Romosozumab, clinical trials, and real-world care of patients with osteoporosis.
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ABSTRACT:
SUBMITTER: Lewiecki EM
PROVIDER: S-EPMC7475409 | biostudies-literature | 2020 Aug
REPOSITORIES: biostudies-literature
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Romosozumab, clinical trials, and real-world care of patients with osteoporosis.
Annals of translational medicine 20200801 15
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Project description:IntroductionThe results of clinical trials in metastatic breast cancer (MBC) are generalized to real-world patients. This study determines the proportion of real-world patients who would be eligible for clinical trials and compares outcomes in eligible versus ineligible patients.MethodsPatients diagnosed with MBC from 2004 to 2015 in a large Canadian province were included. Patients with one of the following criteria were considered ineligible: the presence of comorbid conditions (anemia, uncontrolled diabetes, heart disease, liver disease, and kidney disease) or a history of immunosuppression or prior malignancy. The likelihood of receiving cancer therapy was analysed using logistic regression models and factors affecting overall survival (OS) were assessed by Cox proportional hazards models.ResultsA total of 1585 patients with MBC were identified. The median age at diagnosis was 63 years. Of these, 512 (32.3%) patients were deemed ineligible in whom the two most common reasons for ineligibility were renal dysfunction (17.2%), and previous immunosuppression (7.8%). In the real world, ineligible patients were less likely to receive chemotherapy (29.5% vs 45.8%; P < 0.001) but not radiation treatment (7.6% vs 9.6%; P = 0.196) or hormonal therapy (57.6% vs 60.6%; P = 0.261). The 5-year OS of ineligible patients who received systemic therapy in the real-world was significantly better than those who did not.ConclusionsDespite being ineligible for clinical trials based on common eligibility criteria, many real-world patients receive systemic treatment and derive possible benefit. Broadening of inclusion criteria in clinical trials will enhance the representation of real-world patients and increase the generalizability of results.
| S-EPMC7586241 | biostudies-literature
Project description:Real-world data on the new anti-sclerostin antibody drug, romosozumab, remain scarce. There is a strong need to accumulate and analyze data on romosozumab treatment for such conditions as osteoporosis. The purpose of this study was to investigate the therapeutic and adverse effects of romosozumab for osteoporosis treatment in clinical practice. Of the 230 osteoporosis patients prescribed romosozumab from September 2019 in this prospective multicenter cohort study, 204 patients completed 12 months of treatment. The primary outcome of interest was the rate of change in bone mineral density (BMD) of the lumbar spine, total hip, and femoral neck as measured by dual-energy X-ray absorptiometry. Secondary outcomes included changes in bone turnover markers and serum-corrected calcium level as well as the incidence of adverse events. At 6 and 12 months of romosozumab treatment, the respective percentage change in BMD from baseline was 7.4% and 12.2% for the lumbar spine, 1.8% and 5.8% for the total hip, and 2.9% and 6.0% for the femoral neck, all of which were significantly higher (P < 0.001) than baseline values. Patients who switched from another osteoporosis regimen exhibited significantly lower lumbar spine BMD gains versus treatment-naïve patients, especially for cases switching from denosumab. P1NP was significantly increased at 6 months (58.9%; P < 0.01), while TRACP-5b was significantly decreased at 6 months (-14.7%; P < 0.001) and 12 months (-18.8%; P < 0.001) versus baseline values. The largest rate of decrease in serum-corrected calcium was 3.7% at 12 months. Sixty-four (27.8%) of 230 patients experienced an adverse event, and 7 (3.0%) new fractures were recorded. In sum, romosozumab treatment for 12 months significantly improved lumbar spine, total hip, and femoral neck BMD according to real-world data.
