(228) Gastrointestinal Adverse Events Associated with Hedgehog Pathway Inhibitors: A Real-World Pharmacovigilance Study

Publication Number: 1273

Background: The Hedgehog Pathway Inhibitors (HPIs) works by inhibiting the signaling pathway and transmitting information to embryonic cells, required for proper cell differentiation. The main indication of HPIs is for basal cell carcinoma. However, the evidence of Gastrointestinal Adverse Events (GIAEs) associated with HPIs is minimal.

Objectives: To detect possible safety signals of HPI’s associated gastrointestinal associated adverse events through disproportionality analysis in the FDA Adverse Event Reporting System (FAERS) Database.

Methods: A retrospective case/non-case disproportionality analysis was performed in the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database, using OpenVigil 2.1 (2012Q2-2021Q3), which is a web-based pharmacovigilance tool. Vismodegib, Sonidegib, and Glasdegib were the drugs used for the analysis. Reporting Odds Ratio (ROR) was used as the analysis data mining algorithm. All the Gastrointestinal Adverse Events (GIAEs) that fall under the system organ classification of “Gastrointestinal disorders” were used as the events of interest. A value of ROR-1.96SE>1 was considered as the threshold for a signal.

Results: The Hedgehog Pathway Inhibitors accounted for 5,185 events as per the FAERS database, of which GIAEs were reported in 811, 25, and 3 cases for Vismodegib (17.46%), Sonidegib (8.14%), and Glasdegib (1.28%) respectively. Among the GIAEs, we obtained the highest signals for taste disorder [ROR: 47.1 (95% C.I.: 37.4;59.3)], constipation [5.4 (4.6;6.2)] and epigastric discomfort [4.1 (1.3;12.7)] for Vismodegib, followed by diarrhoea [2.3 (1.4;3.8)] and vomiting [2.5 (1.5;4.2)] for Sonidegib and colitis [10 (3.2;31.3)] for Glasdegib. The pooled GIAE signal strength for Vismodegib [3 (2.8;3.2)] was found to be higher when compared with those of Sonidegib [2.1 (1.4;3.2)] and Glasdegib [10 (3.2-31.3)]. We found the median age for Vismodegib to be 70 (IQR: 19) years, while for Sonidegib and Glasdegib, it was 66 (49) and 69 (20.5), respectively.

Conclusions: Hedgehog Pathway produces a spectrum of distinct classes of GIAEs. More research, a superior epidemiological study design, and a defined population are needed to substantiate these discovered data.