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DRUG:

Odomzo (sonidegib)

i
Other names: LDE225, LDE 225, NVP LDE225, NVP-LDE225, LDE-225, NVPLDE225
Company:
Novartis, Sun Pharma
Drug class:
Hedgehog cell-signalling pathway inhibitor
2ms
Images in Immunotherapy and Precision Oncology: Advanced Basal Cell Carcinoma. (PubMed, J Immunother Precis Oncol)
However, targeted therapies such as sonidegib and vismodegib - sonic hedgehog pathway inhibitors - have emerged that have been approved for treating BCC, as have anti-PD1 immunotherapies, such as cemiplimab, with their success likely based on the high tumor mutational burden seen in some of these tumors. Epidermal growth factor receptor (EGFR) inhibitors also serve a role in treating this condition as well. Molecular studies on metastatic/advanced BCC and other rare malignancies may inform treatment therapeutic decisions.
Journal • Tumor mutational burden • PD(L)-1 Biomarker • IO biomarker • Metastases
|
TMB (Tumor Mutational Burden)
|
Libtayo (cemiplimab-rwlc) • Erivedge (vismodegib) • Odomzo (sonidegib)
3ms
Evaluation of the efficacy and safety of LDE225 in the treatment of patients with advanced or metastatic sarcomas (ACTRN12612000533897)
P2, N=84, Completed, Australasian Sarcoma Study Group | Active, not recruiting --> Completed
Trial completion
|
Odomzo (sonidegib)
3ms
PersoMed-I: Personalized Risk-Adapted Therapy in Post-Pubertal Patients With Newly-Diagnosed Medulloblastoma (clinicaltrials.gov)
P2, N=20, Active, not recruiting, European Organisation for Research and Treatment of Cancer - EORTC | Recruiting --> Active, not recruiting | N=205 --> 20 | Trial completion date: Mar 2030 --> Apr 2025 | Trial primary completion date: Mar 2030 --> Apr 2025
Enrollment closed • Enrollment change • Trial completion date • Trial primary completion date
|
TP53 (Tumor protein P53) • BRCA2 (Breast cancer 2, early onset) • MYCN (MYCN Proto-Oncogene BHLH Transcription Factor)
|
cisplatin • vincristine • lomustine • Odomzo (sonidegib)
3ms
Sonidegib and Pembrolizumab in Treating Patients With Advanced Solid Tumors (clinicaltrials.gov)
P1, N=45, Recruiting, Mayo Clinic | Trial completion date: Jul 2024 --> Jul 2025 | Trial primary completion date: Jul 2024 --> Jul 2025
Trial completion date • Trial primary completion date • IO biomarker • Metastases
|
EGFR (Epidermal growth factor receptor) • PD-L1 (Programmed death ligand 1) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • MSI (Microsatellite instability) • BCL2 (B-cell CLL/lymphoma 2) • BCL2L11 (BCL2 Like 11)
|
Keytruda (pembrolizumab) • Odomzo (sonidegib)
4ms
Anti-PD1-antibody and Pulsed HHI for Advanced BCC (clinicaltrials.gov)
P2, N=20, Active, not recruiting, Reinhard Dummer | Recruiting --> Active, not recruiting
Enrollment closed • Combination therapy • Metastases
|
Libtayo (cemiplimab-rwlc) • Odomzo (sonidegib)
4ms
Alterations of ceramide synthesis induce PD-L1 internalization and signaling to regulate tumor metastasis and immunotherapy response. (PubMed, Cell Rep)
While mammary tumors developed in MMTV-PyMT/CerS4-/- were highly metastatic, targeting the Shh/PD-L1 axis using sonidegib and anti-PD-L1 antibody vastly decreased tumor growth and metastasis, consistent with the inhibition of PD-L1 internalization and Shh/Wnt signaling, restoring anti-tumor immune response. These data, validated in clinical samples and databases, provide a mechanism-based therapeutic strategy to improve immunotherapy responses in metastatic TNBCs.
