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|Amgen Submits Applications In The US And Europe To Expand Current Indication For XGEVA® (denosumab) To Include Patients With Multiple Myeloma|
XGEVA is a fully human monoclonal antibody that binds to and neutralizes RANK ligand (RANKL) – a protein essential for the formation, function and survival of osteoclasts, which break down bone – thereby inhibiting osteoclast-mediated bone destruction. XGEVA is currently indicated for the prevention of SREs in patients with bone metastases from solid tumors based on results from three previous pivotal Phase 3 head-to-head studies. In these Phase 3 studies, XGEVA demonstrated superiority in the solid tumors studied compared to zoledronic acid. In the U.S., XGEVA has a limitation of use noting that it is not indicated for the prevention of SREs in patients with multiple myeloma.
"Bone lesions are a hallmark of multiple myeloma and often result in bone complications, which can be devastating for patients. Current treatment options for bone complications are limited to bisphosphonates, which are associated with renal toxicity. Approximately 60 percent of all multiple myeloma patients have or will develop renal impairment over the course of the disease," said
The sBLA is based on efficacy and safety data from the pivotal Phase 3 '482 study, which demonstrated that XGEVA is non-inferior to zoledronic acid in delaying the time to first on-study SRE in patients with multiple myeloma (HR=0.98, 95 percent CI: 0.85, 1.14; p=0.01). The secondary endpoints of superiority in delaying time to first SRE and delaying time to first-and-subsequent SRE were not met in this study. Overall survival (OS), another secondary endpoint, was also in favor of XGEVA over zoledronic acid (HR=0.90, 95 percent CI: 0.70, 1.16; p=0.41); however, it was not statistically significant. The hazard ratio of XGEVA versus zoledronic acid for progression-free survival (PFS) was 0.82 (95 percent CI: 0.68, 0.99; descriptive p=0.036). The median PFS difference between arms was 10.7 months in favor of XGEVA. These results were presented during the late-breaking abstract session at the 16th
Adverse events observed in patients treated with XGEVA were consistent with the known safety profile of XGEVA. The most common adverse events (greater than 25 percent) were diarrhea (33.5 percent XGEVA and 32.4 percent zoledronic acid) and nausea (31.5 percent XGEVA and 30.4 percent zoledronic acid).
About '482 Study (NCT01345019)
About Multiple Myeloma and Bone Complications
More than 90 percent of patients develop osteolytic lesions during the course of the disease.3 Current treatment options for bone complications are limited to bisphosphonates, including zoledronic acid; these are cleared by the kidneys and associated with renal toxicity, which is a common complication with myeloma patients.5 Approximately 60 percent of all multiple myeloma patients have or will develop renal impairment over the course of the disease.6 Preventing bone complications is a critical aspect of caring for patients with multiple myeloma, because these events can cause significant morbidity.7
About XGEVA® (denosumab)
U.S. Important Safety Information
An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake.
Drug Products with Same Active Ingredient
Osteonecrosis of the Jaw
Patients with a history of tooth extraction, poor oral hygiene, or use of a dental appliance are at a greater risk to develop ONJ. Other risk factors for the development of ONJ include immunosuppressive therapy, treatment with angiogenesis inhibitors, systemic corticosteroids, diabetes, and gingival infections.
Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA® and periodically during XGEVA® therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA®. Consider temporarily interrupting XGEVA® therapy if an invasive dental procedure must be performed.
Patients who are suspected of having or who develop ONJ while on XGEVA® should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.
Atypical Subtrochanteric and Diaphyseal Femoral Fracture
Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During XGEVA® treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patients presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of XGEVA® therapy should be considered, pending a risk/benefit assessment, on an individual basis.
Hypercalcemia Following Treatment Discontinuation in Patients with Growing Skeletons
Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after the last dose of XGEVA®. Apprise the patient of the potential hazard to a fetus if XGEVA® is used during pregnancy or if the patient becomes pregnant while patients are exposed to XGEVA®.
