Vismodegib 150mg capsules

Sonidegib and vismodegib are hedgehog pathway inhibitors (HhIs) approved for the treatment of advanced basal cell carcinoma (BCC). Until recently, vismodegib was the only targeted treatment available for patients with locally advanced BCC (laBCC) in cases where surgery and radiotherapy are inappropriate. Sonidegib has recently been approved and now presents an alternative treatment option. The clinical differences between the two HhIs in patients with laBCC are unclear, as no head-to-head randomized controlled trials are or will be initiated. Moreover, there were important differences in the designs of their pivotal studies, BOLT (sonidegib) and ERIVANCE (vismodegib), and these differences complicate evidence-based analysis of their relative efficacy and safety profiles. In this paper, a group of clinical experts in the management of laBCC summarizes the clinical and pharmacological profiles of sonidegib and vismodegib based on published data and their own clinical experience. One key difference between the two pivotal studies was the criteria used to assess BCC severity. ERIVANCE (a single-arm phase II trial) used the conventional Response Evaluation Criteria in Solid Tumors (RECIST), while the more recent double-blind randomized BOLT trial used the stringent modified RECIST. A preplanned analysis adjusted the outcomes from BOLT with RECIST-like criteria, and this enabled the experts to discuss relative efficacy outcomes for the two treatments. Centrally reviewed objective response rate (ORR) for vismodegib was 47.6% (95% CI: 35.5-60.6) at 21-month follow-up using RECIST. After adjusting with RECIST-like criteria, the ORR for sonidegib according to central review at 18-month follow-up was 60.6% (95% CI: 47.8-72.4). Both treatments were associated with similar patterns of adverse events. Sonidegib and vismodegib share the same efficacy and tolerability profiles, but their pharmacokinetic profiles show several differences, such as volume of distribution and half-life. Further studies are needed to understand how these differences may impact clinical practice.

Abstract licence: CC BY-NC

The management of periocular basal cell carcinoma (BCC) is challenging due to its proximity to the eyeball. Vismodegib, a Hedgehog pathway inhibitor, has emerged as a therapeutic option for locally advanced and metastatic BCC. To critically appraise the relevant evidence, we conducted a systematic review of observational and experimental studies assessing the efficacy and safety of vismodegib for periocular BCC. Thirty-seven trials, including 435 patients, were eligible. No randomized trials were retrieved. Complete and overall clinical response rates were 20-88 % and 68-100 %, respectively. Disease progression was observed at a maximum rate of 14 %. Recurrence rates varied between 0 % and 31 %. The most common side effects were muscle cramps, dysgeusia, weight loss and alopecia. Treatment with vismodegib improved health-related quality of life. In conclusion, vismodegib represents an important novel treatment for advanced periocular BCC, with good response rates and acceptable tolerability profile. Nevertheless, its full potential needs clarification through randomized controlled trials.

Abstract licence: CC BY

BACKGROUND: Surgery is the primary treatment for basal cell carcinoma (BCC). In locally advanced basal cell carcinoma (laBCC), surgery may cause functional or aesthetic damage. In laBCC, neoadjuvant administration of vismodegib, an inhibitor of the Hedgehog signaling pathway, may reduce tumor size, facilitate resection, and reduce functional and aesthetic consequences of surgery. The VISMONEO study assessed efficacy and safety of vismodegib in neoadjuvant treatment of laBCC. METHODS: VISMONEO (NCT02667574) is an open-label, noncomparative, multicenter, phase 2 study. Patients with ≥1 histologically confirmed facial BCC, inoperable or operable with functional or major aesthetic sequelae risk, were included. Oral vismodegib 150 mg was administered once daily for 4 to 10 months before planned surgery, which was performed once the best response under vismodegib was observed. Primary endpoint was percentage of patients with BCC with tumor downstaging following surgical resection after neoadjuvant vismodegib. Downstaging was defined according to a 6-stage surgical classification related to the aesthetic and functional consequences of surgery. FINDINGS: 55 patients (median age: 73 years) with laBCC were included from November 2014 to June 2015. At inclusion, 4 patients were inoperable, 15 were operable with a major functional risk, and 36 were operable with a minor functional risk or a major aesthetic risk. Mean size of target lesion was 47.3 mm (SD: 27.2 mm). 44 patients presented with downstaging after vismodegib treatment (80%; 95% confidence interval [CI], 67 to 90). Of these 44 patients, 27 had a complete response (25 proved by biopsy). Mean treatment duration was 6.0 months. Overall Response Rate according to RECIST 1.1 criteria was 71% (95% CI, 59 to 88). At 3-years of follow-up, 16/44 patients had known recurrence (36%; 95%CI, 22 to 51). INTERPRETATION: Neoadjuvant vismodegib allows for a downstaging of the surgical procedure for laBCCs in functionally sensitive locations. FUNDING: VISMONEO was funded by F. Hoffmann-La Roche Ltd.

