Regulatory Decision Summary for Ofev

Interstitial lung diseases (ILDs) represent a large, heterogeneous group of pulmonary disorders often associated with autoimmune or other conditions. The ILDs can involve extensive lung fibrosis. Among the ILDs characterized by worsening fibrosis, specific treatments are only currently available for idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-related ILD (SSc-ILD). The grouping of ILD patients based on worsening lung fibrosis and respiratory symptoms, collectively termed progressive fibrosing ILD (PF-ILD), has been used to examine whether the anti-inflammatory/anti-fibrotic drug, nintedanib (Ofev), is effective in slowing the decline of lung function in these patients.

One randomized, double-blind, placebo-controlled phase 3 trial (1199.247) involving over 600 subjects was provided to support the use of nintedanib in PF-ILD patients for the current submission. This trial used the primary efficacy endpoint of annual decline in forced vital capacity (FVC; absolute volume in milliliters [mL]). Change in FVC can demonstrate clinically meaningful differences. This was the same primary endpoint used in studies that assessed nintedanib for its previously approved indications for IPF and SSc-ILD. All secondary efficacy endpoints, including survival, acute ILD exacerbations, and quality of life questionnaires, were considered as exploratory.

The primary endpoint analysis measured FVC change from baseline at 52 weeks. At this time point, patients in the overall population who had received a placebo had a decline in FVC of 187.8 mL. In comparison, patients treated with 150 mg nintedanib twice daily had a decline in FVC of 80.8 mL, for a difference of 107.0 mL. This treatment difference was similar to the treatment benefit with nintedanib seen in previous clinical trials with IPF patients. In Trial 1199.247, subgroup analysis was important to demonstrate effectiveness across the heterogeneous patient population (and was added to the "Clinical Trials" section of the Product Monograph [PM] for this reason). A co-primary patient population with usual interstitial pneumonia (UIP)-like lung fibrosis had a treatment difference of 128.2 mL, in favour of the nintedanib treatment group. Other pre-specified subgroups, including those grouped by gender, age, baseline percent predicted FVC, and underlying disease conditions, showed results consistent with the primary analysis.

Secondary endpoint analyses were all supportive of a treatment benefit with nintedanib. The main secondary endpoint analyses included a combination endpoint of time to first acute ILD exacerbation or death, all-cause mortality, and the Kings Brief Interstitial Lung Disease quality of life questionnaire. Though none showed a statistically significant benefit at 52 weeks, all trended towards showing benefit for the nintedanib treatment group.

Significant safety concerns have previously been identified for nintedanib. These include risk of drug-induced liver injury, adverse cardiovascular effects, and risk of bleeding events. Patients at risk of major adverse cardiovascular events were excluded from Trial 1199.247, as were those with existing or potential liver disease. Nintedanib treatment has also been associated with severe gastrointestinal side effects. Diarrhea, nausea, and vomiting were all common in Trial 1199.247. Though severe in some patients, these were not life-threatening, and were manageable with dose reduction or dose interruption. Liver enzyme elevations were also more common in nintedanib-treated patients compared to those in the placebo group, and were similarly manageable with dose reduction or dose interruption. All adverse events were consistent with the known safety issues associated with nintedanib use. Appropriate labelling regarding risk mitigation, suitable for the PF-ILD patient population, is contained in the PM. No new significant safety issues were observed in Trial 1199.247. A Risk Management Plan highlighting important adverse events relevant to the previous, and currently sought, indications has been reviewed and found acceptable.

Overall, with proper risk mitigation, the data evaluated supported the use of nintedanib to treat patients with chronic fibrosing ILD with a progressive phenotype.