FDA News

FDA panel supports approval of nintedanib for systemic sclerosis-associated ILD

The FDA Arthritis Advisory Committee voted 10-7 to recommend approval of nintedanib for treatment of systemic sclerosis-associated interstitial lung disease.

The committee’s decision came amid concerns about the drug’s modest benefit in FVC without significant improvement in patient-reported outcomes that were balanced by the hope for a treatment option for a disorder that currently lacks any FDA-approved therapies.

“Patients with [systemic sclerosis-associated ILD] have a fatal outcome. We have nothing that really is effective in mitigating that, and even though the effect size is not huge, there is some evidence of benefit,” William Calhoun, MD, FACP, FCCP, FAAAAI, FACAAI, Nelda C and HJ Stark Distinguished Chair in Internal Medicine and professor and vice chair for the Research Department of Internal Medicine at the University of Texas Medical Branch in Galveston, Texas, said during the panel discussion. “Docs always need additional tools and whether this is going to be perfect for every patient is not a question that will be answered with additional data. My guess is, given the heterogeneity of the disease, that it will not be right for everybody, but doctors need the ability to prescribe it.”

Efficacy questions

Currently, nintedanib (Ofev, Boehringer Ingelheim) is approved to treat idiopathic pulmonary fibrosis. The SENSCIS trial — a double-blind, randomized, placebo-controlled, parallel-group trial designed to evaluate the efficacy and safety of nintedanib in patients with systemic sclerosis-associated ILD — formed the basis for FDA review for the new indication.

For the study, FVC served as the primary endpoint. Key secondary endpoints included absolute changes in modified Rodnan Skin Score and Saint George’s Respiratory Questionnaire. Time to death, Health Assessment Questionnaire Disability Index and Functional Assessment of Chronic Illness Therapy dyspnea scale were also analyzed.

The primary efficacy analysis occurred at 52 weeks, but patients could remain on treatment for up to 100 weeks. Study participants scheduled a follow-up visit 28 days after the end-of-treatment visit.

Of 576 patients (75% women) with systemic sclerosis-associated ILD, 288 were assigned oral nintedanib 150 mg twice daily and 288 were assigned placebo. Over the 52-week treatment period, the adjusted annual rate of decline in FVC was lower in the nintedanib group vs. the placebo group (–52 mL per year vs. –93 mL per year), with a treatment difference of 41 mL per year. Notably, in prespecified subgroup analyses, the treatment effect was less pronounced in patients myocophenolate mofetil at baseline and in patients from the U.S. and Canada.

Also, at 52 weeks, there were no significant differences between the treatment and placebo groups in any of the key secondary outcomes, according to the FDA briefing documents.

In another 10-7 vote, the committee determined that the data provide substantial evidence of the efficacy of nintedanib in treatment of systemic sclerosis-associated ILD. However, the SENSCIS findings prompted significant debate.

“This is a disease with an unmet need and the study met a hard endpoint that was prespecified, and while the data are not as robust as anyone would like to see, we are dealing with a disease that is rare and a trial that is difficult to pull off. I believe for now that it is efficacious,” Daniel H. Solomon, MD, MPH, professor of medicine and Matthew H. Liang Distinguished Chair at Harvard Medical School and chief of the section of clinical sciences, division of rheumatology, division of pharmacoepidemiology at Brigham and Women’s Hospital, said during the panel discussion.

However, some committee members cast the data in a different light.

“The magnitude of the effect size was small, at best, and probably not very clinically relevant, certainly at 1 year,” Jeffrey Curtis, MD, MS, MPH, Marguerite Jones Harbert – Gene Ball Endowed Professor of Medicine and from the division of clinical immunology and rheumatology at the University of Alabama at Birmingham, said. He also noted that the lack of improvement in symptoms, mortality or any other secondary endpoint was discouraging. “This was honestly very disappointing to me.”

Safety concerns

During the advisory panel meeting, committee members cited fewer concerns about safety issues, with the panel voting 14-2 with one abstention that the safety profile of nintedanib was adequate to support its approval for treatment of systemic sclerosis-associated ILD.

Nevertheless, the high rate of gastrointestinal problems, including 76% of patients who experienced diarrhea, in the nintedanib group raised questions. Additionally, pneumonia, discontinuation of treatment, dose reduction and weight loss were more common among patients treated with nintedanib, according to the FDA briefing documents.

