Denosumab

Identification

Name
Denosumab
Accession Number
DB06643
Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Description

Denosumab is a novel, fully human IgG2 monoclonal antibody specific to receptor activator of nuclear factor kappa-B ligand (RANKL), suppresses bone resorption markers in patients with a variety of metastatic tumors and is being investigated in multiple clinical trials for the prevention and treatment of bone metastases. Chemically, it consists of 2 heavy and 2 light chains. Each light chain consists of 215 amino acids. Each heavy chain consists of 448 amino acids with 4 intramolecular disulfides. FDA approved on June 1, 2010.

Protein structure
Db06643
Protein chemical formula
C6404H9912N1724O2004S50
Protein average weight
144700.0 Da
Sequences
> Denosumab αOPGL-1 heavy chain sequence
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSGITGSGGSTYY
ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDPGTTVIMSWFDPWGQGTLVTV
SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ
SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELL
GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ
YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR
DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS
RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
> Denosumab αOPGL-1 light chain sequence
EIVLTQSPGTLSLSPGERATLSCRASQSVRGRYLAWYQQKPGQAPRLLIYGASSRATGIP
DRFSGSGSGTDFTLTISRLEPEDFAVFYCQQYGSSPRTFGQGTKVEIKRTVAAPSVFIFP
PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL
TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
Download FASTA Format
Synonyms
Not Available
External IDs
AMG-162
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ProliaSolution60 mgSubcutaneousAmgen2010-08-12Not applicableCanada
ProliaSolution60 mgSubcutaneousAmgenNot applicableNot applicableCanada
ProliaInjection60 mg/1mLSubcutaneousAmgen2010-06-05Not applicableUs
XgevaInjection, solution120 mgSubcutaneousAmgen Europe B.V.2011-07-13Not applicableEu
XgevaSolution120 mgSubcutaneousAmgen2011-06-06Not applicableCanada
XgevaInjection, solution120 mgSubcutaneousAmgen Europe B.V.2011-07-13Not applicableEu
XgevaInjection120 mg/1.7mLSubcutaneousAmgen2010-11-18Not applicableUs
XgevaInjection, solution120 mgSubcutaneousAmgen Europe B.V.2011-07-13Not applicableEu
International/Other Brands
Ranmark (Daiichi Sankyo)
Categories
UNII
4EQZ6YO2HI
CAS number
615258-40-7

Pharmacology

Indication

Prolia is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture. It reduces the incidence of vertebral, nonvertebral, and hip fractures. Prolia is also indicated as a treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer. It can also be used in men with osteoporosis at high risk for fracture or in men receiving androgen deprivation therapy for nonmetastatic prostate cancer to increase bone mass. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

Associated Conditions
Pharmacodynamics

In clinical studies, treatment with 60 mg of Prolia resulted in reduction in the bone resorption marker serum type 1 C-telopeptide (CTX) by approximately 85% by 3 days. Consistent with the physiological coupling of bone formation and resorption in skeletal remodeling, subsequent reductions in bone formation markers (i.e. osteocalcin and procollagen type 1 N-terminal peptide [PlNP]) were observed starting 1 month after the first dose of Prolia.

Mechanism of action

Denosumab is designed to target RANKL (RANK ligand), a protein that acts as the primary signal to promote bone removal/resorption. In many bone loss conditions, RANKL overwhelms the body's natural defense against bone destruction. Denosumab prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption and increasing bone mass and strength in both cortical and trabecular bone.

TargetActionsOrganism
ATumor necrosis factor ligand superfamily member 11
antibody
Human
Absorption

When 60 mg of denosumab was subcutaneously administered to healthy subjects after fasting for 12 hours, the pharmacokinetic parameters are as follows: Cmax = 6.75 mcg/mL; Tmax= 10 days (range of 3 to 21 days); AUC (0-16 weeks) = 316 mcg•day/mL. Denosumab does not accumulate following multiple doses once every 6 months. The pharmacokinetics of denosumab were not affected by the formation of antibodies.

