and she began to be seen by Dr. Barst. The third thing I did is I had read these early reports of lung transplantation in my research and it was remarkable to me that none of the transplant patients had ever redeveloped pulmonary hypertension after their transplant. So it seemed to me like this was really a cure. The problem was that the availability of lungs was so small and the availability of sizes was so hit and miss and then there were tolerability problems due to the immunology. So I hit on the idea of developing an unlimited supply of transplantable lungs starting with genetic modification of the pig genome. Inspired in part because my own grandmother had received a porcine valve replacement several decades earlier.
So at this point in my journey there was some good news and things were turning from the bleakness of like Lorenzo's oil to some hope. First of all Dr. Barst immediately increased my daughter's dose of calcium channel blockers tenfold and the dose that she prescribed was so high that every time we went to a different pharmacy to get it filled the pharmacist refused to fill it, assured me it was an error of prescription and I had to get the pharmacist in touch with Dr. Barst and her staff to persuade them that they really did intend this large a dose of nifedipine. Well, the benefit of this very aggressive treatment of Genesis by Dr. Barst and the good fortune that she was a calcium channel blocker responder was that Genesis's pulmonary artery pressures nosedived from way up above 60 or 70 millimeters of mercury down to below 40 millimeters of mercury. And I believe that that aggressive dosing by Dr. Barst was instrumental in saving Genesis's life and provided a strong insight into the future that dosing the pressure is the way to go with pulmonary hypertension. The second bit of good fortune is shown in the left panel. Sir John Vane. After Glaxo refused to develop the drug that they had tested but failed in, I asked them would they license it to me and I would do it. And they kind of chuckled and said, you know, we're very sorry that you're a parent of a pulmonary hypertension patient, but big pharmaceutical companies don't license their drugs to parents of patients and especially ones who only know how to launch satellites. So, we're sorry. Maybe if you, you know, had a biotechnology company, we could engage in licensing discussions. Well, there was, you know, time was running out. And both Dr. Barst as well as previously Dr. Ruckman had told me that there was no saying how long this therapy would work and Genesis could fall off the cliff at any time. So I formed my own biotechnology company, the one called United Therapeutics Today, whose logo you see at the top of the screen, the kind of radiograph of heart and lungs. Some people think it looks like a Sphinx, which is kind of appropriate since Sir Magdi has formed a great hospital in Aswan, not far from the Sphinx. But we formed this company and I went back to Glaxo Wellcome and they again rejected me. They said that the company didn't have any credibility. It was just a company. I needed to have credibility for them to go to their bosses and get permission to out-license the drug. So I was able to hire some dyed-in-the-wool drug developers who had retired from Glaxo. And most importantly I was able to fly to London, meet with Sir John Vane who won the Nobel Prize in part for discovering the mechanism of action and the synthesis of prostacyclin as well as the mechanism of action of COX-2 inhibitors. Sir John Vane and I became very good friends. He agreed to be chairman of my scientific advisory board. And the next time I went to Glaxo and I said, 'How about the guy who won the Nobel Prize for this molecule? Is that credible enough?' And they said, 'Yeah, that's credible enough.' So they then licensed me the treprostinil molecule and now I had a little bit longer lease on life with Genesis thanks to Dr. Barst. I had the rights to develop a compound that could be a good pharmaceutical treatment thanks to Sir John Vane and I had a longer pathway to fight the ultimate battle to find the cure through an unlimited supply of organ transplants pursuant to my xenotransplantation PhD work. Next slide please.
