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Objective: To evaluate the long-term efficacy and safety of maintaining baricitinib monotherapy in patients with active rheumatoid arthritis (RA) originally treated with baricitinib monotherapy or switched from methotrexate (MTX) or the combination of baricitinib plus MTX to baricitinib monotherapy.Methods: This is a post hoc analysis of patients from the RA-BEGIN study who entered a long-term extension, RA-BEYOND, and were assessed for up to 24 weeks. In RA-BEGIN, MTX-naive patients with early active RA were randomized to MTX monotherapy, baricitinib 4 mg monotherapy, or baricitinib 4 mg plus MTX. At week 52, all patients entering RA-BEYOND received baricitinib 4 mg monotherapy. MTX could be prescribed during RA-BEYOND at the investigator's discretion.Results: Patients in RA-BEYOND who were not rescued in RA-BEGIN (n = 423) were evaluated. Of these, 47% continued baricitinib monotherapy and 53% added MTX, with similar proportions from the 3 original arms. Patients with lower disease activity at the RA-BEYOND baseline generally continued to do well with baricitinib monotherapy as assessed by the Simplified Disease Activity Index, the Clinical Disease Activity Index, and the Health Assessment Questionnaire disability index scores. Patients prescribed MTX had higher disease activity at the RA-BEYOND baseline and had improved disease activity after the addition of MTX. Safety outcomes were similar across treatment groups.Conclusion: Many patients responded well to continued baricitinib monotherapy or to switching to baricitinib monotherapy from MTX monotherapy or baricitinib plus MTX, showing sustained or improved disease control. The groups of patients who had less disease control on their original therapies showed sustained or improved disease control with the addition of MTX to baricitinib. [ABSTRACT FROM AUTHOR]

Odanacatib (ODN), a selective oral inhibitor of cathepsin K, was an investigational agent previously in development for the treatment of osteoporosis. In this analysis, the effects of ODN on bone remodeling/modeling and structure were examined in the randomized, double‐blind, placebo‐controlled, event‐driven, Phase 3, Long‐term Odanacatib Fracture Trial (LOFT; NCT00529373) and planned double‐blind extension in postmenopausal women with osteoporosis. A total of 386 transilial bone biopsies, obtained from consenting patients at baseline (ODN n = 17, placebo n = 23), month 24 (ODN n = 112, placebo n = 104), month 36 (ODN n = 42, placebo n = 41), and month 60 (ODN n = 27, placebo n = 20) were assessed by dynamic and static bone histomorphometry. Patient characteristics at baseline and BMD changes over 5 years for this subset were comparable to the overall LOFT population. Qualitative assessment of biopsies revealed no abnormalities. Consistent with the mechanism of ODN, osteoclast number was higher with ODN versus placebo over time. Regarding bone remodeling, dynamic bone formation indices in trabecular, intracortical, and endocortical surfaces were generally similar in ODN‐treated versus placebo‐treated patients after 2 years of treatment. Regarding periosteal modeling, the proportion of patients with periosteal double labels and the bone formation indices increased over time in the ODN‐treated patients compared with placebo. This finding supported the observed numerical increase in cortical thickness at month 60 versus placebo. In conclusion, ODN treatment for 5 years did not reduce bone remodeling and increased the proportion of patients with periosteal bone formation. These results are consistent with the mechanism of action of ODN, and are associated with continued BMD increases and reduced risk of fractures compared with placebo in the LOFT Phase 3 fracture trial. © 2020 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

ABSTRACT: In the pivotal Fracture Study in Postmenopausal Women with Osteoporosis (FRAME; NCT01575834), 1 year of the bone‐forming agent romosozumab significantly reduced new vertebral and clinical fracture risk versus placebo. Nonvertebral fracture risk was not significantly reduced in the overall population, influenced by a low placebo‐group fracture rate, observed particularly in the highest‐enrolling region of Latin America. In year 1 of FRAME, postmenopausal women with a T‐score of –2.5 to –3.5 at the total hip or femoral neck were randomized to subcutaneous romosozumab 210 mg or placebo once monthly for 12 months. Of 7180 randomized women, 43% were from Latin America, largely Colombia and Brazil. Prespecified analyses assessed fracture risk reductions by geographic regions. A significant treatment‐by‐geographic region interaction for the clinical (p = 0.029) and nonvertebral fracture (p = 0.042) endpoints led to further characterization of the Latin American population and comparison with the remaining study population, grouped post hoc as rest‐of‐world. Nonvertebral fracture efficacy in the overall population was also assessed by baseline fracture risk using the Fracture Risk Assessment Tool (FRAX). Romosozumab significantly and consistently reduced new vertebral fracture risk in Latin America (70% reduction; p = 0.014) and rest‐of‐world (74% reduction; p < 0.001). For nonvertebral fracture, risk reductions were observed in rest‐of‐world (42% reduction; p = 0.012), with no treatment effect observed in Latin America, where background nonvertebral fracture risk was low (1.2% in the placebo group). Consistent with this finding, in the overall population, greater reductions in nonvertebral fracture risk were observed among women with higher FRAX scores. These findings suggest that fracture risk assessment should consider regional factors in addition to classical risk factors, such as bone mineral density. In women at high risk for fracture, romosozumab reduced nonvertebral fracture risk within 1 year. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Objectives: Biological disease-modifying antirheumatic drugs (bDMARDs) have shown diminished clinical response following an inadequate response (IR) to ≥1 previous bDMARD. Here, tofacitinib was compared with placebo in patients with an IR to conventional synthetic DMARDs (csDMARDs; bDMARD-naive) and in patients with an IR to bDMARDs (bDMARD-IR).Methods: Data were taken from phase II and phase III studies of tofacitinib in patients with rheumatoid arthritis (RA). Patients received tofacitinib 5 or 10 mg twice daily, or placebo, as monotherapy or with background methotrexate or other csDMARDs. Efficacy endpoints and incidence rates of adverse events (AEs) of special interest were assessed.Results: 2812 bDMARD-naive and 705 bDMARD-IR patients were analysed. Baseline demographics and disease characteristics were generally similar between treatment groups within subpopulations. Across subpopulations, improvements in efficacy parameters at month 3 were generally significantly greater for both tofacitinib doses versus placebo. Clinical response was numerically greater with bDMARD-naive versus bDMARD-IR patients (overlapping 95% CIs). Rates of safety events of special interest were generally similar between tofacitinib doses and subpopulations; however, patients receiving glucocorticoids had more serious AEs, discontinuations due to AEs, serious infection events and herpes zoster. Numerically greater clinical responses and incidence rates of AEs of special interest were generally reported for tofacitinib 10 mg twice daily versus tofacitinib 5 mg twice daily (overlapping 95% CIs).Conclusions: Tofacitinib demonstrated efficacy in both bDMARD-naive and bDMARD-IR patients with RA. Clinical response to tofacitinib was generally numerically greater in bDMARD-naive than bDMARD-IR patients. The safety profile appeared similar between subpopulations.Trial Registration Numbers: (NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385). [ABSTRACT FROM AUTHOR]

