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Epidemiologic and economic data regarding osteoporotic fractures in Mexico is scarce and mostly outdated. Through a model, we estimated the incidence and costs of osteoporotic fractures in adults ≥ 50 years old in Mexico during the year 2023. Results showed that these events are both frequent and costly, leading to a considerable economic impact., Purpose: Osteoporosis and its fractures impose a high clinical and economic burden. The objective of this analysis was to estimate the frequency and costs owing to incident fragility fractures (FFs) during the year 2023 in Mexico., Methods: This is an incidence-based cost-of-illness study. The target population is adults ≥ 50 years old sustaining a fracture related to osteoporosis (caused by a fall on the same level). The model estimates the costs and productivity losses associated with their treatment within 1 year post-fracture. National epidemiologic databases supplemented with information, derived from literature when appropriate, were used to estimate the frequency of new FFs during 2023 in the study population. Resource use included surgical and non-surgical inpatient or ambulatory care the patients received immediately after fracture plus the outpatient physiotherapy post-discharge and the eventual follow-up with a specialist who may prescribe pharmacotherapy. Sick days taken in employed patients were estimated from the literature. Local unitary costs of services and drugs for both public and private settings as well as average income in those occupied were applied. All costs are reported in Mexican pesos (MXN) from 2023., Results: The model estimated a total of 229,239 FFs, among which 63% were classified as a major osteoporotic fracture, including 53,842 and 41,459 fractures located at the hip and vertebral, respectively. The total costs were estimated at 15,593 million MXN; most of them (75.2%) were attributable to acute-phase care., Conclusions: Fragility fractures represent a serious health problem for Mexico. Better preventive/therapeutic strategies may help to mitigate their significant financial toll., (© 2024. The Author(s).)

The rapid progress in artificial intelligence (AI) has revolutionized problem-solving across various domains. The global challenge of pharmaceutical product recalls imposes the development of effective tools to control and reduce shortage of pharmaceutical products and help avoid such recalls. This study employs AI, specifically machine learning (MI), to analyze critical factors influencing formulation, manufacturing, and formulation complexity which could offer promising avenue for optimizing drug development processes. Utilizing FDAZilla and SafeRX tools, an open database model was constructed, and predictive statistical models were developed using Multivariate Analysis and the Least Absolute Shrinkage and Selection Operator (LASSO) Approach. The study focuses on key descriptors such as delivery route, dosage form, dose, BCS classification, solid-state and physicochemical properties, release type, half-life, and manufacturing complexity. Through statistical analysis, a data simplification process identifies critical descriptors, assigning risk numbers and computing a cumulative risk number to assess product complexity and recall likelihood. Partial Least Square Regression and the LASSO approach established quantitative relationships between key descriptors and cumulative risk numbers. Results have identified key descriptors; BCS Class I, dose number, release profile, and drug half-life influencing product recall risk. The LASSO model further confirms these identified descriptors with 71% accuracy. In conclusion, the study presents a holistic AI and machine learning approach for evaluating and forecasting pharmaceutical product recalls, underscoring the importance of descriptors, formulation complexity, and manufacturing processes in mitigating risks associated with product quality., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

This study demonstrated a large treatment gap in elderly subjects experiencing fragility fracture in Spanish primary care, a low treatment persistence among subjects who do receive treatment, and more than one-quarter having no follow-up visits post-fracture. These data highlight the need to improve secondary fracture prevention in primary care., Purpose: To describe osteoporosis (OP) treatment patterns and follow-up in subjects with fragility fracture seen in Spanish primary care (PC)., Methods: This observational, retrospective chart review included subjects aged ≥ 70 years listed in the centers' records (November 2018 to March 2020), with ≥ 1 fragility fracture and prior consultation for any reason; subjects who had participated in another study were excluded. Outcomes included OP treatments and follow-up visits post-fragility fracture., Results: Of 665 subjects included, most (87%) were women; overall mean (SD) age, 82 years. Fewer than two thirds (61%) had received any prior OP treatment (women, 65%; men, 38%); of these, 38% had received > 1 treatment (women, 25%; men, 13%). Among treated subjects, the most frequent first-line treatments were alendronate (43%) and RANKL inhibitor denosumab (22%), with a higher discontinuation rate and shorter treatment duration observed for alendronate (discontinuation, 42% vs 16%; median treatment duration, 2.5 vs 2.1 years). Over one-quarter (26%) of subjects had no follow-up visits post-fragility fracture, with this gap higher in women than men (35% versus 25%). The most common schedule of follow-up visits was yearly (43% of subjects with a fragility fracture), followed by half-yearly (17%) and biennial (10%), with a similar trend in men and women. Most OP treatments were prescribed by PC physicians, other than teriparatide and zoledronate., Conclusions: Across Spanish PC, we observed a large gap in the treatment and follow-up of elderly subjects experiencing a fragility fracture. Our data highlights the urgent need to improve secondary fracture prevention in PC., (© 2024. The Author(s).)

Osteoporosis is the most common bone disorder. Our data gives an estimate of around 5.87 million cases of osteoporosis in the general German population in 2018. Only 30% of insured individuals who suffered an osteoporotic fracture and/or had a confirmed diagnosis of osteoporosis, received an appropriate prescription., Purpose: Osteoporosis is the most common bone disorder. It particularly affects elderly people and increases the risk of atraumatic fractures. The aim of this study was to estimate the prevalence of osteoporosis in the general German population aged ≥ 50 years and to collect data on the frequency of prescription of osteoporosis-specific medication in order to assess the treatment gap., Methods: Retrospective analysis of anonymized data of individuals aged ≥ 50 years insured under statutory healthcare schemes from the database of the Institute for Applied Health Research Berlin (InGef) for 2018 (study population). Insured individuals with osteoporosis were identified based on osteoporosis diagnoses, osteoporosis-specific prescriptions, or osteoporotic fractures. Thus, we estimated the prevalence of osteoporosis in the general German population aged ≥ 50 years. The prevalence of diagnoses, fractures, and prescriptions was determined for the study population and stratified by age and gender., Results: Within the study population of 1,599,299 insured individuals, a prevalence of osteoporosis of 15.9% was determined. This estimated approximately 5.87 million cases of osteoporosis for the general German population. 81.6% of the cases were women. Osteoporosis-specific prescriptions were received by 30.0% of the insured individuals in the study population who had been diagnosed with osteoporosis and/or suffered an osteoporotic fracture., Conclusions: Germany has a high prevalence of osteoporosis. Only a small portion of individuals who may require osteoporosis-specific treatment actually receive it., (© 2024. The Author(s).)

Introduction: Annual influenza vaccinations are recommended for adolescents and adults with moderate to severe asthma. This study investigated the effect of tezepelumab, a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin, on the humoral immune response to the quadrivalent seasonal influenza vaccine in patients with moderate to severe asthma., Methods: VECTOR was a phase 3b, randomized, multicenter, double-blind, parallel-group, placebo-controlled study. Adolescents (aged 12-17 years) and young adults (aged 18-21 years) with moderate to severe asthma were enrolled across 15 centers in the USA. Patients received tezepelumab 210 mg or placebo subcutaneously at weeks 0, 4, 8, and 12, and a single dose of inactivated quadrivalent seasonal influenza vaccine at week 12 before receiving study treatment. Immediately before vaccination and at 4 weeks postvaccination (week 16), strain-specific antibody responses were assessed for four influenza antigens by hemagglutination inhibition (HAI) and microneutralization (MN) assays. Safety was assessed., Results: Seventy patients were randomized to tezepelumab (n = 35) or placebo (n = 35). There were no meaningful differences in HAI or MN antibody responses between treatment groups at week 16. HAI assay geometric mean fold rises (GMFRs) for influenza strains were 1.76-7.34 for tezepelumab and 1.46-4.75 for placebo. MN assay GMFRs were 4.00-14.56 for tezepelumab and 3.56-10.62 for placebo. In the HAI assay, a fourfold or larger rise in antibody titer from weeks 12 to 16 occurred in 15.2-78.8% and 15.2-51.5% of tezepelumab and placebo recipients, respectively, and 97.0-100% of patients in both treatment groups achieved an antibody titer of at least 40 at week 16. No unexpected safety findings occurred., Conclusion: There was no observed suppression of the humoral immune response after influenza vaccination in adolescents and young adults with moderate to severe asthma treated with tezepelumab. Therefore, the influenza vaccine can be administered to this patient population during tezepelumab treatment., Gov Identifier: NCT05062759., (© 2023. The Author(s).)

Background: This real-world study examined clinical characteristics and dyslipidemia management among patients initiating evolocumab across 12 European countries. Austrian data are reported., Methods: Data of consenting adults were collected for ≤ 6 months prior to evolocumab initiation (baseline) and ≤ 30 months post-initiation. Patient characteristics, lipid lowering therapy (LLT, i.e. statin and/or ezetimibe) and lipid values were collected from medical records., Results: In Austria, 363 patients were enrolled. At baseline, 52% of patients initiated evolocumab without background LLT; the median (Q1, Q3) initial low-density lipoprotein cholesterol (LDL-C) level was 142 (111, 187) mg/dL. Within 3 months of evolocumab treatment, median LDL‑C decreased by 59% to 58 (37, 91) mg/dL. This reduction was maintained over time, despite consistently infrequent use of background LLT. LDL-C < 55 mg/dL was attained by 65% of patients (76% with, 55% without background LLT). Evolocumab persistence was ≥ 90% at month 12 and month 30., Conclusion: In Austria, patients were initiated on evolocumab at LDL‑C levels almost 3‑times higher than the guideline-recommended clinical goal (< 55 mg/dL). Persistence with evolocumab was very high. Evolocumab led to a rapid and sustained LDL‑C reduction with 65% attaining the LDL‑C goal. Patients using evolocumab in combination with statins and/or ezetimibe were more likely to attain their LDL‑C goal and thus decrease cardiovascular risk., (© 2023. The Author(s).)

