Meeting News

INBUILD: Nintedanib slows progression of fibrosing ILD

When compared with placebo, nintedanib slowed the annual rate of decline in FVC in patients with progressive fibrosing interstitial lung disease other than idiopathic pulmonary fibrosis, researchers reported at the European Respiratory Society International Congress.

In the double-blind, placebo-controlled phase 3 INBUILD trial, Kevin R. Flaherty, MD, from the division of pulmonary and critical care medicine at the University of Michigan in Ann Arbor, and colleagues randomly assigned patients with fibrosing lung disease to nintedanib (Ofev, Boehringer Ingelheim) 150 mg twice daily or placebo.

The trial, which was simultaneously published in The New England Journal of Medicine, included adults who, despite standard treatment during the previous 24 months, had progression of ILD, defined as a relative decline in FVC of at least 10% of the predicted value, a relative decline in FVC of 5% to less than 10% of the predicted value and worsening of respiratory symptoms or an increased extent of fibrosis on high-resolution CT, or worsening of respiratory symptoms and an increased extent of fibrosis.

At enrollment, patients also had to have fibrosing lung disease affecting more than 10% of lung volume on high-resolution CT, had FVC of at least 45% of the predicted value and had a diffusing capacity of the lung for carbon monoxide ranging from 30% to less than 80% of the predicted value.

Because studies suggest that progression of fibrosing ILD is more rapid with an imaging pattern of usual interstitial pneumonia on high-resolution CT, the researchers evaluated outcomes in the overall study population as well as in those with a usual interstitial pneumonia-like fibrotic pattern.

Efforts were also made to exclude patients with an IPF diagnosis, as nintedanib has already been studied in and approved by the FDA for that patient population.

“We know many ILDs are not targeted yet, so the concept of this trial was the need to focus on those patients with ILD that progress and are fibrotic. Therefore, any other non-IPF progressive ILD was considered for this trial because, for these patients, we have no treatment options,” Luca Richeldi, MD, from A. Gemelli University Hospital IRCCS and the Catholic University of the Sacred Heart in Rome, said during a media webcast.

Encouraging efficacy, safety data

Among the 663 patients who underwent randomization, the mean age was 65.8 years, the FVC was 69% of the predicted value, the diffusing capacity of the lung for carbon monoxide was 46.1% and 412 patients had usual interstitial pneumonia-like fibrotic pattern. Overall, the most common ILD diagnoses were hypersensitivity pneumonitis (26.1%) and autoimmune ILD (25.6%).

At 52 weeks, the adjusted rate of decline in FVC — the primary endpoint — was significantly lower in the nintedanib group vs. the placebo group (–80.8 mL vs. –187.8 mL per year), with a between-group difference of 107 mL in the overall population (95% CI, 65.4-148.5). Similar results were seen for patients treated with nintedanib vs. placebo in the population with usual interstitial pneumonia-like fibrotic pattern (–82.9 mL vs. –211.1 mL per year; between-group difference, 128.2 mL; 95% CI, 70.8-185.6).

However, there were no significant changes in health-related quality of life. At 52 weeks, the adjusted mean absolute change from baseline on the King’s Brief Interstitial Lung Disease questionnaire, which measured activity level, psychological factors and chest symptoms, was 0.55 points with nintedanib and –0.79 points with placebo in the overall study population (between-group difference, 1.34 points; 95% CI, –0.31 to 2.98) and 0.75 points with nintedanib and –0.78 points with placebo in patients with usual interstitial pneumonia-like fibrotic pattern (between-group difference, 1.53; 95% CI, –0.68 to 3.74).

Although the percentage of patients with any or serious adverse events were similar in the nintedanib and placebo groups in the overall study population, more patients assigned nintedanib had adverse events leading to a permanent dose reduction (33.1% vs. 4.2%) and discontinuation of treatment (19.6% vs. 10.3%). However, fatal events were less common in the nintedanib group than in the placebo group (3.3% vs. 5.1%).

The most frequently reported adverse event was diarrhea, occurring in 66.9% of the nintedanib group and 23.9% of the placebo group.

Hepatic abnormalities were also more common in the nintedanib group. Elevations in alanine aminotransferase, aspartate aminotransferase or both to at least three times the upper limit of normal range occurred in 13% of patients taking nintedanib vs. 1.8% of patients taking placebo during the 52-week period.

Results were similar for patients with usual interstitial pneumonia-like fibrotic pattern, the researchers noted. Further, they added that the safety and adverse event profile of nintedanib was similar to that observed in patients with IPF and patients with systemic sclerosis-associated ILD.

