14 CLINICAL STUDIES

14.1 Treatment of Osteoporosis in Postmenopausal Women

Study 1 (NCT01575834) was 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. Women were randomized to receive subcutaneous injections of either EVENITY (N = 3589) or placebo (N = 3591) for 12 months. At baseline, 18% of women 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 initial treatment. Women received 500 to 1000 mg calcium and 600 to 800 international units vitamin D supplementation daily. The coprimary efficacy endpoints were new vertebral fracture at month 12 and month 24.

Effect on Fractures

EVENITY significantly reduced the incidence of new vertebral fractures through month 12 compared to placebo. In addition, the significant reduction in fracture risk persisted through the second year in women who received EVENITY during the first year and transitioned to denosumab compared to those who transitioned 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)*	Relative Risk Reduction (%) (95% CI)*	p-value†
N = Number of subjects randomized
* Absolute and relative risk reduction are based on the Mantel-Haenszel method adjusting for age and prevalent vertebral fracture strata. † P-value is based on logistic regression model adjusting for age and prevalent vertebral fracture strata.
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

EVENITY significantly reduced the incidence of clinical fracture (a composite endpoint of symptomatic vertebral fracture and nonvertebral fracture) at 12 months. However, 88% of these clinical fractures were nonvertebral fractures and the incidence of nonvertebral fractures was not statistically significantly different when comparing EVENITY-treated women to placebo-treated women at month 12 or month 24.

Effect on Bone Mineral Density (BMD)

EVENITY significantly increased BMD at the lumbar spine, total hip, and femoral neck compared with placebo at month 12. The treatment differences in BMD were 12.7% at the lumbar spine, 5.8% at the total hip, and 5.2% at the femoral neck.

Following the transition from EVENITY to denosumab at month 12, BMD continued to increase through month 24. In patients who transitioned from placebo to denosumab, BMD also increased with denosumab use. The differences in BMD achieved at month 12 between EVENITY and placebo patients were overall maintained at month 24, when comparing patients who transitioned from EVENITY to denosumab to those who transitioned from placebo to denosumab. There was no evidence of differences in effects on BMD at the lumbar spine or total hip across subgroups defined by baseline age, baseline BMD, or geographic region.

After EVENITY discontinuation, BMD returns to approximately baseline levels within 12 months in the absence of follow-on antiresorptive therapy [see Indications and Usage (1.2)].

Bone Histology and Histomorphometry

A total of 154 transiliac crest bone biopsy specimens were obtained from 139 postmenopausal women with osteoporosis at month 2, month 12, and/or month 24. All of these biopsies were adequate for qualitative histology and 138 (90%) were adequate for full quantitative histomorphometry assessment. Qualitative histology assessments from women treated with EVENITY showed normal bone architecture and quality at all time points. There was no evidence of woven bone, mineralization defects, or marrow fibrosis.

Histomorphometry assessments on biopsies at months 2 and 12 compared the effect of EVENITY with placebo (15 specimens at month 2 and 39 specimens at month 12 in the EVENITY group, 14 specimens at month 2 and 31 specimens at month 12 in the placebo group). At month 2 in women treated with EVENITY, histomorphometric indices of bone formation at trabecular and endocortical surfaces were increased. These effects on bone formation were accompanied by a decrease in indices of bone resorption. At month 12, both bone formation and resorption indices were decreased with EVENITY, while bone volume, and trabecular and cortical thickness were increased.

Study 2 (NCT01631214) was 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. Women were randomized (1:1) to receive either monthly subcutaneous injections of EVENITY (N = 2046) or oral alendronate 70 mg weekly (N = 2047) for 12 months, with 500 to 1000 mg calcium and 600 to 800 international units vitamin D supplementation daily. After the 12-month treatment period, women in both arms transitioned to open-label alendronate 70 mg weekly while remaining blinded to their initial treatment.

This was an event driven trial. The two primary efficacy endpoints were the incidence of morphometric vertebral fracture at 24 months and time to the first clinical fracture through the primary analysis period, which ended when at least 330 subjects had a clinical fracture and all subjects had completed the 24-month visit. Clinical fracture was a composite endpoint of nonvertebral fracture and symptomatic vertebral fracture.

Effect on Fractures

EVENITY significantly reduced the incidence of new vertebral fracture at 24 months (see Table 3).

Table 3 Effect of EVENITY on the Incidence of New Vertebral Fractures in Study 2
	Proportion of Women with Fracture (%)		Risk Reduction		p-value *
	Alendronate Alone (N = 2047)	EVENITY Followed by Alendronate (N = 2046)	Absolute Risk Reduction (%) (95% CI)†	Relative Risk Reduction (%) (95% CI)†
N = Number of subjects randomized
* P-value is based on logistic regression model for new vertebral fracture) adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. † Absolute and relative risk reductions are based on the Mantel-Haenszel method adjusting for age strata, baseline total hip BMD T-score (≤ -2.5, > -2.5), and presence of severe vertebral fracture at baseline.
New vertebral fracture through Month 24	8.0%	4.1%	4.0 (2.5, 5.6)	50 (34, 62)	<0.001

EVENITY significantly reduced the risk of clinical fracture through the end of the primary analysis period (see Table 4). This was an event-driven trial and the duration of follow-up varied across subjects. The median duration of subject follow-up for the primary analysis period was 33 months. Subjects with nonvertebral fracture comprised 83% of the subjects with clinical fracture during the primary analysis period.

Table 4 Effect of EVENITY on the Risk of Clinical Fractures in Study 2
	Proportion of Women with Fracture (%)*		Hazard Ratio (95% CI)†	p-value†
	Alendronate Alone (N = 2047)	EVENITY Followed by Alendronate (N = 2046)	Hazard Ratio (95% CI)†	p-value†
N = Number of subjects randomized
* % = number of subjects who had a clinical fracture through the primary analysis period/N*100%; the duration of follow-up varied across subjects. † Hazard ratio and P-value are based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline ‡ Primary analysis period ended when clinical fracture events were confirmed for at least 330 subjects and all subjects completed the month 24 study visit. The median duration of follow-up for the primary analysis period was 33 months.
Clinical fracture through primary analysis period‡	13.0%	9.7%	0.73 (0.61, 0.88)	<0.001

EVENITY followed by alendronate also significantly reduced the risk of nonvertebral fracture through the primary analysis period (with a median follow-up of 33 months), with a hazard ratio of 0.81 (95% CI: 0.66, 0.99; p = 0.04) compared to alendronate alone.

Effect on Bone Mineral Density (BMD)

EVENITY significantly increased BMD at the lumbar spine, total hip, and femoral neck compared with alendronate at month 12. The treatment differences in BMD were 8.7% at the lumbar spine, 3.3% at the total hip, and 3.2% at the femoral neck.

Twelve months of treatment with EVENITY followed by 12 months of treatment with alendronate significantly increased BMD compared with alendronate alone. The BMD increase with EVENITY over alendronate observed at month 12 was maintained at month 24. The treatment differences in BMD at month 24 were 8.1% at the lumbar spine, 3.8% at the total hip, and 3.8% at the femoral neck.

There was no evidence of differences in effects on BMD at the lumbar spine or total hip across subgroups defined by baseline age, baseline BMD, or geographic region.