Have the New Pulmonary Hypertension Drugs Changed the Game?

In March, we reported on back-to-back FDA approvals for two treatments in pulmonary arterial hypertension (PAH). In this report, we follow up on what has happened since.

After the FDA approved both combination macitentan/tadalafil (Opsynvi) and the biologic therapy sotatercept (Winrevair) for WHO group 1 pulmonary hypertension (PH, or PAH) over the course of one week in March, one treatment appears to have had a more successful launch than the other.

Sotatercept uptake “has been rapid and, I believe, even better than projected,” said Kristin Highland, MD, a pulmonologist at the Cleveland Clinic.

In contrast, “the uptake of Opsynvi has been slow due to restrictions by payors given the availability of generic [single-agent] formulations and cumbersome prior-authorization and patient assistance programs for PAH medications as a whole, making the desire to go through yet another prior-approval process less appealing for patients already on therapy,” observed Highland.

However, the landscape of PAH therapy is still evolving, and the roles these drugs play in clinical practice may change as more data are generated.

Sotatercept

A flurry of excitement has surrounded sotatercept since the release of findings from its phase II PULSAR trial. Its approval this year as the first activin-signaling inhibitor for PAH — indicated to increase exercise capacity, improve functional class, and reduce the risk of clinical worsening events for eligible adults — was viewed as opening a new chapter for people with the rare progressive disorder typically associated with high morbidity and mortality.

The case for sotatercept was also recently strengthened by topline results of the ZENITH trial, announced by Merck in late November, which found that sotatercept reduced the risk of morbidity or mortality events atop background PAH therapy in the sickest patients. The initial results were strong enough for the trial to be stopped early.

“We were a lead enroller in the ZENITH study and noted dramatic improvement in some of our study participants, who we inferred must have been on [the] active study drug,” according to Highland. “This included one particularly sick patient who was able to come off of the lung transplant list. Our PH group at the Cleveland Clinic has observed similarly significant benefits in many of our patients that have been treated once sotatercept became FDA approved.”

Highland cautioned that, as a new drug, there are unknowns regarding long-term side effects — bleeding being a particular concern — and the durability of its benefits. On top of that, it remains to be seen whether sotatercept can confer benefits without background prostanoid therapy.

Regulatory approval of sotatercept followed the STELLAR randomized trial finding that the biologic improved 6-minute walk distances for PAH patients atop background therapy. In that phase III trial, sotatercept-treated patients were also less likely to die or experience a clinical worsening event over a median 32.7 weeks.

Both PULSAR and STELLAR “showed impressive results on hemodynamics and other clinical endpoints suggesting that this might be the first disease-modifying drug for PAH. These data were especially impressive given that patients had long-standing disease, were quite ill, and heavily treated (on traditional dual or triple PAH therapy),” Highland told MedPage Today in an email.

This means that a major gap in the literature now exists around how newly diagnosed intermediate- and high-risk PAH patients would fare with sotatercept therapy; this is being tested in the ongoing HYPERION trial.

“We also await data of the use of sotatercept in post-capillary pulmonary hypertension ([WHO] group 2). If the CADENCE study is positive, this would be a game changer,” according to Highland.

Activin-signaling inhibitor use is recommended for patients who do not achieve low-risk status at first follow-up, according to the most recent Seventh World Symposium on Pulmonary Hypertension guidelines.

Macitentan/tadalafil

These guidelines still strongly endorse targeting multiple pathways in PAH, namely an upfront combination of an endothelin receptor antagonist (ERA) and a phosphodiesterase-5 (PDE-5) inhibitor.

In March, just days prior to sotatercept’s approval, macitentan/tadalafil become the first single-tablet dual therapy, comprising an ERA and PDE-5 inhibitor together, to gain an indication for chronic treatment in people who are treatment-naive or who are already on one or both of these agents.

Combination therapy lowers pill count burden, which should improve compliance and patient satisfaction. PAH patients typically take eight or nine medications related to their elevated blood pressure in pulmonary circulation and weakening heart muscle.

The phase III A DUE trial showed significantly greater pulmonary vascular resistance improvements with the fixed-dose combination over macitentan (Opsumit) or tadalafil (Adcirca) monotherapy.

However, besides the payor issues, “providers may have some reluctance to begin upfront combination therapy in patients with comorbidities and would rather do rapid sequential therapy,” Highland noted.

Even so, upfront therapy with combination macitentan/tadalafil was well tolerated in the A DUE trial. And, Highland noted, the reported pricing of the dual therapy is comparable to macitentan alone — “meaning that the patient would essentially get tadalafil for free.”

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