CC-chemokine ligand 2 inhibition in idiopathic pulmonary fibrosis: a phase 2 trial of carlumab

Abstract

The objective of this study was to determine the safety and efficacy of carlumab in the treatment of idiopathic pulmonary fibrosis (IPF).A phase 2, randomised, double-blind placebo-controlled dose-ranging study was conducted in patients with IPF (n=126). Patients were randomised to carlumab (1 mg·kg −1 , 5 mg·kg, or 15 mg·kg −1 ) or placebo every 4 weeks. The primary endpoint was the rate of percentage change in forced vital capacity (FVC). Secondary endpoints were time to disease progression, absolute change in FVC, relative change in diffusing capacity of the lung for carbon monoxide (DLCO), and St George's Respiratory Questionnaire (SGRQ) total score.Due to a pre-planned, unfavourable interim benefit-risk analysis, dosing was suspended. The rate of percentage change in FVC showed no treatment effect (placebo −0.582%, 1 mg·kg −1 −0.533%, 5 mg·kg −1 −0.799% and 15 mg·kg −1 −0.470%; p=0.261). All active treatment groups showed a greater decline in FVC (1 mg·kg −1 −290 mL, 5 mg·kg −1 −370 mL and 15 mg·kg −1 −320 mL) compared with placebo (−130 mL). No effect on disease progression, DLCO, infection rates or mortality was observed. SGRQ scores showed a nonsignificant trend toward worsening with active treatment. Unexpectedly, free CC-chemokine ligand 2 levels were elevated above baseline at both 24 and 52 weeks. A higher proportion of patients with one or more serious adverse events was observed in the 5 mg·kg −1 group (53.1%) compared with 1 mg·kg −1 (15.2%), 15 mg·kg −1 (21.9%) and placebo (46.4%), although no unexpected serious adverse events were noted. Although dosing was stopped prematurely, it is unlikely that carlumab provides benefit to IPF patients. @ERSpublications It is unlikely that carlumab provides benefit to patients with idiopathic pulmonary fibrosis

Epithelial-macrophage interactions determine pulmonary fibrosis susceptibility in Hermansky-Pudlak syndrome

“…Notably, a phase II trial in IPF (NCT00786201) using a human monoclonal antibody to CCL2 (MCP-1) showed no effect on disease progression, pulmonary function parameters, or mortality. However, free CCL2 levels remained elevated above baseline in subjects in this trial, suggesting pharmacologic failure of this particular therapeutic agent (39). Thus, further studies will be needed to determine whether the CCL2/CCR2 axis can be effectively targeted in the lung.…”

Physiology of the lung in idiopathic pulmonary fibrosis

“…The rate of decline in FVC was the most common primary outcome end-point in recent clinical trials in IPF, expressed either in millilitres per year [47] or as percentage of the predicted value [115][116][117]. It is currently debated whether change in FVC over time is the optimal outcome for clinical trials in IPF.…”

Pulmonary CCR2+CD4+T cells are immune regulatory and attenuate lung fibrosis development

“…In particular, in a recent study targeting of CCR2 + signalling with a non-specific CCL2 monoclonal antibody did not improve the clinical outcomes of IPF patients, with an unexpected increase in free CCL2 levels in patients receiving active treatment 12. The authors of that study hypothesised that this might in part be due to compensatory excess release of free CCL2 12. However, it is also possible that the lack of clinical benefit from the CCL2 monoclonal antibody might be because untargeted treatments not only eliminate disease promoting CCR2 + cell populations, but also those that potentially limit disease progression.…”

“…In particular, in a recent study targeting of CCR2 + signalling with a non-specific CCL2 monoclonal antibody did not improve the clinical outcomes of IPF patients, with an unexpected increase in free CCL2 levels in patients receiving active treatment 12. The authors of that study hypothesised that this might in part be due to compensatory excess release of free CCL2 12.…”

“…In patients with IPF, increased levels of CCL2 were found in serum,10 bronchoalveolar lavage fluid (BALF)9 and alveolar epithelium 11. These observations led to the recent clinical investigation of carlumab, an antibody blocking the CCR2 ligand CCL2, as treatment for human lung fibrosis 12. Surprisingly, complete blockade of CCL2 failed to demonstrate clinical advantage for these patients as measured by pulmonary function tests, time to disease progression and quality of life.…”