Sonidegib: mechanism of action, pharmacology, and clinical utility for advanced basal cell carcinomas

Jain, Sachin; Song, Ruolan; Xie, Jingwu

doi:10.2147/ott.s130910

Cited by 78 publications

(56 citation statements)

References 60 publications

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“…The combination of glasdegib with cytarabine/daunorubicin was well tolerated, with a safety profile consistent with those observed in patients with AML receiving intensive chemotherapy . Additionally, the AEs observed with glasdegib in combination cytarabine/daunorubicin were similar to those reported for glasdegib in combination with LDAC, as well as other SMO inhibitors, and the majority of muscle spasms, dysgeusia and alopecia AEs were grades 1 or 2 . The most frequently reported grade > 3 treatment‐related AEs were febrile neutropenia and anemia, with the time to hematologic recovery in line with that previously reported in the literature for patients with AML who received cytarabine/daunorubicin on the 7 + 3 schedule .…”

Section: Discussionsupporting

confidence: 64%

Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high‐risk MDS: Phase 2 study results

et al. 2018

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Glasdegib is a Hedgehog pathway inhibitor. This ongoing, open‐label, phase 2 study (NCT01546038) evaluated glasdegib plus cytarabine/daunorubicin in patients with untreated acute myeloid leukemia (AML) or high‐risk myelodysplastic syndromes (MDS). Patients received glasdegib 100 mg orally, once daily in continuous 28‐day cycles from day −3, with intravenous cytarabine 100 mg/m2 on days 1‐7 and daunorubicin 60 mg/m2 on days 1‐3. Patients in remission then received consolidation therapy (2‐4 cycles of cytarabine 1 g/m2 twice daily on days 1, 3, 5 of each cycle), followed by maintenance glasdegib (maximum 6 cycles). Primary endpoint was complete remission (CR) in patients aged ≥55 years. Secondary endpoints included overall survival (OS), safety and outcome by mutational status. Patients had a median (range) age of 64.0 (27‐75) years, 60.0% were male, and 84.5% were white. In 69 evaluable patients, 46.4% (80% confidence interval [CI]: 38.7‐54.1) achieved investigator‐reported CR. Among patients ≥55 years old (n = 60), 40.0% (80% CI 31.9‐48.1) achieved CR. Among all 69 patients, median OS was 14.9 (80% CI 13.4‐19.3) months, with 12‐month survival probability 66.6% (80% CI 58.5‐73.4). The most common treatment‐related adverse events (≥50% patients) were diarrhea and nausea. There were no significant associations between mutational status (12 genes) and clinical response, suggesting potential benefit across diverse molecular profiles. Glasdegib plus cytarabine/daunorubicin was well tolerated and associated with clinical activity in patients with untreated AML or high‐risk MDS. A randomized phase 3 trial of glasdegib in combination with chemotherapy (7 + 3 schedule) is ongoing.

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Section: Discussionsupporting

confidence: 64%

Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high‐risk MDS: Phase 2 study results

et al. 2018

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“…The correct management of side effects could improve patients' health-related quality of life, thus reducing treatment discontinuation. Experiencing regimen adjustment with potential treatment holiday as well as novel approaches for side profile management might provide options for improving the tolerability of this therapy [49][50][51]. Moreover, positive results from trials conducted in patients with Gorlin syndrome showed the possibility of using this HPI not only for treatment of one laBCC but also for cancer chemoprevention.…”

Section: Perspectives and Conclusionmentioning

confidence: 99%

Sonidegib: Safety and Efficacy in Treatment of Advanced Basal Cell Carcinoma

Villani

Fabbrocini

Costa

et al. 2020

Dermatol Ther (Heidelb)

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Hedgehog inhibitors are promising alternative treatments for patients with advanced basal cell carcinomas. Sonidegib (Odomzo Ò ), an oral smoothened (SMO) antagonist, is indicated for the treatment of adult patients with locally advanced basal cell carcinoma (laBCC) who present recurrence following surgery or radiation therapy, or those who are not candidates for surgery or radiotherapy. Several studies and randomized controlled trials have been conducted to evaluate the efficacy, safety, and tolerability of this new molecule that has demonstrated a good response rate (44%). Grade 1-2 adverse events have also been repor-ted. Further studies of real-world experiences are needed to better understand the correct management of the drug, alternative dosing regimens, and differences with other hedgehog inhibitors. This article provides a complete overview of the pharmacology and pharmacokinetics of sonidegib and a report of the trials and studies conducted. The most frequent adverse events and their correct management are also discussed.

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“…Two SMO inhibitors, vismodegib and sonidegib, are currently FDA approved for use in patients with advanced BCC (17,52), and a number of others are in various stages of clinical trials (53). Although exhibiting dramatic initial efficacy, BCCs typically relapse after treatment due to vismodegib resistance (54,55).…”

Section: Discussionmentioning

confidence: 99%

A CK1α Activator Penetrates the Brain and Shows Efficacy Against Drug-resistant Metastatic Medulloblastoma

Rodríguez-Blanco

Long

et al. 2019

Clinical Cancer Research

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Purpose: Although most children with medulloblastoma are cured of their disease, Sonic Hedgehog (SHH) subgroup medulloblastoma driven by TRP53 mutations is essentially lethal. Casein kinase 1a (CK1a) phosphorylates and destabilizes GLI transcription factors, thereby inhibiting the key effectors of SHH signaling. We therefore tested a secondgeneration CK1a activator against TRP53-mutant, MYCNamplified medulloblastoma.Experimental Design: The ability of this CK1a activator to block SHH signaling was determined in vitro using GLI reporter cells, granular precursor primary cultures, and PATCHED1 (PTCH1)-mutant sphere cultures. While in vivo efficacy was tested using 2 different medulloblastoma mouse models: PTCH1 and ND2:SMOA1. Finally, the clinical relevance of CK1a activators was demonstrated using a TRP53-mutant, MYCN-amplified patient-derived xenograft.Results: SSTC3 inhibited SHH activity in vitro, acting downstream of the vismodegib target SMOOTHENED (SMO), and reduced the viability of sphere cultures derived from SHH medulloblastoma. SSTC3 accumulated in the brain, inhibited growth of SHH medulloblastoma tumors, and blocked metastases in a genetically engineered vismodegib-resistant mouse model of SHH medulloblastoma. Importantly, SSTC3 attenuated growth and metastasis of orthotopic patient-derived TRP53-mutant, MYCN-amplified, SHH subgroup medulloblastoma xenografts, increasing overall survival.Conclusions: Using a newly described small-molecule, SSTC3, we show that CK1a activators could address a significant unmet clinical need for patients with SMO inhibitorresistant medulloblastoma, including those harboring mutations in TRP53. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):

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Sonidegib: mechanism of action, pharmacology, and clinical utility for advanced basal cell carcinomas

Cited by 78 publications

References 60 publications

Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high‐risk MDS: Phase 2 study results

Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high‐risk MDS: Phase 2 study results

Sonidegib: Safety and Efficacy in Treatment of Advanced Basal Cell Carcinoma

A CK1α Activator Penetrates the Brain and Shows Efficacy Against Drug-resistant Metastatic Medulloblastoma

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