Concizumab prophylaxis in persons with hemophilia A or B with inhibitors: patient-reported outcome results from the phase 3 explorer7 study.

Background: Patient-reported outcomes (PROs) reflect patient perceptions of disease and treatment and are important for evaluating new therapies. Objectives: Evaluate the effects of once-daily concizumab prophylaxis on health-related quality of life (HRQoL), treatment burden, and treatment preference in males aged ≥12 years with hemophilia A/B with inhibitors. Methods: Patients enrolled in the multicenter, open-label explorer7 phase 3 study (ClinicalTrials.gov identifier: NCT04083781) were randomized to receive no prophylaxis (arm 1) or concizumab prophylaxis (arm 2) or were nonrandomly allocated to concizumab prophylaxis (arms 3 and 4). The study included questionnaires to assess patients' perception of HRQoL (Haemophilia Quality of Life Questionnaire for Adults), treatment burden (Hemophilia Treatment Experience Measure), and treatment preference (Haemophilia Patient Preference Questionnaire). Results: The estimated treatment difference between patients receiving concizumab prophylaxis vs no prophylaxis at week 24 for Haemophilia Quality of Life Questionnaire for Adults "total score" was -22.6 points (95% CI, -42.5; -2.7), directionally favoring patients receiving concizumab prophylaxis. For Hemophilia Treatment Experience Measure "total score," the estimated treatment difference was -19.9 points (95% CI, -34.3, -5.6) in favor of concizumab vs no prophylaxis. The majority of patients receiving concizumab expressed a preference for concizumab over their previous treatment, the main reasons being "fewer bleeds," "require less time," and "less painful to inject." Across all PROs, there were less responses collected than anticipated, limiting interpretations. Conclusion: PROs collected during the explorer7 study showed improvements in some domains of HRQoL, treatment burden, and patient treatment preference in persons with hemophilia A or B with inhibitors receiving concizumab prophylaxis compared with no prophylaxis.

The Concizumab Pen-Injector is Easy to Use and Preferred by Hemophilia Patients and Caregivers: A Usability Study Assessing Pen-Injector Handling and Preference.

Introduction: Concizumab is a once-daily prophylactic treatment developed for patients with hemophilia A or B (HA/HB) with or without inhibitors. It is the first treatment for hemophilia patients to be delivered subcutaneously using a pre-filled, multi-dose pen-injector with a 4 mm, 32 G needle. Aim: To investigate patient and caregiver handling and preference for the concizumab pen-injector compared with current injection systems used to treat hemophilia. Methods: This preference and handling study was conducted in accordance with authority guidelines for approval of new devices and included adults and adolescents with HA/HB with or without inhibitors and caregivers currently administering factor replacement therapy or factor VIII mimetic (emicizumab) therapy. All participants underwent a training session, followed by a test session during which participants independently administered a single pen-injection into an injection pad or manikin. Time to train, time to prepare and inject, and number of complete independent injections handling the pen were assessed. Participants evaluated handling and preference via the Hemophilia Device Handling and Preference Assessment Questionnaire. Results: 80 participants (44 adults, 21 adolescents, 15 caregivers) currently using factor replacement therapy (n=41, 51%) or emicizumab (n=39, 49%) participated. Average training time and time to complete an injection were 7 min 49s and 1 min 21s. In total, 98% of independent complete injections were achieved at first attempt. 98% (n=78; 95% confidence interval [CI] 91-100%) of participants assessed the pen-injector as either "easy" or "very easy" to use. 88% of participants preferred the pen-injector (n=70; 95% CI 78-94%) over their current injection system, and 9% (n=7) reported "no preference". Conclusion: Participants found the concizumab pen-injector easy to learn and easy to use and preferred it over their current injection systems.

People with hemophilia lack clotting factors that help stop bleeding after an injury. If left untreated, it can lead to life-threatening bleeding episodes. Treatment such as replacement therapy with clotting factors needs to be administered at regular intervals to prevent bleeding. The administration of intravenous (inside the vein) medication can be challenging due to the required skills, injection pain and availability of a good vein to inject into. Factor VIII mimetic therapy now allows people to inject medication under the skin (subcutaneously). However, using vials and syringes still poses challenges with the time to prepare and inject medication. Pen-injectors have been developed to address these challenges and provide additional benefits, including increased dose accuracy, portability, reduced discomfort, and less administration time. Concizumab is a medication developed for once-daily subcutaneous injection for people with hemophilia A or hemophilia B, with or without inhibitors, using a pen-injector. The objective of this preference and handling study was to understand patient and caregiver pen-injector handling experiences, and device preferences compared to their existing devices. In this study, most participants found it easy to learn to use the pen-injector. 98% of participants reported that the pen-injector was easy or very easy to use compared with their current device. 88% of participants reported a preference for the concizumab pen-injector over their current device. This shows that the pen-injector can easily and effectively be used to inject concizumab, providing more control and independence in patients' treatment while reducing the burden caused by intravenous modes of administration.