This study aimed to evaluate the association between treatment duration of osteoporosis medications and clinical outcomes of patients with hip fracture. We found that the risk of subsequent osteoporotic fractures and all-cause mortality showed a decreasing trend as the treatment duration of osteoporosis medications increased., Purpose: To assess the risk of subsequent osteoporotic fracture (SOF) and all-cause mortality (ACM) in elderly patients with hip fracture in South Korea and to evaluate the potential reduction in the risk of SOF and ACM with varying durations of osteoporosis treatment., Methods: Newly diagnosed patients with hip fracture (age ≥ 60 years) who initiated osteoporosis medication within 3 months after the hip fracture from 2003-2014 were identified from the National Health Insurance Service-Senior cohort. The risk of SOF and ACM was estimated after the 1-year exposure-measurement period. Adjusted hazard ratios (aHRs) were calculated for treatment duration of osteoporosis medications categorized as short-term treatment (ST, < 3 months), early discontinuation (ED, ≥ 3- < 6 months), late discontinuation (LD, ≥ 6- < 12 months), and treatment continuation (TC, ≥ 12 months)., Results: A total of 4,421 patients were included in the analysis. The 3-year cumulative incidence of SOF was 22.4%, 22.0%, 23.9%, and 21.6%, and that of 3-year ACM was 29.8%, 27.0%, 19.7%, and 18.9% in the ST, ED, LD, and TC groups, respectively. Compared with the ST group, the risk of SOF showed a decreasing trend in the TC group (aHR [95% CI], 0.77 [0.58-1.00]). The risk of ACM was significantly reduced in the LD (aHR 0.68 [0.57-0.82]) and TC (aHR 0.65 [0.50-0.84]) groups., Conclusion: These findings underscore the importance of early and continuous osteoporosis treatment for elderly patients with hip fracture to improve health outcomes. The benefits of long-term osteoporosis treatment should be discussed in clinical practice to improve overall health outcomes., (© 2024. The Author(s).)

Introduction: Erenumab, a fully human monoclonal antibody against the calcitonin gene-related peptide receptor, is approved in Japan for the prevention of adult migraine. This post-hoc analysis evaluated the efficacy of erenumab in Japanese patients with low-frequency episodic migraine (LFEM) versus those with high-frequency episodic migraine (HFEM) and chronic migraine (CM)., Methods: A pooled analysis of data from the 24-week double-blind treatment phases (DBTPs) of phase 2 and 3 studies evaluated the efficacy of once-monthly erenumab 70 mg in Japanese patients. Patients were categorized into subgroups by monthly migraine days (MMD): LFEM and HFEM/CM. The main efficacy outcomes were change from baseline in MMD, acute migraine-specific medication treatment days (MSMD), and six-item Headache Impact Test (HIT-6™) scores., Results: Patients with migraine (n = 532) were included in the analysis (LFEM, n = 215; HFEM, n = 215; CM, n = 102). Overall, mean age was 44 years, 86.5% were female, and 63.3-88.2% had used or were taking migraine preventive treatment at baseline. Throughout the DBTP, the placebo-adjusted mean change from baseline in MMD, MSMD, and HIT-6 scores with erenumab was similar across LFEM and HFEM/CM subgroups. The proportion of patients achieving at least 50% or 75% reduction from baseline in MMD and MSMD was similar across migraine frequency groups. Reduction in MMD moderately correlated with improvement in HIT-6 scores in the LFEM and HFEM/CM groups. Furthermore, the proportion of patients converting from HFEM/CM to LFEM during the DBTP was higher in the erenumab group than in the placebo., Conclusion: In Japanese patients with different migraine frequencies, erenumab treatment resulted in significant improvements in MMD, MSMD, and headache impact. This pooled analysis of data from phase 2 and 3 studies increases confidence that erenumab is efficacious in patients with high MMD, which is associated with increased disability., (© 2023. The Author(s).)

Bone metastases are common in advanced breast cancer (BC) patients and increase the risk for skeletal-related events (SREs), which present a significant health and economic burden. Bone targeting agents (BTAs) can improve health-related quality of life by delaying or preventing SREs; nevertheless, a significant portion of eligible BC patients are not receiving this therapy. A bone health education needs assessment survey was conducted to examine cancer-related bone health awareness and to identify opportunities to improve bone health education. Direct-to-patient outreach was used to recruit adult BC patients in the USA self-reporting a diagnosis of bone metastasis within the past 3 years. Of the 200 patients, 59% experienced at least one SRE prior to survey participation (44% radiation to bone, 29% bone fracture, 17% spinal cord compression, 15% surgery to bone), and 83% were currently receiving a BTA. Awareness of general cancer bone health, protection strategies against SREs, and screening tests were low to moderate. Patients currently not receiving a BTA were least knowledgeable about cancer bone health, with only 40% aware of BTAs as a protective strategy, and only 26% were very or extremely satisfied with the information received from healthcare providers. Sixty-two percent of patients wanted to receive information by more than one mode of communication. Notable gaps in bone health education were observed in bone metastatic BC patients at risk for SREs, suggesting the need for earlier and more effective communication and education strategies to promote appropriate BTA use and better health outcomes., (© 2023. The Author(s).)

Introduction: Understanding of the patient-perceived symptom burden of small cell lung cancer (SCLC) is limited. The objective of this study was to explore patients' experiences with SCLC, identify which treatment-/disease-related symptoms have the greatest impact on their well-being, and gain caregiver perspectives., Methods: A noninterventional, cross-sectional, multimodal, mixed methods study was conducted from April-June 2021. Adult patients with SCLC and unpaid caregivers were eligible to participate. Patients' experiences, captured via 5-day video diaries and follow-up interviews, were scored 1-10 on how bothersome the patients perceived each symptom/symptomatic adverse event. Patients indicated if they believed a symptom was disease or treatment related. Caregivers participated in an online community board., Results: The study included nine patients (five with extensive-stage [ES] disease, four with limited-stage [LS] disease) and nine caregivers. Except for one patient/caregiver pairing, patients and caregivers were unmatched. The most common impactful symptoms in patients with ES-SCLC were shortness of breath, fatigue, coughing, chest pain, and nausea/vomiting; in LS-SCLC, these were fatigue and shortness of breath. Among patients with ES disease, SCLC had a high impact on physical (leisure/hobbies, work, sleep, ability to do household chores and errands/responsibilities outside home), social (family dynamics, extrafamilial social interaction), and emotional (mental health) aspects. Patients with LS-SCLC faced the long-term physical effects of treatment, financial implications, and emotional toll of an uncertain prognosis. SCLC had a high personal and psychologic burden among caregivers, whose duties consumed much of their time. Caregivers observed similar symptoms and impacts of SCLC as those reported by patients., Conclusions: This study provides valuable insight into patient- and caregiver-perceived burden of SCLC and can inform the design of prospective studies. Clinicians should seek to understand patients' opinions and priorities before making treatment decisions., (© 2023. The Author(s).)

Exposure-response (E-R) analyses are an integral component in the development of oncology products. Characterizing the relationship between drug exposure metrics and response allows the sponsor to use modeling and simulation to address both internal and external drug development questions (e.g., optimal dose, frequency of administration, dose adjustments for special populations). This white paper is the output of an industry-government collaboration among scientists with broad experience in E-R modeling as part of regulatory submissions. The goal of this white paper is to provide guidance on what the preferred methods for E-R analysis in oncology clinical drug development are and what metrics of exposure should be considered., (© 2023. The Author(s).)

A population-level, cross-sectional model was developed to estimate the clinical and economic burden of osteoporosis among women (≥ 70 years) across eight European countries. Results demonstrated that interventions aimed at improving fracture risk assessment and adherence would save 15.2% of annual costs in 2040., Purpose: Osteoporosis is associated with significant clinical and economic burden, expected to further increase with an ageing population. This modelling analysis assessed clinical and economic outcomes under different hypothetical disease management interventions to reduce this burden., Methods: A population-level, cross-sectional cohort model was developed to estimate numbers of incident fractures and direct costs of care among women (≥ 70 years) in eight European countries under different hypothetical interventions: (1) an improvement in the risk assessment rate, (2) an improvement in the treatment adherence rate and (3) a combination of interventions 1 and 2. A 50% improvement from the status quo, based on existing disease management patterns, was evaluated in the main analysis; scenario analyses evaluated improvement of either 10 or 100%., Results: Based on existing disease management patterns, a 44% increase in the annual number of fractures and costs was predicted from 2020 to 2040: from 1.2 million fractures and €12.8 billion in 2020 to 1.8 million fractures and €18.4 billion in 2040. Intervention 3 provided the greatest fracture reduction and cost savings (a decrease of 17.9% and 15.2% in fractures and cost, respectively) in 2040 compared with intervention 1 (decreases of 8.7% and 7.0% in fractures and cost, respectively) and intervention 2 (10.0% and 8.8% reductions in fracture and cost, respectively). Scenario analyses showed similar patterns., Conclusion: These analyses suggest that interventions which improve fracture risk assessment and adherence to treatments would relieve the burden of osteoporosis, and that a combination strategy would achieve greatest benefits., (© 2023. The Author(s).)