Well, once again I ran into problems as always occurs it seems in drug development. The very high dose of calcium channel blockers for Genesis created a huge problem of gingival hyperplasia which in turn created further compliance issues. And again this is a, you will not know a transplant surgeon who has not had compliance issues with pediatric transplant recipients. Another problem is that the treprostinil that Glaxo finally licensed to me, they had so little hope in this compound that they licensed it to me for $25,000 and 10% of any sales I might make, which is pretty much like just nothing. And they said, by the way, there is no known way to make any more quantities of this drug. Certainly no way to make clinical trial quantities of this drug and because it has to be delivered continuously subcutaneously there is no known device that can continuously deliver this drug. So it's like oh my god I went through all this hassle, all these endless visits to Glaxo Wellcome to get the rights to develop a drug that there's basically no way to make the drug and no way to deliver it. Next slide please.
So, in some regards, I felt like I was really in a dark tunnel. And there was a light at the end of the tunnel, but I really didn't know if it was a light of like a new dawn or a light of like a locomotive coming barreling down the tunnel toward me. A drug had finally been approved, Flolan, but it required an indwelling Hickman catheter in a patient's chest, which is a tough nut to crack for a child who wants to swim and be normal like everybody else. I finally was able to find a chemist at the University of Chicago, Dr. Robert Moriarty, head of the department of chemistry, who, after we paid him was able to find a way to synthesize the drug, but he was only synthesizing the drug in small quantities, not yet figured out a way to scale it up to the kilograms that you would need for an approvable drug. And unfortunately when it was delivered subcutaneously this treprostinil molecule which we renamed Remodulin as a trade name was very painful upon passing through the subcutaneous skin. So that too turned out to be quite problematic because what parent wants to put their child on a painful therapy for the rest of their life? You know the good news is you could live longer. The bad news, you're going to be in pain every month. I mean, it's tough. So, again, I felt that this journey, this personal journey had stuck me in a tunnel with a promise of light, but maybe the peril of failure, of the failure of a locomotive barreling down on me. Next slide, please.
Well, I think the first time I saw that the light at the end of the tunnel was really a light was thanks to Dr. Vera Seager. My daughter had, as I briefed her on every stage of this development, she said, 'You know, why would I have to have like a catheter stuck in my body, my friends at school have asthma and they just pull out this little inhaler from their pocket to treat their asthma? Why can't you make this Remodulin medicine into an asthma inhaler?' So, I had to say, 'Sweetheart, it's just not that simple like snapping your fingers and doing it.' First of all, Sir John Vane, as brilliant and wonderful a human being as he was, was adamant that treprostinil would never work via inhalation. Also, these clinical drug developers that I had hired from retirement in the pharmaceutical industry they too were adamant that treprostinil, this prostacyclin analog, would never work as an inhalation. Part of the reason was because the drug had a short half-life and it's not realistic to expect somebody to continuously inhale something all day. However, I had the great fortune to meet Dr. Vera Seager at Giessen Medical Center in Germany and he proved to me beyond a shadow of a doubt that prostacyclin analogs in general and treprostinil in particular could work as an inhalation therapy. And he proved it not only with benchtop models but with data from actual patients in his clinic who he had successfully saved their lives with inhalation of prostacyclin analogs and then showing me that it would work with Tyvaso in particular and work better with Tyvaso than any other prostacyclin analog. So he's right there on the call with me as a moderator. But Vera, I will never stop thanking you for all you've done to bring the true light of day into my journey. So I had to hire a new set of clinical drug developers who would believe in this product and we did successfully get it approved for the treatment of pulmonary hypertension. Next slide, please.
Of course, it was a bit of a bulky thing. It wasn't yet my daughter's inhaler that she could slip into her skinny jean pockets that she wanted. But we continued to work relentlessly and just last month we completed the development and filed for FDA approval a finger-sized version of Vera Seager's inhaler that you can see a picture of it here. It's called Tyvaso DPI and it does everything that big nebulizer did in the previous picture in just one or two inhalations four times a day. So it is like an asthma inhaler. It's even smaller than some of the asthma inhalers. And I hope that this will be approved by the FDA in December of this year. Next slide, please.
