Date: 21 November 2016 Page 1 2. SYNOPSIS Name of Sponsor: Amgen Inc., Thousand Oaks, CA, USA Name of Finished Product: Prolia Name of Active Ingredient: denosumab Title of Study: Randomized, Double-blind, Active-controlled Study to Evaluate the Efficacy and Safety of Denosumab Compared With Risedronate in Glucocorticoid-treated Individuals Investigators and Study Centers: This study was conducted at 79 centers in Europe, North America, Latin America, and Korea. Centers and principal investigators are listed in Section 16.1.4. Publication(s): None as of the date of this report Study Period: 28 March 2012 to data cutoff date of 29 June 2016; study is continuing and treatment remains blinded Development Phase: 3 Previous Reports for This Study: None Objectives: The primary objective in the glucocorticoid-continuing (GC-C) subpopulation of men and women treated with chronic glucocorticoid therapy ( 7.5 mg daily prednisone or its equivalent for 3 months and planning to continue treatment for a total of at least 6 months) is to demonstrate that treatment with denosumab 60 mg subcutaneously (SC) every 6 months (Q6M) is not inferior to treatment with oral risedronate 5 mg once daily (QD) with respect to the percent change from baseline in lumbar spine bone mineral density (BMD) by dual X-ray absorptiometry (DXA) at 12 months. The primary objective in the glucocorticoid-initiating (GC-I) subpopulation of men and women treated with glucocorticoid therapy ( 7.5 mg daily prednisone or its equivalent for < 3 months and planning to continue treatment for a total of at least 6 months) is to demonstrate that treatment with denosumab 60 mg SC Q6M is not inferior to treatment with oral risedronate 5 mg QD with respect to the percent change from baseline in lumbar spine BMD by DXA at 12 months. Secondary objectives are to compare the effects of denosumab with that of risedronate separately in the GC-C and GC-I subpopulations on: Percent change from baseline in lumbar spine BMD by DXA at 12 months Percent change from baseline in total hip BMD by DXA at 12 months Percent change from baseline in lumbar spine BMD by DXA at 24 months Percent change from baseline in total hip BMD by DXA at 24 months Methodology: This is a phase 3 international, multicenter, randomized, 24-month, double-blind, double-dummy, active-controlled, parallel-group study to compare the effects of denosumab 60 mg SC Q6M with risedronate in glucocorticoid-treated subjects. After the 12-month primary analysis period, subjects continue treatment and evaluation and remain blinded through month 24 for assessment of additional efficacy and safety endpoints. This report summarizes results based on 12 months of treatment.
Date: 21 November 2016 Page 2 Two subpopulations (GC-C and GC-I) are under study. Within each subpopulation, subjects were randomized in a 1:1 allocation ratio to receive either denosumab 60 mg SC Q6M and oral placebo for risedronate QD for 24 month, or oral risedronate 5 mg QD and placebo for denosumab SC Q6M for 24 months. In addition, randomization was stratified by sex such that enrollment of men was restricted to between 30% and 40% within each subpopulation. All subjects received daily supplements of calcium (at least 1000 mg elemental calcium) and vitamin D (at least 800 international units). The study includes a Data Monitoring Committee to oversee subject safety and to make recommendations relating to early closure/extension or alteration of the study based on ongoing monitoring of the study data. Number of Subjects Planned: 776 Diagnosis and Main Criteria for Eligibility: Key inclusion criteria were: Men and women 18 years of age who were receiving prednisone 7.5 mg daily or its equivalent and were expected to be treated with oral glucocorticoids for a total of at least 6 months At least 2 lumbar vertebrae and 1 hip had to be evaluable by DXA. Subjects < 50 years of age at the time of screening were required to have a history of osteoporotic fracture. Subjects who had initiated administration of prednisone 7.5 mg daily or its equivalent within 3 months or 3 months before screening were part of the GC-I subpopulation or GC-C subpopulation, respectively. In the GC-C subpopulation, subjects who were 50 years of age at screening were required to have a BMD value equivalent to a T-score -2.0 at the lumbar spine, total hip, or femoral neck; or a BMD value equivalent to a T-score -1.0 at the lumbar spine, total hip, or femoral neck and a history of osteoporotic fracture. Subjects excluded from the study included those who had received other osteoporosis or bone-active treatment, certain hormone-derived treatments, or certain biologic agents within defined time limits. Investigational Products, Dose and Mode of Administration, Manufacturing Batch Number: Denosumab was presented as a prefilled syringe (PFS) of 60 mg. Placebo for denosumab was also presented as a PFS. All subjects received a SC injection of denosumab or placebo for denosumab Q6M. Subjects also self-administered risedronate or placebo for risedronate orally QD starting within 24 hours after the first dose of injectable investigational product on day 1 through month 12; and investigational product administration will continue through the final 24-month visit date. Manufacturing batch numbers are provided in Section 16.1.6. Duration of Treatment: 24 months; this report presents results for the 12-month primary analysis period. Study Endpoints: The primary endpoint is the percent change from baseline in lumbar spine BMD by DXA at 12 months (noninferiority).
