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Prolia (Denosumab) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Prolia (denosumab) is a human IgG2 monoclonal antibody with affinity and specificity for human RANKL (receptor activator of nuclear factor kappa-B ligand). Denosumab has an approximate molecular weight of 147 kDa and is produced in genetically engineered mammalian (Chinese hamster ovary) cells.

Prolia is a sterile, preservative-free, clear, colorless to pale yellow solution.

Each 1 mL single-use prefilled syringe of Prolia contains 60 mg denosumab (60 mg/mL solution), 4.7% sorbitol, 17 mM acetate, 0.01% polysorbate 20, Water for Injection (USP), and sodium hydroxide to a pH of 5.2.

Each 1 mL single-use vial of Prolia contains 60 mg denosumab (60 mg/mL solution), 4.7% sorbitol, 17 mM acetate, Water for Injection, (USP), and sodium hydroxide to a pH of 5.2.

CLINICAL PHARMACOLOGY

Mechanism of Action

Prolia binds to RANKL, a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption. Prolia 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.

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, with maximal reductions occurring by 1 month. CTX levels were below the limit of assay quantitation (0.049 ng/mL) in 39-68% of subjects 1-3 months after dosing of Prolia. At the end of each dosing interval, CTX reductions were partially attenuated from a maximal reduction of ≥ 87% to ≥ 45% (range: 45% to 80%), as serum denosumab levels diminished, reflecting the reversibility of the effects of Prolia on bone remodeling. These effects were sustained with continued treatment. Upon reinitiation, the degree of inhibition of CTX by Prolia was similar to that observed in patients initiating Prolia treatment.

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 [P1NP]), were observed starting 1 month after the first dose of Prolia. After discontinuation of Prolia therapy, markers of bone resorption increased to levels 40-60% above pretreatment values but returned to baseline levels within 12 months.

Pharmacokinetics

In a study conducted in healthy male and female volunteers (n = 73, age range: 18 to 64 years) following a single subcutaneously administered Prolia dose of 60 mg after fasting (at least for 12 hours), the mean maximum denosumab concentration (Cmax) was 6.75 mcg/mL (standard deviation [SD] = 1.89 mcg/mL). The median time to maximum denosumab concentration (Tmax) was 10 days (range: 3 to 21 days). After Cmax, serum denosumab concentrations declined over a period of 4 to 5 months with a mean half-life of 25.4 days (SD = 8.5 days; n = 46). The mean area-under-the-concentration-time curve up to 16 weeks (AUC0-16 weeks) of denosumab was 316 mcg·day/mL (SD = 101 mcg·day/mL).

No accumulation or change in denosumab pharmacokinetics with time was observed upon multiple dosing of 60 mg subcutaneously administered once every 6 months.

Prolia pharmacokinetics were not affected by the formation of binding antibodies.

A population pharmacokinetic analysis was performed to evaluate the effects of demographic characteristics. This analysis showed no notable differences in pharmacokinetics with age (in postmenopausal women), race, or body weight (36 to 140 kg).

Drug Interactions

No drug-drug interaction studies have been conducted with Prolia.

Specific Populations

Gender: Mean serum denosumab concentration-time profiles observed in a study conducted in healthy men ≥ 50 years were similar to those observed in a study conducted in postmenopausal women using the same dose regimen.

Age: The pharmacokinetics of denosumab was not affected by age across all populations studied whose ages ranged from 28-87 years.

Race: The pharmacokinetics of denosumab was not affected by race.

Renal Impairment: In a study of 55 patients with varying degrees of renal function, including patients on dialysis, the degree of renal impairment had no effect on the pharmacokinetics of denosumab; thus, dose adjustment for renal impairment is not necessary.

Hepatic Impairment: No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of denosumab.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity

The carcinogenic potential of denosumab has not been evaluated in long-term animal studies.

Mutagenicity

The genotoxic potential of denosumab has not been evaluated.

Impairment of Fertility

Denosumab had no effect on female fertility or male reproductive organs in monkeys at doses that were 13- to 50-fold higher than the recommended human dose of 60 mg administered once every 6 months, based on body weight (mg/kg).

Animal Toxicology and/or Pharmacology

Prolia is an inhibitor of osteoclastic bone resorption via inhibition of RANKL.

In ovariectomized monkeys, once-monthly treatment with denosumab suppressed bone turnover and increased bone mineral density (BMD) and strength of cancellous and cortical bone at doses 50-fold higher than the recommended human dose of 60 mg administered once every 6 months, based on body weight (mg/kg). Bone tissue was normal with no evidence of mineralization defects, accumulation of osteoid, or woven bone.

Adolescent primates treated with denosumab at doses > 10 times (10 and 50 mg/kg dose) higher than the recommended human dose of 60 mg administered once every 6 months, based on mg/kg, had abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab [see Use in Specific Populations ].

Because the biological activity of denosumab in animals is specific to nonhuman primates, evaluation of genetically engineered (“knockout”) mice or use of other biological inhibitors of the RANK/RANKL pathway, namely OPG-Fc, provided additional information on the pharmacodynamic properties of denosumab. RANK/RANKL knockout mice exhibited absence of lymph node formation, as well as an absence of lactation due to inhibition of mammary gland maturation (lobulo-alveolar gland development during pregnancy). Neonatal RANK/RANKL knockout mice exhibited reduced bone growth and lack of tooth eruption. A corroborative study in 2-week-old rats given the RANKL inhibitor OPG-Fc also showed reduced bone growth, altered growth plates, and impaired tooth eruption. These changes were partially reversible in this model when dosing with the RANKL inhibitors was discontinued [see Use in Specific Populations (8.1, 8.4)].

