5/6/2012

XGEVA® (denosumab) What is important for pharmacists to know ?

Prof. Dr. Irene Krämer University Medical Center Mainz Pharmacy Department

Vicious cycle in osteolytic bone metastasis

Mandeep SV, Lieberman JR. Arthritis Research & Therapy. 2007;Suppl 1:S5

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Denosumab-containing medicinal products

Prolia® (denosumab) XGEVA® (denosumab)

Dose 60 mg SC 120 mg SC

Regimen Every 6 months Every 4 weeks

Indication(s) Treatment of bone loss associated with Prevention of skeletal related events hormone ablation in men with prostate (pathological fracture, radiation to cancer at increased risk of fractures1 bone, spinal cord compression or Treatment of osteoporosis in surgery to bone) in adults with bone postmenopausal women at increased metastases from solid tumours2 risk of fractures1

1. Prolia® (denosumab) prescribing information, Amgen. 2. XGEVA® (denosumab) prescribing information, Amgen.

Denosumab (120 mg) – Solution for sub cutaneous (s.c.) injection

. Denosumab = full-length human monoclonal IgG2 antibody produced in CHO cell line by recombinant DNA technology which targets and binds to RANKL • 2 heavy chains with 448 amino acids, 4 intramolecular disulfides, N-linked glycan • 2 light chains with 215 amino acids 2 intramolecular disulfides . Each vial contains 120 mg of denosumab in 1.7 ml of solution (70 mg/ml) . Excipients • Acetic acid, Sodium hydroxide (for pH adjustment), Sorbitol 78 mg • Water for injections

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SC administration with denosumab

Feature Denosumab SC administration in thigh, abdomen, upper arm under the responsibility of a  healthcare professional No need for IV access Reduced time consumption and  costs

Inject slowly the entire contents of the vial with a 27 gauge needle  convenient for patients

Handling practice . Storage • Store in a refrigerator (2˚C – 8˚C), do not freeze • Protect from light • Solution may contain trace amounts of translucent to white proteinaceous particles • Do not shake excessively

. Shelf life • 3 years under refrigeration • Up to 30 days at room temperature (25˚C) in the original container

XGEVA™ (denosumab), Summary of Product Characteristics, 2011.

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Which of the following therapies is currently used for the treatment and prevention of chemotherapy-induced bone-loss?

. Vitamin D and calcium

. Zoledronic acid

. Denosumab

. All of the above

Denosumab – SRE Efficacy results

Lipton et al. Poster presented at ESMO 2010

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Denosumab – SRE Efficacy

700 608 600 584 494 500 474 436 392 400

300 Number of SREs of Number 200

100

0 Breast cancer Prostate cancer Other solid tumours / multiple myeloma Denosumab Zoledronic acid

Denosumab demonstrates efficacy in the treatment of bone metastases in patients with advanced breast cancer, advanced prostate cancer and in multiple myeloma and other solid tumours1-3

1. Fizazi et al. Lancet. 2011;377:813–822. 2. Henry et al. J Clin Oncol. 2011;29:1125–1132. 3. Stopeck et al. J Clin Oncol. 2010;28:5132-5139.

Denosumab – No dose adjustments

. Patients with renal impairment • Denosumab is not eliminated via the kidneys • No dose adjustment • Not studied in dialysis patients . Patients with hepatic impairment • Denosumab not believed to be eliminated via hepatic metabolic mechanisms, rather via immunoglobulin clearance pathways • Safety and efficacy not studied . Elderly patients (age ≥ 65) • No dose adjustment . Paediatric population • Not recommended in paediatric patients (age < 18)

XGEVA™ (denosumab), Summary of Product Characteristics, 2011. Burkiewicz JS, et al. Ann Pharmacother. 2009;43:1445–55. Lewiecki EM. Expert Opin Biol Ther. 2006;6:1041–50.

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Denosumab – Tolerability

. Risk of Hypocalcaemia • Supplementation with ≥500 mg calcium + 400 IU Vit D unless hypercalcaemia • Correct hypocalcaemia before starting treatment . Risk of ONJ • Oral examination before starting treatment • Avoid invasive dental procedures during treatment . Do not use together with • Prolia® (denosumab 60 mg every 6 months) • Bisphosphonates

Lipton et al. J Clin Oncol. 2007;25:4431-4437. XGEVA™ (denosumab), Summary of Product Characteristics, 2011. .

