Pulmonary Vascular Disease and the birth of the PVRI: An interview with Prof. Ghazwan Butrous by Dr. Michael Seimetz

PVRI Member Authors: Nikki Krol

MS: Professor Butrous, thank you for the opportunity to have this interview with you- it is truly an honor. You were one of the founders of the PVRI; you have been the Managing Director, the Treasurer, and now you are the PVRI President Emeritus. What was your initial idea when you founded the PVRI? How did you recognize the need for the Institute?

GB: It is an interesting story, because at the time I was at Pfizer and working on pulmonary hypertension programs and developing Sildenafil but that’s another story. I started to notice that pulmonary vascular disease was a new area. In the nineties nobody talked about pulmonary hypertension because there were no drugs. But now we had a few drugs. But the interest and the science did not have a real network in which to work together, because as you know, we have the American Cardiology Society, the European Society of Cardiology, but for pulmonary hypertension there was no such thing.

The other thing I noticed is that science is a collaborative work- so you obviously like to work with other centers and scientists and exchange ideas. But there was no such forum available. I had the idea of creating a small network- but I wasn’t thinking about a big organisation.

So one day, I still remember it, I was in a meeting for another function, and Ardi Ghofrani- Professor Ardeschir Ghofrani from Giessen- and Professor Martin Wilkins were both in the meeting. I took them aside and I said, ‘By the way, how about we start a small network between a few centers so that we can work and exchange ideas?’ And they said, “That’s a very good idea, let’s think about it.” Of course, I’m well-known to be a determined person, so I said “Well, let’s take it further.”

That was actually in 2005 around the fall. So the three of us began to talk, and decided to get more people together to discuss this small network. I began to think whom I could involve, and I thought about friends and colleagues. I called Mark Semigran, Evangelos Michelakis, Stuart Rich, of course Ardi Ghofrani and Friedrich Grimminger, and they all liked the idea. So we decided to meet, but of course we didn’t have any money as no one was supporting us, so we all decided to pay for ourselves and meet at Heathrow airport. So indeed, we met at the Holiday Inn at Heathrow airport, and stayed there for two days. We started to develop the idea of this network. We didn’t have a name for it at that time at all. We spent about two days talking and we decided that it would be good to have a network in which we could work together, and we wanted to register it as an educational program, and to see if we could call it an institute. Of course it’s not easy to call something an institute, as you need approval from the UK government to be involved in educational activities. Martin (Wilkins) took that upon himself and later on, to make a long story short, he obtained the approval from the ministry to name our burgeoning network as an ‘Institute’.

But we needed to discuss it further, so we decided to meet whenever it was next possible. This turned out to be in February 2006 during the ATS meeting in New Orleans, and there Marlene Rabinovitch joined us as well at the local Holiday Inn. And that was the first time that we started to think as a proper institute, and think on the global issues rather than our personal research projects.

Of course we needed a name, and someone came up with ‘PVRI’ or Pulmonary Vascular Research Institute- and it fits the other PVRI, which is of course the Pulmonary Vascular Resistance Index. I registered it, and we decided it was time to get more people in. We invited 25 people to meet in Malta in 2007, and that is our first official meeting. We met in Malta for two full days, and I put forward the ideas on how the PVRI work sits - Task Forces, the colleagues, no hierarchy, everybody working together. And everyone was so excited about it- at least, these 25 people!

We decided not to ask people to join directly, because we did not want to be like an invitation only club. Instead, if people wanted to join, they would be welcome. Martin spoke to Professor Chen Wang from China who was very excited by the initiative, and he said that he would establish a PVRI China Centre. And then he invited us all to hold the first meeting in China, and this happened to be in Xian- and this was the first time we had 600 people attend a PVRI meeting! Much like this meeting here in Guangzhou!

The following year we decided to have the annual meeting- but this was not meant to be scientific. I mentioned to a colleague that it may be nice to have a scientific meeting also, to encourage people to attend. In effect, we had one whole day for the Annual General Meeting (AGM) and another day for scientific sessions; this was first established in Marbella. Then everybody got excited, and every year it grew, slowly, slowly. And now to my surprise, it has become too big! People started to love it! After Marbella we began having discussions during the meetings, so everybody felt- and feels- like they are contributing to the subject. From there it grew, and every year we had more and more people, and you know the story.

