Sonidegib

Sonidegib
Clinical data
Trade names	Odomzo
Other names	LDE225, erismodegib
AHFS/Drugs.com	Monograph
MedlinePlus	a615034
License data	EU EMA: by INN; US DailyMed: Sonidegib;
Pregnancy; category	AU: X (High risk)[1]; Contraindicated;
Routes of; administration	By mouth (capsules)
Drug class	Antineoplastic agents
ATC code	L01XJ02 (WHO) ;
Legal status
Legal status	US: ℞-only ; EU: Rx-only ; In general: ℞ (Prescription only);
Pharmacokinetic data
Bioavailability	<10%
Protein binding	>97%
Metabolism	Liver (CYP3A)
Elimination half-life	~28 days
Excretion	Feces (~70%), urine (30%)[2]
Identifiers
	IUPAC name N-[6-[(2S,6R)-2,6-Dimethylmorpholin-4-yl]pyridin-3-yl]-2-methyl-3-[4-(trifluoromethoxy)phenyl]benzamide;
CAS Number	956697-53-3 ;
PubChem CID	24775005;
DrugBank	DB09143;
ChemSpider	25027390;
UNII	0RLU3VTK5M;
KEGG	D10119; as salt: D10729;
ChEBI	CHEBI:90863 ;
ChEMBL	ChEMBL2105737;
CompTox Dashboard (EPA)	DTXSID501009335 ;
Chemical and physical data
Formula	C26H26F3N3O3
Molar mass	485.507 g·mol−1
3D model (JSmol)	Interactive image;
	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;
	InChI InChI=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+; Key:VZZJRYRQSPEMTK-CALCHBBNSA-N;

Sonidegib (INN), sold under the brand name Odomzo, is a medication used to treat cancer.[2]

Sonidegib is Hedgehog signaling pathway inhibitor (via smoothened antagonism).[3][4]

Approvals and indications

It was approved for medical use in the United States and in the European Union in 2015[5][6][7][8]

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.[2]

Pharmacology

Sonidegib is administered by mouth. Common side effects include muscle spasms, hair loss, fatigue, abdominal pain, nausea, headache, and weight loss.[2]

Sonidegib binds to and inhibits smoothened to inhibit activation of the Hedgehog pathway. Sonidegib is primarily metabolized by CYP3A and is eliminated hepatically.[2]

Development

It has been investigated as a potential treatment for:

Pancreatic cancer[9][10][11][12]
Breast cancer[13][14]
Basal cell carcinoma of the skin[15][16][17]
Small cell lung cancer[18]
Medulloblastoma[19][20]
Advanced solid tumors (including ovarian, breast, pancreatic, stomach, oesophageal cancers and glioblastoma multiforme)[21][22][23]
Acute leukemia[24] and chronic myeloid leukemia[25]
Myelofibrosis and essential thrombocythaemia[26]

It has demonstrated significant efficacy against melanoma in vitro and in vivo.[27] It also demonstrated efficacy in a mouse model of pancreatic cancer.[28]

