Esbriet (pirfenidone) has an acceptable level of tolerability in patients with systemic sclerosis (SSc) associated with interstitial lung disease (ILD), and may be tested for efficacy in future clinical trials in these patients, according to the results of a randomized Phase 2 study, the LOTUSS trial.
The study, “An Open-label, Phase II Study of the Safety and Tolerability of Pirfenidone in Patients with Scleroderma-associated Interstitial Lung Disease: the LOTUSS Trial,” published in The Journal of Rheumatology, highlights that increasing the titration period of Esbriet may improve tolerability.
It is estimated that about 90 percent of people with SSc have evidence of ILD on high-resolution computed tomography (HRCT) scans, and 40 percent to 75 percent of them have impaired lung function. These patients are characterized by the presence of interstitial and alveolar inflammation and fibrosis, which is associated with an increased mortality.
Currently, there are no approved treatments for SSc-ILD patients. Cytoxan (cyclophosphamide) and CellCept (mycophenolate mofetil) are currently being tested in SSc patients (NCT00883129), but interim results revealed a modest improvement of 4 percent to 4.5 percent in lung function for both treatments.
Esbriet, approved for patients with idiopathic pulmonary fibrosis (IPF), is an antifibrotic agent with anti-inflammatory properties. Although IPF and SSc-ILD have common pathogenic mechanisms, IPF only affects the lungs whereas SSc-ILD can affect a variety of organs, including the skin, lungs, heart, gastrointestinal tract, and kidneys.
Because Esbriet has been associated with adverse events in the liver, gastrointestinal system, and skin, which may overlap with the organs frequently affected in patients with SSc, it is important to assess the drug’s tolerability in SSc-ILD patients before evaluating its efficacy.
The international, multicenter, randomized and open-label, Phase 2 LOTUSS study (NCT01933334) was designed to assess the tolerability and safety of Esbriet in SSc-ILD patients. The trial enrolled 63 patients who were randomized to receive one of two dose-titration schedules: a two-week titration group (standard for patients with IPF) and a four-week titration group. All patients started Esbriet at a starting dose of 801 mg/day (1 capsule, 3 times a day), which increased over the course of two or four weeks, depending on the group, to a maintenance dose of 2,403 mg/day (3 capsules, 3 times a day).
Patients received Esbriet for up to 16 weeks and were assessed for treatment-emergent adverse events and serious adverse events.
The results showed that 96.8 percent of the patients analyzed experienced an adverse event, reported more often during the titration period versus the maintenance period. The most common adverse events included nausea, headache, and fatigue, which was consistent with those observed in IPF patients treated with Esbriet. These events were similar in both groups, but discontinuation events were more common in the two-week titration group than in the four-week titration arm. All discontinuation events occurred more than three weeks after patients reached the full dose of Esbriet.
The team also tested mycophenolate mofetil in combination to Esbriet to evaluate tolerability. The results showed that in the 63.5 percent of patients who received both treatments, tolerability did not seem to be affected.
Although the study was not designed to assess Esbriet’s efficacy, researchers found no difference in lung function variables between the two-week and four-week titration group, or in any of the subgroup analyses.
“The LOTUSS was a pilot phase 2 trial that revealed that an anti-fibrotic agent, pirfenidone, has an acceptable tolerability profile in patients with scleroderma-associated lung fibrosis,” Dinesh Khanna, MD, MSc, Frederick G. I. Huetwell professor of rheumatology and director of the University of Michigan Scleroderma Program, said in a press release. “Tolerability was not affected by concomitant mycophenolate mofetil (MMF). This provides a unique opportunity to assess if combination of immunosuppressive therapy, [and] pirfenidone has greater efficacy compared to monotherapy with pirfenidone or MMF in scleroderma-associated lung fibrosis.”