Journal
|
PD-L1 (Programmed death ligand 1) • CAPRIN1 (Cell Cycle Associated Protein 1) • FOXP3 (Forkhead Box P3) • TGFBR1 (Transforming Growth Factor Beta Receptor 1)
|
Odomzo (sonidegib)
4ms
AD HOC Trial: Artificial Intelligence-Based Drug Dosing In Hepatocellular Carcinoma (clinicaltrials.gov)
P1, N=12, Recruiting, University of Florida | Suspended --> Recruiting
Enrollment open
|
sorafenib • irinotecan • Odomzo (sonidegib)
5ms
Ferroptosis-related lncRNAs: Distinguishing heterogeneity of the tumour microenvironment and predicting immunotherapy response in bladder cancer. (PubMed, Heliyon)
Our results suggest that patients with BLCA have a greater sensitivity to four drugs (dasatinib, pazopanib, erismodegib and olaparib). Our study provides new insights into the TME, key signalling pathways, genome, and potential therapeutic targets of BLCA, with future guidance for immunotherapy and targeted precision drugs.
Journal • PARP Biomarker • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • PD-1 (Programmed cell death 1) • HMGA2 (High mobility group AT-hook 2) • NFIB (Nuclear Factor I B) • JAZF1 (JAZF Zinc Finger 1) • RBMS3 (RNA Binding Motif Single Stranded Interacting Protein 3) • ESM1 (Endothelial Cell Specific Molecule 1) • SPAG5 (Sperm Associated Antigen 5)
|
Lynparza (olaparib) • dasatinib • pazopanib • Odomzo (sonidegib)
6ms
Enrollment open • Trial initiation date • Pan tumor • Metastases
|
PTCH1 (Patched 1) • SMO (Smoothened Frizzled Class Receptor)
|
Odomzo (sonidegib)
6ms
Trial completion
|
PTCH1 (Patched 1)
|
Mekinist (trametinib) • gemcitabine • Kisqali (ribociclib) • Odomzo (sonidegib) • Neupogen (filgrastim)
6ms
Alopecia due to chemotherapeutics, hedgehog inhibitors, targeted antibody therapies and immune checkpoint inhibitors : Pathogenesis, clinical picture, diagnostics and prophylaxis (PubMed, Dermatologie (Heidelb))
Chemotherapy-induced hair loss (CIA) occurs in up to 65% of cases. Anagen effluvium is observed as early as 1-3 weeks after the start of treatment and is reversible in most cases. Alopecia associated with inhibitors of the Sonic Hedgehog signaling pathway (HHIA) such as vismodegib or sonidegib are observed in up to 60% of cases. They are characterized by telogen effluvium. BRAF or immune checkpoint inhibitors lead significantly less frequently to alopecia (BRAFA, CPIA). According to taxane-based chemotherapy protocols, scalp cooling can help to prevent higher-grade CIA. If CIA or other forms of alopecia are expected, early contact with self-help organizations and early prescriptions for wigs should be offered.
