The US Food and Drug Administration's (FDA's) Arthritis Advisory Committee has recommended approval of nintedanib (Ofev, Boehringer Ingelheim) for the treatment of systemic sclerosis-associated interstitial lung disease (SSc-ILD).
The committee voted 10 to 7 that the data did provide substantial evidence of nintedanib's efficacy for SSc-ILD, and 14 to 2 (with 1 abstention) that the safety profile is adequate to support approval of nintedanib for the treatment of SSc-ILD.
"I voted 'yes'," although "I do think there need to be longer studies to see if there is a sustained effect at 2 years and beyond, and also studies of the subgroups to determine who will respond best to this medication given the side effect profile," said voting committee member Alyce M. Oliver, MD, PhD, Joseph P. Bailey MD Chair in Rheumatology, professor of medicine, Medical College of Georgia at Augusta University.
Large Unmet Need: Nintedanib Would Be First Treatment
Systemic sclerosis (SSc) is a rare connective tissue disorder affecting approximately 100,000 individuals in the United States.
Patients with SSc develop widespread fibrosis and vascular abnormalities in the skin, joints, and internal organs such as the esophagus, lower gastrointestinal tract, heart, lungs, and kidneys.
They also have an increased risk for morbidity and mortality, with a 10-year survival rate below 70%.
Most deaths are caused by pulmonary fibrosis, pulmonary arterial hypertension, heart failure, or cardiac arrhythmia. The median survival for those who develop SSc-ILD is 5 to 8 years.
There are currently no approved treatments for SSc-ILD.
"In clinical practice, patients with SSc are treated based on expert-derived recommendations for the management of organ-specific manifestations and empirically with off-label products used for other rheumatic diseases, such as cyclophosphamide," the FDA explains in a briefing document.
Mycophenolate mofetil (MMF) may also be used.
These therapies have "inherent toxicities" including cytopenias, infections, and malignancies, according to the FDA.
Nintedanib is an oral triple angiokinase inhibitor that simultaneously inhibits vascular endothelial growth factor receptors (VEGFR 1-3), platelet-derived growth factor receptors (PDGFR) and fibroblast growth factor receptors (FGFR 1-3) signaling pathways.
The FDA granted nintedanib orphan drug status July 6, 2016 and fast track designation on March 7, 2018. The agency granted priority review for SSc-ILD on May 3 of this year.
And the FDA approved nintedanib for a related disease, idiopathic pulmonary fibrosis (IPF), on October 15, 2014. Boehringer Ingelheim proposes the same dosing regimen in SSc-ILD as that approved for the treatment of IPF.
Single Clinical Trial in SSc-ILD
The panel's vote follows consideration of data from a single clinical trial, the Safety and Efficacy of Nintedanib in Systemic Sclerosis Study (SENSCIS; Study 1199.214).
That was a double blind, randomized, placebo-controlled, parallel-group trial that studied the efficacy and safety of oral nintedanib 150 mg twice daily vs placebo in 576 patients with SSc-ILD.
The dose of nintedanib could be decreased if the patient experienced adverse effects or elevated liver enzymes and those with clinically significant deterioration of SSc could receive rescue therapy.
Patients had the option of continuing treatment for a maximum of 100 weeks to gather follow-up safety and efficacy data. Those who completed treatment and a follow-up visit could participate in an open-label, long-term extension study (SENSCIS-ON; Study 1199.225), which is ongoing.
The panel also reviewed safety data from the use of nintedanib in patients with IPF.
Primary Endpoint Was Decline in Forced Vital Capacity
The primary endpoint for SENSCIS, the annual rate of decline in forced vital capacity (FVC) over 52 weeks, was lower in the group that received nintedanib (-52 mL/year) compared with placebo (-93 mL/year; treatment difference, 41 mL/year; 95% confidence interval, 2.9 - 79.0).
This meant that nintedanib slowed the loss of pulmonary function by 44% in patients with SSc-ILD relative to placebo; the data were published in the New England Journal of Medicine (NEJM) earlier this year and presented at the American Thoracic Society (ATS) meeting in Dallas.
Forced vital capacity is a surrogate endpoint that has reliably predicted clinical benefit in patients with IPF.
"While the results for the primary endpoint were statistically significant based on the pre-specified analysis, the sensitivity analyses on missing data assumptions and responder analyses with various thresholds showed mixed results, mainly because the magnitude of the effect size was small," the FDA wrote in its briefing document.
"I voted 'no', primarily due to the effect size; I think the efficacy wasn't compelling," noted voting committee member Jeffrey Curtis, MD, MPH, Marguerite Jones Harbert – Gene Ball Endowed Professor of Medicine, Division of Clinical Immunology & Rheumatology, University of Alabama at Birmingham.
"The lack of any secondary endpoints likewise wasn't compelling," he added.
Key secondary endpoints included absolute change in modified Rodnan Skin Score and absolute change in Saint George's Respiratory Questionnaire, a patient-reported outcome, both assessed at week 52. Results were not significantly different between the nintedanib and placebo groups.
Further secondary endpoints included time to death, Health Assessment Questionnaire Disability Index, and Functional Assessment of Chronic Illness Therapy dyspnea scale.
These and other disease-related secondary endpoints, including number of digital ulcers, were also not significantly different between the two groups.
Serious Adverse Events, Deaths Evenly Distributed Between Groups
Adverse events included nausea, vomiting, diarrhea, and liver abnormalities. More people in the nintedanib group experienced adverse events, most of which were gastrointestinal in nature, that led them to decrease or discontinue the drug.
Patients in the nintedanib group also had more weight loss compared with those in the placebo group.
Serious adverse events were distributed evenly between the two groups; 69 patients (24%) in the nintedanib group and 62 patients (21.5%) in the placebo group reported serious adverse events.
Those that occurred more frequently in the nintedanib group included pneumonia (2.8% vs 0.3%), interstitial lung disease (2.4% vs 1.7%), pulmonary arterial hypertension (1.0% vs 0%), and acute kidney injury (1.0% vs 0.3%). With the exception of pneumonia, the differences between groups were mostly the result of small numbers of patients.
"The safety profile is in line with the known safety profile for the use of the drug in IPF," said committee chairperson Daniel H. Solomon, MD, MPH, professor of medicine, Matthew H. Liang Distinguished Chair, Harvard Medical School; Chief, Section of Clinical Sciences, Division of Rheumatology, Division of Pharmacoepidemiology, Brigham and Women's Hospital, Boston, Massachusetts.
"And the fact that it's been on the market for IPF for 5 or 6 years and there hasn't been anything new in post-marketing surveillance is also comforting, and the data that were presented are in line with the many drugs that are used for scleroderma," he noted in support of his 'yes' vote regarding the drug's safety.
Eleven study participants died during the treatment period: 6 in the nintedanib group and 5 in the placebo group. Post-treatment, 4 patients in each treatment group died. Overall, the types of deaths were balanced between the two groups throughout the study.
Study participants underwent safety assessments at weeks 2, 4, 6, 12, 24, 36, 52, 68, 84, and 100, and a follow-up visit 28 days after the end of treatment visit. Participants remained in the study until the last enrolled patient completed 52 weeks of treatment, for a maximum of 100 weeks.
The study drug was discontinued prematurely by 19.4% (n = 56) of those in the nintedanib group and 10.8% (n = 31) of those in the placebo group. Adverse events were the reason for most discontinuations in both groups.
Medscape Medical News © 2019
Cite this: FDA Panel Recommends Nintedanib for Rare Lung Disease - Medscape - Jul 26, 2019.