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

Antje Prasse, Murali Ramaswamy, Shaun Mohan, Lin Pan, Andrew Kenwright, Margaret Neighbors, Paula Belloni, Peter P LaCamera, Antje Prasse, Murali Ramaswamy, Shaun Mohan, Lin Pan, Andrew Kenwright, Margaret Neighbors, Paula Belloni, Peter P LaCamera

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.

Trial registration: ClinicalTrials.gov NCT02648048. Plain language summary available for this article.

Funding: F. Hoffmann-La Roche Ltd. and Genentech, Inc.

Keywords: Hedgehog signaling pathway; Idiopathic pulmonary fibrosis; Pirfenidone; Safety; Tolerability; Vismodegib.

Figures

Fig. 1
Fig. 1
Study design
Fig. 2
Fig. 2
Patient disposition. FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, HRCT high-resolution computed tomography, IPF idiopathic pulmonary fibrosis
Fig. 3
Fig. 3
Individual CXCL14 levels. Plasma CXCL14 levels in individuals over time after initiation of vismodegib treatment. Baseline is the patient’s last observation prior to initiation of vismodegib. Dashed lines connect matched longitudinal samples from individual patients. CXCL14 C-X-C motif chemokine ligand 14
Fig. 4
Fig. 4
Mean change from baseline % predicted FVC score for the 12 patients in the ITT population. Within a given visit, the best (maximum) result for the parameter of interest was used if it was from an acceptable blow as assessed by the over-reader. Baseline is the patient’s last observation prior to initiation of vismodegib. If multiple records were collected during the same visit, then the last record within that last visit was used for the analysis. FVC forced vital capacity, ITT intent to treat

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