The most common adverse reactions in patients receiving XGEVA® for giant cell tumor of bone were arthralgia, headache, nausea, back pain, fatigue, and pain in extremity. The most common serious adverse reactions were osteonecrosis of the jaw and osteomyelitis. The most common adverse reactions resulting in discontinuation of XGEVA® were osteonecrosis of the jaw and tooth abscess or tooth infection.
The most common adverse reactions in patients receiving XGEVA® for hypercalcemia of malignancy were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea.
Denosumab is also marketed as Prolia® in other indications.
Important EU Product Safety Information
Special Warnings and Precautions: Pre-existing hypocalcaemia must be corrected prior to initiating therapy with XGEVA. Hypocalcaemia can occur at any time during therapy. Monitor calcium prior to initial dose, within two weeks of initial dose and if suspected symptoms of hypocalcaemia occur. Severe symptomatic hypocalcaemia has been reported. Consider additional monitoring of calcium level in patients with risk factors for hypocalcaemia or if otherwise indicated based on clinical condition of the patient. If hypocalcaemia occurs while receiving XGEVA, additional calcium supplementation and additional monitoring may be necessary.
Patients with severe renal impairment (creatinine clearance < 30ml/min) or receiving dialysis are at greater risk of developing hypocalcaemia; this risk and accompanying elevations in parathyroid hormone increases with increasing degree of renal impairment. Regular monitoring of calcium levels in these patients is especially important.
Osteonecrosis of the jaw (ONJ) has occurred commonly in patients treated with XGEVA. Delay treatment in patients with unhealed open soft tissue lesions in the mouth. A dental examination with preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment. Refer to the SmPC for risk factors for ONJ. Patients should be encouraged to maintain good oral hygiene, receive routine dental check-ups and immediately report oral symptoms during treatment with XGEVA. While on treatment, invasive dental procedures should be performed only after careful consideration and avoided in close proximity to XGEVA administration. The management plan of patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ.
Atypical femoral fracture (AFF) has been reported in patients receiving XGEVA. Discontinuation of XGEVA therapy in patients suspected to have AFF should be considered pending evaluation of the patient based on an individual benefit risk assessment. XGEVA is not recommended in patients with growing skeletons. Clinically significant hypercalcaemia has been reported in XGEVA-treated patients with growing skeletons weeks to months following treatment discontinuation. Patients being treated with XGEVA should not be treated concomitantly with other denosumab containing medicinal products (for osteoporosis indications) or with bisphosphonates. Patients with rare hereditary problems of fructose intolerance should not use XGEVA.
Adverse reactions in patients receiving XGEVA to prevent the occurrence of skeletal related events: very common (≥ 1/10) dyspnea, diarrhea and musculoskeletal pain; common (≥ 1/100 to < 1/10) hypocalcaemia, hypophosphatemia, tooth extraction, hyperhidrosis and osteonecrosis of the jaw; rare (≥ 1/10,000 to < 1/1000) drug hypersensitivity, anaphylactic reaction, atypical femoral fracture. In three phase III clinical trials, ONJ was confirmed in 1.8% of patients treated with XGEVA and 1.3% of patients treated with zoledronic acid (primary treatment phase). Among subjects with confirmed ONJ, most (81% in both treatment groups) had a history of tooth extraction, poor oral hygiene, and/or use of a dental appliance. Hypocalcaemia was reported in 9.6% of patients treated with XGEVA and 5.0% of patients treated with zoledronic acid. Neutralizing antibodies have not been observed in clinical studies. In the postmarketing setting, severe symptomatic hypocalcaemia (including fatal cases), hypersensitivity (including rare events of anaphylactic reaction) and musculoskeletal pain (including severe cases) have been reported. Please consult the SmPC for a full description of undesirable effects.
Contraindications: Severe, untreated hypocalcaemia; hypersensitivity to the active substance or to any of the excipients; unhealed lesions from dental or oral surgery.
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