You know, it's very interesting that life can be a self-fulfilling prophecy and when you do good things, good compounds often come back in unexpected ways. So, of course, we developed Tyvaso and inhaled treprostinil for pulmonary hypertension. But it turns out that there are many different types of pulmonary hypertension. The type my daughter has is called WHO Group 1 pulmonary hypertension. It's in the case of my daughter in particular it's pulmonary hypertension without any other cause. It's idiopathic or primary pulmonary hypertension. But there is another type of pulmonary hypertension called WHO Group 3 pulmonary hypertension, most commonly known as interstitial lung disease-affiliated pulmonary hypertension. And as you can see from this Kaplan-Meier curve on this chart that the patients who have higher pulmonary hypertension with their interstitial lung disease have much worse outcome than the patients who have the interstitial lung disease without pulmonary hypertension. Unfortunately the nature of this disease is such that they cannot be treated with any systemic treatment. The type of infused treatments that I referred to previously would actually worsen the match between ventilation and perfusion of these patients. So those therapies are contraindicated and until we developed Tyvaso these patients had no therapy at all for their pulmonary hypertension. We did undertake a development of Tyvaso in these patients and just last month, just in April, we received FDA approval as the first treatment ever for the tens of thousands of patients with pulmonary hypertension associated with interstitial lung disease. So, I'm tremendously excited about that. And by December, if the FDA approves our finger-sized version of the inhaler, these patients can also be treated with that very simple one. So, it's really interesting that something that I started to develop for one class of patients has ended up benefiting an entirely different class of patients. And it's remarkable, just like the good compounds are found good, and the story actually even gets better. So when we did this clinical trial in patients with interstitial lung disease pulmonary hypertension, we next determined from the secondary endpoints that the drug was actually disease modifying, appeared to be disease modifying for the patients' fibrosis which was the root cause of their interstitial lung disease. Next slide please.
The patients with the, actually go back to the previous slide sorry. So the patients who had interstitial lung disease due to pulmonary fibrosis as a secondary indication we saw an actual improvement in the forced vital capacity marker of their pulmonary fibrosis meaning it was actually improving their disease markers in reducing their pulmonary fibrosis which none of the existing drugs for pulmonary fibrosis do at all. They just slow the rate of decline in forced vital capacity. So based on this study, we've embarked on yet a new phase three study to test Tyvaso in patients with pulmonary fibrosis that don't have any pulmonary hypertension at all. So as a result of Dr. Seager's brilliance in developing Tyvaso for patients with Group 1 pulmonary hypertension, we were then able to get it approved for that. Also approved for patients with Group 3 pulmonary hypertension and now have a very strong hypothesis to use that therapy as a disease modifying treatment for patients who have pulmonary fibrosis without any pulmonary hypertension at all. I mean it's truly remarkable. Next slide please.
In addition to all of the efforts on developing the parenteral and the inhaled forms of treprostinil, we also were able to finally make a tablet form of treprostinil. And you see our tablets here. We call these tablets Orenitram. And this is very important in terms of the light at the end of the tunnel because with these tablets there then became a way to do what Dr. Barst did to start with Remodulin as an aggressive way to bring down a newly presenting patient's pulmonary hypertension parenterally and then once you get the patient down to switch them to a tablet. Now about 95% of patients are not calcium channel blocker responders. So Dr. Barst's strategy wouldn't have exactly worked but all of those patients are by definition of having a reduction in their pressures from Remodulin prostacyclin responders. So we could then once we get their pressures down instead of sticking them with a painful therapy for the rest of their life or sticking them with an indwelling Hickman catheter for the rest of their life we could then transition them to a nice and normal pharmaceutical tablet. Next slide please.
