sonidegib
{{Short description|Chemical compound}}
{{cs1 config|name-list-style=vanc}}
{{Infobox drug
| drug_name =
| image = Sonidegib.svg
| width = 275
| tradename = Odomzo
| Drugs.com = {{Drugs.com|monograph|sonidegib}}
| MedlinePlus = a615034
| DailyMedID = Sonidegib
| licence_EU = yes
| pregnancy_category= Contraindicated (X)
| routes_of_administration = By mouth
| class = Antineoplastic agents
| ATC_prefix = L01
| ATC_suffix = XJ02
| legal_AU = S4
| legal_BR =
| legal_BR_comment =
| legal_CA = Rx-only
| legal_DE =
| legal_DE_comment =
| legal_NZ =
| legal_NZ_comment =
| legal_UK =
| legal_UK_comment =
| legal_US = Rx-only
| legal_EU = Rx-only
| legal_EU_comment =
| legal_UN =
| legal_UN_comment =
| legal_status = Rx-only
| bioavailability = <10%
| protein_bound = >97%
| elimination_half-life = ~28 days
| excretion = Feces (~70%), urine (30%)
| index2_label = as salt
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 956697-53-3
| PubChem = 24775005
| DrugBank = DB09143
| ChemSpiderID = 25027390
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 90863
| ChEMBL = 2105737
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 0RLU3VTK5M
| KEGG = D10119
| KEGG2 = D10729
| synonyms = LDE225, erismodegib
| IUPAC_name = N-[6-[(2S,6R)-2,6-Dimethylmorpholin-4-yl]pyridin-3-yl]-2-methyl-3-[4-(trifluoromethoxy)phenyl]benzamide
| C=26|H=26|F=3|N=3|O=3
| smiles = C[C@@H]1CN(C[C@@H](O1)C)C2=NC=C(C=C2)NC(=O)C3=CC=CC(=C3C)C4=CC=C(C=C4)OC(F)(F)F
| StdInChI = 1S/C26H26F3N3O3/c1-16-14-32(15-17(2)34-16)24-12-9-20(13-30-24)31-25(33)23-6-4-5-22(18(23)3)19-7-10-21(11-8-19)35-26(27,28)29/h4-13,16-17H,14-15H2,1-3H3,(H,31,33)/t16-,17+
| StdInChIKey = VZZJRYRQSPEMTK-CALCHBBNSA-N
}}
Sonidegib (INN), sold under the brand name Odomzo, is a medication used to treat cancer.
Sonidegib is a Hedgehog signaling pathway inhibitor (via smoothened antagonism).{{Cite web |title=LDE225 - PubChem |url=https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=135626837 |access-date=16 February 2014 |website=PubChem |publisher=National Institutes of Health}}{{Cite journal |display-authors=6 |vauthors=Pan S, Wu X, Jiang J, Gao W, Wan Y, Cheng D, Han D, Liu J, Englund NP, Wang Y, Peukert S, Miller-Moslin K, Yuan J, Guo R, Matsumoto M, Vattay A, Jiang Y, Tsao J, Sun F, Pferdekamper AC, Dodd S, Tuntland T, Maniara W, Kelleher JF, Yao YM, Warmuth M, Williams J, Dorsch M |date=June 2010 |title=Discovery of NVP-LDE225, a Potent and Selective Smoothened Antagonist |journal=ACS Medicinal Chemistry Letters |volume=1 |issue=3 |pages=130–4 |doi=10.1021/ml1000307 |pmc=4007689 |pmid=24900187}}
Approvals and indications
It was approved for medical use in the United States and in the European Union in 2015{{Cite web |title=FDA approves new treatment for most common form of advanced skin cancer |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm455862.htm |url-status=dead |archive-url=https://web.archive.org/web/20150724203724/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm455862.htm |archive-date=2015-07-24 |access-date=2015-07-24 |website=www.fda.gov}}{{Cite web |date=24 July 2015 |title=FDA approves Novartis's advanced skin cancer drug |url=https://news.yahoo.com/fda-approves-novartiss-advanced-skin-cancer-drug-162113308--finance.html |access-date=2015-07-24}}{{Cite web |date=17 September 2018 |title=Odomzo |url=https://www.ema.europa.eu/en/medicines/human/EPAR/odomzo |access-date=9 June 2020 |website=European Medicines Agency}}
It is indicated for the treatment of adults with locally advanced basal-cell carcinoma that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy.
