Nintedanib FDA Approved for Scleroderma Lung Disease Save

Last Friday, the US Food and Drug Administration approved Ofev (nintedanib) to slow the rate of decline in pulmonary function in adults with interstitial lung disease associated with systemic sclerosis or scleroderma, called SSc-ILD.

ILD as a complication of SSc may lead to progressive loss of lung function and may be associated with a significant mortality risk. Approximately 100,000 individuals in the United States have scleroderma, and half of these patients have SSc-ILD.

Prior to the approval of Olev, there were no FDA approved drugs for SSc-ILD.

Nintedanib is a small molecule, tyrosine kinase inhibitor that has anti-fibrotic and anti-inflammatory effects.  Ofev was originally approved in 2014 for adult patients with idiopathic pulmonary fibrosis, which is another interstitial lung condition.

The effectiveness of Ofev to treat SSc-ILD was studied in the SENESIS study - a randomized, double-blind, placebo-controlled trial of 576 patients ages 20-79 with the disease. Patients received treatment for 52 weeks, with some patients treated up to 100 weeks. Among 576 SSC patients, 52% had diffuse cutaneous disease and 48% had limited SSc and nearly half were on background mycophenolate and prednisone.

The results favored the nintedanib group with an FVC change of −52.4 ml per year compared to the placebo group (−93.3 ml per year) (difference, 41.0 ml per year; 95% confidence interval [CI], 2.9 to 79.0; P=0.04). Nintedanib treatment also was associated with 46% relative reduction and absolute change from base line and FVC compared to placebo at 52 weeks.

Importantly, Ofev had no effect on skin sclerosis progression (modified Rodnan skin score) at week 52.

The overall safety profile observed in the Ofev treatment group was consistent with the known safety profile of the therapy. The most frequent serious adverse event reported in patients treated with Ofev was pneumonia (2.8% Ofev vs. 0.3% placebo). Adverse reactions leading to permanent dose reductions were reported in 34% of Ofev-treated patients compared to 4% of placebo-treated patients. Diarrhea was the most frequent adverse reaction that led to permanent dose reduction in patients treated with Ofev. 

For the proposed SSc-ILD indication, the proposed dosing regimen is 150 mg twice daily, the same as the dosing for the currently approved indication for the treatment of idiopathic pulmonary fibrosis (IPF). Package insert can be found here.

While there is no "boxed warning" for Ofev, other warnings and precautions include:

• Hepatic impairment: OFEV is not recommended for use in patients with moderate or severe hepatic impairment.
• Elevated liver enzymes and drug-induced liver injury: ALT, AST, and bilirubin elevations have occurred with OFEV, including cases of drug-induced liver injury
• Gastrointestinal disorders: Diarrhea, nausea, and vomiting  have occurred
• Gastrointestinal perforation has been reported
• Embryo-Fetal toxicity: Ofev can cause fetal harm
• Arterial thromboembolic events have been reported. Use caution, especially in patients at higher cardiovascular risk including known coronaryartery disease.
• Bleeding events have been reported
• Common side effects noted with Ofev include diarrhea, nausea, abdominal pain, vomiting, liver enzyme elevation, decreased appetite, headache, weight loss and hypertension.

Ofev was originally approved in 2014 for adult patients with idiopathic pulmonary fibrosis (IPF), which is another interstitial lung condition.