Review • Journal • Checkpoint inhibition
|
BRAF (B-raf proto-oncogene)
|
Erivedge (vismodegib) • Odomzo (sonidegib)
6ms
AD HOC Trial: Artificial Intelligence-Based Drug Dosing In Hepatocellular Carcinoma (clinicaltrials.gov)
P1, N=12, Suspended, University of Florida | Recruiting --> Suspended
Trial suspension
|
sorafenib • irinotecan • Odomzo (sonidegib)
8ms
AD HOC Trial: Artificial Intelligence-Based Drug Dosing In Hepatocellular Carcinoma (clinicaltrials.gov)
P1, N=12, Recruiting, University of Florida | Not yet recruiting --> Recruiting
Enrollment open
|
sorafenib • irinotecan • Odomzo (sonidegib)
8ms
Trial completion date
|
PTCH1 (Patched 1)
|
PTCH1 mutation
|
Mekinist (trametinib) • gemcitabine • Kisqali (ribociclib) • Odomzo (sonidegib) • Neupogen (filgrastim)
8ms
Plasma ctDNA Monitoring of a PTCH1-Mutant Metastatic Adult Medulloblastoma Showing a Durable Benefit With Vismodegib. (PubMed, Oncologist)
Several small studies demonstrate objective but short-lived responses to SMO inhibitors such as vismodegib or sonidegib. We present the case of a 26-year-old patient with a recurrent MB, in which next-generation sequencing (FoundationOne CDx) revealed a mutation in PTCH1, allowing the patient to be treated with vismodegib in second line, resulting in a durable benefit lasting for 1 year. Using an in-house digital PCR probe, the PTCH1 mutation could be tracked in ctDNA during treatment with first-line chemotherapy and while on treatment with vismodegib, demonstrating a precise correlation with the radiological and clinical behavior of the disease.
Journal • Circulating tumor DNA • Metastases
|
TP53 (Tumor protein P53) • TERT (Telomerase Reverse Transcriptase) • PTCH1 (Patched 1) • SMO (Smoothened Frizzled Class Receptor)
|
TP53 wild-type • PTCH1 mutation • SMO mutation
|
FoundationOne® CDx
|
Erivedge (vismodegib) • Odomzo (sonidegib)
9ms
Beyond cyclopamine: Targeting Hedgehog signaling for cancer intervention. (PubMed, Arch Biochem Biophys)
Inhibiting Hh signaling is an important oncological strategy in which inhibitors of the ligands SMO or GLI have been looked at. This review briefly narrates the Hh ligands, signal transduction, the target genes involved and comprehensively describes the numerous inhibitors that have been evaluated for use in various neoplastic settings.
Review • Journal
|
GLI1 (GLI Family Zinc Finger 1)
|
Erivedge (vismodegib) • Odomzo (sonidegib) • cyclopamine
9ms
SONIB: A Study to Evaluate Neoadjuvant Sonidegib Followed by Surgery or Imiquimod in the Management of Basal Cell Carcinoma (clinicaltrials.gov)
P2, N=20, Recruiting, Melanoma Institute Australia | N=10 --> 20 | Trial completion date: Dec 2023 --> Jun 2024 | Trial primary completion date: Dec 2023 --> Jun 2024
Enrollment change • Trial completion date • Trial primary completion date • Surgery
|
Odomzo (sonidegib) • Zyclara (imiquimod)
9ms
Laser-assisted topical delivery of vismodegib reduces hedgehog gene expression in human basal cell carcinomas in vivo. (PubMed, Lasers Surg Med)
A single AFL-assisted topical application of vismodegib resulted in clinically relevant intratumoral drug concentrations and significant reductions in hedgehog pathway gene expressions.
Preclinical • Journal
|
PTCH1 (Patched 1) • GLI1 (GLI Family Zinc Finger 1) • GLI2 (GLI Family Zinc Finger 2)
|
GLI1 expression
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Erivedge (vismodegib) • Odomzo (sonidegib)
10ms
Dynamic optical coherence tomography evaluation in locally advanced basal cell carcinoma during sonidegib treatment. (PubMed, J Eur Acad Dermatol Venereol)
Sonidegib can be considered an effective treatment option in cases where surgery or radiotherapy would be unfeasible or has previously failed, although pigmented lesions did not show complete clearance, suggesting that there are factors other than the SHH pathway involved in tumour growth. Videodermoscopy and D-OCT were useful in the quick and seamless follow-up of lesions and added valuable information in assessing efficacy.