Now you'll excuse me for showing a kind of a heuristic chart but I am a person whose career is launching satellites into orbit and I cannot stop thinking about almost any dynamic situation in terms of potential and kinetic energy. So when we launch a satellite we try usually to put it in a very stable orbit which is that energy well that you see there on the left side of the chart. It has the number one there and that stable, very stable energy well means that once we put a satellite there we don't have to do anything, it will stay there. A great example of that is like the geostationary orbit where most communication and broadcasting satellites are, where my Sirius XM satellites are now. That to me is very similar, the way I saw that was very similar that healthy normal people have their pulmonary artery pressures in a very stable energy well characterized by 15 to 20 millimeters of mercury. Now, sometimes things push satellites out of their very stable orbit. For example, the solar panels on a satellite are pressed all the time by what's called the solar wind. It's a radiation pressure from the sun. And sometimes things will push satellites out of a stable orbit. And sometimes things in life will push people out of a stable situation of cardiopulmonary hemodynamics. They might take a diet drug like fenfluramine, Fen-Phen or something else might push them out of their stable energy well and they get into this middle zone that's characterized by the number two and the pulmonary artery pressure is 20 to 40 millimeters of mercury. Now when we see that our satellite has moved out of its very stable orbit, well we say bummer. But we always put propellant on every satellite and then we begin using that propellant to push the satellite back into a more stable position. The consequence of that is the satellite will not last as long as if it stayed in
Its very stable orbit, but it can still last many, many years. And it's similar to me in the case of pulmonary hypertension. If we use pharmacological treatments as Dr. Bars did with my daughter Genesis, as so many practitioners do, like Dr. Seager and others with their patients with both oral and inhaled therapies. If you add some therapies to these patients, you could keep this in this somewhat stable situation of 20 to 40 millimeters of mercury. It's not as good as being perfectly healthy and being all the way at the left side of the chart, but you can stay there for a very long time and live a good life.
Now, unfortunately, sometimes things happen. Sometimes they could be idiopathic or exogenous, compliance related, whatever, and push a patient over all the way to the right side to the unstable domain that's characterized by the kind of reddish color. And there you get to a very bad situation. If a satellite moves from a stable orbit to an unstable orbit and we don't have enough energy on the satellite to push it back to a stable orbit, the satellite will crash through the atmosphere of the earth and burn up and die. That's not good. And similarly, if a patient gets too far on the right side of the chart and nobody, nothing is done to push him back to the middle zone, the natural history there is not good. So it's crucial if the patient ends up in this unstable portion of the energy well that is shown with number three that we push them back into the middle zone, which is what I refer to as a dose to pressure and is in fact exactly what Dr. Bars did with my daughter. Next slide please.
This is a little video that I think adds some good explanation and visualization of everything I've just been talking about.
Afterload reduction to improve right ventricular structure and function in pulmonary arterial hypertension. In pulmonary arterial hypertension, PH, distal pulmonary arteries narrow and stiffen leading to increased right ventricular afterload. RV afterload is measured by pulmonary arterial elastance estimated by mean pulmonary artery pressure MPAP over stroke volume. The thin-walled right ventricle RV is unable to cope with high pulmonary artery pressure for an extended period. In response to elevated MPAP and pulmonary vascular resistance PVR, over time, the right ventricle thickens becoming large and dysfunctional. The RV volume increases and ejection fraction declines, eventually progressing to right heart failure and death. Lowering MPAP to near normal levels may reduce hemodynamic stress, restore RV function and shift RVPA coupling towards normal which has been demonstrated clinically after calcium channel blockers therapy for PH and balloon pulmonary angoplasty therapy for inoperable patients with chronic thromboembolic pulmonary hypertension. Similarly, almost any right ventricle will recover within a few weeks after lung transplantation. Clinical study data from several retrospective single and multicenter studies suggest it is possible to near normalize MPAP and PVR with early and aggressive prostanoid therapy in patients with PH to achieve right heart reverse remodeling, PH risk reduction and long-term survival beyond 10 years. Afterload reduction to improve right ventricular structure and function in pulmonary arterial hypertension.
Thank you. Next slide Sophie. So, as explained in the video, rapid dosing is key to reducing mean pulmonary artery pressure and achieving a better result. Next slide, please.
