Uptravi (selexipag) is a medication approved by the U.S. Food and Drug Administration to delay disease progression in patients with pulmonary arterial hypertension (PAH). The therapy is commercialized by Actelion, part of the Johnson & Johnson family of companies.

How Uptravi works

PAH is a chronic disease characterized by high blood pressure in the blood vessels near the lungs and heart. Uptravi is a selective agonist of the prostacyclin receptor, or a molecule that works like prostacyclin, a naturally occurring hormone that regulates blood pressure by attaching to receptors found on the cells of the blood vessel walls, causing the vessels to relax and dilate.

PAH can be caused by low levels of prostacyclin; without this hormone, blood vessels constrict and lead to high blood pressure.

Uptravi mimics the effect of prostacyclin; it binds and activates the receptors which normally bind prostacyclin. This binding causes blood vessels to dilate, decreasing blood pressure and improving pulmonary blood circulation.

Uptravi in clinical trials

The safety and efficacy of Uptravi were first examined in a Phase 2 proof-of-concept study (NCT00993408) in 43 patients with PAH. Results of the study, published in the European Respiratory Journal, showed a statistically significant reduction in pulmonary vascular resistance — the resistance to blood flow through pulmonary circulation — after 17 weeks of treatment with Uptravi compared with a placebo. Uptravi was also well-tolerated.

A Phase 3 clinical trial (NCT01106014), called GRIPHON, assessed Uptravi’s safety its effects on the risk of death or complication in 1,156 patients with PAH. Enrolled patients could not be receiving any treatment for PAH other than a stable dose of an endothelin-receptor antagonist (ERA), a phosphodiesterase type 5 inhibitor (PDE-5i), or both.

In 2015, researchers reported in a study published in the New England Journal of Medicine that the risk of death or a complication was significantly lower in patients treated with Uptravi than with placebo. In 2016, further results from this study were published in the European Respiratory Journal, showing that Uptravi slowed the progression of connective tissue disease associated with PAH.

In 2018, another analysis of this study concluded that the addition of Uptravi to ERA and PDE-5i provides a benefit for patients with PAH. These results were published in the American Journal of Cardiovascular Drugs.

The safety and tolerability of the transition from inhaled Remodulin (treprostinil) to oral Uptravi were assessed in a Phase 3 clinical trial (NCT02471183) called Transit-1. Results from one of the 34 enrolled patients, published in the journal BMC Pulmonary Medicine, confirmed the benefit of replacing Remodulin with Uptravi as a component of triple combination therapy.

Actelion is currently conducting three additional clinical trials involving Uptravi.

The first is a Phase 3 trial (NCT02558231) designed to compare the efficacy and safety of an initial triple oral treatment of three blood pressure medications — Opsumit (macitentan), Adcirca (tadalafil), and Uptravi — in newly diagnosed, previously untreated patients with PAH. The study, called TRITON, is currently recruiting up to 238 participants in the U.S., Australia, Austria, Belgium, Canada, France Germany, Italy, and Switzerland.

Another Phase 3 trial (NCT03187678) is assessing the safety of switching from oral Uptravi to intravenous (injected into the bloodstream) Uptravi in patients with stable PAH. In addition to safety, the study is aimed at verifying the tolerability and pharmacokinetics (the movement of the drug in the body) of the intravenous therapy. The study was completed in May 2018, but results have not yet been published.

Finally, the TRACE trial, which is a Phase 4 trial (NCT03078907), is intended to determine the effect of Uptravi compared with placebo on daily physical activity of PAH patients. During the trial, patients will use a wearable wrist device called an actigraph to monitor their physical activity and rest and activity cycles throughout the day. In addition, researchers will also assess PAH symptoms and their impact on the patients’ daily lives. The study is currently recruiting participants in the U.S., Germany, Austria, and the U.K.

Other details

The most common side effects of Uptravi include headaches, rash, nausea, low red blood cell count, diarrhea, and muscle or joint pain.

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