Denosumab is a human immunoglobulin G2 (IgG2) monoclonal antibody with affinity and specificity for human receptor activator of nuclear factor kappa-B ligand (RANKL). RANKL is a transmembrane or soluble protein that is essential for osteoclasts, cells that are responsible for bone resorption. Increased osteoclast activity, stimulated by RANKL, is a mediator of bone pathology in solid tumors with bone metastases. Denosumab binds to RANKL, thereby decreasing bone resorption and increasing bone mass and strength.
Hypocalcemia may be exacerbated by the use of denosumab; therefore, pre-existing hypocalcemia must be corrected prior to initiating therapy with denosumab. In individuals who are predisposed to hypocalcemia and disturbances of mineral metabolism (e.g., history of hypoparathyroidism, thyroid surgery, parathyroid surgery, excision of small intestine, severe renal impairment or dialysis, malabsorption syndromes), clinical monitoring of calcium, phosphorus, and magnesium levels is highly recommended.
Denosumab is available under two different US Food and Drug Administration (FDA)-approved trade names: Prolia and Xgeva.
Osteoporosis is characterized by low bone mass, deterioration of bone tissue, disruption of bone architecture, compromised bone strength, and increased risk for fracture. According to the World Health Organization (WHO) diagnostic classification, osteoporosis is operationally defined by measurement of bone mineral density (BMD) at the hip or spine that is less than or equal to 2.5 standard deviations (SD) below the young normal mean reference population. In describing BMD, T-scores compare bone density to the optimal peak bone density for an individual's gender. A T-score is the number of units (standard deviations) above (+) or below (-) what is considered standard. A T-score is within the normal range if it is a positive number, or at least no more negative than -1.0. The more negative the number, the thinner the bones. A T-score less than -1.0 but greater than -2.5 is considered osteopenia, and a risk for developing osteoporosis. A T-score of less than -2.5 is indicative of osteoporosis. The WHO definition applies to postmenopausal women as well as men aged 50 years or older. Half of all postmenopausal women will have an osteoporosis-related fracture during their lives; of those, 25 percent will develop a vertebral deformity, and 15 percent will sustain a hip fracture. According to the National Osteoporosis Foundation, two million men in the US have osteoporosis and another 12 million are at risk. Osteoporosis and osteoporotic fractures in men remain under-diagnosed and under-treated.
Denosumab was originally approved under the trade name of Prolia in June 2010. Denosumab (Prolia) is indicated to treat postmenopausal women with osteoporosis who are at risk for bone fractures. In September 2011, denosumab (Prolia) was approved for treatment of bone loss in men receiving androgen deprivation therapy in prostate cancer and for treatment of bone loss in women receiving adjuvant aromatase inhibitor therapy for breast cancer. A new indication was approved for denosumab (Prolia) in September 2012 for the treatment to increase bone mass in men with osteoporosis.
The FDA approval of denosumab (Prolia) for the treatment of osteoporosis in postmenopausal women who are at high risk of fracture is based on a pivotal three-year, Phase 3 study involving 7,808 postmenopausal women with osteoporosis who had a baseline BMD T-score between -2.5 and -4.0 at either the lumbar spine or total hip. A subcutaneous injection of denosumab (Prolia) 60 mg was administered every six months. All women in the study received at least 1000 mg calcium orally once daily and at least 400 IU of vitamin D orally once daily. Denosumab (Prolia) reduced the incidence of vertebral, hip, and nonvertebral fractures. Over three years, denosumab (Prolia) significantly reduced the incidence of new vertebral fractures by 68 percent, reduced the incidence of hip fractures by 40 percent, and reduced the incidence of non-spine fractures by 20 percent.
The approval of denosumab (Prolia) for the treatment of low bone mass in women at high risk for fracture who are receiving adjuvant aromatase inhibitor therapy for breast cancer is based on a two-year, randomized, double-blind, placebo-controlled, multinational study that enrolled women with breast cancer. Women in this study had a baseline BMD T-score between -1.0 and -2.5 and had not experienced fracture after age 25. All women received at least 1000 mg calcium and 400 IU vitamin D daily. After two years denosumab (Prolia) significantly improved BMD in these individuals by 6.2 percent at the lumbar spine, 3.8 percent at the total hip, and 2.8 percent at the femoral neck.