| S-EPMC8085670 | biostudies-literature
Project description:The CASPIAN and IMpower133 trials revealed a significant survival benefit of chemotherapy plus immunotherapy in patients with extensive-stage SCLC. The current study characterizes the proportion of real-world patients who would have met eligibility for these trials and highlights factors influencing eligibility in the real-world setting. A retrospective analysis of patient data was conducted for stage IV patients with SCLC treated at the Cancer Centre of Southeastern Ontario, Canada. Trial eligibility was based on criteria used in the IMpower133 and CASPIAN trials. Data were summarized using descriptive statistics. Overall survival was assessed using the Kaplan-Meier method. Of the 116 patients included, only 12.1% met the overall eligibility criteria for the IMpower133 trial, and 14.7% for the CASPIAN trial. The most common reasons for ineligibility included: Eastern Cooperative Oncology Group (ECOG) 2 or greater (77.5%), inadequate organ function (48%), and the presence of brain metastases at diagnosis (37.3%). Sixty-one patients (59.8%) met two or more major ineligibility criteria. If trial eligibility was expanded to include ECOG 2 patients, an additional 10.3% would have met eligibility. The median overall survival for all-comers was 6.5 months. Only a small minority of real-world patients with extensive-stage SCLC would have met eligibility for the IMpower133 and CASPIAN trials, with ECOG greater than or equal to 2, inadequate organ function, and brain metastases comprising the most common reasons for trial ineligibility. Future clinical trials should expand the inclusion criteria to better represent real-world patient populations.
| S-EPMC11293570 | biostudies-literature
Project description:Romosozumab, a specific inhibitor of sclerostin, is a unique approach to therapy for postmenopausal osteoporosis and related disorders. The elucidation of sclerostin deficiency as the molecular defect of syndromes of high bone mass with normal quality, and the pivotal role of sclerostin as a mediator of osteoblastic activity and bone formation, provided the platform for the evaluation of inhibitors of sclerostin to activate bone formation. An extensive preclinical program and 2 large fracture endpoint trials with romosozumab, a sclerostin-binding antibody, have been completed. This review will highlight the results of those studies and describe the current status of romosozumab as a potential therapy for osteoporosis.
| S-EPMC6362945 | biostudies-literature
Project description:This observational study assessed the impact on the fracture incidence of osteoporosis medications in postmenopausal women in Germany. Continued treatment with osteoporosis medications was associated with reductions of fracture rates in a real-world setting.PurposeThe efficacy of osteoporosis medications has been demonstrated in clinical trials, but a lack of evidence exists of their real-world effectiveness. This real-world study assessed the treatment patterns and impact on the fracture incidence of osteoporosis medications in postmenopausal women in Germany.MethodsThis cohort study used data from the WIG2 benchmark database, a German anonymised healthcare claims database. All women ≥ 50 years of age with ≥ 1 prescription for osteoporosis medication between 1 January 2013 and 31 December 2017 were included. The primary outcome was treatment effectiveness, evaluated as the change in fracture incidence after initiating treatment. Fracture types included all fractures, clinical vertebral, hip and wrist/forearm. Fracture incidence was assessed during the early-treatment period (0-3 months) and the on-treatment period (4-12, 13-24, 25-36 and 37-48 months).ResultsBaseline covariates and treatment patterns were determined for 41,861 patients. The median duration of therapy was longer with denosumab (587 days) than with intravenous ibandronate (451 days), intravenous zoledronate (389 days) or oral bisphosphonates (258 days). The baseline incidence rate of all fractures was higher in patients receiving denosumab than in those receiving other treatments (87.6, 78.2, 56.6 and 66.0 per 1000 person-years for denosumab, oral bisphosphonates, intravenous ibandronate and intravenous zoledronate, respectively). Rates of all fractures declined with continued denosumab (by 38%, 50%, 56% and 67% at 12, 24, 36 and 48 months, respectively) and oral bisphosphonates (by 39%, 44%, 49% and 42%, respectively) treatment.ConclusionContinued treatment with osteoporosis medications was associated with reductions of fracture rates in a real-world setting.
