1. DB06643
Denosumab
C6404H9912N1724O2004S50
144.7 kDa
CATEGORY
Bone Density Conservation Agents
Monoclonal antibodies

2. 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
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.

3. 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.

4. 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.
HALF LIFE days

5. 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
TARGET
Tumor necrosis factor ligand superfamily member 11

6. BRAND NAMES INDICATION
Prolia
Amgen
Ranmark
Daiichi Sankyo
Xgeva
INDICATION
Prolia® (denosumab) is a prescription medicine used to treat osteoporosis in women after menopause who: are at high risk for fracture, meaning women who have had a fracture related to osteoporosis, or who have multiple risk factors for fracture
cannot use another osteoporosis medicine or other osteoporosis medicines did not work well

7. PRECAUTION
Do not take Prolia® if you: have low blood calcium; or are pregnant or plan to become pregnant, as Prolia® may harm your unborn baby; or are allergic to denosumab or any ingredients in Prolia®
ADVERSE REACTIONS
Serious allergic reactions
Low blood calcium (hypocalcemia)
Severe jaw bone problems (osteonecrosis)
Unusual thigh bone fractures
Serious infections
Skin problems
Bone, joint, or muscle pain

8. ADVANTAGES
2 shots of Prolia® (denosumab) a year are proven to help women with postmenopausal osteoporosis at high risk for fracture strengthen their bones.
Prolia® is a prescription medicine used to treat osteoporosis (thinning and weakening of bone) in women after menopause who:
are at high risk for fracture, meaning women who have had a fracture related to osteoporosis, or who have multiple risk factors for fracture
cannot use another osteoporosis medicine or other osteoporosis medicines did not work well.
Prolia® isn't right for everyone. Do not take Prolia® if you: have low blood calcium; or are pregnant or plan to become pregnant, as Prolia® may harm your unborn baby; or are allergic to denosumab or any ingredients in Prolia®. You should take calcium and vitamin D as your doctor tells you to while you receive Prolia®. Talk to your doctor to see if Prolia® is right for you.

9. DRUG INTERACTIONS
Abatacept
Monitor therapy due to enhanced effects of immunosuppressants and the risk of serious infections.
Antithymocyte globulin
Monitor therapy because of the enhanced immunosuppressive effect and increased risk of infections.
Belatacept
Montinor therapy due to enhanced adverse effects of immunosuppressants and the risk of infections.
Belimumab
Belimumab increases the immunosupressive effect. Interaction is significant so monitor closely.
Etanercept
Monitor therapy as there may be an enhanced immunosuppressive effect.
Gemtuzumab ozogamicin Monitor therapy due to enhanced adverse effects of immunosuppressants including the risk of infections.
Glatiramer Acetate Monitor therapy due to enhanced immunosuppressive effects and the risk of infections.
Ibritumomab Monitor therapy for enhanced immunosuppressive effects and increased risk of infections.
Infliximab Therapy should be monitored when combination is initiated as there may be an increase in serious infections.
Obinutuzumab Monitor therapy due to increased risk of infections due to adverse effects of immunosuppressants.
Omalizumab Monitor therapy due to increased risk of infections consequent to increased adverse effects of immunosuppressants.
Pegaspargase Monitor therapy due to increased immunosuppressive effect and risk of infections.

10. Pralatrexate
Increased immunosuppresive effects and risk of infection. Monitor for adverse effects .
Rilonacept
Use caution with patients on concomitant immunosuppressants or those with compromised immune systems; increased risk of serious infection.
Tofacitinib
Denosumab, when used in combination with tofacitinib, may increase tofaciitinib toxicity and worsen side effects. It may specifically increase the risk of serious infection. It is recommended to monitor therapy.

11. SEQUENCE
> Denosumab αOPGL-1 heavy chain sequence
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSGITGSGGSTYY
ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDPGTTVIMSWFDPWGQGTLVTV
SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ
SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELL
GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ
YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR
DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS
RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
> Denosumab αOPGL-1 light chain sequence
EIVLTQSPGTLSLSPGERATLSCRASQSVRGRYLAWYQQKPGQAPRLLIYGASSRATGIP
DRFSGSGSGTDFTLTISRLEPEDFAVFYCQQYGSSPRTFGQGTKVEIKRTVAAPSVFIFP
PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL
TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

12. PATENTS
Country Patent Number Approved Expires (estimated)
Canada
Canada
Canada
Canada
Canada

13. REFERENCES
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 Dec;114(6): doi: /j.oooo