Approval of denosumab (Prolia) for the treatment of low bone mass in men at high risk for fracture who are receiving androgen-deprivation therapy (ADT) for nonmetastatic prostate cancer is based on a three-year trial that enrolled 1,468 men who had prostate cancer and were required to have a BMD T-score between -1.0 and -4.0, or history of osteoporotic fracture. Denosumab (Prolia) significantly increased lumbar spine BMD and significantly reduced the incidence of new vertebral fractures.
In September 2012 denosumab (Prolia) was approved by the FDA for the treatment to increase bone mass in men with osteoporosis based on results from the ADAMO trial 3 (A multicenter, randomized, double-blind, placebo-controlled study to examine the efficacy and safety of DenosumAb [Prolia] 60 mg every six months vs placebo in Men with Osteoporosis). The pivotal Phase 3 study involved 242 men with low BMD of T-score between -2.0 and -3.5 at the lumbar spine or femoral neck or a T-score between -1.0 and -3.5 at the lumbar spine or femoral neck with a history of prior fragility fracture. All men received at least 1000 mg of calcium and at least 800 IU vitamin D daily. In the study, treatment with denosumab (Prolia) resulted in significantly greater gains at the lumbar spine when compared to placebo (5.7 percent vs. 0.9 percent). Effects of denosumab (Prolia) on BMD were independent of age, baseline testosterone levels, BMD status, and estimated fracture risk. Safety findings were consistent with those observed in other studies of Prolia in postmenopausal women with osteoporosis.
In May 2018, denosumab (Prolia) was approved by the FDA for the treatment of glucocorticoid-induced osteoporosis in men and women at high risk for fracture who are either initiating or continuing systemic glucocorticoids in a daily dosage equivalent to greater than or equal to 7.5 mg of prednisone and expected to remain on glucocorticoids for at least six months.
The efficacy and safety of denosumab (Prolia) in the treatment of individuals with glucocorticoid-induced osteoporosis was assessed in the 12 month primary analysis of a two year, randomized, multicenter, double-blind, parallel-group, active-controlled study of 795 individuals (70 percent women and 30 percent men) aged 20 to 94 years (mean age of 63 years) treated with greater than or equal to 7.5 mg/day oral prednisone (or equivalent) for less than three months prior to study enrollment and planning to continue treatment for a total of at least six months (glucocorticoid-initiating subpopulation; n = 290) or greater than or equal to three months prior to study enrollment and planning to continue treatment for a total of at least six months (glucocorticoid-continuing subpopulation, n = 505). Randomization was stratified by gender within each subpopulation. Individuals received at least 1000 mg calcium and 800 IU vitamin D supplementation daily. Enrolled individuals less than 50 years of age were required to have a history of osteoporotic fracture. Enrolled individuals greater than or equal to 50 years of age who were in the glucocorticoid-continuing subpopulation were required to have a baseline BMD T-score of less than or equal to -2.0 at the lumbar spine, total hip, or femoral neck; or a BMD T-score less than or equal to -1.0 at the lumbar spine, total hip, or femoral neck and a history of osteoporotic fracture.
Results showed that compared to the active-control, treatment with denosumab (Prolia) significantly increased lumbar spine BMD at one year in the glucocorticoid-initiating subpopulation (p<.001). In the glucocorticoid-continuing subpopulation, treatment with denosumab (Prolia) was associated with significant increases in lumbar spine BMD compared with active-control (p<.001). The safety of denosumab (Prolia) was found to be consistent with previous trials (Saag et al, 2018).
Weakened bones due to cancer metastases can lead to fractures and compression of the spinal cord. They necessitate procedures such as surgery and radiation, which are designed to prevent or manage bone complications. The primary goal of treatment for bone metastases is to prevent the occurrence of debilitating bone complications that can affect an individual's quality of life. The major cancer types that tend to metastasize to the bone include breast, lung, prostate, thyroid, and kidney.