| S-EPMC9512727 | biostudies-literature
Project description:The glycoprotein sclerostin inhibits activation of the canonical Wnt pathway and thereby suppresses bone formation by inhibiting the osteoblasts. Additionally, sclerostin increases bone resorption by stimulating the production of receptor activator of nuclear factor kappa-?-ligand (RANKL). Romosozumab (ROMO) is a monoclonal antibody against sclerostin. Phase III clinical trials in postmenopausal women with osteoporosis have shown that ROMO increases bone mineral density at the lumbar spine and hip and reduces the risk of vertebral and clinical fractures in comparison with placebo. In women with severe osteoporosis, ROMO reduces the risk of vertebral, nonvertebral and clinical fractures in comparison with alendronate. ROMO is the first treatment for osteoporosis with dual action, and may become a valuable tool for improving the treatment of osteoporosis. At present, the approval of ROMO by the authorities is awaiting further investigations of a potential increased risk of cardiovascular events associated with ROMO treatment.
| S-EPMC6009094 | biostudies-literature
Project description:As one of the most potent osteoanabolic agents with a unique mechanism of action, romosozumab has high efficacy for osteoporosis treatment. It is a monoclonal antibody against sclerostin, a natural inhibitor of the Wnt signaling pathway, and by inhibiting sclerostin, activation of Wnt signaling occurs with a cascade of changes ultimately leading to bone mineral density (BMD) gains. Romosozumab stimulates bone modeling and has a dual effect of activating bone formation while inhibiting bone resorption. With this unique mechanism of action, treatment with romosozumab leads to a rapid and significant gain in BMD; these gains are higher than seen with bisphosphonates, denosumab, or parathyroid hormone (PTH) analogs. The FRAME and ARCH studies represent two pivotal trials demonstrating the efficacy of romosozumab in treating osteoporosis. Treatment with romosozumab should be followed by an antiresorptive agent, as this approach has demonstrated maintenance of or greater increases in BMD and reduced fracture risk even after finishing romosozumab treatment. As an osteoanabolic agent, romosozumab has shown superiority to alendronate in reducing fracture risk, increasing bone density, and potentially more rapid fracture risk reduction. Recent data have suggested that romosozumab prior to antiresorptive therapy may be the ideal treatment sequence, especially in high-risk patients and patients at imminent risk of fracture. Carrying a black box warning, romosozumab should be avoided in patients who have had myocardial infarction or stroke in the past year. Further studies are needed to clarify the increased cardiovascular risk attributed to this drug. Romosozumab has expanded our osteoporosis armamentarium and has enabled novel approaches, including "treat to target." Future studies are needed to evaluate the optimal use sequence and to assess its safety, especially in patients with cardiovascular risk factors.
| S-EPMC9762257 | biostudies-literature
Project description:BackgruoundPersistence with denosumab in male patients has not been adequately investigated, although poor denosumab persistence is associated with a significant risk of rebound vertebral fractures.MethodsWe retrospectively evaluated 294 Korean male osteoporosis patients treated with denosumab at three medical centers and examined their persistence with four doses of denosumab injection over 24 months of treatment. Persistence was defined as the extent to which a patient adhered to denosumab treatment in terms of the prescribed interval and dose, with a permissible gap of 8 weeks. For patients who missed their scheduled treatment appointment(s) during the follow-up period (i.e., no-shows), Cox proportional regression analysis was conducted to explore the factors associated with poor adherence. Several factors were considered, such as age, prior anti-osteoporotic drug use, the treatment provider's medical specialty, the proximity to the medical center, and financial burdens of treatment.ResultsOut of 294 male patients, 77 (26.2%) completed all four sequential rounds of the denosumab treatment. Out of 217 patients who did not complete the denosumab treatment, 138 (63.6%) missed the scheduled treatment(s). Missing treatment was significantly associated with age (odds ratio [OR], 1.03), prior bisphosphonate use (OR, 0.76), and prescription by non-endocrinologists (OR, 2.24). Denosumab was stopped in 44 (20.3%) patients due to medical errors, in 24 (11.1%) patients due to a T-score improvement over -2.5, and in five (2.3%) patients due to expected dental procedures.ConclusionOur study showed that only one-fourth of Korean male osteoporosis patients were fully adherent to 24 months of denosumab treatment.
