A.R. Bihlet's research while affiliated with Nordic Bioscience and other places

Publications (82)

Article
New findings: What is the central question in this study? Atrial natriuretic peptide (ANP) is secreted in response to atrial wall distension and thus allows for an albeit indirect evaluation of the central blood volume (CBV) while adrenaline possesses chronotropic and inotropic effects. We evaluated whether the chronotropic and inotropic effects o...
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Visual Analogue Scale (VAS) and the pain subscale of the Western Ontario and McMaster Universities Arthritis Index (WOMAC) are commonly used measuring tools of osteoarthritis (OA) pain. The objective of this cross-sectional study was to explore the associations between single-question VAS pain and the weight-bearing and non–weight-bearing domains o...
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Introduction: Plasma volume (PV) changes in response to physical activity, possibly as a consequence of adrenergic activation. We estimated changes in PV in response to common exercise modalities; cycling and running as well as adrenaline infusion and control at rest. Methods: On separate days, forty circulatory healthy subjects [aged 60 years (ran...
Article
Background Physical activity can induce acute changes in plasma volume (PV) and thereby influence concentration of plasma constituents, such as biochemical markers 1,2 . However, it remains undocumented to what extent PV changes occur during physical exercise in osteoarthritis (OA) patients. Objectives Investigating the direct course and magnitude...
Article
Objectives: Osteoarthritis (OA) development programmes face challenges due to discordance between structural changes and symptoms. A novel cathepsin-K inhibitor, MIV-711, recently reported structural benefits, but did not demonstrate a significant difference from placebo in symptoms. Previous work suggests that pain from non-target joints may conf...
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PurposeTo investigate acute changes in biochemical markers of bone and cartilage turnover in response to moderate intensity exercise with and without joint impact in healthy human subjects.MethodsA randomized, cross-over, exploratory, clinical study was conducted. Twenty healthy subjects with no history of joint trauma completed 30 min intervention...
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Background: Menopause is associated with detrimental changes in turnover of bone and cartilage and a variety of symptoms with negative impact on the quality of life. Naturally occurring isoflavones from Radix Pueraria lobata , Kudzu root, may possess chondroprotective and symptom-relieving properties, but efficacy and safety of dosing and dose freq...
Article
There is a need for anti-diabetic agents successfully targeting insulin sensitivity and treating obesity control at the same time. The aim of this first-in-human study was 1) to evaluate safety and tolerability; 2) to evaluate pharmacokinetics and 3) to assess indications of receptor engagement of single ascending doses of KBP-042, a Dual Amylin an...
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Objective The FORWARD (FGF-18 Osteoarthritis Randomized Trial with Administration of Repeated Doses) trial assessed efficacy and safety of the potential disease-modifying osteoarthritis drug (DMOAD) sprifermin in patients with knee osteoarthritis. Here, we report 5-year efficacy and safety results. Methods Patients were randomised to intra-articul...
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The heterogeneous nature of osteoarthritis (OA) and the need to subtype patients is widely accepted in the field. The biomarker CRPM, a metabolite of C-reactive protein (CRP), is released to the circulation during inflammation. Blood CRPM levels have shown to be associated with disease activity and response to treatment in rheumatoid arthritis (RA)...
Article
Objective: To investigate acute changes in biochemical markers of cartilage turnover in response to moderate intensity exercise with and without joint impact in humans with knee osteoarthritis. Design: We conducted a randomized, cross-over, exploratory clinical study. Twenty subjects with knee osteoarthritis (OA) were randomized, of which twenty...
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Objective To assess pain outcomes and cartilage thickness change in a subgroup at risk (SAR) of further progression in the FORWARD trial of knee osteoarthritis patients treated with sprifermin. Methods Patients were randomised 1:1:1:1:1 to: sprifermin 100 µg every 6 months (q6mo), 100 µg q12mo, 30 µg q6mo, 30 µg q12mo, or placebo for 18 months. SA...
Preprint
Full-text available
There is a need for anti-diabetic agents successfully targeting insulin sensitivity and treating obesity control at the same time. The aim of this first-in-human study was 1) to evaluate safety and tolerability; 2) to evaluate pharmacokinetics and 3) to assess indications of receptor engagement of single ascending doses of KBP-042, a Dual Amylin an...
Article
Purpose Osteoarthritis Research Society International (OARSI) Expert Consensus Guidelines recommend topical non-steroidal anti-inflammatory drugs as first-line medications for osteoarthritis (OA) knee pain, but several voluminous daily applications are required to achieve efficacy. There is a need to develop new and improved topical analgesics with...
