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Victor F. Tapson, MD - phaware® interview 173

Jul 20, 2018

In this episode Dr. Victor Tapson from Cedars-Sinai discusses novel Pulmonary Hypertension Therapies.

Hi, everyone. I'm Vic Tapson. I'm at Cedars-Sinai Medical Center in Los Angeles. I'm in pulmonary critical care medicine and my main clinical and research interests are pulmonary hypertension and pulmonary embolism.

So today let's talk a little bit about novel PH therapies.

We've really come a long way in the past 20-some years with new drugs. We have three drug classes we use pretty exclusively now. We have prostanoids, we have endothelin receptor antagonists, and we have the nitric oxide pathway drugs, the PDE5 inhibitors and riociguat. Pretty exciting, but we need more. We've reduced the mortality in this disease over the years, but it's still a very significant disease with a mortality.

Novel therapies are important for certain reasons. PAH clearly involves multiple pathways. We know combination therapy is beneficial. We learned that from the AMBITION study. Some patients will fail the current therapies we offer them. Our strongest therapies are pretty inconvenient, IV therapy, subcutaneous therapy. Our current therapies do have some adverse effects, so moving on is important.

There's some new things coming out, I'll mention a couple things, we're lucky to have a couple of new drugs over the past five years. Macitentan, we have selexipag now. A new drug is being studied called ralinepag. Raleinpag is a longer acting kind of oral IP prostanoid receptor agonist. Studies are underway now. We don't have a lot of data yet.

I always like to mention one drug to maybe not forget about and that's Imatinib or Glivec. Remember this CLL drug? Some case reports a few years back showed that this drug really seems to work well in pulmonary hypertension. We did a big study called IMPRES. In IMPRES, Imatinib improved six-minute walk tests, it improved PVR, it improved cardiac output, it improved BMP. But, there was a bleeding complication. In patients on Coumadin, there were eight intercranial hemorrhage events. This pretty much killed the study. It's too bad, because probably without anti-coagulation, the drug may be quite safe.

A real key concept now with novel therapy is up front triple therapy. Triple combination therapy based on Olivier Sitbon, MD, PhD, our French colleague's study of 19 patients with triple up front therapy, which included IV epoprostenol.

The TRITON study was embarked on. The TRITON study includes triple up-front therapy with tadalafil, macitentan, and selexipag, versus just tadalafil and macitentan alone. This study is underway, it's exciting. Maybe we'll find out PH can benefit from triple therapy up front. We'll know soon. We'll probably know more by some time in 2019 or later.

I want to just mention briefly that there are a lot of new mechanisms to explore in PH. One of them is this cancer PH analogy. It's actually very exciting. There's something called the Warburg effect, which aerobic glycolysis. You're not supposed to have aerobic glycolysis. That's supposed to be anaerobic. But, cancer cells do this so they don't have apoptosis, they don't have normal cell death. There's a lot of different mechanisms there with cancer analogy and I'll come back to it in just a minute.

I want to mention, inflammation's a big topic now. We've got a drug we're studying now called Bardoxolone. We've got some early data already with Bardoxolone. There's gene mutations, there's environmental issues, there's something called epigenetics, which to me, is really fascinating. I'm not a geneticist, but these micro RNA's, DNA methylation, you can hypomethylate DNA and that leads to what you see in cancer. We think some of these effects occur in PH, too. We've got to keep in mind this cancer analogy.

Another concept I want to emphasize is this business of inflammation. There's inflammatory cells we see in PH, cell perforations induced by things like urokinase, which is an inflammatory inducer. I mentioned the drug Bardoxolone. Bardoxolone is a Nrf2 activator, and Nf-kappaB inhibitor. This basically prevents inflammation. There's an ongoing LARIAT study right now, we actually have a little bit of data in IPF in sarcoidosis now. Small studies, small numbers of patients, but improved walk distances in both IPF and sarcoid. Again, small numbers. We need more data.

We unfortunately learned that one of our recent drugs we've been studying failed. Ubenimex, this is a leukotriene B4 inhibitor. Thought this might be a good one, but it failed in the phase 2 B study. No improvement in PVR, no improvement in walk distance. So this drug's going to continue to be developed in other areas, but probably not pulmonary hypertension.

There's a number of novel targets, I just want to again emphasize this cancer analogy. The pathogenesis of PAH has some real fundamental similarities with cancer. PH smooth muscle cells adopt this pro-proliferative, pro-survival, invasive phenotype. And in PAH, there's this environment of persistent inflammation. In cancer, we see deregulated cellular metabolism. We see inflammation, we see sustained proliferation, escape from apoptosis, like I mentioned. A number of different mechanisms that have been cancer hallmarks have been found in PAH. I won't go through them all, just to be brief here. But sustained proliferative signaling. There's P21 and P27 implication here. There's P38 MAP-K activation. Things have been found in PAH, and these are kind of cancer hallmarks. Evasion from growth suppressors, resistance to cell death, tumor-promoting inflammation, et cetera. De-regulated cellular energetics, the Warburg effect, like I mentioned. These are things we can kind of attack and consider in the PH world.  A lot of interesting cancer analogies that we need to think about with PAH.

One thing to keep in mind is certain anti-cancer drugs have already demonstrated beneficial effects in experimental PH. One of those is this PDK inhibitor called dichloroacetate, and that has to do with this Warburg effect. There are anti-cancer drugs being tested right now in clinical trials.

One more concept I want to mention is this business of microvascular regeneration. Duncan Stewart's a real expert in this angiogenesis area, up in Canada. They've been doing some great research with gene transfer of angiogenic factors that seem to be effective in preventing PAH in experimental models. Nitric oxide appears to be a critical mediator of angiogenesis. What they do is they load up these cells with endothelin, NO-synthase gene enhanced progenerative cells and they give them. There's a study ongoing now, the SAPPHIRE study, where they're giving these gene-enhanced autologous endothelial proliferative cells in patients with PH, they're giving them monthly injections. Endothelial progenitor cells, EPCs, so we'll learn more.

At Cedars, right now we're doing research with these CDCs, we call cardiac progenitor cells. Eduardo Marbán, MD, PhD is a real world expert in this field. He's involved with our Heart Institute. And Mike Lewis has gotten the alpha study off the ground. We're giving these cardiosphere-derived cells with potent anti-inflammatory, immunomodulatory properties to PH patients, and the study's underway. We got good data in a monochrolian rat model, and now we're studying this in patients. So we'll have more data. We've learned a lot from animals, we're going to learn a lot in people.

One final point I'll mention, and that's this business of pulmonary artery denervation. The group Rothman and colleagues have figured out, mapped the nerves around PAs. They've figured out what the anatomic distribution is. We know sympathetic tones increased in patients with PAH. Increased sympathetic tone increases PA pressure. And by zapping these nerves with radio frequency ablation, it's pretty cool. You zap these things and we're learning the pressure seems to come down. Ongoing trials in China, Croatia, Israel.

So let me summarize here now. A lot of really exciting things going on in PH in addition to what we already have. A computer modeling a pulmonary vasculature, pharmacogenomics, inflammation, epigenetics, endothelial progenitor cells that can be juiced up and given to patients, xenotransplantation, cardiac regeneration. New cellular mechanisms, the cancer analogy. There's so many different things and ongoing studies now.

In conclusion right now, we've got three pathways we're hitting for PAH. This cancer analogy and inflammatory mediator concept, I think, is going to be really important in the future in PAH. Right now, we've got a very good armamentarium, it's going to get better in the future.

I'm Vic Tapson, I'm aware that I'm rare.

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