Nintedanib slows lung function decline in systemic sclerosis-related ILD
Treatment with the tyrosine kinase inhibitor (TKI) nintedanib reduces pulmonary function decline in patients with systemic sclerosis–associated interstitial lung disease (SSc-ILD), according to the phase III SENSCIS* trial which is touted as the largest randomized controlled trial in SSc-ILD thus far.
ILD is a key driver of mortality in patients with SSc, yet currently there is no approved treatment for SSc-ILD. Most patients will experience a slow decline in lung function, but some will progress rapidly as shown by a significant decline in pulmonary function tests (PFTs). As ILD progresses, lung function gradually and irreversibly deteriorates.
In SENSCIS, the primary endpoint of adjusted annual rate of decline in forced vital capacity (FVC), a surrogate marker for SSc-ILD, was 52.4 mL in the nintedanib group during 52 weeks of treatment vs 93.3 mL in the placebo group or a 41.0 mL per-year difference between the two groups(p=0.04). This translated to a 44-percent reduction in the slope of lung function decline in the nintedanib group. [N Eng J Med 2019;doi:10.1056/NEJMoa1903076]
“While SENSCIS suggests that nintedanib is effective in reducing the FVC decline in patients with SSc-ILD, the trial does not support nintedanib as a disease-modifying agent for SSc as a whole,” said Prof Oliver Distler from the University Hospital Zurich, Switzerland, at ATS 2019.
There were no other clinical benefits observed with nintedanib. The key secondary endpoints of changes in skin fibrosis, as assessed by absolute change from baseline in the modified Rodnan skin score (adjusted mean absolute change from baseline, –2.17 with nintedanib vs –1.96 with placebo), and health-related quality of life, as assessed by the St. George’s Respiratory Questionnaire score (at 52 weeks (0.81 with nintedanib vs. –0.88 with placebo), were not significantly different between groups.
SENSCIS included patients (n=576) with fibrosis affecting at least 10 percent of their lungs on CT scans and who were on prednisone, mycophenate, or methotrexate. They were randomized to nintedanib 150 mg given orally twice-daily or placebo. Primary efficacy analysis was conducted at week 52. Among those who received at least one dose of nintedanib, 80.6 percent and 257 patients in the nintedanib and placebo groups, respectively, completed the 52-week intervention. FVC measurements were available for 83.7 percent and 89.2 percent of patients, respectively.
Over the study period, mortality rate was similar between groups at 3.5 percent for nintedanib vs 3.1 percent for placebo (hazard ratio [HR], 1.16, 95 percent confidence interval [CI], 0.47-2.84).
Diarrhoea was the most common adverse event (AE) reported, occurring in 75.7 percent of patients in the nintedanib group vs. 31.6 percent in the placebo group. “As expected, the rate of gastrointestinal [GI] symptom is higher because of the background disease and not because of the study drug,” said Distler.
The safety and AE profile of nintedanib in the SENSCIS trial was comparable to those seen in other trials of nintedanib in idiopathic pulmonary fibrosis (IPF), although as expected, the GI effects were more common in SSc-ILD than in IPF, said Distler.
Commenting on SENSCIS results, Dr Anna Hoffmann-Vold from the Oslo University Hospital in Oslo, Norway, said this is good news for SSc-ILD patients. “We know that FVC decline is associated with mortality in these patients. So, if we treat them early, we slow down the progression or prevent progression, and this will have a positive impact on survival.”
Nintedanib is FDA-approved for IPF in more than 70 countries. Based on the SENSCIS data, a regulatory approval has been filed for the treatment of SSC-ILD both in the US and in Europe. An uncontrolled open-label extension study is ongoing to assess nintedanib for SSc-ILD in the long term.