Disease and treatment burden of patients with haemophilia entering the explorer6 non-interventional study.

OBJECTIVES: We aimed to characterise baseline disease and treatment burden in a large population with haemophilia A/B, both with (HAwI/HBwI) and without (HA/HB) inhibitors. METHODS: The prospective, non-interventional explorer6 study included patients ≥12 years old with severe HA, severe/moderate HB or HAwI/HBwI of any severity, treated according to local standard of care (excluding previous/current exposure to concizumab or emicizumab). Baseline characteristics and historical clinical data were collected and patient-reported outcomes, including treatment burden, were assessed. RESULTS: The explorer6 study enrolled 231 patients with haemophilia (84 HAwI/HBwI) from 33 countries. At baseline, patients with HA/HB treated with prophylaxis had the lowest median annualised bleeding rates (ABRs; 2.0), irrespective of haemophilia type; of these patients, 27.5% (HA) and 31.4% (HB) had target joints. Patients with HAwI/HBwI treated episodically reported the highest treatment burden. Of these patients, 28.5% (HAwI) and 25.1% (HBwI) performed sports activities in the month before screening. CONCLUSION: Despite receiving routine clinical care, historical and baseline information from patients enrolled in explorer6 showed that patients with HA/HB treated episodically and patients with HAwI/HBwI had higher ABRs, higher treatment burden and participated in sports less than those with HA/HB treated with prophylaxis. Emerging treatments could be beneficial in addressing these unmet medical needs.

Understanding treatment burden in hemophilia: development and validation of the Hemophilia Treatment Experience Measure (Hemo-TEM).

BACKGROUND: To capture the broad range of treatment burden issues experienced by adolescent and adult people with hemophilia (PWH), the Hemophilia Treatment Experience Measure (Hemo-TEM) was developed. We describe the development of this new hemophilia-specific patient-reported outcome (PRO) measure including concept elicitation, cognitive debriefing, and psychometric validation. RESULTS: Concept elicitation interviews were conducted with 5 clinical experts and 30 adult PWH in the United States (US). The qualitative analysis of these interviews and a review of the literature informed the PRO measure development. The project team reviewed concept endorsement rates and generated a 27-item preliminary version of the Hemo-TEM. Cognitive debriefing interviews were conducted to ensure participant understanding and item relevance in samples of (adolescent (n = 20) and adult (n = 14)) PWH in the US. The refined, validation-ready version of the Hemo-TEM included 30 items. Lastly, data from 3 clinical trials comprised the 4 analysis sets used for the psychometric validation with a sample size of N = 88. Item reduction dropped 4 items resulting in a final 26-item measure. Factor analysis generated 5 domains in the Hemo-TEM [injection difficulties (3 items), physical impact (6 items), treatment bother (7 items), interference with daily life (4 items), and emotional impact (6 items)] and a total score. All scores were reliable [internally consistent (0.84-0.88)]. For convergent validity, with the exception of one domain, all hypothesized associations were met. Preliminary sensitivity to change effect sizes were between - 0.30 and - 0.70. Meaningful change thresholds ranged from 6 points (physical impact and emotional impact) to 10 points (treatment bother) with 8 points for the Hemo-TEM total score. CONCLUSIONS: Findings from the concept elicitation, cognitive debriefing, and psychometric validation phases provide evidence that the Hemo-TEM is a well-designed, valid, and reliable measure of the burden of hemophilia treatment, including treatment impact on adolescent and adult PWH.

Two novel blood-based biomarker candidates measuring degradation of tau are associated with dementia: A prospective study.

BACKGROUND: Truncated tau appears to be specifically related to disease pathology and recent studies have shown the presence and elevation of several truncated tau species in Cerebrospinal fluid (CSF) of subjects with Alzheimer's disease (AD); however, the relevance of truncated Tau measurements in blood is still being studied. OBJECTIVE: The aim of the current study was to assess the longitudinal associations between baseline levels of two novel blood biomarker candidates measuring truncated tau, Tau-A and Tau-C, and the risk of incident dementia and AD in elderly women. METHODS: Using solid phase competitive ELISA, two tau fragments were detected in serum of 5,309 women from the Prospective Epidemiological Risk Factor study. The study was an observational, prospective study of Danish postmenopausal women. Subjects were followed with registry-linkage for up to 15 years (median follow-up time 13.7 years). Cox regression was used to assess the utility of the biomarker candidates in relation to dementia and AD. RESULTS: High levels of Tau-A and Tau-C (above the median) in blood were associated with lower risk of dementia and AD (Tau-A: Dementia HR[95% CI] = 0.85[0.70-1.04]; AD 0.71[0.52-0.98] and Tau-C: Dementia 0.84[0.70-1.00]; AD 0.78[0.60-1.03]). Tau-C gave a very modest increase in the AUC in a 5-year prediction horizon as compared to a reference model with age and education, while a combination of the two did not improve their predictive capacity. CONCLUSIONS: Measurement of tau in serum is feasible. The serological tau turnover profile may be related to the diagnosis and development of dementia and AD. The exact processing and profile in serum in relation to cognitive disorders remains to be further assessed to provide simple non-invasive tests to identify subjects with progressive cognitive disorders.

