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Prolia (denosumab) Manufacturer: Amgen FDA Approval June 2010 Prolia / denosumab Drug Facts • Pharmacology • Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-kappa B ligand (RANKL). RANKL is a mediator of osteoclast formation, function, and survival. RANKL binds to its receptor (RANK) on the surface of precursor and mature osteoclasts, and stimulates these cells to mature and resorb bone. Denosumab binds with high specificity and affinity to RANKL, inhibiting osteoclast-mediated bone resorption & osteoclast maturation and survival. Prolia / denosumab Clinical Application • Indications: • Treatment and prevention of osteoporosis in postmenopausal women • Place in therapy: • Second-line therapy to bisphosphonates and in high-risk patients due to cost considerations and limited long-term exposure data. Prolia / denosumab Clinical Application • Contraindications: • Known hypersensitivity to denosumab or any of its components • Warnings and Precautions • Serious Infection • Hypocalcemia • Dermatologic Reactions • Osteonecrosis of the Jaw Prolia / denosumab Drug Facts Prolia / denosumab Drug Facts Prolia / denosumab Drug Facts • Pharmacokinetics Bioavailability is probably near 100%. Denosumab has A exhibited nonlinear, dose-dependent pharmacokinetics Following subcutaneous administration, denosumab serum levels are detectable as early as 1 hour after administration D and reach maximum serum concentrations between 3 and 29 days Most likely by the reticuloendothelial system. The mean M half-life is 25 to 46 days Due to the large molecule size, little, if any, intact E denosumab is filtered and excreted by the kidneys Prolia / denosumab Drug Interactions • Drug Interactions • None known Prolia / denosumab Adverse Effects • Common Adverse Effects FREEDOM trial Denosumab (%) Placebo (%) Infection 52.9 54.4 Cancer 4.8 4.3 Falling 4.5 5.7 Eczema 3.0 1.7 Flatulence 2.2 1.4 Cellulitis 0.3 <0.1 Concussion <0.1 0.3 Prolia / denosumab Adverse Effects • Serious Adverse Effects • Osteonecrosis of the jaw • Hypocalcemia • Serious infections • Dermatologic reactions Prolia / denosumab Monitoring Parameters • Efficacy Monitoring • Clinical trials monitored BMD at various sites, including lumbar spine, total hip, femoral neck, and distal third of radius • Incidence of fractures • Toxicity Monitoring • Hypersensitivity reactions • Serum calcium Prolia / denosumab Prescription Information • Dosing • 60 mg subcutaneously every 6 months • Cost • Alendronate 70 mg = $355/year • Zoledronic acid 4 mg IV = $1000/year • Prolia = estimated at $1700 per year (AWP) Pricing from drugstore.com Prolia / denosumab Trial Information Denosumab for Prevention of Fractures in Postmenopausal Women with Osteoporosis Objective • Examine the effect of denosumab on the risk of fracture in postmenopausal women with osteoporosis Trial Design • International, randomized, placebo-controlled, Phase III trial • 7868 women were enrolled in the study, 3933 in the denosumab group and 3935 in the placebo group Cummings SR, et al. N Engl J Med 2009;361:756-65. Prolia / denosumab Trial Information Inclusion Criteria • Women between the ages of 60 and 90 • Bone mineral density T score of less than −2.5 at the lumbar spine or total hip Cummings SR, et al. N Engl J Med 2009;361:756-65. Prolia / denosumab Trial Information Exclusion Criteria • Taken oral bisphosphonates for more than 3 years • If they had taken bisphosphonates for less than 3 years, they were eligible after 12 months without treatment • Intravenous bisphosphonates, fluoride, or strontium for osteoporosis within the past 5 years • Use of parathyroid hormone or its derivatives, corticosteroids, systemic hormone-replacement therapy, selective estrogen-receptor modulators, or tibolone, calcitonin, or calcitriol within 6 weeks • Bone mineral density T score of less than −4.0 at the lumbar spine • Total hip or any severe (or more than two moderate) prevalent vertebral fractures • Serum 25-hydroxyvitamin D level of less than 12 ng/milliliter Cummings SR, et al. N Engl J Med 2009;361:756-65. Prolia / denosumab Trial Information Intervention • 60 mg SQ injection of denosumab or placebo every 6 months • All women received daily supplements containing at least 1000 mg of calcium. Subjects with a baseline 25- hydroxyvitamin D level of 12 to 20 ng/ml were given at least 800 IU of vitamin D daily, and those with a baseline level above 20 ng/ml were given at least 400 IU daily Treatment duration • 36 months Cummings SR, et al. N Engl J Med 2009;361:756-65. Prolia / denosumab Trial Information Primary Efficacy Endpoint • New vertebral fracture Secondary Efficacy Endpoints • Time to first nonvertebral fracture • Time to first hip fracture • Safety endpoints • Deaths and serious adverse events related to CV disease • Hypocalcemia • Osteonecrosis of the jaw Cummings SR, et al. N Engl J Med 2009;361:756-65. Prolia / denosumab Trial Information Endpoints: denosumab(%) placebo(%) ARR NNT P-value 1o New Vertebral Fracture 86 (2.3) 264 (7.2) 4.9 20 <0.001 Cummings SR, et al. N Engl J Med 2009;361:756-65. Prolia / denosumab Trial Information Endpoints: denosumab(%) placebo(%) ARR NNT P-value 2o Nonvertebral Fracture 238 (6.5) 293 (8.0) 1.5 67 0.01 Hip Fracture 26 (0.7) 43 (1.2) 0.5 200 0.04 Cummings SR, et al. N Engl J Med 2009;361:756-65. Prolia / denosumab Trial Information Summary of Adverse Events Cummings SR, et al. N Engl J Med 2009;361:756-65. Prolia / denosumab Trial Information Study Limitations: • Average hip and femoral neck BMD scores fall into the osteopenia category, NOT osteoporosis • No information provided on previous bisphophonate use at baseline Cummings SR, et al. N Engl J Med 2009;361:756-65. Prolia / denosumab Trial Information Trial Conclusions • Denosumab significantly reduced the incidence of new vertebral fractures in elderly women with a baseline T score < -2.5 at the lumbar spine, demonstrating an ARR of 4.9% and a RRR of 68%. • Denosumab had significantly higher rates of eczema, flatulence, and cellulitis when compared to placebo, though the rates of these adverse events was 3% or less. Cummings SR, et al. N Engl J Med 2009;361:756-65. Prolia / denosumab Summary • Prolia, denosumab, binds with high specificity and affinity to RANKL, inhibiting osteoclast- mediated bone resorption and osteoclast maturation and survival • Denosumab is administered subcutaneously every 6 months by a healthcare professional • Clinical trials show that denosumab decreases new vertebral fractures in postmenopausal women with osteoporosis Prolia / denosumab References 1. Cummings SR, et al. Denosumab for Prevention of Fractures in Postmenopausal Women with Osteoporosis. N Engl J Med 2009;361:756-65. 2. Lewiecki ME. Denosumab Update. Curr Opin Rheumatol 2009;21:369-73. 3. Lewiecki ME. RANK ligand inhibition with denosumab for the management of osteoporosis. Expert Opin Biol Ther 2006;6(10):1041-50. 4. Smith MR, et al. Denosumab in Men Receiving Androgen- Deprivation Therapy for Prostate Cancer. N Engl J Med 2009;361:745-55. 5. Prolia package insert. Thousand Oaks, CA: Amgen Manufacturing Ltd; 2010 June.
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