The experimental tyrosine kinase inhibitor BIBF 1120 was associated with a clinically meaningful reduction in the rate of decline in forced vital capacity, compared with placebo, in patients with idiopathic pulmonary fibrosis in a yearlong, phase II dose-ranging trial involving 432 patients.

Active treatment was also associated with a reduction in the incidence of acute exacerbations of the disease and with an increase in quality of life scores, compared with placebo, Dr. Luca Richeldi of the University of Modena (Italy) and Reggio Emilia, Policlinico Hospital, Modena, and his colleagues reported in the Sept. 22 issue of the New England Journal of Medicine.

Specifically, 85 patients randomized to receive an oral dose of BIBF 1120 at 150 mg twice daily had a mean decline in forced vital capacity (FVC) of 0.06 L/year, compared with 0.19 L/year in 83 patients randomized to receive placebo, a 68.4% reduction. This difference is not statistically significant but does approach the threshold for significance. Also, the absolute change in FVC from baseline over time in the treatment group, compared with the placebo group, was statistically significant, the investigators wrote (N. Engl. J. Med. 2011;365:1079-87).

Acute exacerbations occurred at a rate of 2.4 vs. 15.7 per 100 patient-years in the 150-mg twice-daily treatment group and the placebo group, respectively, a significant difference. There was a trend toward a dose response with increasing doses of BIBF 1120. In addition, scores on the St. George’s Respiratory Questionnaire (SGRQ) in the treated patients decreased by 0.66 points on a 0-100 scale, but increased by 5.46 points in the placebo group. This difference was also significant.

"There were improvements in two domains of the SGRQ – symptoms and activity – in the group receiving 150 mg of BIBF 1120 twice a day as compared with the placebo group (–3.14 points vs. 6.45 points and 0.32 points vs. 7.48 points, respectively), and there was a dose-dependent trend toward an improvement in the impact domain, which is a broad measure of the impact of respiratory disease on the patient," they said.

There was also a trend toward fewer deaths from respiratory causes in the 150-mg twice-daily treatment group and the 100-mg twice-daily group, with two such deaths in each of those groups, compared with nine and three deaths in the 50-mg once-daily and the 50-mg twice-daily groups, respectively, and eight in the placebo group.

Study participants were adults aged 40 years or older with high-resolution CT–confirmed idiopathic pulmonary fibrosis diagnosed within the previous 5 years. They were recruited from 92 sites in 25 countries, and were randomized in double-blind fashion to receive either placebo, 50 mg once daily, 50 mg twice daily, 100 mg twice daily, or 150 mg twice daily for 52 weeks.

As for adverse events, the overall incidence was similar in each of the groups, as was the incidence of serious and severe adverse events and adverse events requiring hospitalization. The proportion of patients with serious adverse events was lower in the 150-mg twice-daily treatment group than in the placebo group (27.1% vs. 30.6%), and the lowest proportion was in the 100-mg twice-daily group (14%). Most of the adverse events that led to discontinuation of treatment were gastrointestinal in nature, and included diarrhea, nausea, and vomiting. These occurred most often the 150-mg twice-daily group.

However, the number of fatal adverse events decreased with increasing doses of BIBF 1120, with 12, 10, 4, and 5 patients in the placebo, 50-mg once-daily, 50-mg twice-daily, and 100-mg twice-daily groups experiencing a fatal adverse event, and only 1 in the 150-mg twice-daily group experiencing a fatal adverse event.

While this trial failed to show a significant difference in the predefined multiplicity-corrected end point of the annual rate of decline in FVC, the findings nonetheless suggest that BIBF 1120 is a promising treatment for idiopathic pulmonary fibrosis, particularly given the seriousness of this condition and the paucity of therapeutic options, according to the investigators.

Further, the results of the secondary end point analyses support the 150-mg twice-daily dose – and for some end points, the 100-mg twice-daily dose, they noted.

A particularly important finding was the significantly lower incidence of acute exacerbations in the 150-mg twice-daily group, compared with the placebo group.

"This result is clinically important, since acute exacerbations are associated with rapid disease progression, a severe and abrupt decline in forced vital capacity, and high mortality," the investigators wrote.

This finding may have contributed to the higher quality of life scores seen in the higher-dosage groups than in the other groups, which had higher incidences of exacerbations, they added, concluding that the findings warrant additional investigation in phase III clinical studies.

The study by Dr. Richeldi and his colleagues was supported by Boehringer Ingelheim, which employs some of the study authors. More detailed disclosures are available with the full text of the article at NEJM.org.

Pulmonary Fibrosis: Novel Tyrosine Kinase Inhibitor Promising