Matrix Metalloproteinase Mediated Type I Collagen Degradation is an Independent Predictor of Increased Risk of Acute Myocardial Infarction in Postmenopausal Women.

Acute myocardial infarction (AMI) is often underdiagnosed in women. It is therefore of interest to identify biomarkers that indicate increased risk of AMI and thereby help clinicians to have additional focus on the difficult AMI diagnosis. Type I Collagen, a component of the cardiac extracellular matrix, is cleaved by matrix metalloproteinases (MMPs) generating the neo-epitope C1M. We investigated the association between serum-C1M and AMI and evaluated whether C1M is a prognostic marker for outcome following AMI. This study is based on The Prospective Epidemiological Risk Factor (PERF) Study including postmenopausal women. 316 out of 5,450 women developed AMI within the follow-up period (14 years, median). A multivariate Cox analysis assessed association between serum-C1M and AMI, and re-infaction or death subsequent to AMI. The risk of AMI increased by 18% (p = 0.03) when serum-C1M was doubled and women in the highest quartile had a 33% increased risk compared to those in the low quartiles (p = 0.025). Serum-C1M was, however not related to reinfarction or death subsequent to AMI. In this study C1M was be an independent risk factor for AMI. Measuring MMP degraded type I collagen could be useful for prediction of increased risk of AMI if replicated in other cohorts.

Remodeling of the Tumor Microenvironment Predicts Increased Risk of Cancer in Postmenopausal Women: The Prospective Epidemiologic Risk Factor (PERF I) Study.

BACKGROUND: An altered tumor microenvironment is one of the earliest signs of cancer and an important driver of the disease. We have seen previously that biomarkers reflecting tumor microenvironment modifications, such as matrix metalloproteinase (MMP)-degraded type 1 collagen (C1M), MMP-degraded type IV collagen (C4M), and citrullinated and MMP-degraded vimentin (VICM), were higher in the serum of cancer patients than in healthy controls. However, it is not known if these biomarkers could predict an increased risk of cancer. The aim of this study was to investigate whether C1M, C4M, and VICM were elevated prior to diagnosis of solid cancers in a large prospective study. METHODS: Between 1999 and 2001, 5,855 postmenopausal Danish women ages 48 to 89 years enrolled in the Prospective Epidemiologic Risk Factor study. Baseline demographics and serum were collected at the time of registration. Follow up cancer diagnoses were obtained from the Danish Cancer Registry in 2014. Serum C1M, C4M, and VICM levels were measured by competitive ELISAs. RESULTS: A total of 881 women were diagnosed with solid cancers after baseline. C1M, C4M, and VICM levels were significantly elevated in women diagnosed less than 1 year after baseline. C1M and VICM, but not C4M, were independent predictors of increased risk of cancer. CONCLUSION: C1M, C4M, and VICM are elevated prior to cancer diagnosis. C1M and VICM are both independent predictors of increased cancer risk. IMPACT: C1M and VICM are predictors for increased risk of cancer. Cancer Epidemiol Biomarkers Prev; 25(9); 1348-55. ©2016 AACR.

Late-Life Risk Factors for All-Cause Dementia and Differential Dementia Diagnoses in Women: A Prospective Cohort Study.

Since the first evidence of a decline in dementia incidence was reported in 2011, the focus on modifiable risk factors has increased. The possibility of risk factor intervention as a prevention strategy has been widely discussed; however, further evidence in relation to risk factors is still needed. The Prospective Epidemiologic Risk Factor (PERF I) study was an observational prospective study of postmenopausal Danish women who were initially examined between 1999 and 2001 (n = 5855). Follow-up data on diagnosis and survival as of December 31, 2014 was retrieved from the National Danish Patient Registry and the National Danish Causes of Death Registry. Cox proportional hazards regression model was applied to calculate adjusted hazard ratios (HR) for selected risk factors for dementia. Of 5512 eligible subjects, 592 developed dementia within the follow-up period of maximum 15 years. The independent factors associated with increased risk of all-cause dementia were depression (HR = 1.75 [95% CI 1.32-2.34]) and impaired fasting glucose levels. A dose-response relationship was observed between fasting glucose level and risk of dementia with HRs of 1.25 [1.05-1.49] and 1.45 [1.03-2.06] for impaired (5.6-6.9 mmol/L) and hyperglycemic (≥7.0 mmol/L) glucose levels, respectively. The factors associated with a decreased risk of dementia were overweight in late-life (HR = 0.75 [0. 62-0.89]) and physical activity at least once weekly (HR = 0.77 [0.61-0.96]). The identified risk factors for dementia in women in late-life are all considered modifiable. This supports the notion that prevention strategies may improve the poor future prospects for dementias in the ageing population.