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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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