Ofev (Page 6 of 8)

14.2 Chronic Fibrosing Interstitial Lung Diseases with a Progressive Phenotype

The clinical efficacy of OFEV has been studied in patients with chronic fibrosing ILDs with a progressive phenotype in a randomized, double-blind, placebo-controlled phase 3 trial (Study 5 [NCT02999178]). A total of 663 patients were randomized in a 1:1 ratio to receive either OFEV 150 mg twice daily or matching placebo for at least 52 weeks. Randomization was stratified based on high resolution computed tomography (HRCT) fibrotic pattern as assessed by central readers: 412 patients with UIP-like HRCT pattern and 251 patients with other HRCT fibrotic patterns were randomized. There were 2 co-primary populations defined for the analyses in this trial: all patients (the overall population) and patients with HRCT with UIP-like HRCT fibrotic pattern.

The primary endpoint was the annual rate of decline in FVC (in mL) over 52 weeks. Other endpoints included time to first acute ILD exacerbation and time to death.

Patients with a clinical diagnosis of a chronic fibrosing ILD were selected if they had relevant fibrosis (greater than 10% fibrotic features) on HRCT and presented with clinical signs of progression (defined as FVC decline ≥10%, FVC decline ≥ 5% and <10% with worsening symptoms or imaging, or worsening symptoms and worsening imaging all in the 24 months prior to screening). Patients were required to have an FVC greater than or equal to 45% of predicted and a DLCO 30% to less than 80% of predicted. Patients were required to have progressed despite management deemed appropriate in clinical practice by investigators for the patient’s relevant ILD.

Patients with IPF, relevant airways obstruction (i.e., pre-bronchodilator FEV1/FVC less than 0.7), or significant pulmonary hypertension were excluded from the trial. Patients with greater than 1.5 times ULN of ALT, AST, or bilirubin, patients with a known risk or predisposition to bleeding, patients receiving a full dose of anticoagulation treatment, and patients with a recent history of myocardial infarction or stroke were excluded. Patients were also excluded if they received other investigational therapy, azathioprine, cyclosporine, mycophenolate mofetil, tacrolimus, oral corticosteroids greater than 20 mg/day, or the combination of oral corticosteroids + azathioprine + n-acetylcysteine within 4 weeks of randomization, cyclophosphamide within 8 weeks prior to randomization, rituximab within 6 months, or previous treatment with nintedanib or pirfenidone.

The majority of patients were Caucasian (74%) or Asian (25%). Patients were mostly male (54%) and had a mean age of 66 years and a mean FVC percent predicted of 69%, and 49% were never-smokers. The underlying clinical ILD diagnoses in groups represented in the trial were hypersensitivity pneumonitis (26%), autoimmune ILDs (26%), idiopathic nonspecific interstitial pneumonia (19%), unclassifiable idiopathic interstitial pneumonia (17%), and other ILDs (12%).

Annual Rate of Decline in FVC

There was a statistically significant reduction in the annual rate of decline in FVC (in mL) over 52 weeks in patients receiving OFEV compared to patients receiving placebo. The annual rate of decline in FVC (in mL) over 52 weeks was significantly reduced by 107 mL in patients receiving OFEV compared to patients receiving placebo. Results in the subpopulations of patients with HRCT with UIP-like fibrotic pattern and patients with other fibrotic patterns (Other HRCT) are included with the overall population in Table 4.

Table 4 Annual Rate of Decline in FVC (mL) in Study 5
OverallUIP-like SubpopulationOther HRCT Subpopulation
OFEVPlaceboOFEVPlaceboOFEVPlacebo
a Based on a random coefficient regression model with fixed categorical effects of treatment, HRCT pattern, fixed continuous effects of time, baseline FVC (mL), and including treatment by time and baseline by time interactions
Number of analyzed patients331331206206125125
Adjusted annual rate of decline over 52 weeks-81-188-83-211-79-154
Comparison vs placebo differencea 10712875*
95% CI(65, 148)(71, 186)(16, 135)*
*Comparison based on the Other HRCT subpopulation was not included in the multiple testing procedure. Values shown here are for descriptive purposes.

A post-hoc exploratory analysis by ILD diagnosis was performed and is shown in Figure 4. Treatment response across ILD diagnoses was consistent for FVC.

Figure 4 Annual Rate of Decline in FVC (mL) over 52 Weeks based on Underlying ILD Diagnosis in Study 5*

Figure 4
(click image for full-size original)

ILD = interstitial lung disease; Autoimmune ILDs: includes rheumatoid arthritis-associated ILD, mixed connective tissue disease, systemic sclerosis-associated ILD, and other terms; Other ILDs: includes fibrosing ILDs not categorized under autoimmune ILDs, hypersensitivity pneumonitis, idiopathic nonspecific interstitial pneumonia, or unclassifiable idiopathic interstitial pneumonia. The three most common ILDs in this category are exposure-related ILD, sarcoidosis, and pleuro-parenchymal fibroelastosis. *These results are from a post-hoc exploratory analysis. Values shown here are for descriptive purposes.

Figure 5 shows the change in FVC from baseline over time in the treatment groups. When the mean observed FVC change from baseline was plotted over time, the curves diverged at all timepoints through Week 52.

Figure 5 Mean (SEM) Observed FVC Change from Baseline (mL) Over 52 Weeks in Study 5

Figure 5
(click image for full-size original)

bid = twice daily

Percent Change from Baseline in Forced Vital Capacity

Figure 6 presents the percent change from baseline in FVC in mL at Week 52 for Study 5. For the majority of patients, the decline in lung function was less on OFEV than on placebo.

Figure 6 Histogram of the Percent Change in FVC (mL) from Baseline to Week 52 According to Treatment and Percent Increments or Decrements of 5 (Study 5)a

Figure 6
(click image for full-size original)

a Patients classified as having missing FVC data at Week 52 are those with no FVC assessment between Day 310 and Day 373.bid = twice daily

Time to First Acute ILD Exacerbation

Acute ILD exacerbation was defined as unexplained worsening or development of dyspnea within 30 days, new diffuse pulmonary infiltrates on chest x-ray, and/or new HRCT parenchymal abnormalities with no pneumothorax or pleural effusion, and exclusion of alternative causes. Acute ILD exacerbations were not adjudicated.

The risk of first acute ILD exacerbation did not show a statistically significant difference between the OFEV group compared to placebo (52 week treatment period: HR 0.72, (95% CI: 0.38, 1.37); whole trial: HR 0.63 (95% CI: 0.37, 1.07)).

Survival

Survival was evaluated for OFEV compared to placebo in Study 5 to support the primary endpoint (FVC). All-cause mortality was assessed over the study duration and available follow-up period, irrespective of cause of death and whether patients continued treatment. All-cause mortality did not show a statistically significant difference (52 week treatment period: HR 0.94 (95% CI: 0.47, 1.86); whole trial: HR 0.78 (95% CI: 0.50, 1.21)).

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