d 93 times, respectively, the systemic exposure observed inhumans administered monthly subcutaneous doses of 210 mg based on AUC comparison).
13.2 Animal Toxicology and Pharmacology
No adverse effects were noted in rats and monkeys after 26 once-weekly subcutaneousromosozumab-aqqg doses up to 100 mg/kg, equivalent to systemic exposures of 38 and 93 times,respectively, the systemic exposure observed in humans following a monthly subcutaneous dose of210 mg EVENITY (based on AUC comparison).
Bone safety studies of up to 12-month duration were conducted in ovariectomized rats and monkeys withonce-weekly romosozumab-aqqg doses yielding exposures ranging from 1 to 22 times the systemicexposure in humans given monthly doses of 210 mg, based on AUC comparison. Romosozumab-aqqgincreased bone mass and improved cancellous bone microarchitecture and cortical bone geometry byincreasing bone formation on periosteal, endocortical, and trabecular surfaces, and decreasing boneresorption on trabecular and endocortical surfaces. The increases in bone mass were significantlycorrelated with increases in bone strength. In rats and monkeys, bone quality was maintained at allskeletal sites at doses ranging from 1 to 22 times human exposure, and slightly improved in vertebrae at 19 to 22 times human exposure. There was no evidence of mineralization defects, osteoid accumulation,or woven bone formation.
14 CLINICAL STUDIES
14.1 Treatment of Osteoporosis in Postmenopausal Women
Study 1 (NCT01575834) was a randomized, double-blind, placebo-controlled study of postmenopausalwomen aged 55 to 90 years (mean age of 71 years) with bone mineral density (BMD) T-score less than orequal to −2.5 at the total hip or femoral neck. Women were randomized to receive subcutaneousinjections of either EVENITY (N = 3589) or placebo (N = 3591) for 12 months. At baseline, 18% ofwomen had a vertebral fracture. After the 12-month treatment period, women in both arms transitioned to
open-label anti-resorptive therapy (denosumab) for 12 months while remaining blinded to their initialtreatment. Women received 500 to 1000 mg calcium and 600 to 800 international units vitamin Dsupplementation daily. The coprimary efficacy endpoints were new vertebral fracture at month 12 andmonth 24.
Effect on Fractures
EVENITY significantly reduced the incidence of new vertebral fractures through month 12 compared toplacebo. In addition, the significant reduction in fracture risk persisted through the second year in womenwho received EVENITY during the first year and transitioned to denosumab compared to those whotransitioned from placebo to denosumab (see Table 2).
Table 2 Effect of EVENITY on the Incidence and Risk of Fractures in Study 1
Proportion of Women with Fractures
Absolute
Risk
Reduction
(%)
(95% CI)a
Relative
Risk
Reduction
(%)
(95% CI)a
p-valueb
At Month 12 Placebo
(N = 3591)
EVENITY
(N = 3589)
New vertebral
fracture 1.8% 0.5%
1.3
(0.8, 1.8)
73
(53, 84) < 0.001
At Month 24
Placebo Followed by
Denosumab
(N = 3591)
EVENITY Followed by
Denosumab
(N = 3589)
New vertebral
fracture 2.5% 0.6%
1.9
(1.3, 2.5)
75
(60, 84)
< 0.001
N = Number of subjects randomized
a. Absolute and relative risk reduction are based on the Mantel-Haenszel method adjusting for age and preva lentvertebral fracture strata.
b. P-value is based on logistic regression model |