In January 2018, denosumab received a Supplemental Biologic License Application approval under denosumab (Xgeva) for prevention of skeletal-related events (SREs) in individuals with multiple myeloma. The efficacy was evaluated in an international, randomized double-blinded, active controlled, noninferiority trial comparing denosumab (Xgeva) with zoledronic acid in 1,718 newly diagnosed individuals with multiple myeloma. The main efficacy outcome measure was noninferiority of time to first SRE. Denosumab (Xgeva) was significantly noninferior to zoledronic acid in delaying the time to the first SRE.
In November 2010, denosumab received a Supplemental Biologic License Application approval under denosumab (Xgeva) for prevention of SREs in individuals with bone metastases from solid tumors, which are abnormal masses of tissue that usually do not contain cysts or liquid areas. In June 2013, denosumab (Xgeva) was approved for use in adults and skeletally mature adolescents for the treatment of giant cell tumor of bone (GCTB) that is unresectable or where surgical resection is likely to result in severe morbidity. In December 2014, denosumab (Xgeva) received FDA approval for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.
The safety and effectiveness of denosumab (Xgeva) was confirmed in three randomized, double-blind studies of 5,723 individuals, comparing denosumab (Xgeva) with zoledronic acid (Zometa). One study involved individuals with breast cancer, the second study involved individuals with prostate cancer, and the third study involved individuals with a variety of other cancers. The studies were designed to measure the time until the occurrence of an SRE. SREs include pathological fracture, spinal cord compression due to cancer, or the need for radiation therapy or surgery to bone. In each trial, denosumab (Xgeva) was noninferior to zoledronic acid (Zometa) for the delay of time-to-first SRE in patients with bone metastasis from solid tumors. Supportive outcome measures were superiority of time-to-first SRE and superiority of time-to-first and subsequent SRE; testing for these outcome measures occurred if the main outcome measure was statistically significant.
In June 2013, denosumab (Xgeva) was granted FDA approval for treatment of GCTB, a rare and usually non-cancerous tumor usually occurring in adults between the ages of 20 and 40 years of age. Most of the time, GCTB does not spread to other areas of the body, but destroys normal bone as it grows, which causes pain, limited range of motion, and bone fractures. On rare occasion, GCTB can transform into a cancerous tumor that spreads to the lungs.
Denosumab (Xgeva) is intended for persons with GCTB who are not surgical candidates or when surgery would result in severe morbidity. The safety and effectiveness of denosumab (Xgeva) for use in GCTB is based on two open-label trials involving187 persons who had tumors that could be measured; of this group, 47 individuals experienced a reduction in the size of their tumors. In a follow-up, occurring on average 20 months later, re-growth of GCTB occurred in three individuals whose tumors had originally become smaller during the treatment phase.
The approval of denosumab (Xgeva) for individuals with hypercalcemia was based on an open-label, single-arm trial that assessed safety and effectiveness in 33 individuals with hypercalcemia of malignancy refractory to bisphosphonate therapy. In the trial refractory hypercalcemia of malignancy was defined as an albumin-corrected calcium of >12.5 mg/dL despite treatment with intravenous bisphosphonate therapy in seven to 30 days prior to denosumab (Xgeva) therapy. The median time of complete response was 23 days with a median duration of complete response of 34 days.
There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
On April 9, 2019, romosozumab-aqqg (Evenity) was approved by the FDA for the treatment of osteoporosis in postmenopausal women at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or failed or are intolerant to other available osteoporosis therapy.
Romosozumab-aqqg (Evenity) is a monoclonal antibody that binds to and inhibits sclerostin (a regulatory factor in bone metabolism), increases bone formation, and to a lesser extent, decreases bone resorption. The FDA based its approval of Romosozumab-aqqg (Evenity) on the results of two Phase 3 studies.
