PAH: Understanding the Three New Drug Therapies

Introduction

Editor's Note: Pulmonary arterial hypertension (PAH) is historically an incurable disease with a poor prognosis. However, recent advances in treating PAH have increased arsenal of treatments available to the physician for managing its symptoms.

The actual incidence of PAH, specifically the idiopathic form, is not well characterized, but it is a relatively rare condition in which the pulmonary arterioles in the lungs become narrowed, blocked, or destroyed. As treatment possibilities increase in number and complexity, so does the imperative for hospital physicians to call upon PAH specialists to assist in the comanagement of these complex patients, even if just for a single consultation.

Medscape caught up with Steven D. Nathan, MD, Director of the Advanced Lung Disease and Transplant Program at Inova Fairfax Hospital in Falls Church, Virginia, to talk about these expanding options.

Understanding the New Treatments

Medscape: I understand that three new drugs to treat PAH have been approved in the past year or two.

Dr Nathan: Yes, indeed. The three drugs are riociguat (Adempas®), which acts on the nitric oxide pathway and further downstream as a direct guanylate cyclase stimulator, as well as sensitizing the receptor to endogenous nitric oxide.

The second is an endothelin receptor antagonist (ERA) called macitentan (Opsumit®). The third is oral treprostinil, marketed as Orenitram™, which is the same compound as the treprostinil that is now used for intravenous, subcutaneous, or inhaled administration.

Medscape: How are these new drugs changing overall approaches to treating PAH in the hospital?

Dr Nathan: To start off, riociguat is the first drug in its class. What's interesting about riociguat is that it was studied in two independent studies for both group 1 pulmonary hypertension (PH), which is PAH,^[1] and group 4 PH, which is chronic thromboembolic pulmonary hypertension (CTEPH).^[2] Both of these studies were positive, resulting in the approval of the drug not only for group 1 but also for group 4 PH, where it is the first and only drug approved for this particular group. Previously, there were no medical treatments available for group 4 PH—only surgical therapy in the form of thromboendarterectomy, which still remains the procedure of choice. But it is somewhat of a breakthrough.

The role and place of riociguat in treating group 1 PAH is more complicated, because we already have many different agents available. Because it acts on the nitric oxide pathway, it should not be given with phosphodiesterase-5 (PDE-5) inhibitors. It doesn't seem to have a dominant role in group 1 disease, but it can be used instead of tadalafil (Adcirca®) or sildenafil (Revatio®).

Even though riociguat was studied and approved as a monotherapy, in reality, out in the clinical trenches, it will probably be used as either an add-on therapy with an ERA or prostacyclin—or in combination with both. I think most physicians are going to default to the PDE-5 inhibitors, because these are cheaper and can be given once a day in the case of tadalafil, whereas riociguat has to be given three times a day.

The second drug, macitentan, is now the third ERA to be approved. The study that got it approved was the SERAPHIN study, which was published in the New England Journal of Medicine.^[3] This was the biggest study to date in PAH, with over 700 patients enrolled, and follow-up over a longer period than studies of other drugs available for PAH. This study had a morbidity endpoint, consisting of things that are commonly regarded as representing clinical worsening, including mortality.

Despite the robustness of the study, it remains unknown whether it's any better than the currently available ERAs ambrisentan (Letairis®) and bosentan (Tracleer®). A head-to-head study between the agents would be needed for such a comparison.

Nonetheless, macitentan does provide us another option with regard to the ERA class of agents. Where it shares an advantage with ambrisentan over bosentan is that their liver function toxicity profile is more favorable, and one doesn't need a Risk Evaluation and Mitigation Strategy (REMS) for hepatic toxicity to monitor liver function on a monthly basis.

Oral treprostinil is an interesting drug, given that we've used it in all of the other formulations I mentioned previously, with very good clinical efficacy. It has been a struggle to demonstrate its efficacy as an oral treatment. A couple of previous studies of combination therapies were not positive, but the study of oral treprostinil as monotherapy^[4] was positive, and it was approved as such. Realistically, what's likely to happen in the trenches is it's not going to be used as a first-line oral therapy, but possibly second-line or more likely third-line, and also perhaps to transition patients from parenteral prostanoid therapy.

Medscape: How are these new drugs changing the landscape of treatment, given the wide range of other treatments to choose from?

Dr Nathan: "Revolutionize" is perhaps too strong a word. But what's definitely new and different is the use of riociguat for CTEPH, where we didn't have an approved agent before. That is a bit of a sea change, specific to group 4 PH.

Macitentan, by contrast, is not a game changer, but incremental, giving us a third choice of ERAs. I also think oral treprostinil does change the game a little, because the willingness to prescribe or accept a medication is related to the logistics of its administration, and taking a pill is easier. So through its relative ease of administration, it widens the spectrum of patients who might be candidates for prostanoid therapy.

Medscape: How well do physicians who work in the hospital understand these medications—and what do we want them to take home from this article?

Dr Nathan: Patients with PAH should be managed, or at least comanaged, at a comprehensive care center or center of excellence that has expertise with these drugs. I think the availability of the three new drugs just reinforces this concept, because it makes the treatment algorithms and choices even more complex. Thus, it becomes even more incumbent on hospital physicians to involve pulmonary hypertension experts in the care of these patients. If the drugs are used inappropriately, then the patient's outcomes will be compromised.

Also, the dosing of drugs can be quite difficult, especially for oral treprostinil—where you have to dose-adjust carefully, not dissimilar to what we do with intravenous and subcutaneous treatment. There might also be occasions that patients on oral treprostinil might need to be switched to parenteral therapy—for example, if they are being kept NPO for whatever reason. If you don't have someone with experience and expertise in the various forms of administration, dose titration, and monitoring of these patients, that's not in the patient's best interest.

PH experts are not necessarily looking to assume the total care of these patients, or to channel them away from their primary care physician. But if we have an opportunity to comanage them and be there for support and back-up, then we can make sure everything appropriate—diagnostic, prognostic, and therapeutic—is being done.

Medscape: Are there still some hurdles when it comes to recognizing PAH in patients, and in physician education in terms of recognizing the different categories and when to seek out pulmonary/cardiology PH experts?

Dr Nathan: I think there are still issues and educational needs. There's a wide spectrum, from those who are very savvy to those who are not quite as savvy in making the diagnosis. Assuming that everything has been done appropriately and the patient is now on therapy, I think a lot of times if the patient comes in feeling a little better, physicians tend to be happy with that.

But the bar has been raised with all of these available therapies. We really need to strive to improve patients' functional status as much as possible. Sometimes the patient gets a little better on one drug, but that might not be good enough, because they could get a lot better on two or three drugs.

Medscape: Where do you think the menu of treatments for PAH is going?

Dr Nathan: Thankfully, despite the availability of many treatment options, there's growing interest in developing new drugs. There are a number of agents in development beyond the currently available drugs, which mainly address the balance between vasodilation and vasoconstriction. These investigational therapies include antiproliferative agents, aimed at the root cause of PAH, with the potential of being more potent disease modifiers.

The Pulmonary Hypertension Association is also designating comprehensive care centers. Where I believe we are going with this complex menu of medicines is that patients will be encouraged to be referred to these centers. It might even evolve to where some insurance companies might mandate, before physicians start patients on these expensive therapies, that the patient be seen at least once at one of the comprehensive care centers, to make sure appropriate diagnostic testing has been performed.

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