During discussion of his vote, James Katz, MD, senior research physician and director of the Rheumatology Fellowship and Training Branch of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH, noted that a single trial may not provide enough information on the use of nintedanib in this patient population.

“The danger is the assumption that the adverse event profile is actually manageable. That’s fine if it’s true, but if the drug precipitates renal crisis, causes malabsorption and results in weight loss and increased mortality, only with more time are we going to know that this adverse event profile is actually manageable,” he said.

Many committee members, though, said that the safety profile of nintedanib is consistent with what is already listed in the drug’s label.

“The safety profile is in line with use of the drug in line with use of the drug in idiopathic pulmonary fibrosis. It has been on the market for IPF for 5 to 6 years and there hasn’t been anything new in postmarket surveillance,” Solomon said.

Looking ahead

Although the vote was not unanimous, all panel members advocated for further research on the use of nintedanib in patients with systemic sclerosis-associated ILD.

“There need to be longer studies to see if there is a sustained effect at 2 years and beyond and also studies of subgroups to determine who will respond best to this medication given the side effect profile,” Alyce M. Oliver, MD, PhD, Joseph P. Bailey, MD Chair in Rheumatology and professor of medicine at the Medical College of Georgia at Augusta University, said after the final vote.

In a company press release, Thomas Seck, MD, senior vice president of medical and regulatory affairs at Boehringer Ingelheim, expressed satisfaction with the advisory panel’s decision.

“The committee’s recommendation brings nintedanib one step closer to becoming available to patients who suffer from the devastating impact of systemic sclerosis-associated ILD,” he said in the release. “Based on the strength of the data presented, and the positive recommendation by the committee, we are hopeful that the FDA will approve nintedanib as a treatment option for patients with systemic sclerosis-associated ILD. If approved, nintedanib would be the first treatment approved in the U.S. for these patients.”

Although the FDA is not required to follow the recommendations of the advisory committees, it usually does. – by Melissa Foster

Reference:

Boehringer Ingelheim briefing information. Available at: https://www.fda.gov/media/129233/download. Accessed July 25, 2019.

FDA briefing information. Available at: https://www.fda.gov/media/129232/download. Accessed July 25, 2019.

The FDA Arthritis Advisory Committee voted 10-7 to recommend approval of nintedanib for treatment of systemic sclerosis-associated interstitial lung disease.

The committee’s decision came amid concerns about the drug’s modest benefit in FVC without significant improvement in patient-reported outcomes that were balanced by the hope for a treatment option for a disorder that currently lacks any FDA-approved therapies.

“Patients with [systemic sclerosis-associated ILD] have a fatal outcome. We have nothing that really is effective in mitigating that, and even though the effect size is not huge, there is some evidence of benefit,” William Calhoun, MD, FACP, FCCP, FAAAAI, FACAAI, Nelda C and HJ Stark Distinguished Chair in Internal Medicine and professor and vice chair for the Research Department of Internal Medicine at the University of Texas Medical Branch in Galveston, Texas, said during the panel discussion. “Docs always need additional tools and whether this is going to be perfect for every patient is not a question that will be answered with additional data. My guess is, given the heterogeneity of the disease, that it will not be right for everybody, but doctors need the ability to prescribe it.”

Efficacy questions

Currently, nintedanib (Ofev, Boehringer Ingelheim) is approved to treat idiopathic pulmonary fibrosis. The SENSCIS trial — a double-blind, randomized, placebo-controlled, parallel-group trial designed to evaluate the efficacy and safety of nintedanib in patients with systemic sclerosis-associated ILD — formed the basis for FDA review for the new indication.

For the study, FVC served as the primary endpoint. Key secondary endpoints included absolute changes in modified Rodnan Skin Score and Saint George’s Respiratory Questionnaire. Time to death, Health Assessment Questionnaire Disability Index and Functional Assessment of Chronic Illness Therapy dyspnea scale were also analyzed.

The primary efficacy analysis occurred at 52 weeks, but patients could remain on treatment for up to 100 weeks. Study participants scheduled a follow-up visit 28 days after the end-of-treatment visit.