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life

25.4 days

Clearance
Not Available
Toxicity

In patients with postmenopausal osteoporosis, the most common adverse reactions (> 5% and more common than placebo) were: back pain, pain in extremity, hypercholesterolemia, musculoskeletal pain, and cystitis. Pancreatitis has been reported in clinical trials. In male patients with osteoporosis, the most common adverse reactions (> 5% and more common than placebo) were: back pain, arthralgia, and nasopharyngitis. In patients experiencing bone loss due to hormone ablation for cancer, the most common adverse reactions (≥ 10% and more common than placebo) were: arthralgia and back pain. Pain in extremity and musculoskeletal pain have also been reported in clinical trials

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
2-MethoxyethanolThe risk or severity of adverse effects can be increased when Denosumab is combined with 2-Methoxyethanol.
AbataceptThe risk or severity of adverse effects can be increased when Denosumab is combined with Abatacept.
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Denosumab.
AbetimusThe risk or severity of adverse effects can be increased when Denosumab is combined with Abetimus.
ActeosideThe risk or severity of adverse effects can be increased when Denosumab is combined with Acteoside.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Denosumab.
AdefovirThe risk or severity of adverse effects can be increased when Denosumab is combined with Adefovir.
AfelimomabThe risk or severity of adverse effects can be increased when Denosumab is combined with Afelimomab.
AlclometasoneThe risk or severity of adverse effects can be increased when Alclometasone is combined with Denosumab.
AldesleukinThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Denosumab.
Food Interactions
Not Available