We intend at United Therapeutics to test this hypothesis in what we call the ARTISAN protocol. Basically it is a protocol that tests the hypothesis to quickly, in the after presentation of the patient, and aggressively titrate Remodulin to get mean pulmonary artery pressures to below 40 millimeters of mercury. Then once we do that to transition the patient at a comparable dose of Tyvaso which is much easier to tolerate and achieve better compliance and then hopefully be able to have measurable outcomes. Next slide please.
You can see in the terms of the Kaplan-Meier curves that the outcomes over time here seem to be much better when we reduce pressure. By the way, I keep talking about mean pulmonary artery pressure, but I think, you know, we could probably just as well be talking in terms of pulmonary vascular resistance reduction, but I'm just trying to keep things a little bit cleaner for the diverse audience today. Next slide.
The importance of the aggressiveness, I think, of treatment is very well shown by Dr. Lang's data here from Dr. Irene Lang from Austria. You could see in her top quartile where she dosed the patients most aggressively and achieved the greatest result, she had the best long-term outcome. And in fact, to me, the dream to achieve is shown in the next slide. Sophie, the data from Dr. Matsubara who's really a pioneer in this protocol. This is my goal is to achieve, you know, 100% long-term survival by getting the patients rapidly reduced to under 40 millimeters of mercury as shown in this slide. So these are all of the excellent hypothesis generating and in some cases validating studies that other great researchers have done from Europe to Asia and our hope with the ARTISAN protocol is to prove all of this prospectively. Next slide please.
It would be really amazing and I believe it's going to be probably inevitable to show that this ARTISAN protocol actually is a disease modifying therapy by reversing the adverse remodeling caused by pulmonary hypertension. You know, it seems to me that there is a kind of vicious downward spiral with pulmonary hypertension where events cause an initial remodeling and initial proliferation of the neointimal endothelial cells and then some amount of perhaps smooth muscle hypertrophy. Thereafter the right heart is having to work harder and harder. Pulmonary vascular resistance goes up. You begin to get shear stress at all of the countless branches in the pulmonary arteries and especially in the tiny pulmonary arterioles in the more distal portions of the lung. This shear stress causes additional phenotypic changes in the endothelial cells and smooth muscle cells. The adventitia begins to harden and that causes yet further higher shear stress and higher pressures. So it's a vicious downward spiral. And if we can reduce the pressures and unwind the spiral up in the positive way, I believe that the lung will begin to regenerate into more healthy phenotypes, a more healthy physiological condition in the distal pulmonary vascular bed. So that really is the mechanism of action goal of this ARTISAN study. Next slide please.
I want to emphasize once again that this is not something that can realistically be achieved with like any old therapy for pulmonary hypertension. Here you see a collection of all different studies that have been done in terms of measuring RV afterload reduction. And with rare exception only the prostanoid therapies, which you see on the far right, are able to be titrated aggressively enough and through a wide enough therapeutic window that you can achieve the necessary right ventricle afterload reduction or reduction of mean pulmonary artery pressure to achieve the positive therapeutic benefit that you saw both in my earlier slide and in the slides of Dr. Matsubara, Dr. Lang and others. Next slide, please.
So, I think at this point in, you know, my personal journey on the therapeutic side, things are improving. They're still pretty bad and I'm hoping that this new development that we have with the ARTISAN protocol will make them much better, will give us a slide that looks more like Dr. Matsubara's slide. But now we have to really turn more attention because of this situation to the other battlefront, the transplant battlefront. Next slide please.