References

"Sonidegib (Odomzo) Use During Pregnancy". Drugs.com. 17 May 2019. Retrieved 9 June 2020.
"Odomzo- sonidegib capsule". DailyMed. 29 May 2019. Retrieved 9 June 2020.
"LDE225 - PubChem". PubChem. National Institutes of Health. Retrieved 16 February 2014.
Pan S, Wu X, Jiang J, Gao W, Wan Y, Cheng D, et al. (June 2010). "Discovery of NVP-LDE225, a Potent and Selective Smoothened Antagonist". ACS Medicinal Chemistry Letters. 1 (3): 130–4. doi:10.1021/ml1000307. PMC 4007689. PMID 24900187.
"FDA approves new treatment for most common form of advanced skin cancer". www.fda.gov. Retrieved 2015-07-24.
"Odomzo sonidegib Capsules". U.S. Food and Drug Administration (FDA). 28 August 2015. Retrieved 9 June 2020.
"FDA approves Novartis's advanced skin cancer drug". Retrieved 2015-07-24.
"Odomzo". European Medicines Agency. 17 September 2018. Retrieved 9 June 2020.
"A Biomarker Study to Identify Predictive Signatures of Response to LDE225 (Hedgehog Inhibitor) In Patients With Resectable Pancreatic Cancer". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
"Gemcitabine + Nab-paclitaxel With LDE-225 (Hedgehog Inhibitor) as Neoadjuvant Therapy for Pancreatic Adenocarcinoma". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
"Dose-escalation, and Safety Study of LDE225 and Gemcitabine in Locally Advanced or Metastatic Pancreatic Cancer Patients". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
"A Pilot Study of a Hedgehog Pathway Inhibitor (LDE-225) in Surgically Resectable Pancreas Cancer". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
"Study With LDE225 in Combination With Docetaxel in Triple Negative (TN) Advanced Breast Cancer (ABC) Patients (EDALINE)". ClinicalTrials.gov. National Institutes of Health. 13 February 2014.
"LDE225 in Treating Patients With Stage II-III Estrogen Receptor- and HER2-Negative Breast Cancer". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
"A Phase II Study of Efficacy and Safety in Patients With Locally Advanced or Metastatic Basal Cell Carcinoma (BOLT)". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
"To Evaluate the Safety, Local Tolerability, PK and PD of LDE225 on Sporadic Superficial and Nodular Skin Basal Cell Carcinomas(sBCC)". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
"A Trial to Evaluate the Safety, Local Tolerability, Pharmacokinetics and Pharmacodynamics of LDE225 on Skin Basal Cell Carcinomas in Gorlin Syndrome Patients". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
"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)". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
"A Phase III Study of Oral LDE225 Versus (vs) Temozolomide (TMZ) in Patients With Hedge-Hog (Hh)-Pathway Activated Relapsed Medulloblastoma (MB)". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
"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". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
"Phase Ib, Dose Escalation Study of Oral LDE225 in Combination With BKM120 in Patients With Advanced Solid Tumors". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
"Dose Finding and Safety of Oral LDE225 in Patients With Advanced Solid Tumors". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
"LDE225 and Paclitaxel in Solid Tumors". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
"Study of Efficacy and Safety of LDE225 in Adult Patients With Relapsed/Refractory Acute Leukemia". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
"Nilotinib and LDE225 in the Treatment of Chronic or Accelerated Phase Myeloid Leukemia in Patients Who Developed Resistance to Prior Therapy". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
"A Phase Ib/II Dose-finding Study to Assess the Safety and Efficacy of LDE225 + INC424 in Patients With MF". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
Jalili A, Mertz KD, Romanov J, Wagner C, Kalthoff F, Stuetz A, et al. (30 July 2013). "NVP-LDE225, a potent and selective SMOOTHENED antagonist reduces melanoma growth in vitro and in vivo". PLOS ONE. 8 (7): e69064. Bibcode:2013PLoSO...869064J. doi:10.1371/journal.pone.0069064. PMC 3728309. PMID 23935925.
Fendrich V, Wiese D, Waldmann J, Lauth M, Heverhagen AE, Rehm J, Bartsch DK (November 2011). "Hedgehog inhibition with the orally bioavailable Smo antagonist LDE225 represses tumor growth and prolongs survival in a transgenic mouse model of islet cell neoplasms". Annals of Surgery. 254 (5): 818–23, discussion 823. doi:10.1097/SLA.0b013e318236bc0f. PMID 22042473. S2CID 12947375.

External links

"Sonidegib". Drug Information Portal. U.S. National Library of Medicine.
"Sonidegib phosphate". Drug Information Portal. U.S. National Library of Medicine.

This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.

[Drugs.com_pregnancy-1] "Sonidegib (Odomzo) Use During Pregnancy". Drugs.com. 17 May 2019. Retrieved 9 June 2020.

[Odomzo_FDA_label-2] "Odomzo- sonidegib capsule". DailyMed. 29 May 2019. Retrieved 9 June 2020.

[3] "LDE225 - PubChem". PubChem. National Institutes of Health. Retrieved 16 February 2014.

[4] Pan S, Wu X, Jiang J, Gao W, Wan Y, Cheng D, et al. (June 2010). "Discovery of NVP-LDE225, a Potent and Selective Smoothened Antagonist". ACS Medicinal Chemistry Letters. 1 (3): 130–4. doi:10.1021/ml1000307. PMC 4007689. PMID 24900187.