References

General References
  1. Malan J, Ettinger K, Naumann E, Beirne OR: The relationship of denosumab pharmacology and osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012 Dec;114(6):671-6. doi: 10.1016/j.oooo.2012.08.439. [PubMed:23159111]
  2. Link [Link]
  3. Link [Link]
External Links
KEGG Drug
D03684
PubChem Substance
347910354
ChEMBL
CHEMBL1237023
PharmGKB
PA166048634
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Denosumab
ATC Codes
M05BX04 — Denosumab
AHFS Codes
  • 92:24.00 — Bone Resorption Inhibitors
FDA label
Download (226 KB)
MSDS
Download (97.5 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0CompletedBasic ScienceAging / Bone Loss1
0Not Yet RecruitingPreventionBRCA1 Gene Mutation / Brca2 Gene Mutation / Fallopian Tube Carcinoma / Ovarian Carcinoma / Premenopausal1
0RecruitingTreatmentAnorexia Nervosa (AN) / Atypical Anorexia Nervosa / Bone Density / Bone Loss / Eating Disorder1
0RecruitingTreatmentCancer, Breast1
1CompletedNot AvailableHealthy Volunteers1
1CompletedBasic ScienceHealthy Volunteer, Female, Breast1
1CompletedBasic ScienceHypersensitivity, Delayed / Immune Tolerance/Drug Effects / Immunosuppression / Ultraviolet Rays1
1CompletedTreatmentHealthy Volunteers1
1CompletedTreatmentImpaired Renal Function1
1CompletedTreatmentPostmenopausal Osteoporosis (PMO)1
1CompletedTreatmentBone destruction1
1RecruitingPreventionArthroplasty, Replacement, Hip1
1RecruitingPreventionBreast Cancer Prevention / Mammographic Density1
1RecruitingPreventionHealthy People1
1TerminatedTreatmentBone destruction / One to five years postmenopausal / Osteopenia / Rheumatoid Arthritis1
1WithdrawnPreventionDisorder Related to Bone Marrow Transplantation1
1, 2CompletedTreatmentBone Cyst Aneurysmal / Pathological Fractures / Recurrent Disease / Refractory Tumors1
1, 2Not Yet RecruitingTreatmentBone destruction / Dermatomyositis / Glucocorticoid-induced Osteoporosis / Polyarthritis / Rheumatoid Arthritis, Juvenile / Systemic Lupus Erythematosus (SLE) / Vasculitis1
1, 2RecruitingTreatmentCrohn's Disease (CD)1
1, 2RecruitingTreatmentMelanoma / Melanoma Stage Iii / Melanoma Stage Iv1
2Active Not RecruitingTreatmentBenign GCT / Cancers / GCT / Giant Cell Tumors of Bone1
2Active Not RecruitingTreatmentCancer, Breast2
2Active Not RecruitingTreatmentChildhood Osteosarcoma / Metastatic Bone Sarcomas / Recurrent Osteosarcoma / Stage IV Osteosarcoma AJCC v7 / Stage IVA Osteosarcoma AJCC v7 / Stage IVB Osteosarcoma AJCC v71
2Active Not RecruitingTreatmentEarly Stage Breast Cancer1
2Active Not RecruitingTreatmentInfertilities / Sperm / Testis1
2Active Not RecruitingTreatmentNeoplasms, Breast1
2Active Not RecruitingTreatmentBone destruction1
2CompletedPreventionAmbulation Difficulty / Osteoarthritis, Hip1
2CompletedSupportive CareBone Metastases in Subjects With Advanced Breast Cancer / Cancer, Breast / Metastases1
2CompletedTreatmentCancer, Breast / Endocrine Cancer / Head and Neck Carcinoma / Hypercalcemia of Malignancy / Lung Cancer Non-Small Cell Cancer (NSCLC) / Lung Cancers / Lymphoma, Hodgkins / Malignant Lymphomas / Malignant Neoplasm of Colon / Metastatic Cancers / Multiple Myeloma (MM) / Non-Hodgkin's Lymphoma (NHL) / Parathyroid Neoplasms / Renal Cancers / Thyroid Cancers1
2CompletedTreatmentGCT / Giant Cell Tumors of Bone1
2CompletedTreatmentLow Bone Mineral Density1
2CompletedTreatmentLow Bone Mineral Density / Postmenopausal Osteoporosis (PMO)1
2CompletedTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
2CompletedTreatmentOsteogenesis Imperfecta1
2CompletedTreatmentPostmenopausal Osteoporosis (PMO)1
2CompletedTreatmentRelapsed or Plateau-Phase Multiple Myeloma1
2CompletedTreatmentRheumatoid Arthritis1
2CompletedTreatmentBone destruction / Thalassemia Major (TM)1