Pharmacology
Sonidegib is administered by mouth. Common side effects include muscle spasms, hair loss, fatigue, abdominal pain, nausea, headache, and weight loss.{{Cite web |date=29 May 2019 |title=Odomzo- sonidegib capsule |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=028312dc-d155-4fd5-8abd-6bb9f011d3cc |access-date=9 June 2020 |website=DailyMed}}
Sonidegib binds to and inhibits smoothened to inhibit activation of the Hedgehog pathway. Sonidegib is primarily metabolized by CYP3A and is eliminated hepatically.
Development
It has been investigated as a potential treatment for:
- Pancreatic cancer{{Cite web |date=13 February 2014 |title=A Biomarker Study to Identify Predictive Signatures of Response to LDE225 (Hedgehog Inhibitor) In Patients With Resectable Pancreatic Cancer |url=http://clinicaltrials.gov/show/NCT01911416 |access-date=16 February 2014 |website=ClinicalTrials.gov |publisher=National Institutes of Health}}{{Cite web |date=13 February 2014 |title=Gemcitabine + Nab-paclitaxel With LDE-225 (Hedgehog Inhibitor) as Neoadjuvant Therapy for Pancreatic Adenocarcinoma |url=http://clinicaltrials.gov/ct2/show/NCT01431794 |access-date=16 February 2014 |website=ClinicalTrials.gov |publisher=National Institutes of Health}}{{Cite web |date=13 February 2014 |title=Dose-escalation, and Safety Study of LDE225 and Gemcitabine in Locally Advanced or Metastatic Pancreatic Cancer Patients |url=http://clinicaltrials.gov/ct2/show/NCT02027376 |access-date=16 February 2014 |website=ClinicalTrials.gov |publisher=National Institutes of Health}}{{Cite web |date=13 February 2014 |title=A Pilot Study of a Hedgehog Pathway Inhibitor (LDE-225) in Surgically Resectable Pancreas Cancer |url=http://clinicaltrials.gov/ct2/show/NCT01694589 |access-date=16 February 2014 |website=ClinicalTrials.gov |publisher=National Institutes of Health}}
- Breast cancer{{Cite journal |date=13 February 2014 |title=Study With LDE225 in Combination With Docetaxel in Triple Negative (TN) Advanced Breast Cancer (ABC) Patients (EDALINE) |url=http://clinicaltrials.gov/ct2/show/NCT02027376 |journal=ClinicalTrials.gov |publisher=National Institutes of Health}}{{Cite web |date=13 February 2014 |title=LDE225 in Treating Patients With Stage II-III Estrogen Receptor- and HER2-Negative Breast Cancer |url=http://clinicaltrials.gov/ct2/show/NCT01757327 |access-date=16 February 2014 |website=ClinicalTrials.gov |publisher=National Institutes of Health}}
- Basal cell carcinoma of the skin{{Cite web |date=13 February 2014 |title=A Phase II Study of Efficacy and Safety in Patients With Locally Advanced or Metastatic Basal Cell Carcinoma (BOLT) |url=http://clinicaltrials.gov/ct2/show/NCT01327053 |access-date=16 February 2014 |website=ClinicalTrials.gov |publisher=National Institutes of Health}}{{Cite web |date=13 February 2014 |title=To Evaluate the Safety, Local Tolerability, PK and PD of LDE225 on Sporadic Superficial and Nodular Skin Basal Cell Carcinomas(sBCC) |url=http://clinicaltrials.gov/ct2/show/NCT01033019 |access-date=16 February 2014 |website=ClinicalTrials.gov |publisher=National Institutes of Health}}{{Cite web |date=13 February 2014 |title=A Trial to Evaluate the Safety, Local Tolerability, Pharmacokinetics and Pharmacodynamics of LDE225 on Skin Basal Cell Carcinomas in Gorlin Syndrome Patients |url=http://clinicaltrials.gov/ct2/show/NCT00961896 |access-date=16 February 2014 |website=ClinicalTrials.gov |publisher=National Institutes of Health}}
- Small cell lung cancer{{Cite web |date=13 February 2014 |title=Combination of the Hedgehog Inhibitor, LDE225, With Etoposide and Cisplatin in the First-Line Treatment of Patients With Extensive Stage Small Cell Lung Cancer (ES-SCLC) |url=http://clinicaltrials.gov/ct2/show/NCT01579929 |access-date=16 February 2014 |website=ClinicalTrials.gov |publisher=National Institutes of Health}}
