There is an ongoing debate about whether anti-fibrotic agents should be started immediately after diagnosis of idiopathic pulmonary fibrosis (IPF) even in patients with relatively well-preserved lung function. A couple of presentations during the ERS Meeting shed some light on this debate.
Many physicians start anti-fibrotic therapy for IPF only once lung function has declined below certain levels, such as FVC <80% predicted or when GAP stage II is reached (the GAP index provides 1, 2, and 3-year mortality estimates for IPF patients). In some countries, reimbursement of these agents is also linked to FVC thresholds (usually FVC <80%). There are no clinical trial data that directly assess the disease course of patients with immediate versus delayed therapy.
Early treatment
Paul Noble (Los Angeles, United States of America) presented a pooled analysis of four clinical trials, aimed at assessing whether the treatment effect during the blinded period of a phase III trial is persistent over longer periods of time. In CAPACITY 004, GAP I patients treated with pirfenidone had a slower rate of decline in FVC compared with patients treated with placebo. After switching to pirfenidone, placebo-treated patients showed a similar rate of decline during RECAP as those treated with pirfenidone during CAPACITY. These data support early treatment with pirfenidone of GAP I patients to avoid loss of lung function. Another pooled analysis with pirfenidone, in this case data from three pivotal studies, showed that after starting treatment as early as 3 months after diagnosis, pirfenidone-treated patients had a lower rate of FVC decline than those receiving placebo. This benefit persisted over 12 months across all baseline demographic or disease severity subgroups. In this pooled analysis, all patients randomized to treatment with pirfenidone 2403 mg/day or placebo in the CAPACITY (004 or 006) and ASCEND (016) studies were included.
Post-hoc analysis
An analysis of the INPULSIS® study, two replicate randomised, placebo-controlled phase III trials of nintedanib, was then presented. Athol Wells (London, United Kingdom) showed that in post-hoc subgroup analyses of pooled data from the INPULSIS trials, nintedanib reduced the annual rate of decline in FVC, independently of the composite physiologic index (CPI) at baseline. CPI is a measure of the extent of pulmonary fibrosis in patients with IPF.
A greater proportion of patients with CPI >45 than those with CPI ≤45% at baseline had an acute exacerbation. However, there was no significant difference in the effect of nintedanib between the subgroups. Patients with CPI >45% at baseline had a greater increase (i.e. deterioration) in SGRQ total score than patients with baseline CPI ≤45% and experienced a more pronounced treatment effect of nintedanib. CPI correlated with the extent of fibrosis on CT, irrespective of presence of emphysema.
The final analysis of RECAP
Ulrich Costabel (Essen, Germany) presented the final analysis of RECAP, an open-label extension study that assessed the long-term safety of pirfenidone in patients with IPF who had completed either the ASCEND (016) or CAPACITY (004 or 006) phase III trials. RECAP provides the longest safety follow-up data for pirfenidone, reaching up to 6.7 years of exposure. The data are consistent with the known safety profile of pirfenidone and no new safety signals were observed. According to Costabel, this study supports the long-term safety and tolerability of pirfenidone therapy in patients with IPF.
In a second presentation, Costabel showed the results in patients with a low FVC (<50%). Long-term treatment with pirfenidone resulted in a similar rate of decline in patients with baseline per cent predicted FVC <50% compared with patients with better preserved lung function. Safety profiles were comparable between the two patient populations. This suggests that pirfenidone is an acceptable treatment in patients with more severe lung function impairment.
Simtuzumab
Lysyl-oxidase-like-2 (LOXL2) is an extracellular matrix enzyme that catalyzes the cross-linking of collagen, driving matrix remodeling and formation of pathologic stroma. LOXL2 protein and genetic overexpression in fibroblastic foci are seen in IPF lung tissue compared with healthy lung tissue.
Simtuzumab is a humanized monoclonal antibody that allosterically inhibits LOXL2. AB00023, a murine equivalent of simtuzumab, was effective in decreasing fibrosis in a bleomycin model when administered before or after development of fibrosis. However, a randomized clinical trial, which was presented by Ganesh Raghu (Seatle, United States of America), found no significant difference in progression-free survival (PFS, p=0.33).
Source: Session 333: IPF treatment I. September 5th, 08:30-10:30, Room K.
