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Romosozumab or alendronate for fracture prevention in East Asian patients: a subanalysis of the phase III, randomized ARCH study.

ABSTRACT: Romosozumab, a sclerostin antibody, exerts dual effect to increase bone formation and decrease bone resorption. Among high-risk postmenopausal East Asian women, romosozumab followed by alendronate was associated with lower incidences of fractures vs alendronate alone. Romosozumab demonstrates potential to address an unmet need in osteoporosis management in Asia. INTRODUCTION:Romosozumab, a sclerostin antibody, exerts dual effect to increase bone formation and decrease bone resorption. The global ARCH study demonstrated superiority of romosozumab followed by alendronate in reducing fracture risk in high-risk postmenopausal osteoporotic women vs alendronate alone. We report outcomes among ARCH East Asian patients. METHODS:In ARCH, 4093 postmenopausal osteoporotic women with fragility fracture were randomized 1:1 to monthly romosozumab 210 mg or weekly alendronate 70 mg for 12 months, both followed by open-label alendronate. Primary endpoints were incidence of new vertebral fracture (VF) at 24 months and clinical fracture at primary analysis (confirmed fractures in ??330 patients and all patients had opportunity to attend month 24 visit). This post hoc analysis was not powered to detect fracture-rate differences. RESULTS:This analysis included 275 patients from Hong Kong, Korea, and Taiwan. Romosozumab followed by alendronate reduced risk of new VFs at 24 months by 60% (P?=?0.11) and clinical fractures at primary analysis by 44% (P?=?0.15) vs alendronate alone. Romosozumab followed by alendronate significantly increased mean bone mineral density at 24 months from baseline by a further 9.0%, 3.3%, and 3.0% at the lumbar spine, total hip, and femoral neck vs alendronate alone. Adverse event (AE) rates, including positively adjudicated serious cardiovascular AEs (1.6% vs 1.4% at 12 months for romosozumab vs alendronate), were similar across treatment groups. CONCLUSIONS:Consistent with the global analysis, romosozumab followed by alendronate was associated with lower incidences of new vertebral, clinical, non-vertebral, and hip fractures vs alendronate alone among East Asian patients.

SUBMITTER: Lau EMC

PROVIDER: S-EPMC7075830 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Romosozumab or alendronate for fracture prevention in East Asian patients: a subanalysis of the phase III, randomized ARCH study.

Lau E M C EMC Dinavahi R R Woo Y C YC Wu C-H CH Guan J J Maddox J J Tolman C C Yang W W Shin C S CS

Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 20200211 4

Romosozumab, a sclerostin antibody, exerts dual effect to increase bone formation and decrease bone resorption. Among high-risk postmenopausal East Asian women, romosozumab followed by alendronate was associated with lower incidences of fractures vs alendronate alone. Romosozumab demonstrates potential to address an unmet need in osteoporosis management in Asia.<h4>Introduction</h4>Romosozumab, a sclerostin antibody, exerts dual effect to increase bone formation and decrease bone resorption. The ...[more]