Date: 21 November 2016 Page 3 Secondary endpoints are percent change from baseline in lumbar spine and total hip BMD by DXA at 12 and 24 months. Exploratory endpoints are percent change from baseline in femoral neck, trochanter, and 1/3 radius BMD by DXA at 12 and 24 months; percent change from baseline in lumbar spine BMD by DXA at 6 and 18 months; percent change from baseline in high-resolution peripheral quantitative computed tomography (XtremeCT ) distal radius and distal tibia parameters (cortical thickness, cortical volumetric density, trabecular volumetric density, trabecular number, trabecular thickness, and trabecular spacing) at 12 and 24 months in a subset of subjects; percent change from baseline in the bone turnover markers (BTM) procollagen type 1 N-telopeptide (P1NP) and serum C-telopeptide of type 1 collagen (sctx) at day 10 and months 3, 4, 5, 6, 12, and 24; subject incidence of clinical fractures and new vertebral fractures at 12 and 24 months; bone histology and histomorphometry parameters at 12 or 24 months; subject preference and satisfaction with treatment at 12 and 24 months; and serum denosumab concentrations at baseline, day 10, and months 3, 4, 5, 6, 12, and 24. All BMD endpoints are evaluated separately in the GC-I and GC-C subpopulations. Non-BMD exploratory endpoints are evaluated in the combined subpopulations. The primary and secondary BMD endpoints were part of a fixed-sequence testing procedure to control the experiment-wise type 1 error rate within each subpopulation. Safety endpoints evaluated in the combined subpopulations include the incidence of subjects with adverse events, incidence of serious adverse events, incidence of subjects with laboratory Common Terminology Criteria for Adverse Events (CTCAE) grade 3, incidence of antidenosumab antibodies, and vital signs. Statistical Methods: Efficacy Analyses: The primary hypotheses being evaluated in this study are: (1) the mean percent change from baseline in lumbar spine BMD at month 12 in the GC-C subpopulation receiving denosumab is noninferior to that of subjects receiving risedronate using a noninferiority margin of -0.7 percentage points; and (2) the mean percent change from baseline in lumbar spine BMD at month 12 in the GC-I subpopulation receiving denosumab is noninferior to that of subjects receiving risedronate using a noninferiority margin of -1.1 percentage points. The primary and secondary endpoints of percent changes from baseline in lumbar spine and total hip BMD are evaluated using an analysis of covariance model with main effects for treatment, sex, baseline BMD, and machine type, and the interaction effect for baseline BMD and machine type for each subpopulation. The duration of prior glucocorticoid use (< 12 months versus 12 months) main effect was added to the model for the GC-C subpopulation only. For the primary endpoint, the lower bound of the 2-sided 95% confidence interval (CI) for the treatment difference is compared with the noninferiority margin for each subpopulation (-0.7% for GC-C; -1.1% for GC-I). Exploratory Analyses: The exploratory endpoints percent change from baseline in femoral neck, trochanter, and 1/3 radius BMD by DXA are evaluated the same way as the secondary efficacy endpoints. Percent change from baseline in BTM is evaluated using a Wilcoxon rank sum test. Clinical fracture, new vertebral fracture, bone histology, and bone histomorphometry are evaluated using descriptive statistics.
