Rare Disease Report: FDA Approves Combination Letairis and Adcirca for PAH

October 8, 2015

The U.S. Food and Drug Administration (FDA) has approved the combination of Letairis (ambrisentan) and Adcirca (tadalafil) to treat patients with pulmonary arterial hypertension (PAH) (WHO Group 1) to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability. Both drugs have been previously approved as monotherapy to treat patients with PAH — Letairis is an endothelin receptor antagonist that was first approved in 2007 to improve exercise ability and delay clinical worsening while Adcirca is a PDE5 inhibitor approved in 2009 to improve exercise ability.

The approval stems largely from the Phase 3b/4 data published in the New England Journal of Medicine, showing the combination of the two approved orphan drugs – ambrisentan with tadalafil—is significantly superior to each drug alone.1

Data Reviewed by the FDA

A total of 605 patients with PAH were randomized (2:1:1) to receive ambrisentan and tadalafil (n=302), ambrisentan alone (n=152) or tadalafil alone (n=151) (titrated from 5 mg to 10 mg once-daily and from 20 mg to 40 mg once-daily for ambrisentan and tadalafil, respectively).

The primary end point in a time-to-event analysis was the first event of clinical failure, which was defined as the first occurrence of a composite of death, hospitalization for worsening pulmonary arterial hypertension, disease progression, or unsatisfactory long-term clinical response.


A primary end-point event occurred in 20% of patients in the combination group, 35% of patients in the ambrisentan group, and 30% of patient sin the tadalafil group.

Secondary endpoints (reduced risk of hospitalization; reductions from baseline in N-terminal pro–brain natriuretic peptide levels; satisfactory clinical response; and 6-minute walk test) were also significantly improved on the combination therapy group compared to the pooled monotherapy groups.

The adverse events that occurred more frequently in the combination-therapy group than in either monotherapy group included peripheral edema, headache, nasal congestion, and anemia.
The study, known as the AMBITION study, was co-sponsored by GSK and Gilead. Eli Lilly and Company also provided funding and tadalafil drug supply for the study.

Ronald J. Oudiz, MD, Professor of Medicine, David Geffen School of Medicine at UCLA and Director, Liu Center for Pulmonary Hypertension, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center said in a press release,2 “Based on the data supporting today’s approval, we now know that patients receiving ambrisentan and tadalafil up front are less likely to experience disease progression or be hospitalized, and have more improvement in exercise ability than patients receiving either effective therapy alone. As such, this combination represents a new treatment strategy for patients living with this debilitating and life-threatening disease.”

Ambrisentan and Tadalafil

Ambrisentan is a selective endothelin type-A receptor antagonist that was first approved for PAH in 2007 (exclusivity ended in 2014). Tadalafil is a PDE-5 inhibitor that was approved for PAH in 2009 (exclusivity ends 2016).

Ambrisentan is sold by GSK as Volibris outside the United States and is sold by Gilead as Letairis in the United States.

Tadafil is sold by GSK as Adcirca in Europe and by Eli Lilly in the United States.

Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is one form of pulmonary hypertension and as the name implies, there is high blood pressure in the pulmonary artery – the vessel that carries blood from the heart to the lungs

Symptoms of PAH are similar to those observed with more common heart and lung conditions (chest pain, dizziness, fatigue, leg swelling, etc). As a result, it may not be diagnosed unless symptoms are more severe.

Treatment options for PAH will be dependent on the severity of the symptoms and include treatment to relieve specific symptoms, changes in diet and exercise, warafin, diuretics, oxygen therapy, or even surgery.  Due to the complex nature of the disease and its treatments, PAH patients should be closely followed by experienced clinicians.

There are at least 9 orphan drugs approved for treatment of pulmonary arterial hypertension (and 34 designated). Approved orphan drugs for PAH include:
Adcira (tadalafil)
Adempas (riociguat)
Letairis (ambrisentan)
Opsumit (macitentan)
Remodulin (trepostinil injection)
Tracleer (bosentan)
Tyvaso (trepostinil inhalation)
Veletri (epoprostenol)
Ventavis (iloprost)

At press time, it was not known how the combination Letairis and Adcirca will be marketed.

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