AMBITION Trial a ‘Landmark’ Study in PAH-SSc Patients, GlaxoSmithKline Researcher Tells Scleroderma News

The AMBITION trial was truly a “landmark study,” Dr. Mihaela Ianosev said in an interview with Scleroderma News Today at the 4th Systemic Sclerosis World Congress, both for daring to take clinical failure — a physician’s emphasis — as its primary endpoint, and for marking “an evolution” in clinical trial thinking on a large and, ultimately, successful scale.

A pivotal Phase 3 clinical trial sponsored by Gilead Sciences and GlaxoSmithKline, AMBITION tested a drug combination — Letairis (ambrisentan) and tadalafil — against each as monotherapy, as a first-line or initial therapy for pulmonary arterial hypertension (PAH) patients, including those with systemic sclerosis (SSc). All patients were World Health Organization (WHO) functional class 2 or 3, meaning they were at a moderate to borderline-severe disease stage at diagnosis. The trial’s primary endpoint in a time-to-event analysis was the first event of clinical failure, defined as death, hospitalization for PAH worsening, or disease progression.

“This was the first study in this indication that looked at improvement, and considered the length of improvement as a failure,” Dr. Ianosev, critical disease medical director for GlaxoSmithKline in Europe, recently told Scleroderma News Today correspondent Dr. Ana de Barros in an exclusive interview at the Congress. The first such study to look “at things the physicians want for the patients in real life … to get better. That’s the whole purpose of treating somebody, right?”

The trial was considered an evolution by acknowledging what clinicians were increasingly noting in a range of diseases — that a single drug as initial treatment was failing too many patients — and what scientists were thinking “about hitting hard and early in a disease, which meant combining two or three … drugs from the beginning, from the diagnosis, and trying to achieve better outcomes for their patients.”

“This was what AMBITION looked at,” she said. “You have a patient newly diagnosed with this horrible disease which is PAH, and would it make an impact on the patients if they were treated from beginning with two drugs, suggesting two different pathways involved in the pathology of the disease?”

For its primary analysis, published in The New England Journal of Medicine in August 2015, the AMBITION trial randomly divided 500 participants into three groups — 253 into a Letairis (10 mg) and tadalafil (40 mg) group, 126 into a Letairis (10 mg) monotherapy group, and 121 into a tadalafil a (40 mg) monotherapy — with respective medications taken once a day for 24 weeks. Analysis results were impressive, with the combined therapy dropping the risk of clinical failure by 50 percent in comparison to pooled monotherapy, and, specifically, the risk of PAH worsening and hospitalization by 63 percent. [Among secondary endpoint measures, a higher percentage of combination treatment patients reported satisfactory clinical response (39 percent) than pooled monotherapy patients (29 percent), and showed greater improvement in exercise, with a median change from baseline in the six-minute walk distance test of 48.98 meters versus 23.80 meters, respectively.]

“The answer was yes,” Dr. Ianosev said. “It was a difference. It was a massive improvement, 50 percent reduction in time to clinical failure.”

Letairis (ambrisentan), a selective endothelin type-A receptor antagonist, and tadalafil, a PDE5 inhibitor, as a combination therapy was subsequently approved for WHO functional class 2 and 3 PAH patients with SSc and other connective tissue diseases (WHO Group 1) in both the U.S. (October 2015) and the European Union (November 2015). In the U.S., ambrisentan is available under the tradename Letairis (Gilead); elsewhere, it is available as Volibris (GlaxoSmithKline/GSK).

The complete Scleroderma News Today interview with Dr. Ianosev is available below, or can be accessed through this link.

The 4th Systemic Sclerosis World Congress was held in Lisbon, Portugal, on Feb. 18–20, 2016.