So as mentioned, we began developing this effort based on the PhD that I earned and we have now become at United Therapeutics the world's largest cloners of pigs for therapeutic tissue and organ transplant purposes. And it is a kind of a lengthy trial and error method because you have to modify them. You have to decide which pig genomes you want to modify, which pig genes you want to modify, modify them, birth the pigs, let them grow to size, test the organs in a number of animal models, see what they did and what they didn't do, and then start back at the beginning. And with genes, genes are really complicated because it's a version of that saying that like in ecology or in the earth environment, everything is connected to everything else. And in genes it's the same story. I mean there is no gene that you can modify that does not in some way or another have some effect on something else. It may be subclinical but it may actually manifest itself adversely. So we've gone through years of trial and error and we finally ended up with what we think is an ideal organ donor pig which we call our 10-gene pig. And I will mention that an earlier version of this 10-gene pig was approved for the first time by the FDA last year as a healthy and safe source of meat for people in the United States who have been bitten by this tick called the lone star tick. And a consequence of being bitten by this tick is you have a strong allergic reaction, even a life-threatening allergic reaction to pork or meat. But if you eat the meat from one of our modified pigs, it happens to be the pig with the alpha-gal knocked out, you don't have this allergic reaction. And it's the first genetically modified mammal that's been approved by the FDA. So that was quite an accomplishment and it gives me a lot of confidence that our 10-gene pig will follow in their hoof steps. Next slide.
We're not putting all of our eggs in the xenotransplant basket. We're also developed a way to grow transplantable lungs in the laboratory. So here you see a scene from our organ manufacturing laboratories in Research Triangle Park, North Carolina. What we do here is we decellularize those porcine lungs and we recellularize them with allogeneic cells. Now allogeneic cells are pretty easy to get your hands on. There are a number of companies that sell allogeneic cells in different cell lines and we can HLA separate them into different immunological types. We've then developed the technology at United Therapeutics to grow endothelial, epithelial, mesenchymal cells into the billions of cells and then gradually over a period of two or three weeks cellularize the decellularized scaffolds. So at the end you have a porcine-grown scaffold although it is abiotic. It has no living material on it. That is completely surrounded by a human cellularized lung that is quote-unquote breathing in a bioreactor. And we are now I would say just about according to the latest forecast not more than three years away from being able to take these lungs from animal models into human clinical testing. Because of the nature of this particular product, it has to be a therapeutic test. So it would be a patient who had to have perhaps one or two lobes removed and was having a respiratory problem and then could supplement those removed lobes with these manufactured lobes from our laboratory. Next slide please.
Many times while I'm doing this project of growing lungs in the laboratory I get faced with a lot of skepticism and it takes a great deal of effort to pursue this effort to grow lungs in a laboratory for transplantation to overcome that skepticism and I want to pay great homage to Sir Magdi because he's continuously over all those decades I talked about given me examples from his own career, his own history of why I should be optimistic. You see me here with my arm around him and his very lovely and unfortunately passed away wife Maryanne and my very lovely partner Bina. But Magdi would give me so many examples of how the body can regenerate, how he has left dysfunctional hearts or parts of hearts in people's bodies after doing heart surgery. And years later it turns out that the portions of the heart that he left in the body had successfully regenerated themselves and valves that had successfully recellularized. So, Sir Magdi has given me so much encouragement that even if the lungs that we manufacture in the laboratory are not perfect, if we can get them like maybe 90, 95% of the way, the body may very well take care of the rest. So, Sir Magdi, thank you as well for constant inspiration and encouragement. Next slide, please.