Polysorbates (PS) are nonionic surfactants that are commonly included in protein formulations to mitigate the formation of interfacial stress-induced protein particles and thus increase their long-term storage stability. Nonetheless, factors that dictate the efficiency of different polysorbates in mitigating protein particle formation, especially during the application of interfacial stresses, are often ill defined. Here, we used a Langmuir trough to determine the surface activity of two IgG1 monoclonal antibodies formulated with two different polysorbates (PS20 and PS80) when subjected to interfacial dilatational stress. Interfacial properties of these formulations were then correlated with characterization of subvisible protein particles measured by micro-flow imaging (MFI). Both mAbs, when formulated in PS20, demonstrate faster adsorption kinetics and higher surface activity compared to PS80 or surfactant-free formulations. Compression/expansion results suggest that when exposed to interfacial dilatational stresses, both mAb/PS20 formulations display interfacial properties of PS20 alone. In contrast, interfacial properties of both mAb/PS80 formulations suggest mAbs and PS80 are co-adsorbed to the air-water interface. Further, MFI analysis of the interface and the bulk solution confirms that PS20 is more effective than PS80 at mitigating the formation of larger particles in the bulk solution in both mAbs. Concomitantly, the efficiency of PS to prevent interface-induced protein particle formation also depended on the protein's inherent tendency to aggregate at a surfactant-free interface. Together, the studies presented here highlight the importance of determining the interfacial properties of mAbs, surfactants, and their combinations to make informed formulation decisions about the choice of surfactant., (© 2023. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

In a characterization of treatment rates and healthcare costs among patients with an osteoporotic-related fragility fracture overall and by site of care, costs were high and treatment rates were low., Purpose: Osteoporotic fractures can be debilitating, even fatal, among older adults. The cost of osteoporosis and related fractures is projected to increase to more than $25 billion by 2025. The objective of this analysis is to characterize disease-related treatment rates and healthcare costs of patients with an osteoporotic fragility fracture overall and by site of fracture diagnosis., Methods: In this retrospective analysis, individuals with fragility fractures were identified in the Merative MarketScan® Commercial and Medicare Databases among women 50 years of age or older and diagnosed with fragility fracture between 1/1/2013 and 6/30/2018 (earliest fracture diagnosis = index). Cohorts were categorized by clinical site of care where the diagnosis of fragility fracture was made and were continuously followed for 12 months prior to and following index. Sites of care were inpatient admission, outpatient office, outpatient hospital, emergency room hospital, and urgent care., Results: Of the 108,965 eligible patients with fragility fracture (mean age 68.8), most were diagnosed during an inpatient admission or outpatient office visit (42.7%, 31.9%). The mean annual healthcare costs among patients with fragility fracture were $44,311 (± $67,427) and were highest for those diagnosed in an inpatient setting ($71,561 ± $84,072). Compared with other sites of care at fracture diagnosis, patients diagnosed during an inpatient admission also had highest proportion of subsequent fractures (33.2%), osteoporosis diagnosis (27.7%), and osteoporosis therapy (17.2%) during follow-up., Conclusion: The site of care for diagnosis of fragility fracture affects treatment rates and healthcare costs. Further studies are needed to determine how attitude or knowledge about osteoporosis treatment or healthcare experiences differ at various clinical sites of care in the medical management of osteoporosis., (© 2023. The Author(s).)

Health records of patients hospitalized for osteoporotic fracture were analyzed. Prior to the index hospital admission, most patients were not receiving any antiosteoporotic treatment. During the index hospitalization visit, 25.5% of patients received antiosteoporotic treatment. The most common treatment regimens were active vitamin D 3 , bisphosphonates, and teriparatide., Purpose: To examine the real-world treatment patterns and factors associated with receipt of treatment among Japanese patients with osteoporotic fracture., Methods: We retrospectively analyzed health records of patients who were hospitalized for osteoporotic fracture between February 2016 and February 2018 in Japan. The type and duration of treatment with antiosteoporotic medications prescribed during hospital stays and after discharge were examined using descriptive statistics. Demographic and clinical factors (e.g., age, previous diagnoses, Charlson Comorbidity Index scores) associated with osteoporotic treatment were explored using multivariable logistic regression., Results: A total of 112,275 patient medical records were evaluated, including 56,574 records from patients with hip fracture, 26,681 records from patients with vertebrae fracture, and 29,020 patients with non-vertebral non-hip fractures. Prior to the index hospital admission, most patients (91.7%, n = 102,919) were not receiving any antiosteoporotic treatment. For those receiving treatment, active vitamin D 3 (51.1%, n = 4778) and bisphosphonates (47.5%, n = 4441) were the most common. During the index hospitalization visit, 25.5% (n = 28,678) of patients received treatment for their fracture, including active vitamin D 3 (n = 17,074), bisphosphonates (n = 10,007), and teriparatide (n = 4561). Upon discharge, 41.5% (n = 46,536) of patients returned to their home and 34.3% (n = 38,542) of patients were transferred to a different hospital or medical care facility. Variables associated with receipt of treatment at follow-up included older age, previous diagnoses of osteoporosis and fracture, and higher Charlson Comorbidity Index scores., Conclusion: Despite osteoporotic fracture being a major health concern within older Japanese populations, treatment with antiosteoporotic medication regimens remains generally low., (© 2023. The Author(s).)

Persistence with initial treatment was highest after 1 year, decreasing afterwards. Persistence was highest for denosumab followed by alendronate. We identified several factors associated with treatment persistence, some of which were the same irrespective of OTx agent, which could help target subgroups of patients in terms of social and healthcare support., Purpose: To describe patient characteristics, persistence, and factors associated with the persistence of new users of the bisphosphonates (alendronate, risedronate, and ibandronate) and the RANKL inhibitor denosumab in Denmark., Methods: A population-based cohort study using health registries (2010-2018). We included alendronate (n = 128,590), risedronate (n = 892), ibandronate (n = 5,855), and denosumab (n = 16,469) users, aged ≥ 50 years., Results: The 1-year persistence was 68.2% in the alendronate cohort; 39.3% in the risedronate cohort; 56.3% in the ibandronate cohort; and 84.0% in the denosumab cohort. The 2-year persistence was 58.7% in the alendronate cohort; 28.0% in the risedronate cohort; 42.9% in the ibandronate cohort; and 71.9% in the denosumab cohort. The 4-year persistence was 46.3%, 15.4%, 29.6%, and 56.9%, respectively. Later years of treatment initiation were associated with lower persistence for alendronate (adjusted odds ratio (OR) with 95% CI was 0.86 (0.81-0.91) in 2016 compared to 2010), but not for risedronate (OR was 1.56 (0.60-4.06), ibandronate (OR was 0.92 (0.71-1.19) or denosumab (OR was 1.11 (0.87-1.43). Older age was associated with higher persistence for all medications and the same goes for the female sex except for ibandronate. Dementia was associated with higher persistence for alendronate but not denosumab, whereas prior osteoporosis treatment (OT) was the opposite. Several comorbidities were associated with lower persistence for alendronate, but not denosumab., Conclusion: Persistence was highest for denosumab followed by alendronate. We identified several factors associated with treatment persistence, some of which were the same irrespective of OTx agent, which could help target subgroups of patients in terms of social and healthcare support., (© 2023. The Author(s).)

Background: Targeting the MDM2-p53 interaction using AMG 232 is synergistic with MAPK inhibitors (MAPKi) in preclinical melanoma models. We postulated that AMG 232 plus MAPKi is safe and more effective than MAPKi alone in TP53-wild type, MAPKi-naïve metastatic melanoma., Methods: Patients were treated with increasing (120 mg, 180 mg, 240 mg) oral doses of AMG 232 (seven-days-on, 15-days-off, 21-day cycle) plus dabrafenib (D) and trametinib (T) (Arm 1, BRAFV600-mutant) or T alone (Arm 2, BRAFV600-wild type). Patients were treated for seven days with AMG 232 alone before adding T±D. Safety and efficacy were assessed using CTCAE v4.0 and RECIST v1.1 criteria, respectively. Pharmacokinetic (PK) analysis was performed at baseline and steady-state levels for AMG 232., Results: 31 patients were enrolled. Ten and 21 patients were enrolled in Arm 1 and Arm 2, respectively. The most common AMG 232-related adverse events (AEs) were nausea (87%), diarrhea (77%), and fatigue (74%). Seven patients (23%) were withdrawn from the study due to AMG 232-related AEs. Three dose-limiting AEs occurred (Arm 1, 180 mg, nausea; Arm 2, 240 mg, grade 3 pulmonary embolism; Arm 2, 180 mg, grade 4 thrombocytopenia). AMG 232 PK exposures were not altered when AMG 232 was combined with T±D. Objective responses were seen in 8/10 (Arm 1) and 3/20 (Arm 2) evaluable patients. The median progression-free survival for Arm 1 and Arm 2 was 19.0 months-not reached and 2.8 months, respectively., Conclusion: The maximum tolerated dose of AMG 232 for both arms was 120 mg. AMG 232 plus T±D exhibited a favorable PK profile. Although objective responses occurred in both arms, adding AMG 232 to T±D did not confer additional clinical benefit., (© 2022. The Author(s).)