In 2010, we decided that we needed somebody to help us. I used to employ a couple of temporary administrators, until we found Nikki Krol, who became the first permanent one. And that’s how it happened.

MS: That’s a really amazing story. You mentioned that you started with only a few people, and now the number of members is increasing and increasing. You also mentioned some rather famous people. What do you think- why does the PVRI attract young scientists and experts in the field?

GB: I think the main secret- and without a doubt, this is what I truly believe- is that the PVRI is a flat organization- everybody is important. There is no hierarchy. We’ve always said that a PVRI fellow is any person who works- if you don’t work, even if you are a Nobel Laureate, then you are not important to us. And of course, when you’ve got a lot of energetic young scientists, who are ambitious and they want to do some work they will contribute. In fact, the young people have contributed in a very real way in building the PVRI. Many people tell me, ‘when I attend the PVRI meeting, I feel like I am being listened to, rather than at other meetings where some speakers are up on a podium and everybody else is silent…’. I believe that the idea of that exchange creates a lot of potential, and people start to enjoy and enrich the whole thing. I think that the success of the PVRI is not in the so-called founders, but rather in the people who joined it and made it happen, and I hope it will continue in this way.

MS: I’m pretty sure it will, based on the success of previous meetings. Earlier you mentioned sildenafil- a drug that was initially used for erectile dysfunction, and which is now a standard therapy for pulmonary hypertension. Somehow, it is relatively unknown that you in fact discovered that sildenafil can be used in lung diseases.

GB: Well, it’s one of the more interesting stories of my professional life. I am a cardiologist, and my training in cardiology focused on cardiac arrhythmias. Later in my career, I was asked to become a scientific advisor to Pfizer, mainly in the cardiac arrhythmia area because they were trying to develop drugs for this disease. At the time my job was mainly to give ideas and evaluate points.

You probably know how the process of drug approval works in a pharmaceutical company: the drug usually stays in clinical development, and the scientists will do Phase I followed by Phase II and then Phase III, and when it becomes a drug it will go to the marketing site. So when Viagra was approved for erectile dysfunction, one of the directors in Pfizer came to me and said, “you know Ghazwan, Viagra is no longer with us but there may be some other applications for it- so can you think about what those may be?” To be honest, I had no idea about pulmonary hypertension at that time. But as I like to joke, I went to my monastic cell and closed the door for about three months- literally three months- just looking at the literature about PDE5 and PDE5 inhibitors.

Eventually I created three or four ideas, and started to write them down for the director. I had a couple of chapters which all focused on different ideas for Viagra applications- and one looked at the potential use for Viagra in pulmonary hypertension. That was actually chapter three! So there were another two ideas [that I can’t discuss here].

The reason I thought about the possibility of a link wasn’t due to some miraculous discovery- rather, it was like all proper scientific work- a meticulous process. I noticed that a drug called zaprinast, which was produced by May & Baker before it was discontinued, was a PDE5 inhibitor and was used to treat pulmonary hypertension in hypoxia. And then I noticed that PDE5 is over-expressed in the lungs, and to my own discovery as I didn’t know that previously, I found that PDE5 is present in the lungs more than in the penile system. By then there were a few papers on zaprinast, which was the precursor to sildenafil as the latter was developed from zaprinast. So I realized that there was good science behind the theory. People were talking about cyclic GMP which hadn’t happened before, but erectile dysfunction brought it to light and increased interest. So I wrote a chapter and I discussed it with the director. He appeared interested so I suggested we produce a project in the cath lab. Of course there was no budget for it, but he managed to get a little bit of money together, a few thousand dollars, and I contacted five or six investigators which I knew in England, and asked if they wanted to help us. I won’t mention the name, but one of the top investigators in pulmonary hypertension at that time said that our idea was interesting, and wanted to know the name of the drug. When I answered “Viagra”, he started to laugh and asked if I was joking!