| S-EPMC10164495 | biostudies-literature
Project description:BACKGROUND:There are few third-line or later (3L+) treatment options for advanced/metastatic (adv/met) gastric cancer/gastroesophageal junction cancers (GC/GEJC). 3L+ Nivolumab demonstrated encouraging results in Asian patients in the ATTRACTION-2 study compared with placebo (12-month survival, 26% vs 11%), and in Western patients in the single-arm CheckMate 032 study (12-month survival, 44%). This analysis aimed to establish comparator cohorts of US patients receiving routine care in real-world (RW) clinical practice. METHODS:A 2-step matching process generated RW cohorts from Flatiron Health's oncology database (January 1, 2011-April 30, 2017), for comparison with each trial: (1) clinical trial eligibility criteria were applied; (2) patients were frequency-matched with trial arms for baseline variables significantly associated with survival. Median overall survival (OS) was calculated by Kaplan-Meier analysis from last treatment until death. RESULTS:Of 742 adv/met GC/GEJC patients with at least 2 prior lines of therapy, matching generated 90 US RW ATTRACTION-2-matched patients (median OS: 3.5 months) versus 163 ATTRACTION-2 placebo patients (median OS: 4.1 months), and 100 US RW CheckMate 032-matched patients (median OS: 2.9 months) versus 42 CheckMate 032 nivolumab-treated patients (median OS: 8.5 months). Baseline characteristics were generally similar between clinical trial arms and RW-matched cohorts. CONCLUSIONS:We successfully developed RW cohorts for comparison with data from clinical trials, with comparable baseline characteristics. Survival in US patients receiving RW care was similar to that seen in Asian patients receiving placebo in ATTRACTION-2; survival with nivolumab in CheckMate 032 appeared favorable compared with US RW clinical practice.
| S-EPMC6942583 | biostudies-literature
Project description:IntroductionMore than 70 million people are estimated to be infected with hepatitis C virus (HCV) globally. If left untreated, HCV infection can lead to complications such as extensive liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Evolution of treatments has resulted in highly effective and well-tolerated all-oral direct-acting antivirals. The pangenotypic regimen of glecaprevir/pibrentasvir is approved for treating HCV for patients without cirrhosis or with compensated cirrhosis (CC). Guidelines have evolved to simplify treatment to enable non-specialists to manage and treat HCV-infected patients. Simultaneously, such treatment algorithms provide guidance on the pretreatment identification of small subsets of patients who may require specialist treatment and long-term follow-up for advanced liver disease, including those at risk of developing HCC. This study describes the safety profile of glecaprevir/pibrentasvir in patients identified using previously described noninvasive laboratory measures who may be eligible for treatment by non-liver specialists.MethodsThis post hoc analysis of glecaprevir/pibrentasvir in patients, identified by noninvasive laboratory measures, intended to exclude patients with advanced liver disease and severe renal impairment, who can be managed within non-liver specialist settings. Patients were included from clinical trials and real-world studies of glecaprevir/pibrentasvir for HCV treatment. Baseline demographics, clinical characteristics, and safety assessments, including adverse events and laboratory abnormalities, were summarized.ResultsData across these large-scale studies confirm that glecaprevir/pibrentasvir is well tolerated across different patient populations, with fewer than 0.1% of patients experiencing a serious adverse event related to treatment drugs, and few patients developing HCC during or after treatment.ConclusionThe safety profile of glecaprevir/pibrentasvir enhances the confidence of non-liver specialists to treat the majority of HCV-infected patients, and provides an opportunity to expand the treater pool, potentially increasing diagnosis and treatment rates for HCV, contributing to elimination of HCV.
| S-EPMC8189955 | biostudies-literature