Preprint
Full-text available
Background The heterogeneous nature of osteoarthritis (OA) and the need to subtype patients is widely accepted. The biomarker CRPM, a metabolite of C-reactive protein (CRP), is released to the circulation during inflammation. Blood CRPM levels have shown to be associated with disease activity and response to treatment in rheumatoid arthritis (RA)....
Conference Paper
Full-text available
Background: It is challenging to monitor treatment effects after intra-articular (IA) injection with tissue modifying drugs. Assessment of biomarker levels in synovial fluid may be one solution to the challenge. Sprifermin is a truncated form of fibroblast growth factor (FGF) 18 known to induce chondrocyte proliferation and type II collagen formati...
Article
Background MTX is the first line treatment in early RA. There is robust evidence from cohort studies, but less from RCTs, that a “window of opportunity” exists over 12-16 weeks symptom duration. CR6086 is a selective prostaglandin EP4 receptor antagonist, with an immunomodulatory profile. Objectives To test efficacy and safety of CR6086 added to M...
Article
Background In osteoarthritis (OA), response to different interventions could be more pronounced in different endotypes of cartilage turnover. Data from UK biobank suggest that an endotype of low cartilage repair is associated with structural progression in osteoarthritis (OA)[1]. Sprifermin a truncated and recombinant FGF18 have been shown to induc...
Article
Background Development of improved topical treatments of painful joints is warranted. A novel diclofenac sodium gel formulation, AMZ001, has been developed with the purpose of improving 1) The onset and duration of pain relief, and 2) The ease of use by reducing the required daily frequency of gel application. Previous trials in human subjects have...
Article
Background Exercise is recommended in osteoarthritis (OA) to limit pain and preserve joint function. Cycling is considered healthy, while the safety of running in OA has been controversial. The acute impact on cartilage in response to exercise (weight bearing vs non-weight bearing) remains to be explored. Biomarkers originating from type I-III and...
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Objective To propose a standardized model for exercise-induced cartilage turnover and investigate residual levels and dynamics of biomarker serum ARGS (sARGS) in primary osteoarthritis (OA) patients and a supportive group of young healthy subjects. Method The trial is a randomized, cross-over, exploratory study with interventions of exercise and i...
Conference Paper
Full-text available
Purpose: Sprifermin is a truncated form of fibroblast growth factor (FGF) 18 known to induce chondrocyte proliferation and type II collagen formation [1,2]. Data from preclinical investigations show that cartilage formation happens in different phases after therapy with sprifermin, starting with a phase of cartilage degradation during the induction...
Article
Objectives We aimed to investigate existing literature on the impact of physical activity and exercise (PA) on joint biochemical markers (BM) and magnetic resonance imaging (MRI) outcomes in osteoarthritis (OA), and on this basis propose directions for future research. Design Literature Review. Method Original papers were identified in PubMed, Em...
Article
Objectives Clinical trials of new disease-modifying treatments for osteoarthritis should demonstrate a positive effect on a functional outcome or reduction in joint failure in order to be considered successful. Total joint replacement (TJR) surgery may be considered as joint failure, but great variation in the incidence of TJR complicates its use a...
Conference Paper
Full-text available
Background/Purpose: Osteoarthritis (OA) is a highly heterogeneous disease, which suggest that multiple endotypes exist. Identification and characterization of such endotypes may assist in precision medicine for identification of faster progressors whom may benefit from a given type of intervention. Recent published data have shown that SNPs in grow...
Article
Importance Sprifermin is under investigation as a disease-modifying osteoarthritis drug. Objective To evaluate the effects of sprifermin on changes in total femorotibial joint cartilage thickness in the more symptomatic knee of patients with osteoarthritis. Design, Setting, and Participants FORWARD (FGF-18 Osteoarthritis Randomized Trial with Adm...
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Background: Excessive cartilage degradation is a known characteristic of osteoarthritis (OA). Biochemical markers, such as uCTX-II, have been shown to be associated with disease severity, yet the tissue origin of CTX-II has been disputed. This analysis investigates the association between OA knee joints at different radiographic stages and pain ca...
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Full-text available
Background: Osteoarthritis (OA) leads to joint failure and total joint replacement (TJR, either hip (H) or knee (K)). Worsening of pain and joint space narrowing are believed to be surrogates for joint failure; however, we hypothesize that TJR, as a reflection of joint failure, can be used as an endpoint in event-driven clinical trials within a re...
Conference Paper
Background Osteoarthritis (OA) can lead to joint failure and ultimately total joint replacement (TJR). Identifying risk-factors of developing joint failure is of interest for clinicians and researchers. Currently late-stage clinical trial design for evaluating new treatments in OA is evolving with the possible utilization of accelerated approval pa...
