Denosumab

A COMPREHENSIVE REVIEW OF DENOSUMAB WITH AVAILABLE DATA TILL DATE

1. DONESUMAB DENOSUM B Dr.sandeep

2. NEWER DRUG

3. What is it ? Mechanism of action ? Uses ? Side effects ? Contra indications ? Adverse drug reactions ? Cost ? , availability ? Current recommendations ?

4. What is it ? Monoclonal antibody ( IgG2 ) Developed by AMGEN On 2 June 2010, DENOSUMAB was approved by ( FDA) for use in postmenopausal women with risk of osteoporosis  under the trade name   Prolia ,  and in November 2010, as  Xgeva , for the prevention of skeleton-related events in patients with bone metastases from solid tumors .

5. Denosumab is the first  RANKL inhibitor to be approved by the FDA. On 13 June 2013, the US FDA approved D enosumab for treatment of adults and skeletally mature adolescents with Giant cell tumor of bone that is unresectable or where resection would result in significant morbidity.

6. MECHANISM OF ACTION

7. PROLIA

8. USES Treatment of postmenopausal women with osteoporosis at high risk for fracture Treatment to increase bone mass in men with osteoporosis at high risk for fracture Treatment of glucocorticoid -induced osteoporosis in men and women at high risk for fracture

9. Treatment to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for non-metastatic prostate cancer Treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer

10. DOSAGE AND ADMINISTRATION Pregnancy must be ruled out prior to administration of Prolia Prolia should be administered by a healthcare professional Administer injection every 6 months as a subcutaneous injection in the upper arm, upper thigh, or abdomen Instruct patients to take calcium 1000 mg daily and at least 400 IU vitamin D daily

11. DOSAGE AND STRENGTH Single-use prefilled syringe containing 60 mg in a 1 mL solution

12. CONTRAINDICATIONS Hypocalcemia Pregnancy Known hypersensitivity to Prolia

13. WARNING AND PRECAUTIOS Same Active Ingredient: Patients receiving Prolia should not receive XGEVA Hypersensitivity including anaphylaxis Hypocalcemia : Must be corrected before initiating Prolia . May worsen, Especially in patients with renal impairment. Adequately supplement Patients with calcium and vitamin D Osteonecrosis of the jaw: Has been reported with Prolia .

14. Atypical femoral fractures Multiple vertebral fractures Serious infections including skin infections Dermatologic reactions: Dermatitis, rashes, and eczema have been reported . Severe bone, joint, muscle pain may occur. Suppression of bone turnover

15. ADVERSE DRUG REACTIONS Postmenopausal osteoporosis: 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 Male osteoporosis: Most common adverse reactions (> 5% and more common than placebo) were: back pain, arthralgia , and nasopharyngitis Glucocorticoid -induced osteoporosis: Most common adverse reactions (> 3% and more common than active-control group) were: back pain, hypertension , bronchitis, and headache Bone loss due to hormone ablation for cancer: 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

16. XGEVA

17. INDICATIONS AND USE Prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors. Treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity. Treatment of hypercalcemia of malignancy

18. DOSAGE AND ADMINISTRATION Multiple Myeloma and Bone Metastasis from Solid Tumors: Administer 120 mg every 4 weeks as a subcutaneous injection in the upper arm, upper thigh, or abdomen. Giant Cell Tumor of Bone: Administer 120 mg every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy. Hypercalcemia of Malignancy: Administer 120 mg every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy .

19. DOSAGE FORMS AND STRENGTHS Injection: 120 mg/1.7 mL (70 mg/ mL ) solution in a single-dose vial

20. WARNING SYMPTOMS AND PRECAUTIONS Hypersensitivity reactions including anaphylaxis may occur . Hypocalcemia : Xgeva can cause severe symptomatic hypocalcemia , and fatal cases have been reported. Correct hypocalcemia prior to initiating Xgeva . Monitor calcium levels during therapy, especially in the first weeks of initiating therapy, and adequately supplement all patients with calcium and vitamin D.

21. Osteonecrosis of the jaw (ONJ) has been reported in patients receiving Xgeva Atypical femoral fracture Hypercalcemia Following Treatment Discontinuation in Patients with Giant Cell Tumor of Bone and in Patients with Growing Skeletons: Monitor patients for signs and symptoms of hypercalcemia , and manage as clinically appropriate.

22. Multiple Vertebral Fractures (MVF) Following Treatment Discontinuation: When Xgeva treatment is discontinued, evaluate the individual patient’s risk for vertebral fractures. Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to the fetus and to use effective contraception.

23. ADVERSE REACTIONS Bone Metastasis from Solid Tumors: Most common adverse reactions ( ≥ 25%) were fatigue/asthenia, hypophosphatemia , and nausea. Multiple Myeloma: Most common adverse reactions (≥ 10%) were diarrhea , nausea, anemia, back pain, thrombocytopenia, peripheral edema , hypocalcemia , upper respiratory tract infection, rash, and headache .

24. Giant Cell Tumor of Bone: Most common adverse reactions (≥ 10%) were arthralgia , headache, nausea, back pain, fatigue, and pain in extremity. Hypercalcemia of Malignancy: Most common adverse reactions (> 20%) were nausea, dyspnea , decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea.

25. DENOSUMAB IN GCT GCT : locally aggressive benign neoplasm Malignant transformation with out radiotherapy is uncommon and occurs in less than 1% of cases Decrease in activity and control of symptoms Malignant transformation is seen mostly following radiation therapy

26. To enhance surgeons ability to perform joint preserving intralesional surgery with an acceptable low risk of recurrence

27. Sample : 20 adults with recurrent / unresectable GCT Dosage : SC Denosumab 120 mg every 4 wks (with additional doses on day 8 and day 15 ) End point : 90 % or more elimination of giant cells from tumour 100% subjects achieved end point . 65 % increased portion of RANKL- positive stromal cells replaced by dense fibro-osseous tissue / new owen bone

28. CASE REPORT

29. JULY 2009

30. SEPT 2009

31. 1 year later

32. AUG 2010

33. JAN 2013

34. MAY 2013 DENOSUMAB started 360 mg subcutaneous dose Followed by 120 mg every month

35. OCT 2013

36. Pain around knee joint diminished Further resection ?? Patient refused Clinical improvement persisted until jan 14 Presented with Rapidly growing painful palpable mass Open biopsy : high grade sarcoma A/K amputation

37. CASE 1

38. CASE 2

39. CASE 3

40. CASE 4

41. CASE 5

42. RESULTS 54 patients with 30 primary and 25 recurrent tumours 17 patients treated with out denosumab 6 doses before surgery ( planned arbitrarily) Clinical improvement in all (3 to 4 doses) 3 doses prior in whom surgery was planned

43. 14 recurrences out of 37 curetted tumours(38%) 11 of 25 patients in donesumab -treated curettage group had recurrences (44%) compared with 7 of 34 (21%) in the non denosumab -treated control group : not significant No recurrence in the resection group One malignant transformation in a pt with proximal humeral GCT. Denosumab reduces risk of recurrence ???? Further trials needed !!!!!!

44. SOURCES Freedome trial Freedome extension trial Luis et.al case report Mainsh et.al article on Denosumab in GCT Xu et.al Denosumab in GCT review AMGEN annual Denosumab update

45. THANK OU