This happened in the mid-nineties, and at the time we could only treat very severely ill patients with pulmonary hypertension as there were no drugs available. And this investigator referenced this, and said ‘these patients are dying in the cath lab, and if I give them Viagra, you know what will be all over the news the next day!’ I said ‘Listen, it works.’

I knew we had an excellent rationale behind it and and there was no reason not to do it. The investigator didn’t say no, but it was clear he didn’t want to be involved. Nonetheless, he wanted to help me and was likely a little curious. So he gave it to a patient with COPD- and we now know that COPD patients are generally least respondent to the drug. But by chance this patient showed a 50% decrease in the pulmonary pressure. So he phoned me in the evening and said ‘Ghazwan you’re absolutely right! I’ve never seen a drug like that!’ and I said ‘I told you the science would work.’

In 1998, he actually started to prescribe it to patients but he didn’t tell me as it was an off-label thing. I only discovered this was happening six months later when one of the patients was travelling and needed a bigger supply. I have the results of all these patients- they all improved their six minute walk test.

By then I had about 12 patients and they all showed good results. People were starting to get encouraged- but not everybody. After all, it’s Viagra- it’s considered a lifestyle drug. Again and again I heard that ‘You cannot give it for life threatening conditions.’ In 1999 people were starting to take note of the on-going research, and it was mentioned at the American Heart meeting, a small meeting for pulmonary hypertension attended by about 50 people. In response, the audience started laughing- loudly- because we were giving Viagra.

But to answer your question: I was the person who was on the receiving end of all the information, which allowed me to develop this idea. One of the things I always say to young scientists is to be persistent. If I hadn’t been persistent about this, none of this would have happened; everything would be dead. Even many people in Pfizer weren’t sure about this project, because the drug is for erectile dysfunction and not for this kind of thing, and it hadn’t been done before which meant many investigators did not believe in it. But some case reports started appearing here and there. The first case report was a small little letter that appeared in the New England Journal of Medicine in 2000. The patient was almost dying and was even rejected for heart transplantation. So the doctor at that time gave him 500 mg of Viagra. And the patient started to improve! This encouraged the doctor to write the case report. I didn’t know about that, and just read about in the New England Journal like everybody else.

So I phoned the doctor and I said, “in my experience, that dosage is too high.” And he said “I don’t know about dosage, so I just gave it like that.” So I said, “from what we’ve seen in the cath labs, 75 mg is enough.”

By the way, the patient is still alive and here now, even though he was on the transplant list at the time way back in 2000.

So these kinds of reports, popping up here and there, encouraged other doctors to try giving Viagra for pulmonary hypertension. And I started receiving thank you letters from patients, whom gave me a lot of impetus. This was crucial to me, because two years after we began investigating it, there was the possibility that the program would be axed and we would no longer offer the medication. I started to fight and said “what about all these patients- you cannot just deny these things.” I still remember, it was an agony for me to continue.

But anyway, out of this came a miracle. Eventually the company was convinced and, I have to say it publicly because I’m proud that he did it, Dr. Declan Doogan became the president of this research. He decided that it was worthy of becoming a program, and created it himself. This led to Phase III, and within two years, despite many investigators believing that it would never include patients, the drug was approved. And following this approval, it became the number one drug for pulmonary hypertension even until now.

Admittedly, it’s the most commonly used drug mainly because it was the cheapest drug at that time.

MS: And because it works.

GB: Yes, and because it was available all over the world because of erectile dysfunction. It’s not the only nor the most ideal drug- but for that time it was the best drug available. Yet its popularity is mostly because it was the cheapest drug at that time- other drugs cost three times as much. So it was attractive to use, especially in the developing world, and because it was available.

MS: And probably its background regarding erectile dysfunction is also a good advertisement.

GB: Yes, but it doesn’t effect patients very much in that way. Even when the drug had just been developed Pfizer didn’t advertise it for pulmonary hypertension at all- in fact, they didn’t advertise it for that for three or four years, even after the approval. They thought that this was a small altruistic treatment, not the one that was important, which was erectile dysfunction.