Of 576 patients (75% women) with systemic sclerosis-associated ILD, 288 were assigned oral nintedanib 150 mg twice daily and 288 were assigned placebo. Over the 52-week treatment period, the adjusted annual rate of decline in FVC was lower in the nintedanib group vs. the placebo group (–52 mL per year vs. –93 mL per year), with a treatment difference of 41 mL per year. Notably, in prespecified subgroup analyses, the treatment effect was less pronounced in patients myocophenolate mofetil at baseline and in patients from the U.S. and Canada.

PAGE BREAK

Also, at 52 weeks, there were no significant differences between the treatment and placebo groups in any of the key secondary outcomes, according to the FDA briefing documents.

In another 10-7 vote, the committee determined that the data provide substantial evidence of the efficacy of nintedanib in treatment of systemic sclerosis-associated ILD. However, the SENSCIS findings prompted significant debate.

“This is a disease with an unmet need and the study met a hard endpoint that was prespecified, and while the data are not as robust as anyone would like to see, we are dealing with a disease that is rare and a trial that is difficult to pull off. I believe for now that it is efficacious,” Daniel H. Solomon, MD, MPH, professor of medicine and Matthew H. Liang Distinguished Chair at Harvard Medical School and chief of the section of clinical sciences, division of rheumatology, division of pharmacoepidemiology at Brigham and Women’s Hospital, said during the panel discussion.

However, some committee members cast the data in a different light.

“The magnitude of the effect size was small, at best, and probably not very clinically relevant, certainly at 1 year,” Jeffrey Curtis, MD, MS, MPH, Marguerite Jones Harbert – Gene Ball Endowed Professor of Medicine and from the division of clinical immunology and rheumatology at the University of Alabama at Birmingham, said. He also noted that the lack of improvement in symptoms, mortality or any other secondary endpoint was discouraging. “This was honestly very disappointing to me.”

Safety concerns

During the advisory panel meeting, committee members cited fewer concerns about safety issues, with the panel voting 14-2 with one abstention that the safety profile of nintedanib was adequate to support its approval for treatment of systemic sclerosis-associated ILD.

Nevertheless, the high rate of gastrointestinal problems, including 76% of patients who experienced diarrhea, in the nintedanib group raised questions. Additionally, pneumonia, discontinuation of treatment, dose reduction and weight loss were more common among patients treated with nintedanib, according to the FDA briefing documents.

During discussion of his vote, James Katz, MD, senior research physician and director of the Rheumatology Fellowship and Training Branch of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH, noted that a single trial may not provide enough information on the use of nintedanib in this patient population.

“The danger is the assumption that the adverse event profile is actually manageable. That’s fine if it’s true, but if the drug precipitates renal crisis, causes malabsorption and results in weight loss and increased mortality, only with more time are we going to know that this adverse event profile is actually manageable,” he said.

PAGE BREAK

Many committee members, though, said that the safety profile of nintedanib is consistent with what is already listed in the drug’s label.

“The safety profile is in line with use of the drug in line with use of the drug in idiopathic pulmonary fibrosis. It has been on the market for IPF for 5 to 6 years and there hasn’t been anything new in postmarket surveillance,” Solomon said.

Looking ahead

Although the vote was not unanimous, all panel members advocated for further research on the use of nintedanib in patients with systemic sclerosis-associated ILD.

“There need to be longer studies to see if there is a sustained effect at 2 years and beyond and also studies of subgroups to determine who will respond best to this medication given the side effect profile,” Alyce M. Oliver, MD, PhD, Joseph P. Bailey, MD Chair in Rheumatology and professor of medicine at the Medical College of Georgia at Augusta University, said after the final vote.

In a company press release, Thomas Seck, MD, senior vice president of medical and regulatory affairs at Boehringer Ingelheim, expressed satisfaction with the advisory panel’s decision.

“The committee’s recommendation brings nintedanib one step closer to becoming available to patients who suffer from the devastating impact of systemic sclerosis-associated ILD,” he said in the release. “Based on the strength of the data presented, and the positive recommendation by the committee, we are hopeful that the FDA will approve nintedanib as a treatment option for patients with systemic sclerosis-associated ILD. If approved, nintedanib would be the first treatment approved in the U.S. for these patients.”

Although the FDA is not required to follow the recommendations of the advisory committees, it usually does. – by Melissa Foster

Reference:

Boehringer Ingelheim briefing information. Available at: https://www.fda.gov/media/129233/download. Accessed July 25, 2019.

FDA briefing information. Available at: https://www.fda.gov/media/129232/download. Accessed July 25, 2019.