Denosumab – Tolerability . Renal monitoring is not required, unlike zoledronic acid

. Renal adverse events • 9.2% denusomab 120 mg 4 weekly • 11.8% zoledronic acid 4 mg 4 weekly

. Acute phase reaction adverse events • 8.7% 120 mg 4 weekly • 20.2% zoledronic acid 4 mg 4 weekly

Fizazi et al. Lancet. 2011;377:813-822. Henry DH. J Clin Oncol. 2011;29:1125-1132. Stopeck et al. J Clin Oncol . 2010;28:5132-5139.

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Denosumab – Adverse reactions in clinical studies

MedDRA system organ class Frequency category Adverse reactions

Infections Uncommon Cellulitis Immune system disorder Uncommon Drug hypersensitivity Metabolism and nutrition Common Hypocalcaemia disorders Common Hypophosphataemia Respiratory, thoracic and Very common Dyspnoea mediastinal disorders Gastrointestinal disorders Very common Diarrhoea Skin and subcutaneous tissues Common Tooth extraction disorders Common Hyperhidrosis Musculoskeletal and Common Osteonecrosis of the jaw connective tissue disorders

Denosumab exhibits a favorable safety profile (EPAR, SPC)

XGEVA™ (denosumab), Summary of Product Characteristics, 2011

XGEVA™ EPAR, EMA, 2011

Which is your most important consideration, when choosing medicinal products for prevention of SREs?

. Ease of administration

. Cost

. Efficacy

. Safety

. Impact on quality of life

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Denosumab – Cost-Considerations

. Patients with bone metastases often experience SREs that • have a significant effect on quality of life • require significant use of healthcare resources • are associated with substantial increases in healthcare costs

Therapies that Cost assumptions (€) reduce the risk Cost of XGEVA 307 of SREs are Cost of zoledronic acid 256 likely to improve Cost of SC injection 0.23 patients’ lives Cost of IV infusion 100 and reduce Physician office visit 79 health resource Serum creatinine test 2.20 use Average SRE cost 4135

Delea et al. J Support Oncol. 2006;4:341-347; Schulman et al. Cancer. 2007;109:2334-2342; Pockett et al. Eur J Cancer Care. 2009. Delea et al. Oncology. 2004;67:390-396.

Denosumab – Cost-Effectiveness . Cost data from The Netherlands and efficacy data from phase 3 studies

Incremental cost of Denosumab per SRE avoided (€)

Breast cancer 1644

Prostate cancer 3475

Other solid tumours 690

Denosumab is cost effective

Lothgren et al. ISPOR EU 2011

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Denosumab – Cost-Utility-Analysis . Health utility data (EQ-5D) obtained from phase 3 studies

Cost per QALY (€)

Breast cancer 26 524

Prostate cancer 44 622

Other solid tumours 11 660

Lothgren et al. ISPOR EU 2011

Which agents do you stock in the hospital pharmacy for the treatment of bone metastases?

. Zoledronic acid?

. Pamidronic acid?

. Denosumab?

. Both bisphosphonates?

. One bisphosphonate and denosumab?

. Both bisphosphonates and denosumab?

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Denosumab – Hospital Formulary . First approved RANKL Inhibitor . Denosumab demonstrated superior efficacy in the prevention of SRE's over zoledronic acid . s.c. administration . Denosumab exhibits a favorable safety profile . Use in patients which can not tolerate bisphosphonates . Efficacy in patients who are refractory to IV bisphosphonates . Favourable cost-benefit-relationship

Lipton et al. Poster presented at ESMO, Milan 2010. Fizazi K, et al. Lancet. 2011;377:813-822. Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139. Muir, Scott. BioDrugs. 2010;24:379-386. Fizazi K, et al. Lancet. 2011;377:813-822.

Denosumab – Hospital Pharmacist’s duties

. First ensure delivery . Ensure good handling

. Inform cancer patients about bone targeted therapy . Educate denosumab patients in oral care . Ensure compliance of denosumab patients

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