Jul 27, 2018
Dunbar Ivy, MD discusses the pipeline of potential PAH pediatric therapies.
Hi, this is Dunbar Ivy. I'm Chief of Pediatric Cardiology at the University of Colorado's School of Medicine, and Director of the Pediatric Pulmonary Hypertension Program, at Children's Hospital of Colorado.
I'm excited to talk to you today about the potential therapies that are in the pipeline for treatment of pulmonary arterial hypertension.
Most of these therapies are going to be studied in adults first, and then as we learn about them, we will apply them to children. There have been some very exciting discoveries in the last several years, by the group at Stanford. One is looking at the drug FK506, or Tacrolimus, and this drug is used in patients with transplants, but it's also been found, by their group, to stimulate BMPR2 signaling.
We know that BMPR2 is the most common mutation, but we now are realizing that, as a field, that there is a decrease in BMPR2 in most forms of pulmonary hypertension, so they have some very early, but exciting, work suggesting that this drug, that's already approved for different use, at very low doses may stimulate BMPR2 and help patients in a different way than the common three classes of drugs that we have. So that's very exciting.
The other interesting avenue is the avenue of sex hormones, and in particular, estradiol, estrogen. So we know that women are much more likely to have pulmonary hypertension. We know, however, that women with pulmonary hypertension do better than men. We know women that are pregnant can be at risk for pulmonary hypertension, and we also know that estrogen levels are higher in men and women with pulmonary hypertension. So several groups have begun to look at blocking estrogen as a way to potentially treat pulmonary hypertension, and there are some animal studies that suggest this may be a reasonable approach. Steven M. Kawut, MD at the University of Pennsylvania, has completed an initial trial with a drug called Anastrozole, which blocks the conversion of androgen to estrogens, and so that trial had some initial positive results, and so there's a new trial that's going to be larger Phase 3 trial, will be starting soon. Likewise, the group a Vanderbilt are looking at Tamoxifen as a potential treatment, so I think this is an interesting area, that hopefully will help us understand the role of estrogens, and maybe provide a different treatment, as well.
We are finding new genes that are implicated in pulmonary hypertension, and particularly in children. One is the TBX4 gene, and so we have seen patients who have lung parenchymal disease and pulmonary hypertension, that this has been found in, so this is an exciting avenue to learn about why some patients may develop pulmonary hypertension. There've been some attempts to treat patients with potassium channel mutations. As we learn more about the genes it will again send us in directions that will help us to find new avenues for treatment.
One challenge for children is that, and I think somewhat appropriately, trials need to be done first in adults, to look, particularly at safety and efficacy. The challenge for looking for drug therapies in children, is that once these drugs are FDA approved, then they are used off-label, and so then families, understandably, are hesitant to enroll in a clinical trial. However, we know that when we do that, when we are not sure of the dosing, of the drug exposure and the effect, and so many people are working with the FDA and the European medicine agencies to try to get some of these trials started earlier so we can get real information in children, with regards to how do we use the drugs, and do they work as well in children as they do in adults, and what are the effects of combinations. So, for example, children's metabolism of drugs is much higher, so certain combinations may not be as effective.
So I think that clinical trials are very important. I think the physician community and the regulatory agencies realize that parents don't want to enroll their children in a placebo-controlled, or sugar pill, trial, but we're looking at ways to say, "What if you're on a background therapy?" And if we're not sure about a new drug, maybe some people could get it, and some not, and really show that it works.
So we're looking at trial designs that would have a strong safety net, and minimal risk to patients, and further, the use of cardiac catheterization has pretty much gone by the wayside to be used in clinical trials in children.
My name is Dr. Dunbar Ivy, and I'm aware that I'm rare.
Learn more about pulmonary hypertension at www.phaware365.global. Never miss an episode with the phaware® podcast app. Follow us @phaware on Facebook, Twitter, Instagram, YouTube & Linkedin Engage for a cure: www.phaware.global/donate #phaware #phawareMD @ChildrensColo @DunbarIvy