A Review of Hedgehog Inhibitors Sonidegib and Vismodegib for Treatment of Advanced Basal Cell Carcinoma

February 2021 | Volume 20 | Issue 2 | Original Article | 156 | Copyright © February 2021

Published online January 21, 2021

Michael Migden MD,a Aaron S. Farberg MD,b Reinhard Dummer MD,c Nicholas Squittieri MD,d C. William Hanke MDe

aDepartments of Dermatology and Head and Neck Surgery, The University of Texas–MD Anderson Cancer Center, Houston, TX
bSection of Dermatology, Baylor University Medical Center, Dallas, TX
cDepartment of Dermatology, University of Zürich, Skin Cancer Center, University Hospital, Zürich, Switzerland
dSun Pharmaceutical Industries, Inc., Princeton, NJ
eAscension Saint Vincent Hospital, Indianapolis, IN

cell.28,29 Interestingly, significant reduction of muscle cramps was observed in 8 patients treated with vismodegib who were co-administered the calcium channel blocker amlodipine.30

Muscle spasms were the most common AE in the BOLT, ERIVANCE, STEVIE, and MIKIE studies.11,12,16,17 They were reported in 43 (54%) patients receiving sonidegib 200 mg in BOLT, 74 (71%) patients in ERIVANCE, 807 (66%) patients in STEVIE, and 79 (69%) and 81 (72%) patients (grade ≤2 only) in the MIKIE 12-week and 24-week regimen groups, respectively.11,12,16,17 The majority of muscle spasms were grade 1 or 2, with 2.5% of patients experiencing grade ≥3 muscle spasms in the BOLT 200 mg group, 6 (5.8%) patients in ERIVANCE, 95 (8%) in STEVIE, and 4 (4%) and 12 (11%) patients in the MIKIE 12-week and 24-week regimen groups, respectively.11,12,16,17 Guidelines for managing muscle-related AEs with dose reductions and interruptions were developed during the BOLT study, for treating patients receiving sonidegib.31

Safety assessments in BOLT included routine monitoring of CK levels. Grade <3 CK elevation was reported as an AE in 24%, of patients, while grade ≥3 CK elevation was reported in 6% of patients receiving sonidegib 200 mg.11 CK monitoring was not part of the ERIVANCE protocol, and the number of patients with serum CK elevation was not reported in the final analysis.12 In STEVIE, ≥1 evaluable CK measurement was available for a subset of 180 (15%) patients.16 Among 121 patients with ≥1 CK measurement who did not experience muscle spasms, an AE of elevated CK levels was reported in 44 (36%) patients, and grade ≥3 CK elevation was reported in 4 (3%) patients.16 Among 59 patients with ≥1 CK measurement who experienced muscle spasms, 20 (34%) experienced elevated CK levels and 2 (3%) had grade ≥3 CK elevation. In MIKIE, grade ≤2 CK elevation was reported in 10 (9%) and 11 (10%) patients, and grade 3 in 1 (1%) and 4 (4%) patients, for the 12-week and 24-week regimen groups, respectively.17 

During hair follicle morphogenesis, the Hedgehog pathway promotes the expansion of the follicular epithelium in response to an upstream signal from the canonical Wingless (Wnt) pathway.32 Abnormal Hedgehog activation in BCC is associated with abnormal Wnt pathway activation and upregulation of Wnt target genes, constituting a reversal of the Wnt-Hedgehog relationship in the healthy developing organism.32

Alopecia is commonly observed with sonidegib and vismodegib treatment, and is thought to occur due to blocked transition to the anagen phase in the hair follicle after telogen phase hair shedding.32 Compared with hair loss due to chemotherapy, alopecia due to HHI treatment has a longer time to onset, and manifests as gradual hair thinning.32 Alopecia was observed in 39 (49%) patients in BOLT who received sonidegib 200 mg, 69 (66%) patients in ERIVANCE, 747 (62%) patients in STEVIE, and 72 (63%) and 73 (65%) patients in the MIKIE 12-week and 24-week regimen groups.11,12,16,17

Dysgeusia and weight loss
Dysgeusia was reported in 44% patients in the BOLT 200 mg group, 58 (56%) in ERIVANCE, 663 (55%) in STEVIE, and 75 (66%) in each of the MIKIE treatment groups.11,12,16,17 Grade <3 and grade ≥3 weight loss was experienced by 25% and 5% of patients in the BOLT 200 mg arm, respectively.11 Weight loss was reported in 54 (52%) patients in ERIVANCE, 493 (41%) in STEVIE, and 24 (21%) and 21 (19%) in the MIKIE 12-week and 24-week regimen groups.12,16,17 Nutritional management has been suggested to mitigate weight loss and malnutrition in patients treated with HHIs.33

The PK of sonidegib was studied in healthy volunteers, patients with advanced solid tumors, and patients from the BOLT study. Sonidegib reaches peak concentration in plasma within 2–4 hours of dosing, and has a large apparent volume of distribution of approximately 9000–33000 L and an elimination half-life of 30–41 days.34-36 In patients from the BOLT study, steady state of sonidegib in plasma was achieved by week 17 of treatment for both the 200 and 800 mg QD doses.15 Absorbed sonidegib is metabolized predominantly by CYP3A4, while unabsorbed sonidegib is eliminated in excreta.36,37 Co-administration with the proton pump inhibitor esomeprazole results in a modest reduction of sonidegib absorption and no metabolic drug-drug interaction, suggesting stomach acidity has no substantial impact on sonidegib bioavailability.38 PK exposure-safety analyses suggests lower exposure to sonidegib correlates with lower risk of grade ≥3 CK elevation.39

Vismodegib PK was investigated in healthy volunteers, and in patients with refractory, locally advanced, or metastatic solid tumors. Vismodegib has an elimination half-life of 4–12 days, reaches peak plasma concentration approximately 2 days after a single dose and steady state within 7–21 days of repeated dosing, and has a volume of distribution of approximately 16– 27 L.8,40,41 More than 99% of vismodegib in plasma binds serum albumin and alpha-1-acid glycoprotein, therefore administration of doses greater than 150 mg QD does not result in an increase of unbound steady-state plasma concentration.40,42 Vismodegib administration 3 times per week or weekly is not sufficient to achieve an efficacious plasma concentration.43

Sonidegib appears to be highly lipophilic due to its large volume of distribution. Resultantly, steady-state levels of sonidegib are 6 times higher in skin than in plasma.5 In contrast, the smaller volume of distribution of vismodegib indicates that it is predominantly confined to plasma. The differing volumes of distribution for sonidegib and vismodegib may potentially