A Phase 1b Study of Vismodegib with Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis

Abstract

Introduction: Components of the hedgehog signaling pathway are upregulated in patients with idiopathic pulmonary fibrosis (IPF). Vismodegib, a small-molecule inhibitor of hedgehog signaling, when used in combination with currently available antifibrotic therapy, may be more efficacious than antifibrotics alone. The objective of this study was to evaluate the safety and tolerability of vismodegib plus pirfenidone in patients with IPF.Methods: Twenty-one patients were enrolled in a phase 1b open-label trial to receive vismodegib 150 mg plus pirfenidone 2403 mg/day once daily. Key endpoints were safety, tolerability, and pharmacokinetics. Exploratory endpoints included change from baseline to week 24 in % predicted forced vital capacity (FVC) and University of California, San Diego Shortness of Breath Questionnaire (UCSD-SOBQ) scores, as well as pharmacodynamic changes in hedgehog biomarker C-X-C motif chemokine ligand 14 (CXCL14). Results: All patients reported at least one treatment-emergent adverse event (AE), most frequently muscle spasms (76.2%). Serious AEs were reported in 14.3% of patients; one event of dehydration was considered related to vismodegib. One patient died due to IPF progression, unrelated to either treatment. More patients discontinued vismodegib than pirfenidone (42.9% vs. 33.3%, respectively). Changes from baseline to week 24 in % predicted FVC and UCSD-SOBQ scores were within known endpoint variability. In contrast to findings in basal cell carcinoma, vismodegib had no effect on circulating CXCL14 levels. Conclusion:The safety profile was generally consistent with the known profiles of both drugs, with no new safety signals observed in this small cohort. There was no pharmacodynamic effect on CXCL14 levels. Future development of vismodegib for IPF may be limited due to tolerability issues.

Chaotic activation of developmental signalling pathways drives idiopathic pulmonary fibrosis

“…However, the alkaline cyclopamine (derived from the plant Veratrum californicum) has anti-proliferative and anti-tumoural effects that are driven by its ability to directly bind Smoothened [81]. A cyclopamine derivative, vismodegib, has been recently tested in a Phase 1b clinical study in combination with pirfenidone (clinicaltrials.gov identifier: NCT02648048) [89]. In future studies, CXCL14, a molecule induced by SHH stimulation, could be also a biomarker reflecting the activity of SHH inhibitors [90].…”

Oxy210, a Semi-Synthetic Oxysterol, Inhibits Profibrotic Signaling in Cellular Models of Lung and Kidney Fibrosis

“…Since activation of Hh signaling has been reported in IPF, attempts have been made to examine one of these FDA-approved drugs, vismodegib, for the treatment of pulmonary fibrosis in a phase 1b clinical study, administered in combination with pirfenidone. Unfortunately, drug safety issues of vismodegib emerged as a limiting factor for treating IPF during the study [ 87 ]. Based on a different mechanism of Hh pathway inhibition, we propose that Oxy210 could potentially be a safer and more effective compound for applications in fibrosis compared to vismodegib.…”

The Hedgehog Signaling Pathway in Idiopathic Pulmonary Fibrosis: Resurrection Time

“…On the contrary, the role of Gli1, but not Gli2, in bleomycin-induced fibrosis was limited [ 90 ]. Indeed, Smo-independent signaling might contribute more to hedgehog pathway activity in the pathogenesis of IPF [ 91 ].…”

“…Vismodegib is the first oral Hh inhibitor that has been approved to treat patients with locally advanced or metastatic basal cell carcinoma [ 150 ]. However, a phase 1b study determining the appropriateness of using vismodegib for IPF treatment was discontinued due to safety issues [ 91 ]. Another Smo antagonist, cyclopamine, reduced the migration and myofibroblast differentiation of human dermal fibroblasts [ 151 ].…”