Effect of nintedanib on biomarkers of extracellular matrix (ECM) turnover and FVC decline in patients with IPF: results from the INMARK study*

Rationale: The pathogenesis of IPF involves excess accumulation of ECM in the lungs. Degradation of ECM generates free-circulating protein fragments called neoepitopes. In the PROFILE study, a higher rate of increase in certain neoepitopes, including CRPM, over 3 months was predictive of mortality. The INMARK trial investigated changes in neoepitopes as predictors of IPF disease progression and the effect of nintedanib on these biomarkers.

Methods: Subjects with IPF and FVC ≥ 80% predicted were randomized 1 : 2 to nintedanib or placebo for 12 weeks followed by open-label nintedanib for 40 weeks. The primary endpoint was the rate of change in CRPM from baseline to week 12. The key secondary endpoint was the proportion of subjects with disease progression (absolute decline in FVC ≥ 10% predicted or death) over 52 weeks.

Results: In the randomized treatment period, 116 and 230 subjects were treated with nintedanib and placebo, respectively. The majority were male (75.7%), white (61.8%) and ex-smokers (68.8%); at baseline, mean (SD) FVC was 97.5 (13.5) % predicted and DLco was 64.0 (19.8) % predicted. The adjusted rate (SE) of change in log₁₀ transformed serum CRPM values from baseline to week 12 was − 0.00257 (0.00232) with nintedanib and − 0.00190 (0.00165) with placebo (difference − 0.00066 [95% CI: − 0.00621, 0.00488]; p = 0.81). Less subjects who initially received nintedanib had disease progression over 52 weeks ([Table 1]). In subjects who initially received placebo, 36.0% with rising versus 26.4% with stable/falling CRPM over 12 weeks (n = 89 and n = 140, respectively) had disease progression at week 52 (p = 0.0428). The adjusted rate (SE) of change in FVC was + 5.9 (18.5) mL/12 weeks in the nintedanib group and − 70.2 (13.1) mL/12 weeks in the placebo group (difference 76.1 mL/12 weeks [95% CI: 31.7, 120.4]; p = 0.0008).

Table 1 

Initial 12-week period	Nintedanib (n = 116)	Placebo (n = 230)
Not all patients provided data for all analyses. * Based on logistic regression with terms log10 transformed baseline serum CRPM and treatment.
Mean (SD) change from baseline in FVC at week 12, mL	− 1.4 (172.9)	− 72.6 (227.5)
Adjusted rate (SE) of change in FVC (mL/12 weeks)	5.9 (18.5)	− 70.2 (13.1)
Difference (95% CI) in adjusted rate of change in FVC	76.1 (31.7, 120.4)
p-value for difference in adjusted rate of change in FVC	0.0008
Overall 52-week period	Nintedanib (n = 116)	Placebo/ Nintedanib (n = 230)
FVC decline ≥ 10% predicted or death over 52 weeks, n (%)	29 (25.0)	70 (30.4)
Odds ratio (95% CI)*	0.77 (0.46, 1.27)
p-value	0.3116
Mean (SD) change from baseline in FVC at week 52, mL	− 105.0 (243.7)	− 111.1 (250.8)
Adjusted annual rate (SE) of change in FVC (mL/year)	− 88.8 (23.9)	− 104.1 (17.0)
Difference (95% CI) in adjusted rate of change in FVC	15.3 (− 42.5, 73.0)
p-value for difference in adjusted rate of change in FVC	0.6027

Conclusions: In the INMARK trial, treatment of subjects with nintedanib did not result in a different rate of change in serum CRPM over 12 weeks compared with placebo. In subjects who initially received placebo, rising CRPM over 12 weeks was associated with disease progression over 52 weeks, consistent with the PROFILE study. The rate of decline in FVC was lower in subjects treated with nintedanib versus placebo over 12 weeks and similar to that observed in the INPULSIS trials in both groups over 52 weeks.

* presented at ATS 2019