By Becky McCall Medscape Pulmonary Medicine
October 4, 2011 (Amsterdam, the Netherlands) — A decline in forced vital capacity (FVC) was reduced by 68.4% with investigational drug BIBF 1120 in a phase 2 trial of patients with idiopathic pulmonary fibrosis (IPF), indicating that it might actually slow the progression of the disease. The results justify the launch of phase 3 trials, investigators reported here at the European Respiratory Society (ERS) 2011 Annual Congress.
Luca Richeldi, MD, PhD, from the Center for Rare Lung Diseases, Modena, Italy, who was on the steering committee for the TOMORROW study, presented the results, which were published in the September 22 issue of the New England Journal of Medicine.
"In this study, we saw signals in the reduction of FVC, in acute exacerbations, and in stabilization of quality of life. These 3 signals reflect each other in terms of slowing the progression of IPF," Dr. Richeldi told Medscape Medical News.
In IPF, mean survival after diagnosis is 2.5 to 3.5 years.
Dr. Richeldi pointed out that these findings are significant because this is the first time that this class of drug — tyrosine kinase inhibitors — has been used outside the cancer field for a nonneoplastic disease with some effect. "As a new concept, this is important."
Animal models show that all 3 tyrosine kinase receptors (FGF, PDGF, and VEGF) that are involved in lung fibrosis are blocked by this drug. Preclinical trials indicated that the drug slows the progression of IPF, which provided researchers with a solid foundation for human studies.
The only other drug for this disease is pirfenidone (Esbriet, InterMune). It is approved in the European Union and Japan, but is not yet approved in the United States; the US Food and Drug Administration requires evidence from 1 more trial.
"We need to be cautious in interpreting these results, but if you look at these data over 1 year, by using the drug at the highest dose, we see a reduction in FVC decline of 70%. This is huge. These people almost stabilize their lung function," said Dr. Richeldi.
In comparison, patients in the placebo group lost about 200 mL of their FVC per year.
The TOMORROW study was a 12-month, phase 2, randomized, double-blind, placebo-controlled trial of BIBF 1120 in 425 patients with IPF. Patients were randomized to receive placebo or BIBF 1120 50 mg once daily or BIBF 1120 50 mg, 100 mg, or 150 mg twice daily. There were approximately 85 patients in each group.
The annual rate of decline in FVC, which has previously been shown to predict mortality, was the study's primary end point. Secondary end points included change from baseline to 12 months in percent of predicted FVC and absolute FVC, oxygen saturation, diffusing capacity of carbon monoxide, total lung capacity, 6-minute walk test, quality of life (St. Georges' Respiratory Questionnaire), categorical change in FVC and oxygen saturation, incidence of acute exacerbations, all-cause and respiratory cause mortality, and safety and tolerability.
Results showed that in the patients receiving 150 mg twice daily, FVC declined at a slower rate — by 0.06 L/year — compared with 0.19 L/year in patients randomized to placebo, which represents a 68.4% reduction in rate of loss of FVC (P = .06).
"According to the predefined statistical analysis, this was a multiple-dose study, so we conducted a primary analysis of each arm against placebo, with correction for multiple comparisons using the closed testing procedure. This is an appropriate, although conservative, view; with this statistical approach, the results failed by a short amount (P = .06) to reach statistical significance," noted Dr. Richeldi.
"However, there was a highly statistically significant change in FVC when comparing placebo with the highest dose (150 mg twice daily) using another predefined statistical analysis [hierarchical testing procedure; P = .01]. In our conclusion, we say that the use of BIBF 1120, compared with placebo, is associated with a trend toward a reduction in the rate of FVC decline," reported Dr. Richeldi.
Regarding secondary end points, there were fewer acute exacerbations with active treatment than with placebo (2.4 vs 15.7 episodes per 100 patient-years; P = .02). In the treatment group, quality of life was preserved, whereas in the placebo group, it was reduced.
"We are now conducting 2 concomitant phase 3 studies [testing] the highest dose against placebo," Dr. Richeldi announced. The phase 3 studies are enrolling 970 patients in 20 countries. The first patients entered the trials in April and May (Clinicaltrials.gov identifiers NCT01335464 and NCT01335477).
He reported that there is also a rollover study being conducted for patients from the phase 2 study that will provide safety information.
The highest dose was associated with significant adverse effects, mainly diarrhea and nausea. There were clinically significant elevations in liver enzymes, which were at least 3 times the upper limit of the normal range for aspartate aminotransferase or alanine aminotransferase in 7.4% of patients in the 150 mg twice-daily group.
"The fact that the New England Journal of Medicine published this is a good indicator of the general enthusiasm for these results. We have very little to help these patients. In the United States, it is estimated that there are about 75,000 new cases per year. It is also an interesting concept to translate a cancer drug to a noncancer disease — this is quite exciting," Dr. Richeldi said.
In an editorial that accompanies the paper, Gregory P. Downey, MD, from the division of pulmonary and critical care medicine at National Jewish Health, University of Colorado, Denver, writes that, "compared with other treatment approaches...the beneficial effects of BINF 1120 shine like a beacon over a turbulent sea of unfulfilled promises and failed clinical trials."
Commenting on the trial for Medscape Medical News, Fernando Martinez, MD, from the Department of Internal Medicine, University of Michigan Health System, in Ann Arbor, said: "Although the study did not strictly meet the primary end point, there is a suggestion of potential benefit. Well-designed, prospective, placebo-controlled studies with clinically relevant end points are sorely required with this innovative agent."
The study was sponsored by Boehringer Ingelheim, Germany. Dr. Richeldi is on the study steering committee, but has declared no other relevant financial relationships. Dr. Martinez reports being on the advisory boards for IPF for Elan, Quark, Novartis, Genzyme, Sanofi-Aventis, Nycomed, and Ikaria; being a member of steering committees for IPF studies sponsored by Actelion, Genzyme, Gilead, and Johnson & Johnson/Centocor. Dr. Martinez reports serving on speaker's bureaus or in CME activities sponsored by GSK, NACE, MedEd, Potomac, Pfizer, Boehringer Ingelheim, Schering, Vox Medic, American Lung Association, WebMD, ePocrates, AstraZeneca, France Foundation, Altana/Nycomed, and UpToDate; and receiving royalties from Associates in Medical Marketing and Castle Connolly. The University of Michigan received funds from Actelion for an IPF study.
N Engl J Med. 2011;365:1079-1087, 1140-1114. Abstract, Editorial
European Respiratory Society (ERS) 2011 Annual Congress: Abstract 172. Presented September 25, 2011.
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