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., Purpose: The 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., Methods: This 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)., Results: Baseline 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., Conclusion: Continued treatment with osteoporosis medications was associated with reductions of fracture rates in a real-world setting., (© 2022. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

Fragility fractures (i.e., low-energy fractures) account for most fractures among older Canadians and are associated with significant increases in morbidity and mortality. Study results suggest that low-energy fracture rates (associated with surgical intervention and outcomes) declined slightly, but largely remained stable in the first few months of the COVID-19 pandemic., Purpose/introduction: This study describes rates of low-energy fractures, time-to-surgery, complications, and deaths post-surgery in patients with fractures during the coronavirus disease (COVID-19) pandemic in Alberta, Canada, compared to the three years prior., Methods: A repeated cross-sectional study was conducted using provincial-level administrative health data. Outcomes were assessed in 3-month periods in the 3 years preceding the COVID-19 pandemic and in the first two 3-month periods after restrictions were implemented. Patterns of fracture- and hospital-related outcomes over the control years (2017-2019) and COVID-19 restrictions periods (2020) were calculated., Results: Relative to the average from the control periods, there was a slight decrease in the absolute number of low-energy fractures (n = 4733 versus n = 4308) during the first COVID-19 period, followed by a slight rise in the second COVID-19 period (n = 4520 versus n = 4831). While the absolute number of patients with low-energy fractures receiving surgery within the same episode of care decreased slightly during the COVID-19 periods, the proportion receiving surgery and the proportion receiving surgery within 24 h of admission remained stable. Across all periods, hip fractures accounted for the majority of patients with low-energy fractures receiving surgery (range: 58.9-64.2%). Patients with complications following surgery and in-hospital deaths following fracture repair decreased slightly during the COVID-19 periods., Conclusions: These results suggest that low-energy fracture rates, associated surgeries, and surgical outcomes declined slightly, but largely remained stable in the first few months of the pandemic. Further investigation is warranted to explore patterns during subsequent COVID-19 waves when the healthcare system experienced severe strain., (© 2022. The Author(s).)

Purpose/introduction: The objective of this study was to describe osteoporosis-related care patterns during the coronavirus disease 2019 (COVID-19) pandemic in Alberta, Canada, relative to the 3-year preceding., Methods: A repeated cross-sectional study design encompassing 3-month periods of continuous administrative health data between March 15, 2017, and September 14, 2020, described osteoporosis-related healthcare resource utilization (HCRU) and treatment patterns. Outcomes included patients with osteoporosis-related healthcare encounters, physician visits, diagnostic and laboratory test volumes, and treatment initiations and disruptions. The percent change between outcomes was calculated, averaged across the control periods (2017-2019), relative to the COVID-19 periods (2020)., Results: Relative to the average control March to June period, all HCRU declined during the corresponding COVID-19 period. There was a reduction of 14% in patients with osteoporosis healthcare encounters, 13% in general practitioner visits, 9% in specialist practitioner visits, 47% in bone mineral density tests, and 13% in vitamin D tests. Treatment initiations declined 43%, 26%, and 35% for oral bisphosphonates, intravenous bisphosphonates, and denosumab, respectively. Slight increases were observed in the proportion of patients with treatment disruptions. In the subsequent June to September period, HCRU either returned to or surpassed pre-pandemic levels, when including telehealth visits accounting for 33-45% of healthcare encounters during the COVID periods. Oral bisphosphonate treatment initiations remained lower than pre-pandemic levels., Conclusions: This study demonstrates the COVID-19 pandemic and corresponding public health lockdowns further heightened the "crisis" around the known gap in osteoporosis care and altered the provision of care (e.g., use of telehealth and initiation of treatment). Osteoporosis has a known substantial care and management disparity, which has been classified as a crisis. The COVID-19 pandemic created additional burden on osteoporosis patient care with healthcare encounters, physician visits, diagnostic and laboratory tests, and treatment initiations all declining during the initial pandemic period, relative to previous years., (© 2022. The Author(s).)

KRAS has long been referred to as an 'undruggable' target due to its high affinity for its cognate ligands (GDP and GTP) and its lack of readily exploited allosteric binding pockets. Recent progress in the development of covalent inhibitors of KRAS G12C has revealed that occupancy of an allosteric binding site located between the α3-helix and switch-II loop of KRAS G12C -sometimes referred to as the 'switch-II pocket'-holds great potential in the design of direct inhibitors of KRAS G12C . In studying diverse switch-II pocket binders during the development of sotorasib (AMG 510), the first FDA-approved inhibitor of KRAS G12C , we found the dramatic conformational flexibility of the switch-II pocket posing significant challenges toward the structure-based design of inhibitors. Here, we present our computational approaches for dealing with receptor flexibility in the prediction of ligand binding pose and binding affinity. For binding pose prediction, we modified the covalent docking program CovDock to allow for protein conformational mobility. This new docking approach, termed as FlexCovDock, improves success rates from 55 to 89% for binding pose prediction on a dataset of 10 cross-docking cases and has been prospectively validated across diverse ligand chemotypes. For binding affinity prediction, we found standard free energy perturbation (FEP) methods could not adequately handle the significant conformational change of the switch-II loop. We developed a new computational strategy to accelerate conformational transitions through the use of targeted protein mutations. Using this methodology, the mean unsigned error (MUE) of binding affinity prediction were reduced from 1.44 to 0.89 kcal/mol on a set of 14 compounds. These approaches were of significant use in facilitating the structure-based design of KRAS G12C inhibitors and are anticipated to be of further use in the design of covalent (and noncovalent) inhibitors of other conformationally labile protein targets., (© 2022. The Author(s).)

measures such as progression-free survival (PFS) and overall survival (OS) are commonly reported in literature for oncology trials, while time to progression (TTP) and post progression survival (PPS) are not usually reported. A time-variant transition hazard model was developed using an ordinary differential equation (ODE) model to estimate TTP and PPS from summary level PFS and OS. The model was applied to published data from immune checkpoint inhibitor trials for non-small cell lung cancer (NSCLC) in a meta-analysis framework. This model-based method was able to robustly estimate TTP and PPS from summary level OS and PFS data, provided a quantitative approach for understanding the patterns of disease progression across different treatments through the time-variant disease progression rate function, and provided a summary of how different treatments affect TTP and PPS. The proposed method can be generalized to characterize and quantify multiple time-to-event endpoints jointly in oncology trials and improve our understanding of disease prognostics for different treatments., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In Spanish primary care (PC), the prevalence of fragility fractures (FF) in subjects ≥ 70 years old is high, especially in women. One-third of subjects with an FF lacked osteoporosis (OP) diagnosis and >50% were not currently receiving OP medication. An improvement of the FF management in this population is needed., Purpose: In Spanish PC, the prevalence of FF is high, especially in women. One-third of subjects with a FF lacked an OP diagnosis and more than half were not currently receiving OP medication. Several studies reported underdiagnosis/undertreatment of OP in PC among elderly subjects with FF. To date, no such data exist for Spain. The purpose is to estimate the prevalence of FF in the elderly population (≥ 70 years old) and to describe the characteristics, risk factors, comorbidities, and OP diagnosis and treatment rates of subjects with FF in Spanish PC centers., Methods: This is an observational, retrospective study in Spain consisting of two phases. Phase A included all subjects ≥ 70 years old listed in the center's medical records from November 2018 to March 2020. Phase B included subjects with FF and prior consultation at the center for any reason. Subjects were excluded only if they had previously participated in another study. Primary outcomes were prevalence of FF (phase A) and characteristics of subjects with at least one FF (phase B)., Results: The overall prevalence of FF was 17.7% among subjects visiting medical centers for any reason (24.1% women vs. 8.0% men) (30 PC centers from 14 Spanish regions). Vertebral (5.1%) was the most prevalent fracture. Of 665 subjects in phase B, most (87%) were women and ≥ 80 years old (57%), suffered mainly major OP fracture (68%), and had multiple comorbidities (≥ 2, 89.2%). While two-thirds had OP diagnosis and 61.1% received OP medication anytime in the past, 56.8% were not currently receiving OP medication. Diagnosis and treatment rates were lower among men (43% and 38% vs. 70% and 65%, respectively)., Conclusion: Prevalence of FF was high, especially in women. One-third of subjects lacked OP diagnosis and ≥ 50% were not receiving OP treatment; diagnosis and treatment gaps were larger among men. This reinforces the need to improve the management of FF in the elderly population. However, as PC centers participating in this study had high OP experience that have the potential to do better in terms of diagnosis and treatment, caution in the generalization of these data should be taken., (© 2022. The Author(s).)

Treatment persistence was higher among the patients who initially received an anti-osteoporosis medication (AOM) with a long-dose-interval., Purpose: With long-dose-interval anti-osteoporosis medications (AOMs) available for osteoporosis management, it is important to evaluate persistence of any AOM as long as it is continuously used. The purpose of this study was to investigate the treatment pattern and persistence of AOMs, allowing for medication switch., Methods: This study was an observational retrospective cohort study using Taiwan's National Health Insurance claims data. We selected patients who first initiated an AOM between January 1, 2013, and June 30, 2016. AOM therapy included alendronate, raloxifene, teriparatide, denosumab, zoledronate, and ibandronate; the latter three were categorized as long-dose-interval medications. Persistence was defined as continual prescription of any AOM at a given time point with a grace period of 45 days within which to obtain prescription refill. The competing risk model was used to examine the factors affecting patients switching their initial AOM., Results: During the study period, 126,539 patients with mean age of 75 years met the inclusion criteria; 85% were female. For initial AOM, 43.3%, 25.6%, 14.6%, 9.3%, 5.3%, and 1.9% of the patients received alendronate, denosumab, raloxifene, zoledronate, ibandronate, and teriparatide, respectively. During a mean 36-month follow-up, 29.6% of the patients who received at least two AOM pharmacy claims throughout the study period have ever switched their initial medication. Long-dose-interval medications, mainly denosumab and zoledronate, were the preferred choice for medication switch. Treatment persistence was higher in patients who initiated with long-dose-interval AOMs., Conclusion: The real-world data reveal long-dose-interval therapy as an initial treatment or at the first switch stage may improve management of persistent AOM treatment., (© 2022. International Osteoporosis Foundation and National Osteoporosis Foundation.)