PMID: 32047951

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Project description:In the Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH) clinical trial (NCT01631214), 1 year of romosozumab followed by alendronate reduced the risk of vertebral and nonvertebral fractures compared to alendronate alone in women with prevalent fracture. We performed post hoc analyses of data from patients in ARCH (romosozumab, n = 1739; alendronate, n = 1726) who had a baseline BMD measurement and received at least one open-label alendronate dose. We evaluated 1-year mean BMD and corresponding T-score changes; proportions of patients achieving T-scores > -2.5 at the total hip (TH), femoral neck (FN), and lumbar spine (LS); and group differences in fracture rates after 12 months, while all participants were on alendronate. Subsequently, we investigated the relationship between T-scores achieved at the TH, FN, and LS at 12 months and subsequent fracture incidence. At 1 year, mean change from baseline in TH BMD was 6.3% (T-score change 0.31) with romosozumab versus 2.9% (T-score change 0.15) with alendronate (p < .001). The proportion of patients with TH T-score > -2.5 increased from 34% at baseline to 55% after 1 year of romosozumab and from 32% at baseline to 44% after 1 year of alendronate. Compared with patients receiving alendronate in year 1, those receiving romosozumab had a 75% reduction in new or worsening vertebral fracture (p < .001) in year 2, and a 19% reduction in nonvertebral fracture (p = .120) and 40% reduction in hip fracture (p = .041) during the open-label period. TH and FN T-scores achieved at month 12 were associated with subsequent nonvertebral and vertebral fracture rates and the relationships were independent of treatment received. LS T-score at 12 months was associated with vertebral but not nonvertebral fracture risk. We conclude that 1 year of romosozumab leads to larger BMD gains versus alendronate, and that the T-score achieved with either therapy is related to subsequent fracture risk. These data support the use of T-score as a therapeutic target for patients with osteoporosis. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Project description:The Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH) trial (NCT01631214; https://clinicaltrials.gov/ct2/show/NCT01631214) showed that romosozumab for 1 year followed by alendronate led to larger areal bone mineral density (aBMD) gains and superior fracture risk reduction versus alendronate alone. aBMD correlates with bone strength but does not capture all determinants of bone strength that might be differentially affected by various osteoporosis therapeutic agents. We therefore used quantitative computed tomography (QCT) and finite element analysis (FEA) to assess changes in lumbar spine volumetric bone mineral density (vBMD), bone volume, bone mineral content (BMC), and bone strength with romosozumab versus alendronate in a subset of ARCH patients. In ARCH, 4093 postmenopausal women with severe osteoporosis received monthly romosozumab 210 mg sc or weekly oral alendronate 70 mg for 12 months, followed by open-label weekly oral alendronate 70 mg for ≥12 months. Of these, 90 (49 romosozumab, 41 alendronate) enrolled in the QCT/FEA imaging substudy. QCT scans at baseline and at months 6, 12, and 24 were assessed to determine changes in integral (total), cortical, and trabecular lumbar spine vBMD and corresponding bone strength by FEA. Additional outcomes assessed include changes in aBMD, bone volume, and BMC. Romosozumab caused greater gains in lumbar spine integral, cortical, and trabecular vBMD and BMC than alendronate at months 6 and 12, with the greater gains maintained upon transition to alendronate through month 24. These improvements were accompanied by significantly greater increases in FEA bone strength (p < 0.001 at all time points). Most newly formed bone was accrued in the cortical compartment, with romosozumab showing larger absolute BMC gains than alendronate (p < 0.001 at all time points). In conclusion, romosozumab significantly improved bone mass and bone strength parameters at the lumbar spine compared with alendronate. These results are consistent with greater vertebral fracture risk reduction observed with romosozumab versus alendronate in ARCH and provide insights into structural determinants of this differential treatment effect. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Project description:BACKGROUND:Fluticasone furoate (FF)/vilanterol (VI) is a once daily (OD) inhaled corticosteroid/long-acting ?2-agonist combination asthma therapy approved in Japan and the EU. FF/VI efficacy and safety data from asthma studies including patients in East Asia were evaluated to assess ethnic sensitivity. METHODS:Randomized, double-blind, multicenter Phase IIb/III trials were assessed. Change from baseline relative to placebo or twice-daily fluticasone propionate 500 ?g in trough FEV1 was compared between patients from Japan (N?=?148) and Not-Japan (N?=?3,066; three studies). Adverse events (AEs), laboratory results, and electrocardiograms were compared between patients from Japan?+?Korea (N?=?188) and Not-Japan?+?Korea (N?=?3,840; five studies). RESULTS:For trough FEV1, improvements from baseline (least-squares mean difference [95% confidence interval]) were reported for FF/VI 100/25 ?g OD versus placebo at Week 12 (Japan: 0.323 L [0.104-0.542]; Not-Japan: 0.168 L [0.095-0.241]). Improvements from baseline (least-squares mean change [standard error]) were reported with FF/VI 200/25 ?g OD at Week 24 (Japan: 0.355 L [0.1152]; Not-Japan: 0.396 L [0.0313]). A greater proportion of patients from Japan?+?Korea versus Not-Japan?+?Korea reported AEs in all treatment arms including placebo (FF/VI 100/25 ?g: 79% versus 57%; FF/VI 200/25 ?g: 64% versus 45%; placebo: 41% versus 23%). There were no notable differences in treatment-related or class-related AEs. No clinically significant changes in electrocardiogram assessments or statistically significant differences in 24 h urinary cortisol excretion were observed between the Japan?+?Korea and Not-Japan?+?Korea cohorts. CONCLUSIONS:Good efficacy and an acceptable safety profile were observed for FF/VI 100/25 ?g and 200/25 ?g OD in East Asian asthma patients; these globally recommended doses are appropriate for asthma patients in Japan. TRIAL REGISTRATION:Clinicaltrials.gov registration numbers: NCT01165138 , NCT01134042 , NCT01086384 , NCT00603278 , NCT00603382 .

Project description:BackgroundRECORD-4 assessed everolimus in patients with metastatic renal cell carcinoma (mRCC) who progressed after 1 prior anti-vascular endothelial growth factor (VEGF) or cytokine and reinforced the clinical benefit of second-line everolimus. Because of the high percentage of patients from China enrolled in RECORD-4 (41%) and some reported differences in responses to certain targeted agents between Chinese and Western patients, this subanalysis evaluated outcomes in Asian versus non-Asian patients.MethodsRECORD-4 enrolled patients with clear cell mRCC into 3 cohorts based on prior first-line therapy: sunitinib, other anti-VEGF (sorafenib, bevacizumab, pazopanib, other), or cytokines. Patients received everolimus 10 mg/d until progression of disease (RECIST, v1.0) or intolerance. Primary end point was progression-free survival per investigator review. Data cutoff was Sept 1, 2014.ResultsAmong Asian (n = 55) versus non-Asian (n = 79) patients, 98% versus 84% had good/intermediate MSKCC prognosis; 73% versus 65% were men, and 85% versus 73% were < 65 years of age. All (100%) Asian patients were of Chinese ethnicity. Median duration of exposure was 5.5 mo for Asian and 6.0 mo for non-Asian patients. Among Asian versus non-Asian patients, median progression-free survival (months) was 7.4 versus 7.8 overall, 7.4 versus 4.0 with prior sunitinib, and 5.7 versus 9.2 with prior other anti-VEGFs. Clinical benefit rate was similar between populations: 74.5% (95% CI 61.0-85.3) for Asian patients and 74.7% (95% CI 63.6-83.8) for non-Asian patients. Most patients achieved stable disease as best overall response (Asian, 63.6%; non-Asian, 69.6%). Overall rate of grade 3/4 adverse events appeared similar for Asian (58%) and non-Asian patients (54%).ConclusionsThis RECORD-4 subanalysis demonstrated comparable efficacy and adverse event profiles of second-line everolimus in Asian and non-Asian patients. Efficacy and safety outcomes by prior therapy should be interpreted with caution because of small patient numbers in some subpopulations.Trial registrationEverolimus as Second-line Therapy in Metastatic Renal Cell. Carcinoma (RECORD-4); ClinicalTrials.gov identifier: NCT01491672 . Registration date: December 14, 2011.

Dataset Information

Romosozumab or alendronate for fracture prevention in East Asian patients: a subanalysis of the phase III, randomized ARCH study.

Publications

Romosozumab or alendronate for fracture prevention in East Asian patients: a subanalysis of the phase III, randomized ARCH study.

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