Journal • Metastases
|
PTCH1 (Patched 1) • SMO (Smoothened Frizzled Class Receptor)
|
PTCH1 mutation • SMO mutation
|
Erivedge (vismodegib) • Odomzo (sonidegib)
11ms
Trial completion date • Trial primary completion date
|
sorafenib • irinotecan • Odomzo (sonidegib)
11ms
Trial completion date
|
PTCH1 (Patched 1)
|
PTCH1 mutation
|
Mekinist (trametinib) • gemcitabine • Kisqali (ribociclib) • Odomzo (sonidegib) • Neupogen (filgrastim)
12ms
New P2 trial • Pan tumor • Metastases
|
PTCH1 (Patched 1) • SMO (Smoothened Frizzled Class Receptor)
|
PTCH1 mutation • SMO mutation
|
Odomzo (sonidegib)
12ms
Ligand-dependent hedgehog signaling maintains an undifferentiated, malignant osteosarcoma phenotype. (PubMed, Oncogene)
Finally, we demonstrate that the SMO antagonist sonidegib (LDE225) induces growth arrest and terminal differentiation in vivo in osteosarcomas that express primary cilia and Hh ligand combined with mutations in TP53. These results provide a mechanistic framework for aberrant Hh signaling in osteosarcoma based on defining mutations in the tumor suppressor, TP53.
Journal
|
TP53 (Tumor protein P53) • RB1 (RB Transcriptional Corepressor 1) • SMO (Smoothened Frizzled Class Receptor) • SHH (Sonic Hedgehog Signaling Molecule)
|
TP53 mutation • SMO mutation
|
Odomzo (sonidegib)
12ms
Targeted Delivery of 5-Fluorouracil and Sonidegib via Surface-Modified ZIF-8 MOFs for Effective Basal Cell Carcinoma Therapy. (PubMed, Pharmaceutics)
Additionally, immunohistochemistry and protein expression studies demonstrated the improved effectiveness of the 5-FU@ZIF-8-SDG MOFs, which displayed a considerable reduction in the expression of Bcl-2 protein. Overall, the developed MOF gels showed good potential for the targeted delivery of multifunctional MOFs in topical formulations for treating BCC cancer.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2)
|
BCL2 expression
|
5-fluorouracil • Odomzo (sonidegib)
almost1year
Signaling Pathways and Therapeutic Strategies in Advanced Basal Cell Carcinoma. (PubMed, Cells)
The discovery of mutations in the Hh signaling pathway has paved the way for the development of Hh pathway inhibiting agents, such as vismodegib and sonidegib, which have represented a breakthrough in the aBCC management. However, the use of these agents is limited by the frequent occurrence of adverse events or the development of drug resistance. In this review, we thoroughly describe the current knowledge regarding the available options for the pharmacological management of aBCCs and provide a forward-looking update on novel therapeutic strategies that could enrich the therapeutic armamentarium of BCC in the near future.
Review • Journal • Metastases
|
SMO (Smoothened Frizzled Class Receptor)
|
Erivedge (vismodegib) • Odomzo (sonidegib)
1year
Inhibiting the SHH pathway and PARP1 in combination enhances the radiation sensitivity of pediatric sonic hedgehog medulloblastoma (SNO 2023)
We found that in vitro treatment with Sonidegib, GANT61, and Veliparib alone and in combination with was sufficient to significantly decrease tumor cell viability and self-renewal as measured by clonogenic survival assays (p < 0.01). 24 hours following these targeted treatments, 2 Gy of radiation was administered which resulted in a greater degree of decreased cell viability and self-renewal (p < 0.01), as well as in increased cell death. Together, this data suggests that inhibition of Smo, Gli1, and PARP1 either alone as single agents, or in combination is a promising therapeutic strategy for increasing the radiation sensitivity of pediatric SHH medulloblastoma.
Clinical
|
GLI1 (GLI Family Zinc Finger 1)
|
veliparib (ABT-888) • Odomzo (sonidegib)
1year
Whole exome sequencing of intracranial epidermoid cysts (IECs) reveals potential somatic drivers (SNO 2023)
Digital droplet PCR (ddPCR) of these samples is underway to validate the low tumor allele frequencies ( < 4%). The discovery of activating mutations in SMO is significant because it potentiates FDA-approved SMO-inhibitors like Vismodegib and Sonidegib as viable treatment options for patients with IECs.