Date: 21 November 2016 Page 4 Pharmacokinetic Analyses: Noncompartmental analysis of denosumab was performed on individual serum denosumab concentrations to estimate the following PK parameters: maximum concentration (C max ), time to C max (t max ), area under the concentration-time curve (AUC) from time zero to time of last quantifiable concentration (AUC last ), AUC from time zero to infinity (AUC ); and the terminal half-life (t 1/2 ). Individual concentration-time profiles were summarized by subpopulation (GC-I and GC-C), while mean (± standard deviation [SD]) concentration-time profiles were summarized by subpopulation as well as for the combined data for both subpopulations. Safety Analyses: Subject incidence of treatment-emergent adverse events during the 12-month primary analysis period is summarized by treatment for all adverse events, treatment-related adverse events, serious adverse events, fatal adverse events, and adverse events leading to withdrawal of investigational product or to withdrawal from study. All adverse events, treatment-related adverse events, serious adverse events, and fatal adverse events are also summarized by sex. Adverse events of interest are summarized, including hypocalcemia, positively adjudicated osteonecrosis of the jaw (ONJ), adverse events potentially associated with hypersensitivity, serious infection, serious bacterial cellulitis (skin infection), malignancy, cardiac disorders, vascular disorders, positively adjudicated atypical femoral fracture, eczema, acute pancreatitis, and musculoskeletal pain. Osteonecrosis outside the jaw is also summarized. Serious infections are summarized in subjects with or without concomitant biologics use and in subjects with or without non-biologic immunosuppressant agents (other than glucocorticoids) or concomitant biologics use. For laboratory tests, the actual value by visit, change from baseline by visit, and CTCAE version 3.0 shift tables for the largest shift from baseline are summarized for each parameter. Percent change from baseline was summarized for albumin-corrected calcium, serum phosphorus, and alkaline phosphatase. Subjects with aspartate aminotransferase or alanine aminotransferase > 3 times the upper limit of normal (ULN), total bilirubin > 2 times ULN, and alkaline phosphatase < 2 times ULN within 7 days are also evaluated. For vital signs, summary statistics are provided for blood pressure, pulse, and temperature by treatment and visit for actual values, changes, and percent changes from baseline. Summary of Results: Subject Disposition: Overall, 795 subjects were enrolled, 398 who were randomized to denosumab and 397 who were randomized to risedronate. Overall, 394 subjects received denosumab and 384 subjects received risedronate. In the GC-I subpopulation, 145 subjects were randomized to denosumab and 145 subjects were randomized to risedronate. In the GC-C subpopulation, 253 subjects were randomized to denosumab and 252 subjects were randomized to risedronate. During the 12-month primary analysis period in the GC-I subpopulation, the study discontinuation rate was somewhat higher in the denosumab group (15.9%) than in the risedronate group (9.7%), which was related to a higher rate of withdrawal of consent in the denosumab group. The rate of discontinuation from the study due to adverse events was similar between treatment groups (denosumab, 3.4%; risedronate, 2.8%). In the GC-C subpopulation, the study discontinuation rate was similar in the denosumab
Date: 21 November 2016 Page 5 (14.2%) and risedronate (12.3%) groups, and the rate of discontinuation from the study due to adverse events was also similar between treatment groups (denosumab, 3.6%; risedronate, 3.2%). Baseline Demographics by Subpopulation (all randomized subjects) Sex: GC-I: 104 men (35.9%), 186 women (64.1%); GC-C: 135 men (26.7%), 370 women (73.3%) Age: GC-I: mean (standard deviation [SD]) 65.9 (10.1) years; GC-C: mean (SD) 61.4 (11.3) years Race: GC-I: white, 245 (84.5%); other, 23 (7.9%); Asian, 18 (6.2%); black or African-American, 4 (1.4%) GC-C: white, 453 (89.7%); other, 24 (4.8%), Asian 18 (3.6%); black or African-American, 8 (1.6%); American Indian or Alaskan native, 1 (0.2%); multiple, 1 (0.2%). Ethnicity: GC-I: Hispanic/Latino 38 (13.1%); not Hispanic/Latino, 252 (86.9%) GC-C: Hispanic/Latino, 97 (19.2%); not Hispanic/Latino, 408 (80.8%) Efficacy Results: Results of the primary analysis of the primary endpoint, percent change from baseline in lumbar spine BMD at 12 months (noninferiority) for the GC-I and GC-C subpopulations at month 12, are shown in Table S-1. The difference in mean percent change from baseline in lumbar spine BMD at 12 months between treatment groups (denosumab versus risedronate) was 2.9 percentage points (95% CI: 2.0, 3.9) in the GC-I subpopulation; the lower bound of the 95% CI was above the noninferiority margin of -1.1 percentage points (p < 0.001). The difference in mean percent change from baseline in lumbar spine BMD at 12 months between treatment groups (denosumab versus risedronate) was 2.2 percentage points (95% CI: 1.4, 3.0) in the GC-C subpopulation; the lower bound of the 95% CI was above the noninferiority margin of -0.7 percentage points (p < 0.001). Noninferiority was demonstrated for the primary endpoint in both the GC-I and GC-C subpopulations.
