Sustained Efficacy for Preventing Pulmonary Progression of Drugs in Systemic Sclerosis
Patients with systemic sclerosis-related interstitial lung disease (ILD) continued to see less progression when treated with nintedanib (Ofev) in the pivotal 100-week SENSCIS trial, the researchers said.
Among participants who remained on the drug until the protocol stopped them, forced vital capacity (FVC) decreased by 55.1 ml/year, compared to 94.0 ml/year in the placebo group of l trial (difference 38.9, 95% CI 5.6-72.1), according to Shervin Assassi, MD, of the McGovern School of Medicine at the University of Texas at Houston, and colleagues.
A modified intention-to-treat analysis that also included post-treatment data from patients who quit early also favored nintedanib, the researchers reported in ACR Open Rheumatology: FVC decreased by 54.9 and 88.8 mL/year with drug and placebo, respectively, for a difference of 34.0 mL/year (95% CI 3.4-64.5).
Nintedanib gained FDA approval in September 2019 for this patient population, based on results analyzed at week 52, when the drug slowed FVC decline by an average of 41 mL/yr per compared to placebo. The drug was first approved in 2014 to treat idiopathic pulmonary fibrosis (IPF) and also, in March 2020, for any type of progressive PID.
The new report covers the full 100-week results which was the predefined goal of the trial, although not all patients received the drug for that long.
Nintedanib inhibits tyrosine kinases that regulate the expression of fibroblast growth factor, vascular endothelial growth factor, and platelet-derived growth factor receptors. (In fact, the drug was originally designed as an anti-angiogenic therapy for solid tumor cancers.) Its developers eventually realized that this mode of action could also be effective against processes involved in pulmonary fibrosis. , leading to successful trials first in IPF and then ILD.
For SENSCIS, Assassi and colleagues recruited 576 patients with systemic sclerosis, randomized in equal numbers to receive nintedanib (150 mg orally twice daily) and placebo. Eligibility criteria included having a first non-Raynaud symptom less than 7 years ago, a FVC of at least 40% of the predicted value, the presence of a fibrous ILD of at least 10 % on CT scans and a carbon monoxide diffusing capacity of 30%-89% expected. Participants taking corticosteroids (no more than 10 mg/day prednisone equivalent) and/or methotrexate or mycophenolate mofetil at stable doses were allowed to continue taking them.
FVC was the only measure of lung function in the trial, although it was analyzed in several ways. In addition to the average rate of decline (the primary outcome), the researchers also counted the number of participants with declines of 5% and 10% over the full 100 weeks. The modified Rodnan Skin Score was also assessed to determine the effects, if any, on the skin manifestations of systemic sclerosis. No statistically significant differences in these secondary outcomes were observed, although there were numerical trends in favor of nintedanib.
The design of the trial made efficacy analyzes somewhat complicated. Blinded treatment continued until the last patient enrolled completed 52 weeks of treatment, so follow-up varied among participants. Patients who decided to quit before that date (74 and 46 in the nintedanib and placebo groups, respectively) were then asked to continue with their scheduled clinic visits, and most did.
Therefore, the modified intention-to-treat analysis included all data from those who discontinued treatment but continued follow-up, but post-treatment data from participants whose treatment was discontinued per protocol (because the last enrolled had reached week 52) were excluded. In-treatment analysis, as the name suggests, included data obtained on treatment, but not results after patients stopped for any reason.
Regarding safety, the most common side effect was diarrhea, which was observed in 76% of patients in the nintedanib group and 33% of those assigned to the placebo group. About 8% of patients receiving nintedanib discontinued treatment for this reason. Liver enzyme elevations above three times the upper limit of normal occurred in 6% of the nintedanib group versus 1% of the placebo group, although no one in either arm met Hy’s Law criteria. Other adverse events, including all those classified as serious and those ending in death, were balanced between the groups.
Overall, the safety results at 100 weeks were similar to those of the 52-week analysis. The nintedanib label includes a warning about liver abnormalities and gastrointestinal effects, and recommends periodic monitoring of liver enzymes while patients remain on treatment.
The trial was funded by Boehringer Ingelheim; two co-authors were company employees. Other authors, including Assassi, reported relationships with a large number of pharmaceutical companies and other commercial entities.