- Medulloblastoma{{Cite web |date=13 February 2014 |title=A Phase III Study of Oral LDE225 Versus (vs) Temozolomide (TMZ) in Patients With Hedge-Hog (Hh)-Pathway Activated Relapsed Medulloblastoma (MB) |url=http://clinicaltrials.gov/ct2/show/NCT01708174 |access-date=16 February 2014 |website=ClinicalTrials.gov |publisher=National Institutes of Health}}{{Cite web |date=13 February 2014 |title=A Phase I Dose Finding and Safety Study of Oral LDE225 in Children and a Phase II Portion to Assess Preliminary Efficacy in Recurrent or Refractory MB |url=http://clinicaltrials.gov/ct2/show/NCT01125800 |access-date=16 February 2014 |website=ClinicalTrials.gov |publisher=National Institutes of Health}}
- Advanced solid tumors (including ovarian, breast, pancreatic, stomach, oesophageal cancers and glioblastoma multiforme){{Cite web |date=13 February 2014 |title=Phase Ib, Dose Escalation Study of Oral LDE225 in Combination With BKM120 in Patients With Advanced Solid Tumors |url=http://clinicaltrials.gov/ct2/show/NCT01576666 |access-date=16 February 2014 |website=ClinicalTrials.gov |publisher=National Institutes of Health}}{{Cite web |date=13 February 2014 |title=Dose Finding and Safety of Oral LDE225 in Patients With Advanced Solid Tumors |url=http://clinicaltrials.gov/ct2/show/NCT00880308 |access-date=16 February 2014 |website=ClinicalTrials.gov |publisher=National Institutes of Health}}{{Cite web |date=13 February 2014 |title=LDE225 and Paclitaxel in Solid Tumors |url=http://clinicaltrials.gov/ct2/show/NCT01954355 |access-date=16 February 2014 |website=ClinicalTrials.gov |publisher=National Institutes of Health}}
- Acute leukemia{{Cite web |date=13 February 2014 |title=Study of Efficacy and Safety of LDE225 in Adult Patients With Relapsed/Refractory Acute Leukemia |url=http://clinicaltrials.gov/ct2/show/NCT01826214 |access-date=16 February 2014 |website=ClinicalTrials.gov |publisher=National Institutes of Health}} and chronic myeloid leukemia{{Cite web |date=13 February 2014 |title=Nilotinib and LDE225 in the Treatment of Chronic or Accelerated Phase Myeloid Leukemia in Patients Who Developed Resistance to Prior Therapy |url=http://clinicaltrials.gov/ct2/show/NCT01456676 |access-date=16 February 2014 |website=ClinicalTrials.gov |publisher=National Institutes of Health}}
- Myelofibrosis and essential thrombocythaemia{{Cite web |date=13 February 2014 |title=A Phase Ib/II Dose-finding Study to Assess the Safety and Efficacy of LDE225 + INC424 in Patients With MF |url=http://clinicaltrials.gov/ct2/show/NCT01787552 |access-date=16 February 2014 |website=ClinicalTrials.gov |publisher=National Institutes of Health}}
It has demonstrated significant efficacy against melanoma in vitro and in vivo.{{Cite journal |display-authors=6 |vauthors=Jalili A, Mertz KD, Romanov J, Wagner C, Kalthoff F, Stuetz A, Pathria G, Gschaider M, Stingl G, Wagner SN |date=30 July 2013 |title=NVP-LDE225, a potent and selective SMOOTHENED antagonist reduces melanoma growth in vitro and in vivo |journal=PLOS ONE |volume=8 |issue=7 |pages=e69064 |bibcode=2013PLoSO...869064J |doi=10.1371/journal.pone.0069064 |pmc=3728309 |pmid=23935925 |doi-access=free}} It also demonstrated efficacy in a mouse model of pancreatic cancer.{{Cite journal |vauthors=Fendrich V, Wiese D, Waldmann J, Lauth M, Heverhagen AE, Rehm J, Bartsch DK |date=November 2011 |title=Hedgehog inhibition with the orally bioavailable Smo antagonist LDE225 represses tumor growth and prolongs survival in a transgenic mouse model of islet cell neoplasms |journal=Annals of Surgery |volume=254 |issue=5 |pages=818–23; discussion 823 |doi=10.1097/SLA.0b013e318236bc0f |pmid=22042473 |s2cid=12947375}}
References
{{reflist}}
External links
- {{Cite web |title=Sonidegib |url=https://druginfo.nlm.nih.gov/drugportal/name/sonidegib |website=Drug Information Portal |publisher=U.S. National Library of Medicine}}
- {{Cite web |title=Sonidegib phosphate |url=https://druginfo.nlm.nih.gov/drugportal/name/sonidegib%20phosphate |website=Drug Information Portal |publisher=U.S. National Library of Medicine}}
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Category:Drugs developed by Novartis