“This is the first trial to confirm that a drug effective and safe in patients with IPF is also safe and effective in a phenotype sharing different diagnoses,” Richeldi said, noting that the emergence of no new safety concerns is also reassuring.

‘Remarkable’ results

In an accompanying editorial, Hilary J. Goldberg, MD, MPH, from the division of pulmonary and critical care medicine at Brigham and Women’s Hospital in Boston, noted that the results showing that the magnitude of efficacy of nintedanib in this trial was comparable to that observed in patients with IPF were “remarkable” given the inclusion of patients with a variety of underlying ILDs.

“Past therapeutic trials involving patients with IPF have been vulnerable to the limitations of enrollment of heterogeneous patient populations, because of the spectrum of diseases that can be seen in the IPF population and the overlap of IPF with other fibrotic lung diseases. The investigators in the current trial do not shy away from this risk but rather embrace the consideration of a phenotypic or endotypic approach to the study of therapeutic agents in fibrosing ILD,” she wrote. “Their apparent success in this trial suggests a final common pathway to fibrosis.”

Moving forward, though, there likely will be a need to understand disease-specific mechanisms to prevent “each of these diseases from gaining a foothold,” according to Goldberg.

“The use of nintedanib may slow the disease progression, but our challenge for the future is to design studies that identify earlier targets to prevent the establishment of this still highly morbid condition,” she wrote. – by Melissa Foster

References:

Flaherty KR, et al. ALERT: Abstracts leading to evolution in respiratory medicine trials: Interstitial lung disease and pulmonary hypertension. Presented at: European Respiratory Society International Congress; Sept. 28-Oct. 2, 2019; Madrid.

Flaherty KR, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1908681.

Goldberg HJ. N Engl J Med. 2019;doi:10.1056/NEJMe1911794.

Disclosures: This study was funded by Boehringer Ingelheim. Flaherty reports no relevant financial disclosures. Richeldi reports he has received grants and personal fees from Boehringer Ingelheim and Roche/Genentech, and he has received personal fees from Bellerophon, Blade Therapeutics, Celgene, FibroGen, Respivant, Sanofi-Genzyme and Veracyte. Goldberg reports she was a site co-investigator for this trial and saw patients for study visits.

 

When compared with placebo, nintedanib slowed the annual rate of decline in FVC in patients with progressive fibrosing interstitial lung disease other than idiopathic pulmonary fibrosis, researchers reported at the European Respiratory Society International Congress.

In the double-blind, placebo-controlled phase 3 INBUILD trial, Kevin R. Flaherty, MD, from the division of pulmonary and critical care medicine at the University of Michigan in Ann Arbor, and colleagues randomly assigned patients with fibrosing lung disease to nintedanib (Ofev, Boehringer Ingelheim) 150 mg twice daily or placebo.

The trial, which was simultaneously published in The New England Journal of Medicine, included adults who, despite standard treatment during the previous 24 months, had progression of ILD, defined as a relative decline in FVC of at least 10% of the predicted value, a relative decline in FVC of 5% to less than 10% of the predicted value and worsening of respiratory symptoms or an increased extent of fibrosis on high-resolution CT, or worsening of respiratory symptoms and an increased extent of fibrosis.

At enrollment, patients also had to have fibrosing lung disease affecting more than 10% of lung volume on high-resolution CT, had FVC of at least 45% of the predicted value and had a diffusing capacity of the lung for carbon monoxide ranging from 30% to less than 80% of the predicted value.

Because studies suggest that progression of fibrosing ILD is more rapid with an imaging pattern of usual interstitial pneumonia on high-resolution CT, the researchers evaluated outcomes in the overall study population as well as in those with a usual interstitial pneumonia-like fibrotic pattern.

Efforts were also made to exclude patients with an IPF diagnosis, as nintedanib has already been studied in and approved by the FDA for that patient population.

“We know many ILDs are not targeted yet, so the concept of this trial was the need to focus on those patients with ILD that progress and are fibrotic. Therefore, any other non-IPF progressive ILD was considered for this trial because, for these patients, we have no treatment options,” Luca Richeldi, MD, from A. Gemelli University Hospital IRCCS and the Catholic University of the Sacred Heart in Rome, said during a media webcast.

Encouraging efficacy, safety data

Among the 663 patients who underwent randomization, the mean age was 65.8 years, the FVC was 69% of the predicted value, the diffusing capacity of the lung for carbon monoxide was 46.1% and 412 patients had usual interstitial pneumonia-like fibrotic pattern. Overall, the most common ILD diagnoses were hypersensitivity pneumonitis (26.1%) and autoimmune ILD (25.6%).

