Novel Drug May Slow Lung Decline in IPF
By Charles Bankhead, Staff Writer, MedPage Today
Published: September 22, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
Patients with idiopathic pulmonary fibrosis had significantly fewer acute exacerbations and exhibited a trend toward slower decline in lung function when treated with an investigational tyrosine kinase inhibitor, investigators in a multinational study found.
The rate of progression declined by almost 70% in patients treated with the highest dose of BIBF 1120 compared with placebo, and acute exacerbations were 84% less frequent, according to Luca Richeldi, MD, PhD, of the University of Modena in Italy, and co-authors.
Quality of life improved with the drug and deteriorated during a year of placebo treatment. Gastrointestinal toxicity was more common with high-dose BIBF 1120, but the incidence of severe adverse events did not differ significantly from placebo, they reported in the Sept. 22 issue of the New England Journal of Medicine.
- Explain that patients with idiopathic pulmonary fibrosis had significantly fewer acute exacerbations when treated with an investigational tyrosine kinase inhibitor and that there was a trend toward a decrease in loss of lung function.
- Point out that quality of life improved with the drug and deteriorated during a year of placebo treatment.
"This phase II trial comparing an oral tyrosine kinase inhibitor with placebo in patients with idiopathic pulmonary fibrosis failed, by a small margin, to show a significant difference in the predefined, multiplicity-corrected endpoint (closed testing procedure), the rate of loss of FVC over a 12-month period," Luca wrote in their discussion.
"The closed testing procedure is a conservative method of testing multiple hypotheses (in this case, four groups, each receiving a different dose) simultaneously. As compared with placebo, the dose of150 mg of BIBF 1120 twice a day reduced the annual decline in FVC by two thirds.
"Treatment with BIBF 1120 was associated with improvements in many of the secondary outcomes, suggesting that this agent is a promising treatment for idiopathic pulmonary fibrosis, a serious medical condition for which there are few therapeutic options."
IPF manifests as destruction of the gas-exchange regions of the lung, resulting in progressive tissue injury and scarring, leading to coughing, dyspnea, and other symptoms that limit physical activity and substantially reduce a patient's quality of life.
The condition has an unpredictable clinical course but generally causes progressive deterioration, associated with a median survival of 2.5 to 3.5 years from diagnosis, the authors wrote in their introduction. Some patients have unpredictable acute exacerbations, which often prove fatal.
Although the etiology if IPF remains unclear, the disease is thought to arise from abnormal wound healing associated with multiple signaling pathways.
BIBF 1120 is an intracellular inhibitor of multiple tyrosine kinases. The agent targets vascular endothelial growth factor (VEGF) receptors, platelet-derived growth factor (PDGF) receptors, and fibroblast growth factor (FGF) receptors.
To assess the efficacy and safety of BIBF 1120, investigators at 92 centers in 25 countries enrolled patients with IPF who were 40 and older and who were less than 5 years removed from diagnosis. The final analysis included 432 patients.
Eligible patients had undergone high-resolution CT in the year before randomization, had an FVC at least 50% of predicted, diffusing capacity for carbon monoxide of 30% to 79% of predicted, and a partial pressure of arterial oxygen of at least 50 to 55 mmHg.
The patients were randomized to placebo or to one of four doses of oral BIBF 1120, ranging from 50 mg QD to 150 mg BID. Treatment continued for a year, and the primary endpoint was the annual rate of decline in FVC.
When the trial ended none of the four BIBF 1120 groups showed a significant reduction in the rate of disease progression as determined by the closed testing procedure for multiplicity.
Patients randomized to the highest dose of BIBF 1120 exhibited a trend toward significant slowing of disease progression (P=0.06).
The annual rate of decline in FVC averaged 0.19 liter as compared with 0.06 liter in the patients who received the 150 mg BID dose of BIBF 1120. The difference represented a 68% reduction in the rate of decline and met criteria for statistical significance by the hierarchical testing procedure (P=0.01).
The 150 mg BID group also had a significantly lower incidence of acute exacerbations compared with placebo (2.4 versus 15.7 per 100 patient-years, P=0.02).
Quality of life, as assessed by the St. George's Respiratory Questionnaire declined (indicating improvement) by 0.66 as compared with an increase of 5.46 in the placebo group (P=0.007).
More patients in the 150-mg BID BIBF 1120 group dropped out before the end of the trial, 32 of 85 (37.6%) versus 24 of 85 (28.2%) in the placebo group.
Discontinuation rates in the other BIBF 1120 groups were 27.9% (50 mg QD), 20.6% (50 mg BID), and 16.3% (100 mg BID).
Adverse events were the reason given by 96 of the 112 patients (85.7%) who stopped treatment during the trial.
The most common adverse events were diarrhea (27.6% of all patients), cough (17.1%), nausea (14.5%), bronchitis (12.6%), dyspnea (11.9%), IPF progression (9.8%), vomiting (7.7%), and upper abdominal pain (7.2%).
Despite the lack of a statistically significant benefit with BIBF 1120, the investigators remained positive about the drug's potential in IPF.
"The results of this phase II study showed an acceptable safety profile and potential clinical benefits of treatment with 150 mg of BIBF 1120 twice a day in patients with idiopathic pulmonary fibrosis," they wrote in conclusion. "These results warrant the investigation of BIBF in phase III clinical studies."
Primary source: New England Journal of Medicine
Richeldi L, et al "Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis" N Engl J Med 2011; 365: 1079-1087.