Among women ≥ 50 years with fracture, 76% had not received osteoporosis diagnosis or treatment at 6 months and only 14% underwent a DXA scan. Nearly half of all and 90% of hip fracture patients required surgery. Fractures cause substantial clinical burden and are not linked to osteoporosis diagnosis or treatment., Purpose: Osteoporosis (OP) and OP-related fractures are a major public health concern, associated with significant economic burden. This study describes management patterns following a nontraumatic fracture for commercially insured patients., Methods: This retrospective cohort study identified women aged ≥ 50 years having their first nontraumatic index fracture (IF) between January 1, 2015 and June 30, 2019, from IQVIA's PharMetrics® Plus claims database. Medical management patterns at month 6 and medication use patterns at months 6, 12, and 24 following the IF were described., Results: Among 48,939 women (mean (SD) age: 62.7 (9.5) years), the most common fracture types were vertebral (30.6%), radius/ulna (24.9%), and hip (HF; 12.1%). By month 6, 76% of patients had not received an OP diagnosis or treatment, 13.6% underwent a DXA scan, and 11.2% received any OP treatment. Surgery was required in 43.1% of all patients and 90.0% of HF patients on or within 6 months of the fracture date. Among HF patients, 41.4% were admitted to a skilled nursing facility, 96.7% were hospitalized an average of 5.5 days, and 38.1% required durable medical equipment use. The 30-day all-cause readmission rate was 14.3% among those hospitalized for the IF. Overall, 7.4%, 9.9%, and 13.2% had a subsequent fracture at months 6, 12, and 24, respectively., Conclusion: Our findings provide an overview of post-fracture management patterns using real-world data. OP was remarkably underdiagnosed and undertreated following the initial fracture. Nontraumatic fracture, particularly HF, resulted in substantial ongoing clinical burden., (© 2022. The Author(s).)

In many countries, osteoporosis is predominantly managed by primary care physicians; however, management after a fragility fracture has not been widely investigated. We describe osteoporosis care gaps in a real-world patient cohort. Our findings help inform initiatives to identify and overcome obstacles to effective management of patients after fragility fracture., Purpose: A fragility fracture is a major risk factor for subsequent fracture in adults aged ≥ 50 years. This retrospective observational study aimed to characterize post-fracture management in Canadian primary care., Methods: A total of 778 patients with an index fragility fracture (low-trauma, excluding small bones) occurring between 2014 and 2016 were identified from medical records at 76 primary care centers in Canada, with follow-up until January 2018., Results: Of 778 patients (80.5% female, median age [IQR] 73 [64-80]), 215 were on osteoporosis treatment and 269 had osteoporosis diagnosis recorded prior to their index fracture. The median follow-up was 363 (IQR 91-808) days. Of patients not on osteoporosis treatment at their index fracture, 60.2% (n = 339/563) remained untreated after their index fracture and 62.2% (n = 23/37) continued untreated after their subsequent fracture. After their index fracture, fracture risk assessment (FRAX or CAROC) was not performed in 83.2% (n = 647/778) of patients, and 59.9% (n = 466/778) of patients did not receive bone mineral density testing. Of patients without osteoporosis diagnosis recorded prior to their index date, 61.3% (n = 300/489) remained undiagnosed after their index fracture. At least one subsequent fracture occurred in 11.5% (n = 86/778) of patients., Conclusion: In the primary care setting, fragility fracture infrequently resulted in osteoporosis treatment or fracture risk assessment, even after multiple fragility fractures. These results suggest a fragility fracture is not recognized as a major risk factor for subsequent fracture and its occurrence does not prompt primary care physicians to intervene. These data urge initiatives to identify and overcome obstacles to primary care physicians' effective management of patients after fragility fractures., (© 2022. The Author(s).)

This study evaluated the cost-effectiveness of 1 year of romosozumab followed by alendronate versus oral bisphosphonates alone in women with postmenopausal osteoporosis at very high risk for fracture in Canada. Results showed that romosozumab sequenced to alendronate is a cost-effective treatment option, dominating both alendronate and risedronate alone., Purpose: To demonstrate the value of romosozumab sequenced to alendronate compared to alendronate or risedronate alone, for the treatment of osteoporosis in postmenopausal women with a history of osteoporotic fracture and who are at very high risk for future fracture in Canada., Methods: A Markov model followed a hypothetical cohort of postmenopausal osteoporotic women at very high risk for future fractures, to estimate the cost-effectiveness of romosozumab and alendronate compared to oral bisphosphonates alone. A total treatment period of 5 years was assumed. Quality-adjusted life years and costs were estimated for each comparator across health states defined by different types of fragility fractures., Results: Romosozumab/alendronate was associated with a lifetime gain of 0.103 and 0.127 QALYs and a cost reduction of $343 and $3805, relative to alendronate and risedronate, respectively. These results were driven by a reduction of the number of fractures (2561 per 1000 patients, versus 2700 for alendronate and 2724 for risedronate over lifetime). Romosozumab/alendronate had the highest probability of being cost-effective, relative to alendronate and risedronate, at any willingness to pay threshold value., Conclusion: Romosozumab/alendronate was associated with reduced costs and greater benefit relative to other comparators. Probabilistic, deterministic, and scenario analyses indicate that romosozumab/alendronate represents the best value for money; the uncertainty analyses are robust, and therefore romosozumab should be considered for reimbursement by public drug plans in Canada ., (© 2022. The Author(s).)

Background: Cardiovascular disease (CVD) is the most frequent cause of death in Austria. The European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines recommend intensive lipid lowering therapy (LLT) in patients at high or very high CV risk. Lipid management and achievement of low-density lipoprotein cholesterol (LDL-C) goals in Austria have not recently been assessed., Methods: Subgroup analysis for Austria of a European 18 country, cross-sectional, observational study. Patients received LLT for primary (PP) or secondary prevention (SP). Data including LLT in the preceding 12 months and most recent LDL‑C were collected during a single visit between June 2017 and November 2018. Achievement of the risk-based 2016 and 2019 ESC/EAS LDL‑C goal while receiving stabilized LLT was assessed., Results: A total of 293 patients were enrolled from 8 Austrian sites, of which 200 (PP = 104, SP = 96) received stabilized LLT at the LDL‑C measurement date. Overall, 58% (71% PP, 43% SP) and 38% (52% PP, 23% SP) achieved the risk-based 2016 and 2019 goals, respectively. Most patients received moderate-intensity statin monotherapy (46%), while 34% used high-intensity statin monotherapy. Combination therapy of moderate/high-intensity statin with ezetimibe (12%), or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors with statin ± ezetimibe (1%), was used infrequently., Conclusion: The current Austrian routine lipid management using mainly moderate-intensity or high-intensity statin monotherapy is insufficient to attain ESC/EAS guideline goals, in particular the more stringent 2019 recommendations, a situation comparable to other participating European countries. In addition to switching to and optimizing doses of high-intensity statins, a combination with ezetimibe or PCSK9 inhibitors will be needed in many cases., (© 2021. The Author(s).)

Hip fracture is the most common type of fracture to occur within 2 years after an initial fracture. Mortality risk increases when a subsequent fracture occurs. The occurrence of subsequent fracture is significantly higher in patients with hip fractures than others. Prevention of subsequent fracture is of paramount important., Purpose: Osteoporotic fracture significantly increases risk of subsequent fracture. In this retrospective cohort study, we used the Taiwan National Health Insurance Database (NHIRD) to analyze data on fractures in a group at high risk of osteoporosis. We aimed to distinguish differences in subsequent fracture types and their relationship with mortality., Methods: We enrolled patients aged ≥ 50 years old who were diagnosed with an initial fracture classified as hip, vertebral, upper end of the humerus, or wrist. Data from 2 years of follow-up were analyzed. Risks of subsequent fracture events and mortality were calculated by Kaplan-Meier estimation and assessed with Cox proportional hazards models., Results: We included 375,836 patients from the 2011-2015 NHIRD. Patients with initial hip fracture had the highest incidence of subsequent fracture at both 1- and 2-year follow-up (7.0% and 10.9%). Subsequent fractures occurred mainly at the hip. Conversely, other patients had a higher proportion of subsequent vertebral fracture. Patients with subsequent fracture classified as hip, vertebral, and upper end of the humerus had significantly higher cumulative mortality rates than that of patients who had no subsequent fracture, with adjusted hazard ratios of 1.64 (95% CI = 1.57-1.71, p < 0.01), 1.06 (95% CI = 1.00-1.12, p = 0.04), 1.31 (95% CI = 1.17-1.46, p < 0.01), respectively., Conclusion: Patients who experienced an initial hip fracture are at greatest risk of subsequent fracture, most commonly the hip. Occurrence of subsequent fractures was associated with an increased mortality risk. Thus, there is a need for early intervention following initial hip fractures., (© 2022. International Osteoporosis Foundation and National Osteoporosis Foundation.)