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At 52 weeks, the adjusted rate of decline in FVC — the primary endpoint — was significantly lower in the nintedanib group vs. the placebo group (–80.8 mL vs. –187.8 mL per year), with a between-group difference of 107 mL in the overall population (95% CI, 65.4-148.5). Similar results were seen for patients treated with nintedanib vs. placebo in the population with usual interstitial pneumonia-like fibrotic pattern (–82.9 mL vs. –211.1 mL per year; between-group difference, 128.2 mL; 95% CI, 70.8-185.6).

However, there were no significant changes in health-related quality of life. At 52 weeks, the adjusted mean absolute change from baseline on the King’s Brief Interstitial Lung Disease questionnaire, which measured activity level, psychological factors and chest symptoms, was 0.55 points with nintedanib and –0.79 points with placebo in the overall study population (between-group difference, 1.34 points; 95% CI, –0.31 to 2.98) and 0.75 points with nintedanib and –0.78 points with placebo in patients with usual interstitial pneumonia-like fibrotic pattern (between-group difference, 1.53; 95% CI, –0.68 to 3.74).

Although the percentage of patients with any or serious adverse events were similar in the nintedanib and placebo groups in the overall study population, more patients assigned nintedanib had adverse events leading to a permanent dose reduction (33.1% vs. 4.2%) and discontinuation of treatment (19.6% vs. 10.3%). However, fatal events were less common in the nintedanib group than in the placebo group (3.3% vs. 5.1%).

The most frequently reported adverse event was diarrhea, occurring in 66.9% of the nintedanib group and 23.9% of the placebo group.

Hepatic abnormalities were also more common in the nintedanib group. Elevations in alanine aminotransferase, aspartate aminotransferase or both to at least three times the upper limit of normal range occurred in 13% of patients taking nintedanib vs. 1.8% of patients taking placebo during the 52-week period.

Results were similar for patients with usual interstitial pneumonia-like fibrotic pattern, the researchers noted. Further, they added that the safety and adverse event profile of nintedanib was similar to that observed in patients with IPF and patients with systemic sclerosis-associated ILD.

“This is the first trial to confirm that a drug effective and safe in patients with IPF is also safe and effective in a phenotype sharing different diagnoses,” Richeldi said, noting that the emergence of no new safety concerns is also reassuring.

‘Remarkable’ results

In an accompanying editorial, Hilary J. Goldberg, MD, MPH, from the division of pulmonary and critical care medicine at Brigham and Women’s Hospital in Boston, noted that the results showing that the magnitude of efficacy of nintedanib in this trial was comparable to that observed in patients with IPF were “remarkable” given the inclusion of patients with a variety of underlying ILDs.

PAGE BREAK

“Past therapeutic trials involving patients with IPF have been vulnerable to the limitations of enrollment of heterogeneous patient populations, because of the spectrum of diseases that can be seen in the IPF population and the overlap of IPF with other fibrotic lung diseases. The investigators in the current trial do not shy away from this risk but rather embrace the consideration of a phenotypic or endotypic approach to the study of therapeutic agents in fibrosing ILD,” she wrote. “Their apparent success in this trial suggests a final common pathway to fibrosis.”

Moving forward, though, there likely will be a need to understand disease-specific mechanisms to prevent “each of these diseases from gaining a foothold,” according to Goldberg.

“The use of nintedanib may slow the disease progression, but our challenge for the future is to design studies that identify earlier targets to prevent the establishment of this still highly morbid condition,” she wrote. – by Melissa Foster

References:

Flaherty KR, et al. ALERT: Abstracts leading to evolution in respiratory medicine trials: Interstitial lung disease and pulmonary hypertension. Presented at: European Respiratory Society International Congress; Sept. 28-Oct. 2, 2019; Madrid.

Flaherty KR, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1908681.

Goldberg HJ. N Engl J Med. 2019;doi:10.1056/NEJMe1911794.

Disclosures: This study was funded by Boehringer Ingelheim. Flaherty reports no relevant financial disclosures. Richeldi reports he has received grants and personal fees from Boehringer Ingelheim and Roche/Genentech, and he has received personal fees from Bellerophon, Blade Therapeutics, Celgene, FibroGen, Respivant, Sanofi-Genzyme and Veracyte. Goldberg reports she was a site co-investigator for this trial and saw patients for study visits.