Clinical Pharmacology Corner: FDA Approves EVENITY (romosozumab-aqqg)

FDA Approves EVENITY (romosozumab-aqqg) for the Treatment of Osteoporosis in Postmenopausal Women at High Risk for Fracture

On April 9, 2019, the U.S. Food and Drug Administration (FDA) approved EVENITY (romosozumab-aqqg) 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 patients who have failed or are intolerant to other available osteoporosis therapy. EVENITY should be administered by a healthcare provider. The approved recommended dosage of EVENITY is 210 mg administered subcutaneously, as two separate 105 mg injections, in the abdomen, thigh or upper arm once every month for 12 doses. Pre-existing hypocalcemia must be corrected prior to initiating therapy with EVENITY. Patients should be adequately supplemented with calcium and vitamin D during treatment with EVENITY. Limitation of Use: The anabolic effect of EVENITY wanes after 12 monthly doses of therapy. Therefore, the duration of EVENITY use should be limited to 12 monthly doses. If osteoporosis therapy remains warranted, continued therapy with an anti-resorptive agent should be considered. EVENITY is contraindicated in patients with hypocalcemia and in patients with a history of systemic hypersensitivity to romosozumab or to any component of the product formulation. Additional information regarding dosage and administration, contraindications, and important warnings and precautions about major adverse cardiac events, hypersensitivity, hypocalcemia, osteonecrosis of the jaw, or atypical femoral fracture can be found in the full prescribing information linked below. Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD) MOA: Romosozumab-aqqg is a humanized monoclonal antibody (IgG2) that binds to and inhibits the action of sclerostin, a regulatory factor in bone metabolism. EVENITY increases bone formation and, to a lesser extent, decreases bone resorption. General PK: The mean (standard deviation [SD]) maximum romosozumab-aqqg serum concentration (Cmax) is 22.2 (5.8) mcg/mL and AUC is 389 (127) mcg*day/mL following a single 210 mg dose. Steady-state concentrations were achieved by month 3. The mean trough serum romosozumab-aqqg concentrations at months 3, 6, 9, and 12 ranged from 8 to 13 mcg/mL. Dose Proportionality: Romosozumab-aqqg exposure increased greater than dose proportionally (e.g., 550-fold increase in mean AUCinf for the 100-fold increase in subcutaneous doses ranging from 0.1 to 10 mg/kg [0.03 to 3.3 times the approved recommended dosage for a 70 kg woman). Absorption: The median time to maximum romosozumab-aqqg concentration is 5 days (range: 2 to 7 days). Distribution: The estimated volume of distribution at steady-state is approximately 3.92 L. Elimination: Romosozumab-aqqg exhibited nonlinear pharmacokinetics with the clearance of romosozumab-aqqg decreasing as the dose increased. The estimated mean systemic clearance of romosozumab-aqqg was 0.38 mL/hr/kg, following a single subcutaneous administration of 3 mg/kg (the approved recommended dosage for a 70 kg woman). The mean effective t1/2 was 12.8 days after 3 doses of 3 mg/kg (the approved recommended dosage for a 70 kg woman) every 4 weeks. Metabolism: The metabolic pathway of romosozumab-aqqg has not been characterized. As a humanized IgG2 monoclonal antibody, romosozumab-aqqg is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG. PD: In postmenopausal women with osteoporosis, EVENITY increased the bone formation marker procollagen type 1 N-telopeptide (P1NP) and decreased the bone resorption marker type 1 collagen C-telopeptide (CTX). After discontinuation of EVENITY, P1NP levels returned to baseline within 12 months; CTX increased above baseline levels within 3 months and returned toward baseline levels by month 12. Immunogenicity: Among 5914 postmenopausal women treated with EVENITY 210 mg monthly, 18.1% of subjects developed antibodies to romosozumab-aqqg. Of the subjects who developed antibodies to romosozumab-aqqg, 4.7% had antibodies that were classified as neutralizing. Development of antibodies to romosozumab-aqqg was associated with lower serum romosozumab-aqqg concentrations. The presence of anti-romosozumab-aqqg antibodies led to decreased mean romosozumab-aqqg concentrations up to 22%. The presence of neutralizing antibodies led to decreased mean romosozumab-aqqg concentrations up to 63%. Antibodies to romosozumab-aqqg were generally not associated with changes in the efficacy or safety of EVENITY. Use in Specific Populations The exposure of romosozumab-aqqg decreases with increasing body weight. No clinically significant differences in the pharmacokinetics of romosozumab-aqqg were observed based on age (20-89 years), sex, race, disease state (low bone mass or osteoporosis), prior exposure to alendronate, or renal impairment including end-stage renal disease (ESRD) requiring dialysis. The effect of ESRD not requiring dialysis on the pharmacokinetics of romosozumab-aqqg is unknown. Patients with severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to 29 mL/min/1.73 m2by MDRD equation) or receiving dialysis are at greater risk of developing hypocalcemia. Monitor calcium concentrations and adequately supplement calcium and vitamin D in patients who have severe renal impairment or are receiving dialysis. Efficacy and Safety Efficacy of EVENITY was demonstrated in the following studies: A randomized, double-blind, placebo-controlled study of postmenopausal women aged 55 to 90 years (mean age of 71 years) with bone mineral density (BMD) T-score less than or equal to −2.5 at the total hip or femoral neck. The coprimary efficacy endpoints were new vertebral fracture at month 12 and month 24. A randomized, double-blind, alendronate-controlled study of postmenopausal women aged 55 to 90 years (mean age of 74 years) with BMD T-score less than or equal to −2.5 at the total hip or femoral neck and either one moderate or severe vertebral fracture or two mild vertebral fractures, or BMD T-score less than or equal to -2.0 at the total hip or femoral neck and either two moderate or severe vertebral fractures or a history of a proximal femur fracture. The coprimary efficacy endpoints were the incidence of morphometric vertebral fracture at 24 months and time to the first clinical fracture through the primary analysis period. Additional information regarding efficacy trials can be found in the full prescribing information linked below. The most common adverse reactions (≥ 5%) reported with EVENITY in clinical trials were arthralgia and headache.

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