The use of anti-osteoporosis treatment following a diagnosis of osteoporosis with fracture or a relevant fragility fracture remains low in France. Initiating an anti-resorptive may reduce the incidence of a subsequent fracture by 60%., Purpose: To describe real-world osteoporosis treatment patterns in individuals with a fragility fracture in France and to explore the impact of initiating treatment on the risk of subsequent fracture., Methods: A retrospective cohort study, using the national French Health Insurance claims database. Males and females 50 years and over, with a hospital discharge diagnosis of osteoporosis with fracture or a relevant fragility fracture between 2011 and 2014, were included and followed until death or the end of 2016, whichever came first. The primary outcome was the proportion of patients receiving anti-osteoporosis treatments prior to and post-index fracture. Change in fracture rates before and after treatment initiation was assessed in an exploratory analysis., Results: A total of 574,133 patients (138,567 males, 435,566 females) had a qualifying index fracture. The proportion of patients receiving any anti-osteoporosis treatment increased pre-index fracture to post-index fracture from 2.2 to 5.6% among males, and from 11.8 to 18.2% among females. Oral bisphosphonates were the most prescribed anti-osteoporosis treatment for both males and females among post-index fractures (60.6% and 68.8% of patients initiating treatment). Following initiation of anti-resorptives, the incidence of subsequent fracture was reduced by 60% (rate ratio (RR): 0.40, 95% confidence interval [CI]: 0.34-0.45)., Conclusion: Anti-osteoporosis treatment following an index fracture in France remains low. Improved identification and pharmacologic management of patients at risk of fragility fractures are necessary to reduce the risk of subsequent fractures., (© 2022. International Osteoporosis Foundation and National Osteoporosis Foundation.)

We studied whether elderly women at risk for fractures receive primary care treatment to prevent fracture. We found that across Europe, women at risk are often not identified, and less than half of such women receive appropriate treatment. Finally, women diagnosed with osteoporosis are much more likely to receive treatment., Purpose: To examine the relationship between risk factors for fragility fracture (FF) and osteoporosis (OP) treatment gap in elderly women across Europe, and compare the prevalence of risk factors between countries., Methods: Demographic and clinical information was collected from women ≥ 70 years visiting primary care physicians in Belgium, France, Germany, Ireland, Poland, Slovakia, Switzerland, and the UK. Increased risk of FF was defined by the presence of 1 or more criteria (history of fracture, 10-year fracture probability, or T-score ≤  - 2.5)., Results: There were 3798 women in total. Treatment gap (proportion at increased risk of FF not receiving treatment for OP) varied from 53.1 to 90.8% across countries, and the proportion of patients at increased risk of FF varied from 41.2 to 76.1%. Across countries, less than 50% of patients with increased risk of FF had a diagnosis of OP. Previous fracture was the most common risk factor, with similar prevalence across most countries; other risk factors varied widely. The treatment gap was reduced in patients with an OP diagnosis in all countries, but this reduction varied from 36.5 to 79.4%. The countries with the lowest rates of bone densitometry scans (Poland, France, and Germany; 8.3-12.3%) also had the highest treatment gap (82.2 to 90.8%)., Conclusions: This study highlights differences across Europe in clinical risk factors for fracture, rates of densitometry scanning, and the rates of OP diagnosis. More emphasis is needed on risk assessment to improve the identification and treatment of elderly women at risk for fracture., (© 2022. The Author(s).)

Impact of increased osteoporosis diagnosis and treatment among postmenopausal women (PMW) on reduction in fractures and associated costs in Japan from 2020 to 2040 was modeled., Introduction: Japan is currently home to the world's oldest population and the 65 + years demographic is expected to grow to 35% by 2040. Thus, identifying strategies to reduce clinical and economic burden associated with osteoporosis among this at-risk population is critical., Methods: A microsimulation model was developed to project osteoporotic annual fracture incidence and costs among PMW 2020-2040. Fracture risk was estimated using a simplified Fracture Risk Assessment Tool (FRAX). Fracture estimates were based on annualized FRAX risk and treatment impact. Published literature informed inputs for direct and indirect fracture costs, DXA screening costs, and treatment costs and efficacy. Japan's current screening and treatment rates were compared against 50% increases to (1) case finding (screening rate and subsequent treatment rate) and (2) treatment rate among those at highest fracture risk., Results: From 2020 to 2040, 21.6 million fractures are projected costing US $410.2 billion. Increased case finding scenario resulted in the prevention of 456.9 thousand primary and 340.9 thousand second + fractures saving US $4.25 billion. Increased treatment scenario led to 500.5 thousand and 435.5 thousand fewer primary and second + fractures, respectively, and reduced economic burden by $3.1 billion., Conclusion: Improvements to rates of osteoporosis screening and preventive treatment in Japan's aging population through disease awareness campaigns and post-fracture care programs, among others, will likely reduce osteoporosis-associated clinical and economic burden., (© 2021. International Osteoporosis Foundation and National Osteoporosis Foundation.)

This study assessed the cost-effectiveness of continued denosumab treatment, compared with discontinuation of denosumab after one dose, for the treatment of postmenopausal osteoporosis in Taiwan, using real-world fracture reduction effectiveness and cost data. Outcomes indicate that continued denosumab treatment produces an incremental cost-effectiveness ratio of USD $16,743 per QALY., Purpose: To evaluate the cost-effectiveness of continued denosumab use versus discontinuation after one dose, for the treatment of postmenopausal osteoporosis in Taiwan, using real-world fracture reduction effectiveness and cost data., Methods: A Markov cohort model was used to evaluate the lifetime costs and QALYs associated with continued denosumab treatment versus discontinuation of treatment after one dose. The evaluation was conducted from the perspective of Taiwan's healthcare system and used a discount rate of 3% per annum. The patient population consisted of postmenopausal women with osteoporosis with a mean age of 77 years who initiated denosumab treatment. Fracture reduction effectiveness data, baseline fracture rates, mortality data, and costs of fracture were informed by Taiwan's National Health Insurance Research Database., Results: Model outcomes showed that continued treatment with denosumab produced an expected gain of 0.042 QALYs and an incremental cost of USD $704, compared with discontinuation of denosumab after one dose. This corresponds to an incremental cost-effectiveness ratio of USD $16,743 per QALY gained. Probabilistic and scenario analysis showed that results are stable to variations in model assumptions and parameters., Conclusion: In a real-world setting, at a cost per QALY threshold equivalent to gross domestic product per capita in 2020 in Taiwan (USD $30,038), continued treatment with denosumab in postmenopausal women with osteoporosis is cost-effective compared with treatment discontinuation., (© 2021. The Author(s).)

Molecular dispersions are a highly effective method of increasing bioavailability for a poorly soluble active pharmaceutical ingredient (API) and can be prepared on a large scale by hot melt extrusion (HME). Processing thermally labile active pharmaceutical ingredients (APIs) via HME is generally more difficult, with operating temperatures limited to below that of the API melting point. API melting is considered essential to facilitate the formation of a fully homogeneous amorphous system. Processing below the melting point renders the system much more susceptible to residual crystalline content; hence, HME is not suitable for APIs which degrade upon melting. In the following work, meloxicam (MEL) was used as a model API, possessing properties of high melting temperature and thermal lability. In this proof of concept work, a modified HME method, termed solvent-assisted HME, was used to overcome this issue and prepare an amorphous solid dispersion using HME, wherein a solvent was incorporated in the formulation blend during extrusion and removed post-processing. Formulations containing 10%wt meloxicam (MEL) and 90%wt polyvinylpyrrolidone vinyl acetate (PVPVA) copolymer were extruded using a twin-screw extruder at temperatures below the melting point of MEL. Dimethylformamide (DMF) solvent was added directly into the extruder barrel through a liquid addition port, resulting in extrudate products having a higher conversion of API to the amorphous form. The incorporation of solvent allowed a significant reduction in processing temperatures due to its increased mobility, while also driving the conversion of the API to its amorphous form. The solvent was successfully reduced through a secondary drying step using a vacuum oven. This advancement has demonstrated the potential for thermally labile APIs to be processed via HME expanding the applications of this technology., (© 2021. American Association of Pharmaceutical Scientists.)

Osteoporosis-related fragility fractures increase the risk of subsequent fractures and are associated with substantial morbidity and mortality. Emphasis should be placed on the prevention of recurrent fractures, which will decrease both the clinical burden on patients and the economic burden on the health system., Introduction: Fragility fractures are associated with increased morbidity and mortality. Quantifying the clinical and economic burden of subsequent fractures following an initial osteoporosis-related fracture is a key to informing public health policies., Methods: A retrospective cohort study, using the national French health insurance claims database. Males and females ≥ 50 years, with a hospital discharge diagnosis of osteoporosis with fracture or a relevant fragility fracture (hip, vertebrae, femur, pelvis, wrist/hand, forearm, humerus/clavicle) between 2011 and 2014, were included and followed until death or end of 2016, whichever came first. Index fracture was the first qualifying hospitalization; subsequent fractures were defined as those occurring either at a different site from the index fracture or at the same site ≥ 90 days apart. Costs abstracted included hospitalization, external consultation, outpatient visits, and treatment., Results: A total of 544,426 participants (132,148 [24.3%] males and 412,278 [75.7%] females), of whom 16,110 (12.2%) males and 73,538 (17.8%) females had at least one subsequent fracture during follow-up, were included. Incidence of subsequent fracture was highest in the first year following index fracture. During follow-up, 161,179 patients died; mortality was highest among those with a hip fracture at index (29,971 (51.6%) males and 65,254 (39.6%) females). Total mean costs per patient in the year following index fracture were highest for males and females with a hip fracture (€18,585 and €15,754, respectively)., Conclusion: Subsequent fractures among osteoporotic participants with an initial fracture result in increased clinical mortality and high healthcare resource use. Emphasis should be placed on the prevention of recurrent fractures., (© 2021. International Osteoporosis Foundation and National Osteoporosis Foundation.)