Date: 21 November 2016 Page 6 Table S-1. Primary Efficacy Analysis: Percent Change From Baseline in Bone Mineral Density in the Lumbar Spine at Month 12, (ANCOVA Model, Noninferiority) (Primary Efficacy Analysis Set, Observed Data) Risedronate 5 mg QD Denosumab 60 mg Q6M GC-I subpopulation (N = 133) (N = 128) n 126 119 Difference From Risedronate LS mean (95% CI) a,b 0.8 (0.2, 1.5) 3.8 (3.1, 4.5) 2.9 (2.0, 3.9) p-value (noninferiority) c < 0.001 GC-C subpopulation (N = 230) (N = 228) n 211 209 LS mean (95% CI) a,b 2.3 (1.7, 2.9) 4.4 (3.8, 5.0) 2.2 (1.4, 3.0) p-value (noninferiority) c < 0.001 ANCOVA = analysis of covariance; BMD = bone mineral density; CI = confidence interval; GC-C = glucocorticoid-continuing; GC-I = glucocorticoid-initiating; LS = least squares; n = number of subjects with observed values; N = number of subjects randomized with a baseline measurement and at least 1 postbaseline measurement for the lumbar spine BMD; QD = once daily; Q6M = every 6 months. a Based on ANCOVA model adjusting for treatment, baseline BMD value, sex, machine type, and baseline BMD value-by-machine type interaction. The duration of prior glucocorticoid use (< 12 months versus 12 months) was also added for the GC-C subpopulation only. b Two-sided confidence interval. c One-sided p-value based on the prespecified noninferiority margins for lumbar spine of -1.1% in the GC-I subpopulation and -0.7% in the GC-C subpopulation. Source: Table 14-4.1.1, Table 14-4.1.2 For lumbar spine and total hip BMD, the increase in BMD was significantly greater with denosumab treatment than with risedronate treatment in both subpopulations (p < 0.001 in all comparisons) (Figure S-1).
Date: 21 November 2016 Page 7 Figure S-1. Percent Change From Baseline to Month 12 in Lumbar Spine Bone Mineral Density by Visit and Treatment in (A) Glucocorticoid-initiating and (B) Glucocorticoid-continuing Subpopulations (ANCOVA Model), Least Squares Means and 95% Confidence Intervals) A Percent Change From Baseline 4 3 2 1 Denosumab 60 mg Q6M (N = 128) Risedronate 5 mg QD (N = 133) 0 Denosumab (n=) Risedronate (n=) *** *** 128 127 119 133 128 126 BL 6 12 N = Number of subjects randomized w ith a baseline measurement and at least one postbaseline measurement for the lumbar spine BMD n = Number of subjects w ith observed data Point estimates and nominal 95% confidence intervals are based on ANCOVA model adjusting for treatment, baseline BMD value, gender, machine type, and baseline BMD value-by-machine type interaction. * p-value 0.05; ** p-value 0.025; *** p-value 0.001 Percent Change From Baseline 5 4 3 2 1 Denosumab 60 mg Q6M (N = 228) Risedronate 5 mg QD (N = 230) B Study Month 0 Denosumab (n=) Risedronate (n=) ** *** 228 224 209 230 227 211 BL 6 12 N = Number of subjects randomized w ith a baseline measurement and at least one postbaseline measurement for the lumbar spine BMD n = Number of subjects w ith observed data Point estimates and nominal 95% confidence intervals are based on ANCOVA model adjusting for treatment, baseline BMD value, gender, machine type, baseline BMD value-by-machine type interaction, and duration of prior glucocorticoid use (< 12 months vs 12 months). * p-value 0.05; ** p-value 0.025; *** p-value 0.001 Study Month BL = baseline; ANCOVA = analysis of covariance; BMD = bone mineral density; Q6M = every 6 months, QD = once daily.
