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Richard Channick, MD - phaware® interview 180

Aug 14, 2018

Richard Channick, MD discusses the importance of clinical trials and how various approved pulmonary hypertension therapies work on specific pathways.

I'm Rich Channick. I'm from Mass General Hospital in Boston and I run the pulmonary hypertension program there.

The field of clinical trials in pulmonary hypertension has evolved greatly from back when I started doing this many years ago when there really were no therapies and so the clinical trial meant that the patient was getting a drug or they were getting nothing, a placebo, but they had no other option. Then, obviously starting in the mid 90s when Flolan got approved and subsequently when all these other therapies came on, it's been amazing the progression in this area.

We now have ostensibly 14 approved therapies for pulmonary hypertension, but we're not done yet. All of us who do clinical research understand that even though we have an incredible number of options that have really changed people's lives and extended people's lives with this disease, we're not curing the disease. There are patients still who don't respond to these medicines, so it's very clear that more is needed.

We don't want to sort of rest on our laurels and think that because we have all these therapies, we don't need to do anything more. We need to do more clinical trials. We need to develop novel ways to treat this disease and that may be medication. It may be devices. It may be procedures. All of us who have been in this field for a long time understand that we just can't sit still. Fortunately, that's not happening. There are many areas of clinical research going on.

From the patient's point of view, we think it's equally important to understand that without patients kindly agreeing to go in trials, and it clearly is a selfless act, because we don't know if a new therapy is effective or even safe. That's why we do research to be able to advance this field. Our approved drugs work on specific pathways.  Now, what do we mean by pathways?

Within the cells, in the blood vessels, in your lungs, there are different molecules that work on all the cells in your blood vessels. And we know that, with pulmonary hypertension, the problem is that what we call the smooth muscle cells are too constricted. So they're squeezing and that narrows the vessel. And we also know that the cells in the blood vessels thicken over time, and that narrows the blood vessels as well. So why does that happen? How does that happen?

A lot of research has determined that there are certain substances within the blood vessels that get out of whack in patients with pulmonary hypertension. And that leads to this thickening and narrowing of the blood vessels. And fortunately investigators in labs have identified what chemicals those are that do those bad things to the blood vessels and the therapies have been developed to address that problem.

So there's really three chemicals or three pathways that have been identified and for which we have approved therapies. There's what we called the prostacyclin pathway. Prostacyclin is a chemical produced in blood vessels throughout the body, including the lungs, that when produced and released relaxes the blood vessels. So, there's good things. And we know very clearly that patients with pulmonary hypertension have a deficiency of prostacyclin. So, it makes a lot of sense to either give back what's missing of the good stuff or make the patient produce more of the good stuff. And so for that reason, these drugs work through the prostacyclin pathway to enhance it, to increase it.

The second big pathway is the nitric oxide pathway. Now, similar to a prostacyclin, nitric oxide is produced by blood vessels and the cells in the blood vessels, and relaxes the blood vessel and keeps it from thickening. And we know similarly that patients with pulmonary hypertension have a deficiency of nitric oxide. You can't give back nitric oxide. It's in a gas, although there are studies looking at doing that. But you can do things to enhance the effects of the nitric oxide. And you can either block the breakdown of the substance it produces, which is called Cyclic GMP. And so drugs like PDE5 inhibitors, Sildenafil and Tadalafil, block that. Or drugs like Riociguat actually work in a different way on the nitric oxide pathway, where it increases the enzyme that then produces the Cyclic GMP and has good effects. So there are different ways to work on the nitric oxide pathway.

Then the last pathway is the endothelin pathway. Unlike nitric oxide and prostacyclin, endothelin does bad things when it's overproduced. It causes constriction and thickening of the blood vessels. So it makes sense you give a drug that blocks that effect, so those drugs are called endothelial receptor antagonist or ERAs. And they bind to the receptor and block the endothelium from binding to that receptor so it can't do those bad things.

The neat thing about it is that we now have studies that have come out that shows that blocking more or even all of the pathways in a patient does more than each one alone. So the whole idea of combination therapy makes total sense biologically and it works clinically. So it's a beautiful example of science partnered with clinical investigators to produce these very effective treatments.

I'm Rich Channick and I'm aware that I'm rare.

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