Annual osteoporotic fractures is projected to increase by 135% from 6.9 M (2020) to 16.2 M (2040), increasing the economic burden by 121% from $29.9B (2020) to $65.9B (2040)., Introduction: Globally, aging populations drive significant increases in osteoporosis prevalence. In China, the number of women aged ≥ 65 years is expected to more than double from 2020 (91.5 M) to 2040 (183.6 M). Using a microsimulation model, impact of increased diagnosis and treatment of postmenopausal women (PMW) with osteoporosis on anticipated reduction in fractures and associated costs in China from 2020 to 2040 was projected., Methods: A microsimulation model was developed to project annual incidence and costs of osteoporotic fractures among PMW in China from 2020 to 2040. Fracture risk was estimated using the simplified Fracture Risk Assessment Tool (FRAX). Fractures estimates were based on annualized FRAX risk and impact of treatment. Published literature informed inputs for direct and indirect fracture costs, DXA screening costs, and treatment costs and efficacy. China's current screening and treatment rates were compared against 50% increases to (i) case finding (screening rate and subsequent treatment rate) and (ii) treatment rate among those at highest fracture risk., Results: From 2020 to 2040, 241.7 M osteoporotic fractures are projected to cost $997B. Increased treatment scenario prevented 24.6 M fractures and saved $56B. Increased case finding scenario prevented 26 M fractures and saved $61.7B., Conclusion: Osteoporosis underdiagnosis and undertreatment among the aging Chinese population will considerably burden patients, caregivers, and society. Policy changes to increase screening and treatment rates may result in significant cost savings and clinical benefits., (© 2021. International Osteoporosis Foundation and National Osteoporosis Foundation.)

Using a microsimulation model, the impact of increased diagnosis and treatment of postmenopausal women with osteoporosis on anticipated reduction in fractures and associated costs in South Korea from 2020 to 2040 was projected., Introduction: The economic burden of osteoporosis was US $5.1B in 2011 in South Korea. Osteoporosis is expected to strain resources in South Korea as the population most susceptible to osteoporotic fracture, females > 50 years old, is projected to increase by 32% from 2020 to 2040., Methods: A microsimulation model was developed to project annual incidence and costs of osteoporotic fractures among postmenopausal women from 2020 to 2040. Fracture risk was estimated using the simplified Fracture Risk Assessment Tool (FRAX). The fracture estimates were based on annualized FRAX risk and impact of treatment. Korean National Health Insurance data informed treatment and case-finding rates in the reference case. Two scenarios were evaluated: 50% increases to (i) case finding (screening rate and subsequent treatment rate) and (ii) treatment rate among those at highest risk., Results: Among individuals modeled in the reference case from 2020 to 2040, 41.2 M fractures at a cost of US $263.6B were projected. Increased treatment scenario prevented 4.4 M fractures and saved US $13.5B. Increased case-finding scenario prevented 4.0 M fractures and saved US $11.1B., Conclusion: Implementation of policies to enable increasing case finding or treatment may result in fewer fractures and substantial cost savings across the healthcare system. These results highlight the importance of early screening, diagnosis, and preventive treatment., (© 2021. International Osteoporosis Foundation and National Osteoporosis Foundation.)

Introduction: Erenumab, a first-in-class monoclonal antibody targeting the calcitonin gene-related peptide pathway, was approved by the US Food and Drug Administration in 2018 for the prevention of migraine in adults. There is limited data available on its impact in real-world settings. The study aim was to characterize the real-world treatment profiles, clinical outcomes, and healthcare resource utilization of patients prescribed erenumab from select major US headache centers., Methods: A retrospective chart review of patients with migraine treated with erenumab for at least 3 months across five major headache centers was conducted. Data was collected from patient charts between April 2019 and April 2020 and included patient and clinical characteristics, migraine medication use, and outpatient visits. The date of the first prescription fill of erenumab was defined as the index date. The baseline period comprised the 3 months prior to the index date and the study period comprised the at least 3 months on erenumab treatment., Results: Data from a total of 1034 patients with chronic migraine with a mean of 9.3 months of erenumab treatment were analyzed. Patients were on average 48 years old, 86% were female, and 79% were white. Patients had a mean of 5 preventive treatment failures prior to erenumab initiation. Patients used a mean of 2 preventive treatments (excluding erenumab) and 2 acute treatments during baseline and study periods. Among patients with effectiveness data, 45% of patients had improvement in physician-reported migraine severity and 35% experienced at least 50% reduction in mean headache/migraine days per month. The average number of monthly outpatient visits was 0.43 and 0.30 before and after erenumab initiation, respectively., Conclusion: In this predominantly refractory chronic migraine population treated in select headache centers, patients had fewer headache/migraine days per month and outpatient visits after initiating erenumab. However, patients largely continued to be managed via a polypharmacy approach after erenumab initiation.

The study aimed to achieve expert consensus to optimize secondary fracture prevention in Spain. Relevant gaps in current patient management were identified. However, some aspects were considered difficult to apply. Future efforts should focus on those items with greatest divergences between importance and feasibility., Purpose: To establish a Spanish multidisciplinary expert consensus on secondary fracture prevention., Methods: A two-round Delphi consensus was conducted, guided by a Scientific Committee. The 43-item study questionnaire was designed from a literature review and a subsequent multidisciplinary expert group (n = 12) discussion. The first-round questionnaire, using a 7-point Likert scale, assessed the experts' opinion of the current situation, their wish for items to happen, and their prognosis that items would be implemented within 5 years. Items for which consensus was not achieved were included in the second round. Consensus was defined as ≥ 75% agreement or ≥ 75% disagreement. A total of 102 experts from 14 scientific societies were invited to participate., Results: A total of 75 (response rate 73.5%) and 69 (92.0%) experts answered the first and second Delphi rounds, respectively. Participants mean age was 51.8 years [standard deviation (SD): 10.1 years]; being 24.0% rheumatologists, 21.3% primary care physicians, 14.7% geriatricians, 8.0% internal medicine specialists, 8.0% rehabilitation physicians, and 8.0% gynecologists. Consensus was achieved for 79.1% of items (wish, 100%; prognosis, 58.1%). Effective secondary prevention strategies identified as requiring improvement included: clinical report standardization, effective hospital primary care communication (telephone/mail and case managers), health-related quality of life (HRQoL) questionnaires use, and treatment compliance monitoring (prognosis agreement 33.3%, 47.8%, 18.8%, and 55.1%, respectively)., Conclusion: A consensus was reached by health professionals in their wish to implement strategies to optimize secondary fracture prevention; however, they considered some difficult to apply. Efforts should focus on those items with currently low application and those with greatest divergence between wish and prognosis.

As the packaging of choice for many therapeutic proteins, prefilled syringes have been widely used in biopharmaceutical industry as primary containers, where silicone oil is applied to ensure their proper functionality. Adequate lubrication from sufficient amount of silicone oil and its appropriate distribution across syringe barrels is crucial for successful administration of drug product (DP) from the prefilled syringes; however, silicone oil is also susceptible to leaching from the syringe surface into the formulation with the potential to interact with therapeutic proteins, which could lead to the formation of visible and sub-visible aggregates and/or particles that are potentially immunogenic. Accurate determination and careful control of silicone oil levels in both empty syringes and protein drug products are therefore critical in process development to ensure syringe functionality, drug product quality, and patient safety. On the other hand, analysis of silicone oil can be challenging especially when the analysis is performed on formulated protein drug products, where matrix effects could be significant. It is demonstrated in this study that silicone oil in empty syringes or formulated drug products can be extracted effectively using organic solvents and quantitatively determined using high-performance liquid chromatography (HPLC) coupled with a universal detector. It was also shown that direct extraction of silicone oil from formulated protein drug products can be very challenging, but pretreatment of the protein drug products with pepsin enzymatic digestion facilitated the extraction process, which enabled the analysis of silicone oil in the drug product at low ppm levels.

This study analyzed the incidence and risk factors of subsequent osteoporotic fractures in South Korea. The results showed that the incidence rate of subsequent fractures within 24 months was 10.23 per 100 person-years. Additionally, the index hip fracture site was a significant risk factor for a subsequent fracture., Purpose: To identify and analyze the incidence and risk factors of subsequent osteoporotic fractures in South Korea., Methods: This retrospective cohort study analyzed data from the National Health Insurance Review and Assessment claims database from 2012 to 2017. Men and women with osteoporosis, aged ≥50 years, with index fractures between July 1, 2014, and July 1, 2015, were included. The incidence rate of subsequent fractures was calculated by determining the number of second event within 2 years from the index fracture. To identify the risk factors for subsequent fractures, we applied the Cox proportional hazard model to estimate the hazard ratios (HRs)., Results: Of the 73,717 patients with osteoporotic fractures, 13,203 (17.91%) had a subsequent fracture. The incidence rate of subsequent fractures within 24 months was 10.23/100 person-years. The index fracture site was a significant risk factor for a subsequent fracture, with the hip showing the highest risk (HR, 7.51; 95% confidence interval [CI], 6.77-8.34), followed by the vertebra (HR, 1.99; 95% CI, 1.91-2.06). The risk of subsequent fractures increased with a higher Charlson Comorbidity Index (CCI) score (CCI score ≥ 5: HR, 1.79; 95% CI, 1.67-1.92)., Conclusion: The incidence rate of subsequent osteoporotic fractures in South Korea is similar or higher than that reported in the USA and Europe. A hip fracture within the prior 2 years, relative to other fracture sites, significantly increased the risk of subsequent fractures in osteoporosis patients. Patients who have these risk factors need closer disease management to prevent subsequent fractures.

