Regulatory Decision Summary for Ofev

The clinical efficacy and safety of Ofev (nintedanib) in patients with systemic sclerosis associated interstitial lung disease (SSc-ILD) was evaluated in a randomized, double-blind, placebo-controlled phase 3 clinical trial. The primary efficacy endpoint was the annual rate of decline in Forced Vital Capacity (FVC) over 52 weeks. Key secondary efficacy endpoints were change from baseline in modified Rodnan Skin Score (mRSS) at 52 weeks and change from baseline in the St. Georges Respiratory Questionnaire (SGRQ) total score at 52 weeks. Mortality over the whole trial was an additional secondary endpoint. A total of 576 patients were randomized and treated in a 1:1 ratio with Ofev (nintedanib) 150 mg twice daily or placebo for at least 52 weeks.

Key Benefit
The results of the primary efficacy endpoint showed that the adjusted annual rate of decline in FVC in mL over 52 weeks was lower in the Ofev group (-52.4 mL/year) than in the placebo group (-93.3 mL/year). The adjusted difference between the treatment groups was 40.95 mL/year, 95% CI (2.88, 79.01) (p=0.0350), corresponding to a relative treatment effect of 43.8%. Additionally, the adjusted annual rate of decline in FVC in percent predicted over 52 weeks was lower in patients treated with Ofev (-1.4%) compared with patients treated with placebo (-2.6%).

The adjusted mean absolute change from baseline in mRSS at week 52 was comparable between the Ofev group (-2.17, 95% CI -2.69, -1.65) and the placebo group (-1.96, 95% CI -2.48, -1.45). The adjusted mean difference between the treatment groups was -0.21 (95% CI -0.94, 0.53; p = 0.5785). The adjusted mean absolute change from baseline in SGRQ total score at week 52 was comparable between the Ofev group (0.81, 95% CI -0.92, 2.55) and the placebo group (-0.88, 95% CI -2.58, 0.82). The adjusted mean difference between the treatment groups was 1.69 (95% CI -0.73, 4.12; p = 0.1711). The absolute change from baseline in Carbon Monoxide Diffusion Capacity (DLco) in percent predicted at Week 52 was comparable between the Ofev and the placebo group, no meaningful treatment difference was observed. Mortality over the whole trial was also comparable between the Ofev group (number (N) = 10; 3.5%) and the placebo group (N = 9; 3.1%). The exploratory analysis of time to death over the whole trial resulted in a Hazard Ratio (HR) of 1.16 (95% CI 0.47, 2.84; p = 0.7535).

Key Harm
The most common adverse reactions, with an incidence of >3% in Ofev-treated patients and more commonly than in placebo, were diarrhoea (75.7% vs. 31.6%), nausea (31.6% vs. 13.5%), vomiting (24.7% vs. 10.4%), abdominal pain (18.4% vs. 11.1%), pneumonia (4.2% vs. 2.1%), weight decreased (11.8% vs. 4.2%), liver enzyme elevation (13.2% vs. 3.1%), hypertension (4.9% vs. 1.7%), fatigue (10.8% vs. 6.9%), and dizziness (5.9% vs. 4.2%). The most frequently reported drug-related adverse events (AE) were diarrhoea (68.4% vs. 19.8%), nausea (24.7% vs. 7.3%), vomiting (17.7% vs. 4.2%), and alanine aminotransferase (ALT) increased (5.6% vs. 0.7%).

The most frequent serious AEs reported in the study were worsening of interstitial lung disease (4.5% in both treatment groups) and pneumonia (2.8% Ofev vs. 0.3% placebo). No cases of gastrointestinal perforation or hyperbilirubinemia were reported. There were no observed treatment differences regarding arterial thromboembolic events, myocardial infarction, and drug-induced liver injury. A maximum ALT and/or aspartate transaminase (AST) ≥3x upper limit of normal (ULN) was reported for 4.9% of patients treated with Ofev and for 0.7% in placebo. Over the whole trial including post-treatment (28 days), 10 patients (3.5%) in the Ofev group and 9 patients (3.1%) in the placebo group died. There was no pattern among adverse events leading to death in either treatment group.

Adverse reactions leading to permanent dose reductions were reported in 34% of Ofev-treated patients and 4% of placebo-treated patients. The most frequent adverse reaction that led to permanent dose reduction in the patients treated with Ofev was diarrhea (22.2%), nausea (2.1%), vomiting (2.1%), and ALT increased (1.4%). Adverse reactions leading to discontinuation were reported in 16% of Ofev-treated patients and 9% of placebo-treated patients. The most frequent adverse reactions that led to discontinuation in Ofev-treated patients were diarrhea (6.9%), nausea (2.1%), vomiting (1.4%), and abdominal pain (1%). All adverse reactions were reversible after dose reduction or discontinuation.

Key Uncertainties
Uncertainties of Benefit: Although Ofev significantly reduced the annual rate of decline in FVC over 52 weeks compared with placebo, the lower rate of decline in FVC was not accompanied by a benefit with respect to skin fibrosis as assessed by the mRSS or clinical symptoms measured by the SGRQ. Survival is an important clinical outcome; in this 52-week study, treatment with Ofev did not show benefit over patient survival. Long-term impact of Ofev on survival in SSc-ILD patients is unknown.

Efficacy of Ofev on annual rate of decline in FVC in patients beyond 52 weeks was not assessed in the pivotal trial and remains unknown. In addition, patients with significant pulmonary hypertension (PH) or cardiovascular diseases including severe hypertension, myocardial infarction and unstable cardiac angina, and patients with bleeding risk, were excluded from this study. Therefore, efficacy of Ofev for those patients remains unknown.

Uncertainties of Harm: An increased rate of pneumonia as a serious AE was reported in the pivotal trial among SSc-ILD patients receiving Ofev (2.8%) versus placebo (0.3%). However, none of the serious pneumonia cases were considered as being related to Ofev treatment by the investigators. The sponsor will continue closely monitoring the risk of pneumonia in patients treated with Ofev in the post-marketing surveillance systems.

Management
The Product Monograph of Ofev provides risk mitigation measures to reduce the risk of liver toxicity.

In light of the above, the benefit-harm-uncertainty assessment of Ofev is considered favourable, for an indication to slow the rate of decline in pulmonary function in patients with systemic sclerosis associated interstitial lung disease (SSc-ILD).