Ron Zolty, MD - phaware® interview 516

Dr. Ron Zolty delves into groundbreaking advancements in treating pulmonary arterial hypertension. From the historical use of vasodilators to the revolutionary promise of sotatercept and seralutinib, Dr. Zolty unpacks how science is moving closer to halting—and possibly even reversing—PAH.

This Special Edition episode is sponsored by Gossamer Bio.

My name is Ron Zolty. I'm a cardiologist working in advanced heart failure and heart transplantation. In my training, I had to do a lot of catheterizations in patients with pulmonary arterial hypertension. I trained at the University of Colorado in Denver, which is considered one of the best centers in pulmonary arterial hypertension. Working with patients in the cath lab, I fell in love with PAH, now leading a pulmonary hypertension program here in Omaha, Nebraska.

Today, I would like to speak about some innovations in the field of pulmonary hypertension. As you may know, pulmonary arterial hypertension is a progressive, lethal disease. Patients, unfortunately, die from pulmonary hypertension if not treated.

We should go back a little bit to the pathogenesis at the mechanism of what we believe causes pulmonary arterial hypertension. We know that when patients suffer from pulmonary arterial hypertension, they have what we call endothelial disruption. Endothelial is the inner layer covering the vessel of any vessel and especially the pulmonary arterial tree. If you have any damage of this endothelial layer, you are going to make some small thrombi, some small clots.

One of the initial treatments of pulmonary hypertension was in the eighties to treat these patients with anticoagulation. Unfortunately, there was never any prospective study looking at the benefit of anticoagulation, only retrospective studies. Most of them showed that there is some benefit of anticoagulation blood thinner. However, because there was never any prospective study, it's just a 2b indication, not everyone needs to be on anticoagulation because again, it hasn't been shown really to improve survival in patients with PAH.

The second main phenomenon that patients have with pulmonary hypertension is vasoconstriction. Vasoconstriction, meaning that the vessels tighten when you do have the disease. That's the reason for the three classic pathways we treat today. Pulmonary arterial hypertension, we know that patients with PAH have too much endothelin, which is one of the most potent vasoconstrictors we have in our body. So we block this endothelin causing less vasoconstriction and vasodilator effect.

We also know that patients with PAH don't have enough prostacyclin, so we do substitute this lack of prostacyclin with some prostacyclin. We do have IV, inhaled, and oral prostacyclin to give to patients. The third pathway, which is also a vasodilator pathway, is the lack of nitric oxide. Patients with pulmonary hypertension have a lack of nitric oxide, and therefore we give them a PDE5 inhibitor like sildenafil or tadalafil or a SGC stimulator like riociguat to increase the nitric oxide pathway, increasing cyclic GMP. Cyclic GMP, really vasodilates.

But all these therapies, these classic therapies do not stop the progression of the disease. They slow down the progression of the disease without stopping the disease. We also know, and that's the last point and the newest point I want to make, when patients do have pulmonary arterial hypertension, the wall of the vessel gets thicker. If the wall gets thicker, the lumen where the blood travels gets smaller and smaller. That's the reason why patients get less blood, less oxygen, less hemoglobin, less oxygen, more shortness of breath. This thickening of the wall gets what we call an increase in the resistance, leading to right side heart failure.

About 15 years ago, there was a paradigm shift in the understanding of pulmonary arterial hypertension thinking, why do these patients have a thickening of their wall? It's because there is proliferation of endothelial cells, smooth muscle cells like neoplasia, like a tumor. Maybe if we block this progression, this proliferation, we may stop the disease and maybe even regress the disease in making the wall thickness less thick and smaller.

Therefore, about 15 years ago, there was a very interesting clinical trial with a drug called Imatinib or Gleevec. Gleevec has, for patients with chronic myelocytic leukemia has been a revolution. Patients with CML in the past needed to have a bone marrow transplant. With the administration today of Gleevec it’s been a revolution and patients can live with CML, with this chronic myelocytic leukemia for years and years with absolutely no progression of their disease.

Similarly to CML, the idea was maybe if we give an agent like Gleevec or Imatinib to these patients, we may stop the proliferation of endothelial cell and smooth muscle cells in the wall of the vessel and stop or even regress the disease. This trial, called IMPRES, was done about 13 years ago. The results of the study were absolutely beneficial. However, more than 30% of patients quit the study because of side effects, and also patients on anticoagulation, on blood thinners developed some intracranial hemorrhage. The FDA, because of the side effect, decided not to approve this drug for pulmonary hypertension.

Just to give you a background that there is really a paradigm shift in the understanding of the disease. The new drug that has recently been approved by the FDA is being called sotatercept. That's another mechanism. We know that in our system, every cell has like a yin and a yang. There is activin, a system which stimulates the gene while the bone morphogenetic protein system is slowed down. The activin slowed down the proliferation of cells.

In our system, in a normal system, you do have a balance between BMP and activin. We also know in patients with pulmonary hypertension, they do have too much activin. This new medicine, sotatercept blocks the activin. Activin is like an accelerator. It does promote proliferation of cells on the gene. If you block the activin, you recalibrate the BMP and the activin, reducing this proliferation of cells. Sotatercept was shown really to improve patient pressure as well as improving their six-minute walk distance as well as their quality of life. Sotatercept has been approved by the FDA for the last year and really has changed the field of PAH.

Another group similar to the Gleevec, but as I said, Gleevec was not approved by the FDA because of the side effects. The idea was maybe if we could give a Gleevec as an inhaler without systemic effect, patients would absorb the drug into the lungs without having any side effects. There was a clinical trial with inhaled imatinib, inhaled Gleevec if you want. Unfortunately, the study was not positive, because most likely Imatinib was not absorbed by the lungs.

However, another company was able to produce a super imatinib, which is being absorbed by the lungs called GB002 or seralutinib showing a significant improvement in the pressure, as well as the PVR. Currently, there is a Phase 3 with this drug as an inhaler.

So, in summary, I just want to say the drugs we have currently until now were vasodilators, they do slow down the progression of the disease but don't stop the disease. Now, we do have one drug approved by the FDA. Hopefully, a second one will be approved. These two drugs stop the proliferation that occur in pulmonary hypertension and hopefully will stop the disease and potentially even regress the disease. We are getting closer to maybe a cure of the disease with agents like sotatercept and seralutinib. 

Thank you for listening. My name is Ron Zolty and I'm aware that my patients are rare.

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