Background/objectives: ABP 798 is a proposed biosimilar to the originator biologic rituximab, an anti-CD20 monoclonal antibody. This comparative clinical study evaluated the pharmacokinetics (PK), safety, and efficacy of ABP 798 versus rituximab reference product (RP) in patients with moderate-to-severe rheumatoid arthritis (RA)., Methods: Adults with moderate-to-severe RA with an inadequate response or intolerance to other disease-modifying anti-rheumatic drugs including 1 or more tumor necrosis factor inhibitor therapies (n = 311) received ABP 798, US-sourced rituximab RP (rituximab US), or EU-sourced rituximab RP (rituximab EU) (1000 mg, 2 weeks apart). At week 24, ABP 798- or rituximab EU-treated subjects received a second dose of the same treatment, while rituximab US-treated subjects transitioned to receive ABP 798. The key efficacy endpoint was DAS28-CRP change from baseline at week 24. Other efficacy endpoints included DAS28-CRP at other time points; ACR20, ACR50, and ACR70 criteria; and hybrid ACR. The rituximab RP groups were pooled for all efficacy endpoints since PK equivalence had been established between rituximab US and rituximab EU., Results: Clinical equivalence between ABP 798 and rituximab RP was established as the 90% confidence interval for DAS28-CRP change from baseline at week 24 fell within the prespecified equivalence margin (- 0.6, 0.6). Safety and immunogenicity profiles of ABP 798 were comparable across treatment groups and not affected by single transition from RP to ABP 798., Conclusions: Clinical equivalence in terms of efficacy, safety, and immunogenicity was established between ABP 798 and rituximab RP in this comparative clinical trial in patients with moderate-to-severe RA. Key Points • ABP 798 provided similar efficacy as rituximab reference product (RP) in patients with moderate-severe rheumatoid arthritis. • The safety and immunogenicity profiles for ABP 798 were similar to those for the rituximab RP. • The single transition from rituximab RP to ABP 798 did not show differences in efficacy, safety, or immunogenicity.

The burden of osteoporosis in Turkey is not well characterized. Our results indicate that osteoporosis is undertreated in Turkey with 1.35 million fractures predicted to occur from 2019 to 2023 at an associated cost of 2.42 billion USD. Interventions are needed to close the treatment gap and minimize the economic burden., Purpose: The number of osteoporotic fractures is expected to increase as populations age, posing a major risk to health systems and patients. We created a scorecard summarizing the burden of disease, policy framework, service provision, and service uptake for osteoporosis in Turkey and estimated the economic burden of osteoporotic fractures in Turkey., Methods: A systematic review of osteoporosis in Turkey was performed. Gaps in the literature were supplemented by surveys with osteoporosis experts. The findings were used to populate a scorecard and burden of illness model focused on adults aged 50 to 89 years in Turkey. The scorecard provided a visual representation of osteoporosis burden and management using a traffic light color coding system. The model quantified osteoporosis-related fracture costs (2019 USD) including hospitalizations, dual-energy x-ray absorptiometry testing, hip fracture surgery, prescription drugs, and patient productivity losses., Results: The scorecard showed that osteoporosis is undertreated in Turkey. Despite timely access to diagnosis, > 75% of high-risk patients fail to initiate on appropriate therapies. In 2019, the economic model predicted that 255,183 osteoporosis-related fractures would occur in Turkey with an associated annual cost of approximately 455 million USD and an average burden per 1000 at risk of 23,987 USD. The cumulative 5-year cost of 1,354,817 fractures was 2.42 billion USD., Conclusions: Approximately 1.35 million fragility fractures are predicted to occur in Turkey during the next 5 years with costs of 2.42 billion USD. Closing the treatment gap will be imperative for preventing these fractures and minimizing the burden of osteoporosis in Turkey.

Advancing age, female sex, recent prior fracture and falls, and specific comorbidities and medications contribute to imminent (within 1-2 years) risk of fracture in Medicare enrollees. Clinician awareness of these risk factors and their dynamic nature may lead to improved osteoporosis care for elderly patients., Purpose: The burden of osteoporotic fracture disproportionately affects the elderly. Growing awareness that fracture risk can change substantially over time underscores the need to understand risk factors for imminent (within 1-2 years) fracture. This study assessed predictors of imminent risk of fracture in the US Medicare population., Methods: Administrative claims data from a random sample of Medicare beneficiaries were analyzed for patients aged ≥ 67 years on January 1, 2011 (index date), with continuous coverage between January 1, 2009 and March 31, 2011, excluding patients with non-melanoma cancer or Paget's disease. Incident osteoporotic fractures were identified during 12 and 24 months post-index. Potential predictors were age, sex, race, history of fracture, history of falls, presence of osteoporosis, cardiovascular diseases, chronic obstructive pulmonary disorder (COPD), mood/anxiety disorders, polyinflammatory conditions, difficulty walking, use of durable medical equipment, ambulance/life support, and pre-index use of osteoporosis medications, steroids, or central nervous system medications. Cox proportional hazards models were used to evaluate predictors of fracture risk in the two follow-up intervals., Results: Among 1,780,451 individuals included (mean age 77.7 years, 66% female), 8.3% had prior fracture and 6.1% had a history of falls. During the 12- and 24-month follow-up periods, 3.0% and 5.4% of patients had an incident osteoporotic fracture, respectively. Imminent risk of fracture increased with older age (double/triple), female sex (> 80%), recent prior fracture (> double) and falls, and specific comorbidities and medications., Conclusions: Demographics and factors including fall/fracture history, comorbidities, and medications contribute to imminent risk of fracture in elderly patients.

Background: Calcimimetic treatment of secondary hyperparathyroidism in chronic dialysis patients is often followed by hypocalcemia., Methods: We investigated the frequency, predictors, consequences and therapeutic responses following cinacalcet-induced hypocalcemia in an incident European hemodialysis cohort of 1068 patients with a cinacalcet prescription., Results: Of 905 normocalcemic patients initiating cinacalcet, 67% developed hypocalcemia within 12 months: 68% mild, 23% moderate, 9% severe. Compared to persistently normocalcemic patients, those with severe hypocalcemia were more often diabetic, overweight, had cardiovascular disease, shorter dialysis vintage, used a catheter dialysis access, had fewer active vitamin-D sterols, and exhibited higher CRP and iPTH and lower calcium levels. Multivariate predictors of hypocalcemia included a catheter for vascular access, low albumin and high iPTH. Generally, no therapeutic intervention to prevent hypocalcemia was taken prior to cinacalcet initiation. After the hypocalcemic event, the most common clinical response was no change of the dialysis or medical regimen. Following the hypocalcemic event, iPTH remained low even in those with severe hypocalcemia. The number of deaths and cardiovascular events did not differ between patients with and without hypocalcemia within six months following cinacalcet initiation., Conclusion: Two-thirds of cinacalcet initiated patients experienced hypocalcaemia with 9% being severe. Hypocalcemia was mostly asymptomatic, transient (with and without targeted intervention to correct it) and not associated with an increase in cardiovascular events or deaths.

Background This open-label, first-in-human, phase 1 study evaluated AMG 232, an oral selective MDM2 inhibitor in patients with TP53 wild-type (P53WT), advanced solid tumors or multiple myeloma (MM). Methods In the dose escalation (n = 39), patients with P53WT refractory solid tumors enrolled to receive once-daily AMG 232 (15, 30, 60, 120, 240, 480, and 960 mg) for seven days every 3 weeks (Q3W). In the dose expansion (n = 68), patients with MDM2-amplified (well-differentiated and de-differentiated liposarcomas [WDLPS and DDLPS], glioblastoma multiforme [GBM], or other solid tumors [OST]), MDM2-overexpressing ER+ breast cancer (BC), or MM received AMG 232 at the maximum tolerated dose (MTD). Safety, pharmacokinetics, pharmacodynamics, and efficacy were assessed. Results AMG 232 had acceptable safety up to up to 240 mg. Three patients had dose-limiting toxicities of thrombocytopenia (n = 2) and neutropenia (n = 1). Due to these and other delayed cytopenias, AMG 232 240 mg Q3W was determined as the highest tolerable dose assessed in the dose expansion. Adverse events were typically mild/moderate and included diarrhea, nausea, vomiting, fatigue, decreased appetite, and anemia. AMG 232 plasma concentrations increased dose proportionally. Increases in serum macrophage inhibitor cytokine-1 from baseline were generally dose dependent, indicating p53 pathway activation. Per local review, there were no responses. Stable disease (durability in months) was observed in patients with WDLPS (3.9), OST (3.3), DDLPS (2.0), GBM (1.8), and BC (1.4-2.0). Conclusions In patients with P53WT advanced solid tumors or MM, AMG 232 showed acceptable safety and dose-proportional pharmacokinetics, and stable disease was observed.