So in this slide I kind of show a schematic of all the different efforts that we're working on to create an unlimited supply of transplantable lungs with the first human transplantable products being available by 2025. I've already talked about the green flagged items, the EVLP XVIVO lung perfusion. You've seen that work. I just got done talking about the blue flagged items, the scaffold recell. I should mention that we today make over 500 lung scaffolds that are manufactured according to good manufacturing practices. We make them available to researchers anywhere in the world who have a good research protocol to use them. I took out a full page ad in the International Journal of Heart and Lung Transplantation offering these scaffolds to researchers anywhere in the world who would like to perhaps try to recellularize them using perhaps paracorporeal or cross-circulation techniques. We have them for you. We also recellularize about 500 lungs a year and grow now over two trillion allogeneic cells each year to use in the recellularization process. And then what's most exciting to me and what really is like my kind of holy grail is the gray flagged item called autologous cellularized bioprinted scaffolds. So here what we're doing as an alternative to using decellularized porcine scaffolds we are 3D printing scaffolds from peptides, basic peptides that are non-biologic, are the same peptides that you see in human lung scaffolds. So we've developed an ability to 3D print these scaffolds and we now do successfully 3D print out to about 13 or 14 branching points almost all the way to the alveoli and then what we are doing is cellularizing these scaffolds with autologous cells meaning that all the cells are of the same DNA. They ultimately come from one person and in our program they would ultimately come from the patient to receive the lung. So the patient once they're diagnosed with pulmonary hypertension they would provide a small skin biopsy, we will extract a cell from the skin biopsy, turn it into an induced pluripotent stem cell, then we'll further differentiate that stem cell into endothelial, epithelial, airway cells and stromal cells. We do that right now in United Therapeutics in our laboratories in La Jolla, California, have successfully differentiated all these different cell types and are expanding them into the millions and into the billions. We would then take the patient's own expanded population of cells and cellularize the scaffold with them just as today we cellularize hundreds of these porcine decellularized scaffolds with allogeneic cells. So exact same cellularization techniques except with autologous cells rather than allogeneic cells. The end result of course is that the patient would not have to take any immunosuppression for their transplanted organ. We would literally be allowing the patient to grow a fresh lung, although it would be grown outside of their body in our laboratories. I want to share with you it is a huge challenge to manufacture under good manufacturing practice standards autologous products because each lung is for one patient. It's not like the same drug for thousands of patients. It's kind of like one drug, one patient. But I'm confident that the technology is here to do it and I'm confident that we will accomplish it in the first half of this decade. Next slide please.
You know, as I've gone through my journey with you, you've seen all the twists and turns, and I cannot overemphasize how complicated and complex human biology is. It is thousands of times more complicated than launching satellites and rockets into space. So right now we spend all of our time figuring out the best medicines and the best ways to outsmart the immune system largely through a process of trial and error that has taken us the decades I've talked about in this talk. But we've now have a tool with computational biology to greatly accelerate the process and unlock the secrets of the human immune system and human pharmacology much faster than ever before. So within our company we've established a laboratory that we call the Computational Laboratory for In Silico Molecular Biology, you know, from in vitro, in vivo, in silico, and the acronym is CLIMB and it's a really good acronym because it's allowing us to climb to the next level. Instead of taking years or even decades to develop a new therapy, we can run clinical trials within literally days or even at most a week using the computational power available in the cloud and using digital twins of the lungs and portions of the lung and digital twins of the immune system that we're building up in our Computational Laboratory for In Silico Molecular Biology. So I believe that the future is going to come much more quickly than we have trudged through the past and I'm also pleased to say that we are collaborating, continuing our collaboration with Dr. Seager and his group of computational biologists at Geisinger Medical Center in our collaboration to unlock yet better therapeutics on the pharmaceutical side and yet better transplantable organs on the transplant side using the power of computational biology. Next slide, please.
Well, I'm going to wrap up here with two thank yous. I want to thank my partner Bina for 40 years and our wonderful daughter Genesis who have both shown immense courage and constancy, perseverance, positive energy as we've gone through this entire journey together. And I next would like to thank in the next slide two of the wonderful researchers at United Therapeutics. Dr. Gil Golden, our chief medical officer, and Dr. Yan Lou, another medical doctor working in our medical department. And Dr. Lou and Dr. Golden have really done a yeoman's effort of being true to the T.S. Eliot quote at the beginning of looking at pulmonary hypertension, looking at prostanoid therapy, looking at methods to relieve right ventricle afterload and seeing all of this domain through new eyes. Seeing it in a way that really nobody has seen it before even though we've been fighting these wars for some three decades and coming up with the ARTISAN protocol and helping me so much with this presentation. Thank you Dr. Golden, thank you Dr. Lou. And thank you especially Sir Magdi and Verer for your absolutely essential activities over so many decades helping so many lives and certainly making this the critical difference in the success of my own efforts and those of United Therapeutics. I'm happy to now turn the moderation back to the PVRI folks.