[5] "FDA approves new treatment for most common form of advanced skin cancer". www.fda.gov. Retrieved 2015-07-24.

[6] "Odomzo sonidegib Capsules". U.S. Food and Drug Administration (FDA). 28 August 2015. Retrieved 9 June 2020.

[:0-7] "FDA approves Novartis's advanced skin cancer drug". Retrieved 2015-07-24.

[8] "Odomzo". European Medicines Agency. 17 September 2018. Retrieved 9 June 2020.

[9] "A Biomarker Study to Identify Predictive Signatures of Response to LDE225 (Hedgehog Inhibitor) In Patients With Resectable Pancreatic Cancer". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.

[10] "Gemcitabine + Nab-paclitaxel With LDE-225 (Hedgehog Inhibitor) as Neoadjuvant Therapy for Pancreatic Adenocarcinoma". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.

[11] "Dose-escalation, and Safety Study of LDE225 and Gemcitabine in Locally Advanced or Metastatic Pancreatic Cancer Patients". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.

[12] "A Pilot Study of a Hedgehog Pathway Inhibitor (LDE-225) in Surgically Resectable Pancreas Cancer". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.

[13] "Study With LDE225 in Combination With Docetaxel in Triple Negative (TN) Advanced Breast Cancer (ABC) Patients (EDALINE)". ClinicalTrials.gov. National Institutes of Health. 13 February 2014.

[14] "LDE225 in Treating Patients With Stage II-III Estrogen Receptor- and HER2-Negative Breast Cancer". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.

[15] "A Phase II Study of Efficacy and Safety in Patients With Locally Advanced or Metastatic Basal Cell Carcinoma (BOLT)". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.

[16] "To Evaluate the Safety, Local Tolerability, PK and PD of LDE225 on Sporadic Superficial and Nodular Skin Basal Cell Carcinomas(sBCC)". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.

[17] "A Trial to Evaluate the Safety, Local Tolerability, Pharmacokinetics and Pharmacodynamics of LDE225 on Skin Basal Cell Carcinomas in Gorlin Syndrome Patients". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.

[18] "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)". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.

[19] "A Phase III Study of Oral LDE225 Versus (vs) Temozolomide (TMZ) in Patients With Hedge-Hog (Hh)-Pathway Activated Relapsed Medulloblastoma (MB)". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.

[20] "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". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.

[21] "Phase Ib, Dose Escalation Study of Oral LDE225 in Combination With BKM120 in Patients With Advanced Solid Tumors". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.

[22] "Dose Finding and Safety of Oral LDE225 in Patients With Advanced Solid Tumors". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.

[23] "LDE225 and Paclitaxel in Solid Tumors". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.

[24] "Study of Efficacy and Safety of LDE225 in Adult Patients With Relapsed/Refractory Acute Leukemia". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.

[25] "Nilotinib and LDE225 in the Treatment of Chronic or Accelerated Phase Myeloid Leukemia in Patients Who Developed Resistance to Prior Therapy". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.

[26] "A Phase Ib/II Dose-finding Study to Assess the Safety and Efficacy of LDE225 + INC424 in Patients With MF". ClinicalTrials.gov. National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.

[27] Jalili A, Mertz KD, Romanov J, Wagner C, Kalthoff F, Stuetz A, et al. (30 July 2013). "NVP-LDE225, a potent and selective SMOOTHENED antagonist reduces melanoma growth in vitro and in vivo". PLOS ONE. 8 (7): e69064. Bibcode:2013PLoSO...869064J. doi:10.1371/journal.pone.0069064. PMC 3728309. PMID 23935925.

[28] Fendrich V, Wiese D, Waldmann J, Lauth M, Heverhagen AE, Rehm J, Bartsch DK (November 2011). "Hedgehog inhibition with the orally bioavailable Smo antagonist LDE225 represses tumor growth and prolongs survival in a transgenic mouse model of islet cell neoplasms". Annals of Surgery. 254 (5): 818–23, discussion 823. doi:10.1097/SLA.0b013e318236bc0f. PMID 22042473. S2CID 12947375.