Whole exome sequencing
|
SMO (Smoothened Frizzled Class Receptor) • STIM1 (Stromal Interaction Molecule 1)
|
SMO mutation
|
Erivedge (vismodegib) • Odomzo (sonidegib)
1year
SONIB: A Study to Evaluate Neoadjuvant Sonidegib Followed by Surgery or Imiquimod in the Management of Basal Cell Carcinoma (clinicaltrials.gov)
P2, N=10, Recruiting, Melanoma Institute Australia | Trial completion date: Sep 2023 --> Dec 2023 | Trial primary completion date: Sep 2023 --> Dec 2023
Trial completion date • Trial primary completion date • Surgery
|
Odomzo (sonidegib) • Zyclara (imiquimod)
1year
Integrated PK/PD modeling relates Smoothened inhibitor biomarkers to the heterogeneous intratumor disposition of cetuximab in pancreatic cancer tumor models. (PubMed, J Pharm Sci)
A minimal, physiologically-based pharmacokinetic (mPBPK) model was constructed to link sHHi effects upon mechanistic effectors of tumor barrier compromise with the intratumor distribution of CTX, and CTX occupancy of EGFR in tumors. Integration of the mPBPK model of mAb deposition and intratumor distribution with the PK/PD model of tumor responses to priming not only identified physiological parameters that are critical for tumor antibody distribution, but also provides insight into dosing regimens that could achieve maximal tumor disposition of therapeutic antibodies under conditions of transient PDAC tumor permeability barrier compromise that mechanistically-diverse tumor priming strategies may achieve.
PK/PD data • Preclinical • Journal
|
EGFR (Epidermal growth factor receptor) • GLI1 (GLI Family Zinc Finger 1)
|
Erbitux (cetuximab) • Odomzo (sonidegib)
1year
Surgery after sonidegib treatment achieves complete response in locally advanced basal cell carcinoma of the face. (PubMed, J Dermatol)
Vismodegib as a neoadjuvant treatment before surgery has been investigated in a single, multicentre, open-label, phase II trial (VISMONEO); however, sonidegib has not yet been evaluated in this setting. We report the cases of two patients with locally advanced basal cell carcinoma of the face who achieved complete remission with sonidegib followed by a more limited surgical excision than would have been needed without target therapy.
Journal • Surgery • Metastases
|
Erivedge (vismodegib) • Odomzo (sonidegib)
1year
European consensus-based interdisciplinary guideline for diagnosis and treatment of basal cell carcinoma-update 2023. (PubMed, Eur J Cancer)
Hedgehog inhibitors (HHIs), vismodegib or sonidegib, should be offered to patients with locally advanced and metastatic BCC. Immunotherapy with anti-PD1 antibodies (cemiplimab) is a second-line treatment in patients with a progression of disease, contraindication, or intolerance to HHI therapy...In Gorlin patients, regular skin examinations are required to diagnose and treat BCCs at an early stage. Long-term follow-up is recommended in patients with high-risk BCC, multiple BCCs, and Gorlin syndrome.
Review • Journal
|
Libtayo (cemiplimab-rwlc) • Erivedge (vismodegib) • Odomzo (sonidegib)
1year
Multicenter Retrospective Andalusian Study of the Use of Sonidegib for the Treatment of Local Advanced Basal Cell Carcinoma in Real Clinical Practice. (PubMed, J Clin Med)
Sonidegib is the second iHh authorized for the treatment of adult patients with locally advanced BCC who are not amenable to curative surgery or radiotherapy, based on the results of the phase II clinical trial, BOLT. Sonidegib shows good effectiveness and an acceptable safety profile in routine clinical practice in the sample presented.
