The Future of PAH

Charles Burger, MD: Universally, it appears that the more modern studies of the agents approved for pulmonary arterial hypertension are having a positive impact on hard clinical outcomes. This is all very exciting. We’re also learning that it is quite likely that combination therapy used earlier in the course of the disease will have a positive impact on these hard outcomes. What’s not known, of course, is what exactly the best combination is. So, for example, in AMBITION, we know that tadalafil and ambrisentan work together in a positive way. But, if you took sildenafil, which is in the same class of tadalafil, and combined it with macitentan, which is in the same class as the ambrisentan, would you have a similar type of positive impact on outcome? We would hope that that would be true, but it’s not known. And it makes a difference, of course, when you’re talking about which drugs are prescribed, which drugs are approved, and which drugs are on formulary and available to the patient. There’s some unknown in that regard, and I think making assumptions could be somewhat precarious.

Secondly, if 2 drugs are better than one drug, is a 3-drug combination better than a 2-drug combination? And going forward, there are plans to study combination triple-drug therapy with combination 2-drug therapy. It will be very illustrative to see whether that has an additional positive impact on outcome. Lastly, I think we have to keep our eye on the ball. These therapies are expensive. They have high-profile adverse events, so we really need to show in a scientific way that combining therapies are the right thing to do for our patients, and get away from making assumptions where we can over time. Obviously, before we know for sure, we have to make clinical judgments. But, it would be very nice to have these issues settled in a prospective study, and I anticipate that we will over time.

The genetic studies have demonstrated that approximately 5% to 6% of patients with group 1 pulmonary arterial hypertension will have a mutation in what’s called bone morphogenetic protein receptor II, which controls cellular activity. It is part of a larger family of molecules called transforming growth factors that act on cells that basically result in gene transcription. And then, the gene, when it’s transcribed, produces proteins, which basically is how a cell works. When there’s a mutation in that signaling system, there’s a predisposition to developing pulmonary arterial hypertension. Only 20% of the patients with this genetic mutation demonstrate the disease, however. There is an issue of what we call penetrance, so the mutation is there, but the disease doesn’t declare itself clinically. So, it’s the beginning of understanding that there are subsets of patients with predisposition to pulmonary arterial hypertension, as it would relate to genetic mutations.

But, moving beyond that, it is still going to be a challenge, because only 1 in 5 patients with a mutation genetically acquired a manifestation of the disease. How useful is it to know if you have the mutation? Our patients are sent to a medical genetics counselor to make a decision about whether they want testing, either for themselves or in their families, based on the information that I just provided and other additional information, so that they can decide whether the testing is right for them. Really, at this point, it’s at an experimental stage to help us track patients with this particular mutation to see if their outcomes are different. We don’t treat them differently in terms of drug decisions. We don’t necessarily screen for this in all patients because of the problems that I just articulated. So, more needs to be teased out as to the usefulness of identifying these mutations in terms of its implications for clinical decisions. It’s a very useful line of scientific inquiry, which is very actively pursued in a lot of academic centers, but it’s not really ready for prime-time, if you will, in the clinical environment.