Abstract licence: CC BY-NC-ND

The Wnt/β-catenin, EGFR, and PI3K pathways frequently undergo upregulation in head and neck squamous carcinoma (HNSCC) cells. Moreover, the Wnt/β-catenin pathway together with Hedgehog (Hh) signaling regulate the activity of cancer stem cells (CSCs). The aim of this study was to investigate the effects of the combinatorial use of the Wnt/β-catenin and Hh pathway inhibitors on viability, cell cycle progression, apoptosis induction, cell migration, and expression of CSC markers in tongue (CAL 27) and hypopharynx (FaDu) cancer cells. Co-inhibition of Wnt signaling with EGFR or PI3K pathways was additionally tested. The cells were treated with selective inhibitors of signaling pathways: Wnt/β-catenin (PRI-724), Hh (vismodegib), EGFR (erlotinib), and PI3K (HS-173). Cell viability was evaluated by the resazurin assay. Cell cycle progression and apoptosis induction were tested by flow cytometric analysis after staining with propidium iodide and Annexin V, respectively. Cell migration was detected by the scratch assay and CSC marker expression by the R-T PCR method. Mixtures of PRI-724 and vismodegib affected cell cycle distribution, greatly reduced cell migration, and downregulated the transcript level of CSC markers, especially POU5F1 encoding OCT4. Combinations of PRI-724 with erlotinib or HS-173 were more potent in inducing apoptosis.

Abstract licence: CC BY

Artificial intelligence algorithms have been increasingly applied in drug development due to their efficiency and effectiveness. Deep-learning-based drug repurposing can contribute to the identification of novel therapeutic applications for drugs with other indications. The current study used a trained deep-learning model to screen an FDA-approved drug library for novel COX-2 inhibitors. Reference COX-2 data sets, composed of active and decoy compounds, were obtained from the DUD-E database. To extract molecular features, compounds were subjected to RDKit, a cheminformatic toolkit. GraphConvMol, a graph convolutional network model from DeepChem, was applied to obtain a predictive model from the DUD-E data sets. Then, the COX-2 inhibitory potential of the FDA-approved drugs was predicted using the trained deep-learning model. Vismodegib, an anticancer agent that inhibits the hedgehog signaling pathway by binding to smoothened, was predicted to inhibit COX-2. Noticeably, some compounds that exhibit high potential from the prediction were known to be COX-2 inhibitors, indicating the prediction model's liability. To confirm the COX-2 inhibition activity of vismodegib, molecular docking was carried out with the reference compounds of the COX-2 inhibitor, celecoxib, and ibuprofen. Furthermore, the experimental examination of COX-2 inhibition was also carried out using a cell culture study. Results showed that vismodegib exhibited a highly comparable COX-2 inhibitory activity compared to celecoxib and ibuprofen. In conclusion, the deep-learning model can efficiently improve the virtual screening of drugs, and vismodegib can be used as a novel COX-2 inhibitor.

Abstract licence: CC BY-NC-ND