CLINICAL STUDIES

Postmenopausal Women with Osteoporosis

The efficacy and safety of Prolia in the treatment of postmenopausal osteoporosis was demonstrated in a 3-year, randomized, double-blind, placebo-controlled, trial. Enrolled women had a baseline BMD T-score between -2.5 and -4.0 at either the lumbar spine or total hip. Women with other diseases (such as rheumatoid arthritis, osteogenesis imperfecta, and Paget's disease) or on therapies that affect bone were excluded from this study. The 7808 enrolled women were aged 60 to 91 years with a mean age of 72 years. Overall, the mean baseline lumbar spine BMD T-score was -2.8 and 23% of women had a vertebral fracture at baseline. Women were randomized to receive SC injections of either placebo (N = 3906) or Prolia 60 mg (N = 3902) once every 6 months. All women received at least 1000 mg calcium and 400 IU vitamin D supplementation daily.

The primary efficacy variable was the incidence of new morphometric (radiologically-diagnosed) vertebral fractures at 3 years. Vertebral fractures were diagnosed based on lateral spine radiographs (T4-L4) using a semiquantitative scoring method. Secondary efficacy variables included the incidence of hip fracture and nonvertebral fracture, assessed at 3 years.

Effect on Vertebral Fractures

Prolia significantly reduced the incidence of new morphometric vertebral fractures at 1, 2, and 3 years (p < 0.0001), as shown in Table 2. The incidence of new vertebral fractures at year 3 was 7.2% in the placebo-treated women compared to 2.3% for the Prolia-treated women. The absolute risk reduction was 4.8% and relative risk reduction was 68% for new morphometric vertebral fractures at year 3.

Table 2. The Effect of Prolia on the Incidence of New Vertebral Fractures
Proportion of Women With Fracture (%) 1

Absolute Risk Reduction (%) 2

(95% CI)

Relative Risk Reduction (%)

(95% CI)

Placebo

N = 3691

(%)

Prolia

N = 3702

(%)

0-1 Year 2.2 0.9 1.4 (0.8, 1.9) 61 (42, 74)
0-2 Years 5.0 1.4 3.5 (2.7, 4.3) 71 (61, 79)
0-3 Years 7.2 2.3 4.8 (3.9, 5.8) 68 (59, 74)

1 Event rates based on crude rates in each interval
2 Absolute risk reduction and relative risk reduction based on Mantel-Haenszel method adjusting for age group variable

Prolia was effective in reducing the risk for new morphometric vertebral fractures regardless of age, baseline rate of bone turnover, baseline BMD, baseline history of fracture, or prior use of a drug for osteoporosis.

Effect on Hip Fractures

The incidence of hip fracture was 1.2% for placebo-treated women compared to 0.7% for Prolia-treated women at year 3. The age-adjusted absolute risk reduction of hip fractures was 0.3% with a relative risk reduction of 40% at 3 years (p = 0.04) (Figure 1).

Figure 1. Cumulative Incidence of Hip Fractures Over 3 Years

Figure 1. Cumulative Incidence of Hip Fractures Over 3 Years

Effect on Nonvertebral Fractures

Treatment with Prolia resulted in a significant reduction in the incidence of nonvertebral fractures (Table 3).

Table 3. The Effect of Prolia on the Incidence of Nonvertebral Fractures at Year 3
Proportion of Women With Fracture (%) 1

Absolute Risk Reduction (%)

(95% CI)

Relative Risk Reduction (%)

(95% CI)

Placebo

N = 3906

(%)

Prolia

N = 3902

(%)

Nonvertebral fracture 2 8.0 6.5 1.5 (0.3, 2.7) 20 (5, 33) 3

1 Event rates based on Kaplan-Meier estimates at 3 years.
2 Excluding those of the vertebrae (cervical, thoracic, and lumbar), skull, facial, mandible, metacarpus, and finger and toe phalanges.
3 p-value = 0.01.

Effect on Bone Mineral Density (BMD)

Treatment with Prolia significantly increased BMD at all anatomic sites measured at 3 years. The treatment differences in BMD at 3 years were 8.8% at the lumbar spine, 6.4% at the total hip, and 5.2% at the femoral neck. Consistent effects on BMD were observed at the lumbar spine, regardless of baseline age, race, weight/body mass index (BMI), baseline BMD, and level of bone turnover.

After Prolia discontinuation, BMD returned to approximately baseline levels within 12 months.

Bone Histology and Histomorphometry

A total of 115 transiliac crest bone biopsy specimens were obtained from 92 postmenopausal women with osteoporosis at either month 24 and/or month 36 (53 specimens in Prolia group, 62 specimens in placebo group). Of the biopsies obtained, 115 (100%) were adequate for qualitative histology and 7 (6%) were adequate for full quantitative histomorphometry assessment.

Qualitative histology assessments showed normal architecture and quality with no evidence of mineralization defects, woven bone, or marrow fibrosis in patients treated with Prolia.

The presence of double tetracycline labeling in a biopsy specimen provides an indication of active bone remodeling, while the absence of tetracycline label suggests suppressed bone formation. In subjects treated with Prolia, 35% had no tetracycline label present at the month 24 biopsy and 38% had no tetracycline label present at the month 36 biopsy, while 100% of placebo-treated patients had double label present at both time points. When compared to placebo, treatment with Prolia resulted in virtually absent activation frequency and markedly reduced bone formation rates. However, the long-term consequences of this degree of suppression of bone remodeling are unknown.

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