2CompletedTreatmentBone destruction1
2Enrolling by InvitationTreatmentBone Diseases / Pain1
2Not Yet RecruitingBasic ScienceNeoplasms, Breast1
2Not Yet RecruitingPreventionBone destruction / Type 2 Diabetes Mellitus1
2Not Yet RecruitingTreatmentBone Giant Cell Tumor1
2RecruitingPreventionAdult Idiopathic Generalized Osteoporosis1
2RecruitingPreventionOsteolysis1
2RecruitingTreatmentAcute Gouty Arthritis1
2RecruitingTreatmentAneurysmal Bone Cysts / Chondroblastoma / Chondromyxoid Fibroma / Giant Cell Granuloma / Osteoblastoma1
2RecruitingTreatmentBladder Cancers / Renal Cancers / Transitional Cell Carcinoma / Ureteral Cancer1
2RecruitingTreatmentBreast Carcinoma Metastatic in the Bone / Circulating Tumor Cell Count / Estrogen Receptor Positive / HER2/Neu Negative / Progesterone Receptor Positive / Stage IV Breast Cancer1
2RecruitingTreatmentCalcific Aortic Stenosis1
2RecruitingTreatmentCancer, Breast1
2RecruitingTreatmentCutaneous Melanoma / Melanoma / Melanoma (Skin) / Melanoma Stage Iii / Melanoma Stage Iv1
2RecruitingTreatmentHER2 Positive Breast Cancers / Inflammatory carcinoma of the breast / Invasive Ductal Breast Carcinoma / Malignant Neoplasm of Female Breast / Mucinous Breast Cancer Stage II / Tubular Breast Cancer Stage II / Tubular Breast Cancer Stage III1
2RecruitingTreatmentHands Osteoarthritis1
2RecruitingTreatmentLangerhans Cell Histiocytosis (LCH)1
2RecruitingTreatmentMale Infertility1
2RecruitingTreatmentMetastatic Kidney Cancer / Renal Cell Carcinoma, Clear Cell1
2RecruitingTreatmentMultiple Myeloma (MM)1
2RecruitingTreatmentRevision Surgery of Total Hip Arthroplasty1
2RecruitingTreatmentRheumatoid Arthritis1
3Active Not RecruitingSupportive CareBone Metastases / Cancers / Malignancies, Hematologic / Multiple Myeloma (MM) / Multiple Myeloma Bone Lesions / Oncology1
3Active Not RecruitingSupportive CareCancer, Breast1
3Active Not RecruitingTreatmentNon-small Cell Lung Cancer (NSCLC), Stage IV1
3CompletedPreventionHormone Refractory Prostate Cancer1
3CompletedSupportive CareBone Metastases3
3CompletedSupportive CareBone destruction / Cancers / Cataracts / Low Bone Mineral Density / Osteopenia / Prostate Cancer1
3CompletedSupportive CareBone destruction / Low Bone Mass / Low Bone Mineral Density / Postmenopausal Osteoporosis (PMO)1
3CompletedTreatmentBone Metastases in Men With Hormone-Refractory Prostate Cancer / Bone Metastases in Subjects With Advanced Breast Cancer1
3CompletedTreatmentCancers / Carcinoma NOS / Castrate-resistant Prostate Cancer (CRPC) / Prostate Cancer / Tumors1
3CompletedTreatmentCastrate-resistant Prostate Cancer (CRPC)1
3CompletedTreatmentBone destruction / Chronic Kidney Disease (CKD)1
3CompletedTreatmentFractures, Bone1
3CompletedTreatmentGlucocorticoid-induced Ostepor / Steroid-induced Osteopor / Steroid-induced Osteopor, Glucocorticoid-induced Ostepor / Steroid-induced Osteopor., Glucocorticoid-induced Ostepor1
3CompletedTreatmentBone destruction / Low Bone Mass / Low Bone Mineral Density / Males With Osteoporosis / Osteopenia1
3CompletedTreatmentBone destruction / Low Bone Mineral Density / Osteopenia1
3CompletedTreatmentBone destruction / Osteopenia2
3CompletedTreatmentPostmenopausal Osteoporosis (PMO)7
3CompletedTreatmentBone destruction4
3Enrolling by InvitationTreatmentParathyroid Adenomas / Parathyroid Hyperplasia / Primary Hyperparathyroidism1
3Not Yet RecruitingTreatmentBone destruction / Thalassemia Majors (Beta-Thalassemia Major)1
3RecruitingPreventionCancer, Breast1
3RecruitingPreventionGiant Cell Tumors of Bone1
3RecruitingSupportive CareBone Metastases / Metastatic Breast Cancer (MBC) / Metastatic Hormone Refractory Prostate Cancer1
3RecruitingSupportive CareMetastatic Renal Cell Carcinoma1