Okay, thank you very much Martin for this really impressive journey against the background of your personal life and with this wealth of ideas which came over and I think so much of inspiration. So thank you and now it's open for questions and we have already several questions in the chat. So first of all several people thanking you for your inspiration and also for remembrance of Robin Bars who passed away too early. So thank you for taking care to keep her in our memory. And a question which is very interesting is of course and this has been provided very similarly by Michelle Sykes and Iman El Guli is the question when you go for your scaffold and then start with skin biopsy and then program stem cells from there in those who have this heritable pulmonary hypertension then you would also have the mutation again in the transplanted organ. So would you expect then pulmonary hypertension to show up again? Probably your answer will be that you combine this with CRISPR-Cas to correct the gene defect. But it's your answer Martin.
Yes. Well, you of course you foresaw the answer Verer and it's good that we have done so much work with the pig genome because we have a lot of expertise in knocking out very precise genes and as I kind of alluded to in the comments, sometimes you read in the journal we knock out this gene we knock out that gene, it's not that simple. Every gene is associated with additional regions in the genome that modulates the level at which a gene is expressed or not expressed. So you have to be really smart in how you do this and exactly where you knock in or knock out a gene. We create little landing platforms in the genome. But yes, most often I get this question in the context of cystic fibrosis for example, which is a large number of the lung transplants go to cystic fibrosis patients. They're generally very young. And so definitely the goal would be to use our expertise in genetic modification to provide a replacement lung for a patient that had a genetic predisposition to lung disease with a modified lung. I haven't yet thought through the additional regulatory consequences of doing it but if you excuse me for saying I think it will be a little bit of a high-class problem that first let me just get you a replacement lung and I know you're going to have a problem in a few years. I'll work on the problem after that.
Okay. Thank you. One more question Martin which is obvious and related to the really great progress that we have now very recently, this first approved drug for pulmonary hypertension in interstitial lung disease. So what is about COPD? There are our observations of inhaled prostanoids and COPD. Can you comment on this?
Yes, thank you so much for asking that Verer. So we have another phase three trial I didn't have a chance to go through it where we are testing Tyvaso in group three pulmonary hypertension and in this case it is the COPD-associated pulmonary hypertension. So that trial is enrolling right now, was based on some very interesting phase 2 work. I believe the phase two work was done by Dr. Waxman up at Brigham and Women's. But it gave us a lot of encouragement that treprostinil would be effective for COPD. I think the underlying mechanism of action would be as compared to how it worked in IPF. But the bottom line was that in the phase two work the six-minute walk distances were quite dramatically better from use of Tyvaso. So that trial is enrolling, it's just enrolling in the US right now. Actually there's a couple of other countries, US and a couple of other countries, should be fully enrolled by the end of 2022 and I think we could unblind it and have the results in the first or second half of 2023, sometime in 2023 we'll announce the results. But I'm glad you asked the question Verer because in parallel with that and very relevant to that condition because now you're talking about a condition, COPD, which is much, much larger than anything that we've thought about for prostanoid therapy before, that we are embarking on a development of a PRN, a use-as-needed form of treprostinil in conjunction with your team, your center, and some companies in Europe. And there we are going to try to undertake this development of a PRN form of treprostinil and we will do that on top of background therapy and we'll do that first in Europe. So I'm hoping that that will produce successful results in Europe and can then pave the way for a really wide use of treprostinil not only in the very large COPD population but also in all of the other patients who are on non-prostanoid therapies, things like PDE5s and ERAs could also then have some benefit of a prostanoid therapy as a very simple convenient PRN inhaler.
