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Victor F. Tapson, MD - phaware® interview 181

Aug 17, 2018

Victor F. Tapson, MD from Cedars-Sinai discusses the different pathways that medical professionals and researchers utilize in treating pulmonary arterial hypertension patients.

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 research interests are pulmonary hypertension and pulmonary embolism.

I want to talk about the different pathways that we utilize in treating pulmonary arterial hypertension.

As you know, our first big drug back in the '90s was prostanoid. The prostanoid pathway is clearly important. Certain patients maybe don't have enough prostanoid or don't have enough prostanoid synthase to produce prostacyclin to help dilate their blood vessels and their lungs and help prevent remodeling. Prostanoid's a big pathway, and that tends to be a really heavy hitter. When we get someone really sick, we get them on parental prostanoid therapy.

The endothelin receptor pathway's a big one. We still think endothelin is probably the most potent inflammatory mediator in the human body, a natural mediator that really causes vasoconstriction and remodeling. So by having an endothelin receptor antagonist, like we do with bosentan and subsequently ambrisentan and now macitentan, this has been pretty exciting being able to hit two pathways, a prostanoid and then in about 2002 when bosentan was approved, bosentan and subsequently new drugs. Hitting both pathways is important.

Another thing we learned about pathways is hitting two pathways at once might be a good idea. We've done the AMBITION Study now with tadalafil versus ambrisentan, versus both tadalafil and ambrisentan up front. We saw that the results of ambrisentan plus tadalafil up front were better than either drug alone. So clearly hitting two pathways makes sense.

Now, the third pathway is the nitric oxide pathway. We all feel like that's a very potent one. We would probably give inhaled nitric oxide to everyone if we could. It's a little bit inconvenient, so work is being done in that area.  But we've got the PD5 inhibitors, sildenafil and tadalafil. And now we've got the soluble guanylate cyclase activator riociguat to use for PAH and CTEPH.

So now we've got three pathways we can use. Should we use all three pathways? We do this in cancer. We treat people upfront. We blast them out of the water. We give them induction therapy, we give them chemo, sometimes radiation. There's a cancer analogy here. I think treating patients aggressively upfront makes sense. That's why the TRITON Study is now underway, which is hitting three pathways all at once. It's hitting the nitric oxide pathway with tadalafil, the ERA pathway with macitentan, and prostanoid pathway with selexipag versus just tadalafil and macitentan alone. So will adding that prostanoid pathway early upfront make a difference? Many of us think it will.

It's probably true that different patients have different pathways that are more important to them than others. Maybe some patients have abnormal endothelin receptors, maybe some have reduced levels of prostacyclin synthase, or an abnormal NO pathway. These are things we need to learn more. Maybe we can tailor our drugs to certain pathways if we learn more about these pathways. Maybe we'll find out a patient can benefit from just two drugs alone, and they'll do just great. So we need a lot more science, a lot more study to learn how important each pathway might be in the individual person.

Now, keep in mind that as I wrap up here that there are other pathways out there, a lot of other exciting areas being studied now. We're specifically looking at inflammation and also the cancer pathway, analogies to PAH. The future is very exciting in PAH.

I'm Vic Tapson and i'm aware that I'm rare.

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