Conference Paper
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Purpose: Currently, there are no approved treatments for osteoarthritis (OA). One of several reasons may be consequent to the patient heterogeneity, and the need for identification drug-specific superior responders. There is an unmet need for stratifying and targeting specific OA patient populations in clinical interventional trials testing the ef...
Conference Paper
Full-text available
Background Sprifermin, a novel recombinant human fibroblast growth factor 18, is currently being investigated as a potential disease-modifying osteoarthritis (OA) drug. Two-year results of the 5 year phase II FORWARD study showed a statistically significant dose-dependent cartilage thickness increase in the total femorotibial joint (TFJ), and in th...
Conference Paper
Background Osteoarthritis (OA) is a heterogeneous disease described by a combination of joint pain, physical disability and radiographic alterations leading to joint failure and total joint replacement (TJR). Commonly used endpoints in OA trials are worsening of pain and joint space narrowing. TJR is normally not considered an endpoint. Age and fem...
Article
Significance: Osteoarthritis (OA) is a heterogenous disease affecting the entire joint, including cartilage, bone and synovium. While pain is the hallmark symptom of osteoarthritis, clear associations between pain and disease processes involved in joint deterioration are lacking. Thus, there is clear need for biomarkers that can accurately describ...
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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 (MMP...
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Background Pain is the principal clinical symptom of osteoarthritis (OA), and development of safe and effective analgesics for OA pain is needed. Drug development of new analgesics for OA pain is impaired by substantial change in pain in patients receiving placebo, and more data describing clinical characteristics and pain categories particularly a...
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Background Change in forced expiratory volume in one second (FEV1) is important for defining severity of chronic obstructive pulmonary disease (COPD). Serological neoepitope markers of collagen turnover may predict rate of change in FEV1. Methods One thousand COPD subjects from the observational, multicentre, three-year ECLIPSE (Evaluation of COPD...
Conference Paper
Background There are two major needs in clinical development of DMOADs: 1) Identifying a suitable population with an active and progressive disease in order to demonstrate significant improvements by an efficacious intervention; and 2) Phenotyping patients and linking them to a corresponding treatment mode-of-action (e.g. anti-inflammatory). The bi...
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Background Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction and loss of lung tissue mainly consisting of extracellular matrix (ECM). Three of the main ECM components are type I collagen, the main constituent in the interstitial matrix, type VI collagen, and elastin, the signature protein of the lungs. During path...
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Background There is a need to identify individuals with COPD at risk for disease progression and mortality. Lung tissue remodeling is associated with the release of extracellular matrix (ECM) fragments into the peripheral circulation. We hypothesized that ECM remodeling was associated with mortality in COPD and measured neo-epitopes originating fro...
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Osteoarthritis (OA) is the biggest unmet medical need among the many musculoskeletal conditions and the most common form of arthritis. It is a major cause of disability and impaired quality of life in the elderly. We review several ambitious but failed attempts to develop joint structure-modifying treatments for OA. Insights gleaned from these atte...
Article
This randomized, double-blind, placebo-controlled phase III study was conducted to assess the efficacy and safety of oral calcitonin (SMC021) for the treatment of postmenopausal osteoporosis. A total of 4665 postmenopausal women with osteoporosis were randomized 1:1 to receive calcium and vitamin D plus either SMC021 tablets (0.8 mg/d) or placebo f...
Article
Background Pain is the principal clinical symptom of osteoarthritis (OA), and development of safe and effective analgesics for OA pain is needed. Trials of new analgesics for OA pain is impaired by substantial placebo-response (PR), and data describing characteristics and pain sub-types particularly associated with placebo-response is needed. Obje...
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Purpose: Monitoring is a costly requirement when conducting clinical trials. New regulatory guidance encourages the industry to consider alternative monitoring methods to the traditional 100 % source data verification (SDV) approach. The purpose of this literature review is to provide an overview of publications on different monitoring methods and...
Article
Background: Markers of extracellular matrix turnover were evaluated in the ECLIPSE study, an observational, multicentre, three-year study (NCT00292552). Methods: 1000 COPD subjects from ECLIPSE (GOLD stage II-IV) selected based on the most or the least rapid lung function decline were included. Tissue turnover was assessed in serum samples from the...
Article
Background: There is a need to identify the patients with COPD at risk for rapid disease progression and mortality. Lung tissue remodeling is associated with release of extracellular matrix (ECM) fragments into the circulation which may serve as candidate biomarkers. We hypothesized that ECM turnover is related to mortality in COPD, and measured a...
Article
Background Cartilage and bone are the central tissues affected by osteoarthritis (OA). Remodeling of these tissues can be measured by soluble biomarkers. Recent data has shown that urinary type II collagen C-terminal telopeptide (u-CTX-II) is a biomarker of cartilage and subchondral bone turnover. Bone resorption may be quantified by type I collage...