3RecruitingTreatmentCharcot Joint of Foot1
3RecruitingTreatmentEvaluate the Safety and Efficacy of Denosumab in Pediatric Subjects With / Glucocorticoid-induced Osteoporosis1
3RecruitingTreatmentOsteogenesis Imperfecta1
3RecruitingTreatmentOsteogenesis Imperfecta (OI)1
3RecruitingTreatmentBone destruction / Systemic Mastocytosis1
3RecruitingTreatmentBone destruction1
3TerminatedTreatmentCancer, Breast1
4Active Not RecruitingTreatmentPostmenopausal Osteoporosis (PMO)2
4CompletedPreventionBone Resorption1
4CompletedPreventionOsteoarthritis, Hip1
4CompletedTreatmentMetabolic Bone Disease1
4CompletedTreatmentPost Menopausal Osteoporosis1
4CompletedTreatmentPostmenopausal Osteoporosis (PMO)1
4CompletedTreatmentPrimary Hyperparathyroidism1
4CompletedTreatmentRheumatoid Arthritis1
4CompletedTreatmentBone destruction2
4Not Yet RecruitingTreatmentFemale With Osteoporosis and Chronic Kidney Disease1
4Not Yet RecruitingTreatmentBone destruction / Postmenopausal Osteoporosis (PMO)1
4RecruitingDiagnosticPostmenopausal Osteoporosis (PMO) / Type 2 Diabetes Mellitus1
4RecruitingTreatmentCancer, Breast / Metastasis / Prostate Cancer1
4RecruitingTreatmentBone destruction / Osteoporotic Fractures / Postmenopausal Osteoporosis (PMO)1
4RecruitingTreatmentSecondary Osteoporosis / Spinal Cord Injuries (SCI)1
4RecruitingTreatmentBone destruction / Spinal Cord Injuries (SCI)1
4RecruitingTreatmentBone destruction2
4SuspendedTreatmentBone Marrow Oedema Syndrome / High Turnover Bone Disease / Quality of Life1
4WithdrawnNot AvailableMetastatic Bone Disease / Tumors, Solid1
Not AvailableActive Not RecruitingNot AvailablePost Menopausal Osteoperosis, Male Osteoperosis1
Not AvailableActive Not RecruitingNot AvailablePost Menopausal Osteoporosis1
Not AvailableCompletedNot AvailableBone destruction / Fractures, Bone1
Not AvailableCompletedNot AvailablePostmenopausal Osteoporosis (PMO)1
Not AvailableCompletedTreatmentPostmenopausal Osteoporosis (PMO)1
Not AvailableCompletedTreatmentRheumatoid Arthritis1
Not AvailableNot Yet RecruitingNot AvailableGiant Cell Tumors of Bone1
Not AvailableRecruitingNot AvailableBone destruction1
Not AvailableTerminatedTreatmentProstate Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
InjectionSubcutaneous60 mg/1mL
SolutionSubcutaneous60 mg
InjectionSubcutaneous120 mg/1.7mL
Injection, solutionSubcutaneous120 mg
SolutionSubcutaneous120 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2257247No2012-09-112018-04-15Canada
CA2274987No2012-01-242017-12-22Canada
CA2285746No2010-09-282018-04-15Canada
CA2400929No2011-05-312021-02-23Canada
CA2328140No2012-03-132019-05-13Canada

Properties

State
Solid
Experimental Properties
Not Available

Taxonomy

Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antibody
General Function
Tumor necrosis factor receptor superfamily binding
Specific Function
Cytokine that binds to TNFRSF11B/OPG and to TNFRSF11A/RANK. Osteoclast differentiation and activation factor. Augments the ability of dendritic cells to stimulate naive T-cell proliferation. May be...
Gene Name
TNFSF11
Uniprot ID
O14788
Uniprot Name
Tumor necrosis factor ligand superfamily member 11
Molecular Weight
35477.81 Da
References
  1. Lipton A, Jun S: RANKL inhibition in the treatment of bone metastases. Curr Opin Support Palliat Care. 2008 Sep;2(3):197-203. doi: 10.1097/SPC.0b013e32830baac2. [PubMed:18685421]
  2. Westenfeld R, Ketteler M, Brandenburg VM: Anti-RANKL therapy--implications for the bone-vascular-axis in CKD? Denosumab in post-menopausal women with low bone mineral density. Nephrol Dial Transplant. 2006 Aug;21(8):2075-7. Epub 2006 May 15. [PubMed:16702197]

Drug created on March 19, 2008 10:43 / Updated on September 25, 2018 00:40