Regulatory Decision Summary for Ofev

The efficacy and safety of Ofev (nintedanib, 150 mg twice daily) were evaluated in two replicate Phase III 52 week, randomized, double-blind, placebo-controlled, parallel-group studies in patients with IPF. The primary endpoint was the annual rate of decline in forced vital capacity (FVC). The key secondary endpoints were change from baseline in St. George’s Respiratory Questionnaire (SGRQ) total score at 52 weeks and time to first acute IPF exacerbation over 52 weeks. Dose reductions to 100 mg twice daily or temporary treatment interruptions were allowed to manage adverse reactions.

In the replicate pivotal clinical studies, Ofev demonstrated a consistent and statistically significant benefit in reducing the decline of FVC (lung function) by 125 mL/year and 94 mL/year compared to placebo in patients with IPF. The decline in FVC over time was similar in both studies, and was more gradual over the 52 weeks than the decline observed with placebo. Divergent results between the replicate studies were observed for SGRQ and time to first acute IPF exacerbation. In one study, there was no difference between the treatment groups for both SGRQ and IPF exacerbation, whereas in the second study, nintedanib was statistically significantly favourable over placebo for both SGRQ and acute IPF exacerbations. In the dose ranging study, the reduction in the decline of FVC by 131 mL/year with nintedanib 150 mg twice daily compared to placebo was similar to the results of the replicate pivotal clinical studies.

The benefit of Ofev in reducing the decline in lung function was consistent over three 52-week clinical studies and is considered robust. However, there is uncertainty regarding the effect of nintedanib on the quality of life and acute exacerbation, which were not consistent. The pathophysiology and symptoms of IPF are predominantly due to the loss of lung function, and therefore, slowing of the rate of decline in lung function may be expected to have secondary benefits on quality of life and potentially IPF exacerbations. There is also uncertainty in the validity of SGRQ as an outcome for patients with IPF as it has not been validated in this patient population. In addition, the Minimal Clinical Important Difference (MCID) for SGRQ total score is 4 points, however, the difference from placebo was <3 points in both Phase III clinical studies. Patients with acute IPF exacerbations have a very poor outcome, and the clinical benefit of nintedanib in reducing exacerbations is not robust, however, for adjudicated IPF exacerbations, a numerical benefit of nintedanib over placebo was observed in both pivotal clinical studies. There is also uncertainty regarding the long-term efficacy of the 100 mg twice-daily dose, which did not significantly reduced the rate of decline in FVC in the dose ranging study. In the pivotal clinical studies, 26-29% of patients had a dose reduction for 4 months on average. Some patients may need to stay on the reduced dose for longer periods of time to manage adverse reactions that may occur with the higher dose.

The safety profile of Ofev was characterized mainly by gastrointestinal disorders and hepatic injury. The most common adverse reactions reported were diarrhea, nausea, abdominal pain, decreased appetite and weight, and increased liver enzymes. The adverse reactions were generally well managed by dose reductions or treatment interruptions. Due to the anti-angiogenic activity of nintedanib, there is also the potential for serious adverse reactions including bleeding and gastrointestinal perforations. Myocardial infarction was also observed infrequently with nintedanib. All of the potential adverse reactions have been addressed in the Product Monograph, and monitoring of liver enzymes is recommended for patients.

In non-clinical studies, impaired fertility was observed in rats and embryo fetal lethality and teratogenicity were observed in rats and rabbits. Therefore, Ofev is contraindicated during pregnancy and is appropriately labelled in the Product Monograph.

Due to the older population with IPF and common co-morbidities, there may be uncertainties regarding the events due to treatment with nintedanib. However, the gastrointestinal adverse reactions and increased liver enzyme elevations that may lead to liver damage are evidently linked to treatment with nintedanib.

Ofev has demonstrated robust clinical benefit in reducing the decline of lung function in patients with IPF. Ofev is the second pharmacological treatment for IPF, which is a disease with a poor prognosis and an unmet medical need. Management of adverse reactions is available and appropriately addressed in the Product Monograph with the recommendation of dose reduction or temporary or permanent treatment discontinuation as required.

Overall, the benefit/risk balance for Ofev is considered favourable for the recommended indication.

For more information on Health Canadas decision, please view the Summary Basis of Decision.