Date: 21 November 2016 Page 8 In the GC-I subpopulation, percent change from baseline to month 12 in femoral neck, trochanter, and 1/3 radius BMD was statistically significantly greater with denosumab than with risedronate treatment. In the GC-C subpopulation, percent change from baseline to month 12 in femoral neck and trochanter BMD was significantly greater with denosumab than with risedronate. Pharmacokinetic Results: Following the first dose of denosumab 60 mg SC, mean (SD) denosumab exposures (C max and AUC last ) were similar in the GC-I (6.01 [2.04] µg/ml and 344 [182] day µg/ml, respectively) and GC-C (6.13 [2.88] µg/ml and 314 [192] day µg/ml, respectively) subpopulations, with a median t max of 9.9 days for both groups. Similar mean half-life values were also observed for the 2 subpopulations (17.6 and 17.4 days for the GC-I and GC-C subpopulations, respectively). Mean serum trough concentrations were similar at 6 and 12 months (< 1.79- and 1.20-fold different for GC-I and GC-C subpopulations, respectively), indicating that denosumab PK did not change with time or upon multiple dosing. Denosumab exposure in subjects with glucocorticoid-induced osteoporosis (GIOP) was consistent with that observed previously in subjects with postmenopausal osteoporosis (Study 20030216). Bone Turnover Marker Results: During the 12-month primary analysis period, levels of sctx decreased significantly more with denosumab than with risedronate treatment at day 10 and months 3, 4, 5, and 6; the difference between treatment groups in percent change from baseline to month 12 was not statistically significant. Levels of P1NP decreased significantly more with denosumab than with risedronate treatment at months 3, 4, 5, and 6; the difference between treatment groups in percent change from baseline to day 10 and to month 12 was not statistically significant. Bone Biopsy Results: A total of 21 subjects agreed to participate in the bone biopsy substudy. Four subjects withdrew consent before a biopsy was obtained. The 17 remaining subjects (6 denosumab, 11 risedronate) received 1 dose of investigational product and had an evaluable biopsy at month 12. All biopsies were evaluable for histology. Bone biopsies collected after 12 months of treatment with denosumab or risedronate showed normal bone histology. There was evidence of normal lamellar bone, normal mineralization, and normal osteoid in both treatment groups. There was no evidence of osteomalacia, marrow fibrosis, woven bone, other clinically significant marrow abnormality in either treatment group. Biopsies from 10 subjects (3 denosumab, 7 risedronate) were evaluable for histomorphometry. As expected, resorption and formation parameters were nominally lower in subjects treated with denosumab than risedronate, consistent with a lower rate of bone remodeling. Wall thickness and width were slightly but statistically significantly higher in the denosumab-treated subjects compared with those treated with risedronate. Antidenosumab Antibody Assay Results: One of 394 subjects who received denosumab (0.3%) tested positive for binding antidenosumab antibodies at month 12; the subject tested negative for neutralizing antibodies.