MS: To reiterate for the readers: you should believe in your idea, you should be brave. Correct?

GB: I am retired now, so my advice to the young people is that they have the better ideas and the most creative ideas. This is why I believe in you and in young people. Because to progress science, you must always think out of the box and outside of the doctrine that you have been taught. Science is a fact that we believe in now, but it is not the only- or the whole- truth. So sometimes you have to deviate. Unfortunately, the way the educational system is currently set up means that we indoctrinate people in one direction. So sometimes a young undergraduate can be more creative than a post-doc, because the post-doc has been programmed, and if you become a reader or a professor or a lecturer, you can sometimes only see in one direction. So often the young people are the only ones who can generate the new ideas and if you have a good mentor, who accepts it and is courageous enough to follow through, that’s excellent. That is number one. But you don’t only need the creativity, you also need the determination. You will do it, even if people say it doesn’t work or it’s rubbish- as long as that isn’t fact, don’t let them dismiss you. This pertains not just to the story about sildenafil discovery- it’s also about the PVRI. People said the PVRI wouldn’t work- many people doubted that it could. And the journal, Pulmonary Circulation- again people said it would not work, and they said it was a crazy idea. But it exists due to the determination of the people who make things. So for the young scientists, to excel in your science, you need two things; 1. to be creative, to think outside of the box, and 2. to be determined to follow through.

Yesterday Prof. Magdi Yacoub told me a story about a successful man, a very well-known person. He is a millionaire, billionaire even. He was was asked, “what is the secret to your success?” And he answered, “very simple. Follow up everything you are doing.”

That’s another form of determination. If you start something, don’t file it- keep doing it, and improve, and improve more. It’s the determination, follow up, and creation of ideas- that’s the only recipe for success for young people, in science and all other things in life.

MS: Fantastic advice from a successful man. With the final question I will touch on the 8th PVRI Annual World Congress. This year it’s in China, in Guangzhou, so the eastern and western world meet here. What do you think is the advantage to different cultures coming together?

GB: Many things. First of all, the PVRI is a global organization, and we also concentrate on the developing world, so we need to engage them more and more. When you set up a meeting, a lot of the local people attend- and many of them may not have the chance to travel and visit many other meetings, so it’s a great opportunity for them to network and engage. We want the other countries to come and appreciate the abilities and benefits of this host country, which is beneficial for both. That’s the idea behind expanding and exploring don’t stay in one place all the time.

For example, you know that some organizations only do the meeting in one place, or three places maybe, which is generally due to logistic reasons. They are too big to go just anywhere and instead need to find a place that can accommodate them. But the PVRI needs to be in all places. I take it from my own experience, because my vision to the world has changed due to the large amount of travel I used to do for my work. I started to see that the world has all the same intellectual activity, the same power- countries and cultures enrich each other. If you only live in one place, you think the rest of the world doesn’t understand anything.

So when PVRI members and fellows and groups travel and meet people, the local people will benefit and so will the PVRI delegates, as they begin to understand the need for other countries. Because the most important thing for pulmonary hypertension right now is increased awareness on a global scale. So, keep travelling from east and west all the time- go north and south too. Don’t always go back to the same place, and dare to go far away at times.

A lot of people complained when the PVRI decided to come to China, because it’s a long way for most of our delegates- most will have spent at least 15 hours travelling, and others may even have had a 50 hour journey. But- it’s worth it.

MS: Yes, and it works both ways. It’s similarly attractive for the people who always attend to see new places, people etc.

GB: Yes, and for them to learn about the various issues and interact with the locals. I mean, all the young Chinese students here- a lot of them may not have the opportunity to travel because travel is not easy, especially nowadays with the expenses and things like that. So learn from them while you are here.

MS: So Prof. Butrous, I thank you very much for this interview, it was very nice.

GB: Okay, my pleasure. Thank you

 

This interviewed was transcribed by Nikki Krol, former PVRI Executive Administrator and Executive Editor of the PVRI.

Published in:

PVRI Chronicle Vol 2: Issue 2 cover image

July 2015

PVRI Chronicle Vol 2: Issue 2

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