Retrospective data • Journal • Metastases
|
Erivedge (vismodegib) • Odomzo (sonidegib)
1year
Sonidegib and Pembrolizumab in Treating Patients With Advanced Solid Tumors (clinicaltrials.gov)
P1, N=45, Recruiting, Mayo Clinic | Trial primary completion date: Jul 2023 --> Jul 2024
Trial primary completion date • Metastases
|
EGFR (Epidermal growth factor receptor) • PD-L1 (Programmed death ligand 1) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • MSI (Microsatellite instability)
|
PD-L1 expression • MSI-H/dMMR
|
Keytruda (pembrolizumab) • Odomzo (sonidegib)
1year
Concomitant medication use does not appear to alter long-term efficacy of sonidegib for advanced basal cell carcinoma: a post hoc analysis based on the 42-month BOLT study. (PubMed, Eur J Dermatol)
Administration of sonidegib with concomitant medications, excluding strong cytochrome P450 3A4/5 inhibitors/inducers, does not appear to alter its efficacy in laBCC patients.
Retrospective data • Journal • Metastases
|
Odomzo (sonidegib)
over1year
Recommendations for Cost-Conscious Treatment of Basal Cell Carcinoma. (PubMed, Dermatol Ther (Heidelb))
For a primary superficial BCC < 0.5 cm arising on Area M, the cost-conscious algorithm prioritizes C&E or cryosurgery. For a primary nodular BCC 1.1-2 cm arising on Area L, the cost-conscious algorithm prioritizes C&E, cryosurgery, or 5-FU. For a giant BCC, the cost-conscious algorithm identifies superficial radiation therapy as first line.
Review • Journal
|
cisplatin • 5-fluorouracil • Libtayo (cemiplimab-rwlc) • Erivedge (vismodegib) • Odomzo (sonidegib) • Zyclara (imiquimod)
over1year
Sonidegib in Locally Advanced Basal Cell Carcinoma: A Monocentric Retrospective Experience and a Review of Published Real-Life Data. (PubMed, Cancers (Basel))
All four patients suffering from Basal Cell Naevus syndrome achieved disease control by being treated with Sonidegib. Consequently, we strongly advise the joint management of laBCCs through a multidisciplinary team whenever feasible.
Retrospective data • Review • Journal • Metastases
|
Odomzo (sonidegib)
over1year
The Efficacy of Sonidegib in Treating Locally Advanced Basal Cell Carcinoma Involving the Periocular Area. (PubMed, Dermatol Ther (Heidelb))
To the best of our knowledge, this is the first study investigating the effectiveness and safety of sonidegib in the management of BCC localized at the periocular region. Even if limited, our study suggests this drug as a valuable and safe option in periocular BCC management.
Journal • Metastases
|
Erivedge (vismodegib) • Odomzo (sonidegib)
over1year
Long-term strategies for management of advanced basal cell carcinoma with hedgehog inhibitors. (PubMed, Crit Rev Oncol Hematol)
The hedgehog inhibitors sonidegib and vismodegib are first-line treatments for advanced BCC with a long-lasting response, but long-term treatment with hedgehog inhibitors is often challenged by tolerability issues. However, several strategies for adverse effect management are available, such as dose interruptions, on-label alternate-day dosing and supportive medications. In conclusion, although BCC shows a high tumor mutational burden that favors a response to immunotherapy, experts recommend keeping patients on hedgehog inhibitors limiting immunotherapy to those who developed resistance during hedgehog inhibitor therapy or in case of persisting toxicity despite long-term management of adverse events.
Review • Journal • Tumor mutational burden • IO biomarker • Metastases
|
TMB (Tumor Mutational Burden)
|
TMB-H
|
Erivedge (vismodegib) • Odomzo (sonidegib)
over1year
Journal • Metastases
|
Erivedge (vismodegib) • Odomzo (sonidegib)
over1year
Retrospective data • Journal • Metastases
|
Erivedge (vismodegib) • Odomzo (sonidegib)