Date: 21 November 2016 Page 9 Safety Results: During the 12-month primary analysis period, the subject incidence of adverse events was similar between treatment groups for all adverse events, serious adverse events, adverse events leading to discontinuation of investigational product, and adverse events leading to discontinuation from the study. Overall, adverse events were reported in 72.3% of subjects in the denosumab group and 69.0% of subjects in the risedronate group. No preferred term was reported at an incidence of > 5% in the denosumab group. The most frequent adverse events in the denosumab group were back pain (denosumab, 4.6%; risedronate 4.4%) and arthralgia (denosumab, 4.3%; risedronate 5.5%). Overall, 25 subjects (6.3%) in the denosumab group and 29 subjects (7.6%) in the risedronate group discontinued investigational product due to adverse events. The most frequent events leading to investigational product discontinuation in the denosumab group were dyspepsia and abdominal distension. By preferred term, no serious adverse event was reported in 2% of subjects in either treatment group. Fatal adverse events were reported in 6 subjects (1.5%) in the denosumab group and 2 subjects (0.5%) in the risedronate group. Three additional deaths were reported in subjects randomized to risedronate. These subjects were not included in the safety analysis set, because it was not possible to confirm that they had taken at least 1 dose of oral investigational product (the 3 subjects died prior to their month 6 visit and oral drug accountability verification). None of the deaths in either treatment group was considered related to investigational product. Adverse events of interest were reported at similar rates in the denosumab and risedronate groups. No positively adjudicated ONJ was reported. One subject in the denosumab group with a long history of receiving glucocorticoid therapy had positively adjudicated atypical femoral fracture. A similar rate of serious adverse events of infection was observed in the denosumab (17 subjects, 4.3%) and risedronate (15 subjects, 3.9%) groups. The most common serious adverse event of infection was pneumonia, which was reported for 5 subjects (1.3%) in the denosumab group and 6 subjects (1.6%) in the risedronate group. By preferred term, no other serious infection was reported in > 1 subject in the denosumab group. Conclusions: Results from the 12-month primary analysis of Study 20101217 demonstrate the following: Noninferiority was demonstrated for the primary endpoint of percent change from baseline in lumbar spine BMD by DXA at 12 months for each subpopulation (GC-I and GC-C). The treatment differences at the lumbar spine were 2.9% (95% CI: 2.0, 3.9) for the GC-I subpopulation and were 2.2% (95% CI: 1.4, 3.0) for the GC-C subpopulation. In each subpopulation, the lower bound of the 95% CI of the treatment difference (denosumab - risedronate) was above the prespecified noninferiority margin (-1.1% for the GC-I subpopulation; -0.7% for the GC-C subpopulation; p < 0.001). For both the GC-C and GC-I subpopulations, the percent increase from baseline in lumbar spine and total hip BMD by DXA at month 12 was significantly greater in the denosumab group compared with the risedronate group (p < 0.001; secondary endpoints).
Date: 21 November 2016 Page 10 Following the first dose of denosumab 60 mg SC, mean (SD) denosumab exposures (C max and AUC last ) were similar in the GC-I (6.01 [2.04] µg/ml and 344 [182] day µg/ml, respectively) and GC-C (6.13 [2.88] µg/ml and 314 [192] day µg/ml, respectively) subpopulations, with a median t max of 9.9 days for both groups. Similar mean half-life values were also observed for the 2 subpopulations (17.6 and 17.4 days for the GC-I and GC-C subpopulations, respectively). Mean serum trough concentrations were similar at 6 and 12 months (< 1.79- and 1.20-fold different for GC-I and GC-C subpopulations, respectively), indicating that denosumab PK did not change with time or upon multiple dosing. Bone turnover markers (sctx and P1NP) decreased statistically significantly more with denosumab than with risedronate treatment at months 3, 4, 5, and 6, but not at month 12. Serum CTX was also significantly decreased compared with risedronate on day 10. Similar subject incidence rates of adverse events, serious adverse events, and adverse events leading to discontinuation of investigational product or to discontinuation from the study over 12 months were observed in the denosumab and risedronate groups (safety endpoints). A similar subject incidence rate of serious adverse events of infection was observed in the denosumab and risedronate groups. In both treatment groups, the most commonly reported serious adverse event of infection was pneumonia. The benefit/risk profile of denosumab is favorable in subjects with GIOP.