I'm Aware That I'm Rare: Mark Nicolls, MD

Dr. Mark Nicolls specializes in the treatment of lung transplant patients. He has practiced pulmonary and critical care medicine for more than 18 years. He discusses the importance of clinical trails including his work in the LIBERTY Phase 2 Study; the goal of which is to block LTB4 production as a novel and potentially disease modifying treatment for PAH.

My name is Mark Nicolls. I am the chief of pulmonary critical care at Stanford University, and I have a laboratory that focuses on the basic mechanisms of why people get pulmonary hypertension, really with a focus on how the immune system contributes to the disease.

We have been interested in how auto-immunity, which is when your body attacks itself contributes to the development of pulmonary vascular disease, and we found a few years ago that cells called macrophages surround the diseased blood vessels in both animal lungs with PH and patient lungs with PH. We weren't the first to describe macrophages being around the lung blood vessels, but we found out that there was a particular pathway in which the immune system attacked the blood vessels of the lung in which these cells, called macrophages, again, secreted a substance called leukotriene b4, which we shorten and say LTB4.

LTB4, it turns out, injures the inner lining of the blood vessels called endothelial cells. It also causes the pulmonary artery smooth muscle cells to grow and proliferate, which means to expand. It also activates these cells on the outermost rim of the vessels called fibroblasts. We would allow animals to get pretty sick so that they were walking around their cages and huffing and puffing from pulmonary hypertension, and that's when we would start therapy directed at blocking LTB4 production. When we did this, we saw in a matter of weeks that the animals started to breathe easier again, and that their blood pressures in their hearts came down. It looked like it really re-opened the closed blood vessels, which is a problem that pulmonary hypertension patients have.

The liberty trial is putting this concept to test. We're hoping that we see the same thing in our patients that we've seen in the laboratory. The other thing that we're encouraged by is that we see evidence of high LTB4 levels in the lungs of patients with this disease, so hopefully at least for a sub-set of these patients with this really bad disease, we're going to see some improvement. In the laboratory, it was interesting, we could give it as an intravenous drug, as a shot, as a pill, or even as an inhaler, and all of the forms of delivery worked.

The good news about the liberty trial is that this is a pill that has been already taken by tens of thousands of patients in Japan without a lot of harmful side effects. We have envisioned that this might be a pill that somebody might take once or twice a day. In Japan, the drug that we're using in the liberty trial is actually used as something that you take as add-on therapy for some kinds of cancers like leukemias, and it's even being used in some lung cancer trials, so it's not used for pulmonary hypertension yet in Japan. The point is that the drug is not used at all for any indication in the United States at this point, so this will be the first time it's used, at least in the modern era, for the treatment of pulmonary hypertension.

We had a good reason to believe that LTB4 was causing bad things in the lung, and we simply went to the pharmaceutical catalog of drugs that we can order for the laboratory, and we found this drug that targeted LTB4 and we ordered it from the company. Not the drug company, but just a chemical company. It turned out that that particular drug under a different name was the drug that was being used in Japan.

When you look at the way we treat certain diseases like lymphomas, we individualize therapies depending on what sub-type of disease patients have. In modern language, this is called precision medicine. We think, a lot of us that do basic research, that there are many different types of pulmonary hypertension, and that in the future, people will be tested for what specific type of pulmonary hypertension they have, and they'll be given a specific cocktail of drugs which may vary from patient to patient.

The people that I do research with and discuss at conferences now believe is that in the modern era, most patients need to be on some form of basic vasodilation. Then on top of that, we want to layer a therapy that will specifically target the mechanism by which their blood vessels are actually closing up. What I mean by that is when you have pulmonary hypertension, the muscles around the blood vessels contract. Those need to be relaxed, and that's what vasodilators do. If you think of the blood vessel as a donut, except that the donut hole is filled with junk that shouldn't be there, that's called vascular remodeling. At least that's one part of vascular remodeling. The new therapies that we're layering on we hope will reverse the vascular remodeling, open up the donut hole so that blood flow can flow through the blood vessel, and that will relax the pressure that's on the right heart, which is currently the reasons why pulmonary hypertension patients don't do well in the end. It's because there's so much pressure building up because they can't get blood flow through those arteries, that the right heart fails, and the patient passes away, or they go on to transplant.

The hardest thing is it's a rare disease, people have different ideas about why pulmonary hypertension is developing, so if you take a rare disease, and you combine it with competing hypotheses about what's going on, that creates barriers. Basic science would push forward strong hypotheses that are confirmed by, not only one group, but several groups. That there's a very strong historic rational for why the case that's being built is strong, and with a mechanistic idea in place, they survive the marketplace of ideas. That is ideally how it would happen.

For example, right now I think there are two very strong ... I was going to say competing ideas, but actually, the more you know about it, I think that it's they're not competing, they're complementary, which is the inflammatory hypothesis, which is that inflammation is an important cause for why people develop pulmonary hypertension, and the metabolic theory for pulmonary hypertension, which means that the way the metabolism of blood vessel cells in the lung and also the right heart contributes to the downfall of the disease. Well, as we learn more and more and more about the metabolic theory and the inflammatory theory, it turns out that abnormal metabolism can drive inflammation, and inflammation can drive abnormal metabolism, so what appears to be competing hypotheses from different investigators may actually be complementary. Again in the future, when you think about a cocktail of medications that you might take, one might be addressing the metabolic problem, and one might be specifically targeting an inflammatory mediator. That doesn't mean that the investigative teams are wrong.

First of all, everybody that has pulmonary hypertension, I think it's irrefutably important that they be on baseline vasodilation. Once we accept that you should be on a vasodilator, and that there's a standard of care that all patients should get, we now have a new starting line. Then putting your toe in the water with regards to clinical trials, what that means is having a willingness at the national level to try out new therapies in smaller trials that are coordinated through a group effort, just like we do with oncology trials across the United States. What that requires is like-minded investigators, a willingness to collaborate, team science, a willingness through groups such as yourself [www.phaware.global], through the NIH, and through simple congregations of academic societies like the American Thoracic Society, and having investigators getting together, potentially even voting once the understand the literature, on let's go into this direction, or let's go into that direction, or let's go into several directions at once. That might be one way of doing it. It's actually the way that I think that cancer treatments have advanced as well.

We have treatments that right now it's not clear if they're going to be effective or not effective. A patient may end up getting what's called a placebo as part of the trial, and sometimes it can be really hard to explain to someone who's suffering from a potentially fatal condition about why they would want to participate in a trial, one, that may not work, but, two, in which they may not even get a placebo. What I tell them is that for a lot of people that participate, the knowledge that they are giving the basic science that we can learn in terms of biomarkers in their blood, how they respond, is in and of itself can give satisfaction in their own lives, regardless of whether the therapy helps or not.

Hopefully it will help, but the way that we move the field forward is not only by having scientists and clinical researchers working as a team, but also having the pulmonary hypertension [community] working together as a family, accepting that, again, they may get a placebo, but they're in the trenches fighting a disease, just like we're in the trenches fighting a war. Just their act of participating is going to give us information about why people develop pulmonary hypertension, and I think now we're in the era where there's a great willingness for people to get together and cooperate, and try different therapies, and get biomarkers which might distinguish different patient subtypes from each other, and come up with whole new regiments for patients such that in five to ten years I think we're going to be looking at a different way of treating patients with PH.

My name is Mark Nicolls, and I'm Aware That I’m Rare!

Listen to “I’m Aware That I’m Rare: the phaware™ podcast” at www.phaware.global/podcast. Learn more about pulmonary hypertension at www.phaware.global. #phaware #phawarepod