FRAME (FRActure study in postmenopausal woMen with osteoporosis) study is a randomized, double-blind, placebo-controlled study that evaluated 7,180 postmenopausal women with osteoporosis. The study evaluated the efficacy of romosozumab-aqqg (Evenity) treatment (210 mg administered monthly), compared with placebo, in reducing the incidence of new vertebral fractures through 12 months. The study also evaluated the efficacy of treating with romosozumab-aqqg (Evenity) for 12 months followed by denosumab (Prolia) for 12 months, compared with placebo followed by denosumab (Prolia), in reducing the incidence of new vertebral fractures through 24 months. The study showed that individuals randomly assigned to receive a monthly subcutaneous 210 mg dose of romosozumab (Evenity) experienced a statistically significant 73 percent reduction in the relative risk of a new vertebral (spine) fracture through 12 months, the first co-primary endpoint, compared to those receiving placebo (fracture incidence 0.5 percent versus 1.8 percent, respectively [p<0.001]). Of interest, the data showed that by six months, new vertebral fractures occurred in 14 romosozumab (Evenity) and 26 placebo individuals, and between six to 12 months, fractures occurred in two additional romosozumab (Evenity) individuals versus 33 additional placebo individuals.
ARCH (Active-contRolled FraCture Study in Postmenopausal Women with Osteoporosis at High Risk of Fracture) is a Phase 3 multicenter, international, randomized, double-blind, alendronate-controlled study of romosozumab-aqqg (Evenity) involving 4,093 postmenopausal women with osteoporosis at high risk for fracture based on previous fracture history. The study evaluated 12 months of subcutaneous romosozumab-aqqg (Evenity) treatment (210 mg administered monthly) followed by at least 12 months of alendronate treatment (70 mg), compared with weekly oral alendronate (70mg) treatment alone, followed by open-label alendronate in both groups. The primary end points were the cumulative incidence of new vertebral fracture at 24 months and the cumulative incidence of clinical fracture (nonvertebral and symptomatic vertebral fracture) at the time of the primary analysis (after clinical fractures had been confirmed in greater than or equal to 330 participants). Secondary end points included the incidences of nonvertebral and hip fracture at the time of the primary analysis. Serious cardiovascular adverse events, osteonecrosis of the jaw, and atypical femoral fractures were adjudicated.
Over a period of 24 months, a 48 percent lower risk of new vertebral fractures was observed in the romosozumab-to-alendronate group (6.2 percent [127 of 2,046 individuals]) than in the alendronate-to-alendronate group (11.9 percent [243 of 2,047 individuals]) (P<0.001). Clinical fractures occurred in 198 of 2,046 individuals (9.7 percent) in the romosozumab-to-alendronate group versus 266 of 2,047 individuals (13.0 percent) in the alendronate-to-alendronate group, representing a 27 percent lower risk with romosozumab-aqqg (Evenity) (P<0.001). The risk of nonvertebral fractures was lower by 19 percent in the romosozumab-to-alendronate group than in the alendronate-to-alendronate group (178 of 2,046 individuals [8.7 percent] vs. 217 of 2,047 individuals [10.6 percent]; P=0.04), and the risk of hip fracture was lower by 38 percent (41 of 2,046 individuals [2.0 percent] vs. 66 of 2,047 individuals [3.2 percent]; P=0.02). Overall adverse events and serious adverse events were balanced between the two groups. During year one, positively adjudicated serious cardiovascular adverse events were observed more often with romosozumab-aqqg (Evenity) than with alendronate (50 of 2,040 individuals [2.5 percent] vs. 38 of 2,014 individuals [1.9 percent]). During the open-label alendronate period, adjudicated events of osteonecrosis of the jaw (one event each in the romosozumab-to-alendronate and alendronate-to-alendronate groups) and atypical femoral fracture (two events and four events, respectively) were observed. The authors concluded that in postmenopausal women with osteoporosis who were at high risk for fracture, romosozumab-aqqg (Evenity) treatment for 12 months followed by alendronate resulted in a significantly lower risk of fracture than alendronate alone. The anabolic effect of romosozumab-aqqg (Evenity) wanes after 12 monthly doses of therapy. Therefore, the duration of romosozumab-aqqg (Evenity) use should be limited to 12 monthly doses. If osteoporosis therapy remains warranted, continued therapy with an anti-resorptive agent should be considered.