ABSTRACT Denosumab reduced bone resorption, increased bone mineral density (BMD), and decreased new vertebral, hip, and nonvertebral fracture risk in postmenopausal women with osteoporosis in the FREEDOM trial. Consistent with its mechanism of action, transiliac crest bone biopsies from subjects treated with denosumab for 1 to 3 years demonstrated reduced bone turnover that was reversible upon treatment cessation. Long-term denosumab treatment for up to 6 years in the FREEDOM extension provides sustained bone turnover reduction and continued low fracture incidence. Here, we evaluate 5 years of denosumab treatment on bone remodeling at the tissue level. Transiliac crest bone biopsies were obtained from 41 subjects (13 cross-over and 28 long-term from the FREEDOM placebo and denosumab groups, respectively) at year 2 of the FREEDOM extension, representing up to 5 years of denosumab treatment. Demographics for this subset were comparable to the overall extension cohort. The mean (SD) duration from the last denosumab dose to the first dose of tetracycline was 5.7 (0.5) months. Qualitative bone histology assessed in all biopsy samples was unremarkable, showing normally mineralized lamellar bone. Structural indices, including trabecular bone volume, number, and surface, were similar between cross-over and long-term groups. Bone resorption was decreased as reflected by eroded surface in cross-over and long-term subjects. A total of 11 of 13 (85%) cross-over subjects and 20 of 28 (71%) long-term subjects had specimens with double or single tetracycline label in trabecular and/or cortical compartments; specimens from 5 cross-over subjects and 10 long-term subjects were evaluable for dynamic trabecular bone parameters. Dynamic remodeling indices were low for both groups and consistent with reduced bone turnover with denosumab. In conclusion, denosumab treatment through 5 years resulted in normal bone quality with reduced bone turnover. These observations are consistent with its mechanism of action and associated with continued BMD increases and low fracture incidence. © 2014 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Objective. To evaluate the efficacy and safety of three dosing and repeat treatment regimens of rituximab (RTX) plus MTX in patients with active RA. [ABSTRACT FROM PUBLISHER]

Abstract: The use of placebo control groups (e.g., subjects using calcium and vitamin D) in osteoporosis trials with subjects at high risk for fracture has been systematically questioned by institutional review boards (IRBs). Regulatory agencies, on the other hand, continue to not only recommend but also require that placebo-controlled trials be presented for the registration of new drugs for osteoporosis treatment. The Declaration of Helsinki and its updates have upheld the principle that protection of research subjects'' rights is of primary concern. Nevertheless, even the Declaration keeps clearly opening the possibility of using placebo-control designs if it is justified for “compelling and scientifically sound methodological reasons.” The use of intermediary endpoints or surrogates to establish the efficacy or safety of new medications in the management of osteoporosis is currently considered scientifically insufficient. This concept has led regulatory agencies, such as the Food and Drug Administration in the United States and the European Medicines Agency in the European Union, to require “fragility fracture reduction” as the primary endpoint in clinical trials for the registration of new drugs. Superiority or noninferiority trials are alternatives to placebo-controlled designs. However, factors such as sample size, cost, and statistical limitations render these models impractical for the registration of new medications for osteoporosis. We recommend collaboration among regulatory agencies, IRBs, scientists, and ethicists on the design of clinical trials for the registration of new medications for reduction of fracture risk. Delay in developing mutually acceptable models may impair scientific development in the field and possibly deprive patients of potentially beneficial treatments. [Copyright &y& Elsevier]