SAR156597 in idiopathic pulmonary fibrosis: a phase 2 placebo-controlled study (DRI11772)

Abstract

A phase 2b trial (NCT02345070) was conducted to evaluate the efficacy and safety of two dose levels/regimens of SAR156597 (a bispecific IgG4 antibody that binds and neutralises both circulating interleukin-4 and interleukin-13), in comparison with placebo, administered to patients with idiopathic pulmonary fibrosis (IPF) over 52 weeks.DRI11772 was a multinational randomised double-blind placebo-controlled phase 2b trial. Patients aged >40 years with a documented diagnosis of IPF received SAR156597 200 mg once every week (QW), SAR156597 200 mg once every 2 weeks (Q2W) or placebo, over 52 weeks. The primary efficacy end-point was absolute change from baseline in forced vital capacity (FVC) % predicted at 52 weeks.Of 327 randomised patients, 325 received treatment with placebo (n=109), SAR156597 Q2W (n=108) or SAR156597 QW (n=108). The mean change from baseline in FVC % pred at 52 weeks was –5.8%, –5.2% and –6.3% for the placebo, Q2W and QW arms, respectively (Q2W versus placebo, p=0.59; QW versus placebo, p=0.63). The safety profile observed in the three treatment arms was generally similar, although serious adverse events were more common in the QW arm than in the other arms.The DRI11772 study failed to demonstrate benefit of SAR156597 in the treatment of IPF.

Targeting interleukin-13 in idiopathic pulmonary fibrosis: from promising path to dead end

“…These observations therefore favoured the use of a drug targeting both IL-4 and IL-13. However, in the current study [7], SAR156597 did not affect IPF progression in terms of FVC decline, suggesting that targeting the IL-13 pathway may not be clinically relevant in IPF. Interestingly, a positive trend was observed on acute exacerbations in SAR156597 treated patients, as reported in the pirfenidone plus lebrikizumab arm of the RIFF study [10,11].…”

“…In this issue of the European Respiratory Journal, RAGHU et al [7] report on the results of the ESTAIR study, a phase 2 RCT evaluating the efficacy and safety of SAR156597, a bispecific monoclonal immunoglobulin G4 antibody binding and neutralising IL-4 and IL-13. Patients were randomly assigned 1:1:1 to placebo, or SAR156597 200 mg once every week or 200 mg once every two weeks, for 52 weeks.…”

“…Surveys estimated the overall uptake of antifibrotic drugs to be 50-60%, with clear regional differences [22,23]. In the study by RAGHU et al [7], 51.1% of patients were taking either nintedanib or pirfenidone, but the sample size calculation was not adjusted for background therapy, which may have led to an underpowering of the study. The differences in sample sizes of the studies targeting IL-13 are illustrative of the difference in assumptions that were likely made when calculating sample sizes and of the complex nature we are facing in current trial design.…”

Trispecific antibodies enhance the therapeutic efficacy of tumor-directed T cells through T cell receptor co-stimulation

“…While the CD38 trispecific antibody has not been evaluated in humans yet, the preliminary characterization of this Ab and a previously described HIV therapeutic in NHPs suggests that they behave analogously to conventional antibodies 13 . While anti-drug responses could potentially arise in vivo, a bispecific antibody to the human cytokines IL-4 and IL-13, using a related format and linkers, indicated that dual variable region antibodies have been safe and well tolerated in humans 63 . The inclusion of multiple specificities into a single protein for cancer immunotherapy simplifies clinical development.…”

Interleukin-13 disrupts type 2 pneumocyte stem cell activity

“…Moreover, our data suggest that IL-4 and IL-13 have redundant effects on AEC2 stem cell biology, and targeting only 1 of these cytokines with a specific monoclonal antibody may be insufficient. This redundancy was addressed in the recent trial with SAR156597, a drug that neutralizes both IL-13 and IL-4, and notably, a positive trend on acute exacerbations was observed (56). Finally, we argue that targeting IL-13 (or IL-13 and IL-4) beyond the early stages of IPF is probably too late because remodeling of the ECM will have occurred and the lung is stiff.…”