Herlev, Denmark
Herlev, Denmark

Time filter

Source Type

Siebuhr A.S.,Nordic Bioscience | Bay-Jensen A.C.,Nordic Bioscience | Leeming D.J.,Nordic Bioscience | Plat A.,Roche Holding AG | And 3 more authors.
Arthritis Research and Therapy | Year: 2013

Introduction: Rheumatoid arthritis (RA) patients with structural progression are in most need of immediate treatment to maintain tissue integrity. The serum protein fingerprint, type I collagen degradation mediated by matrix metalloproteinases (MMP)-cleavage (C1M), is a biomarker of tissue destruction. We investigated whether baseline serum C1M levels could identify structural progressors and if the biomarker levels changed during anti-inflammatory treatment with tocilizumab (TCZ).Methods: The LITHE-biomarker study (NCT00106535, n = 585) was a one-year phase III, double-blind, placebo (PBO)-controlled, parallel group study of TCZ 4 or 8 mg/kg every four weeks, in RA patients on stable doses of methotrexate (MTX). Spearman's ranked correlation was used to assess the correlation between baseline C1M levels and structural progression at baseline and at weeks 24 and 52. Multivariate regression was performed for delta structural progression. Change in C1M levels were studied as a function of time and treatment.Results: At baseline, C1M was significantly correlated to C-reactive protein (P <0.0001), visual analog scale pain (P <0.0001), disease activity score28-erythrocyte sedimentation rate (DAS28-ESR) (P <0.0001), joint space narrowing (JSN) (P = 0.0056) and modified total Sharp score (mTSS) (P = 0.0006). Baseline C1M was significantly correlated with delta-JSN at Week 24 (R2= 0.09, P = 0.0001) and at Week 52 (R2= 0.27, P <0.0001), and with delta-mTSS at 24 weeks (R2= 0.006, P = 0.0015) and strongly at 52 weeks (R2= 0.013, P <0.0001) in the PBO group. C1M levels were dose-dependently reduced in the TCZ + MTX group.Conclusions: Baseline C1M levels correlated with worsening joint structure over one year. Serum C1M levels may enable identification of those RA patients that are in most need of aggressive treatment. Trial registration: ClinicalTrials.gov: NCT00106535. © 2013 Siebuhr et al.; licensee BioMed Central Ltd.


Alexandersen P.,Center for Clinical and Basic Research | Karsdal M.A.,Nordic Bioscience | Byrjalsen I.,Nordic Bioscience | Christiansen C.,Nordic Bioscience
Climacteric | Year: 2011

Objective The objective of this post hoc analysis was to investigate the effect of strontium ranelate on a cartilage degradation marker in postmenopausal women who participated in a randomized, placebo-controlled osteoporosis study. Women were stratified according to reported symptoms of osteoarthritis and to the baseline levels of a cartilage degradation marker. Methods The analysis included the 2617 postmenopausal women (75 years old) with osteoporosis randomized to strontium ranelate or placebo for a 36-month period. Cartilage degradation was evaluated using a validated urinary marker adjusted for creatinine (CTX-II/cr), whereas bone resorption was assessed by serum CTX-I. The presence of osteoarthritis was determined by individual interviews. Results CTX-II was significantly elevated at baseline in subjects with a history of osteoarthritis (OA+) compared to subjects who did not (OA-) (p < 0.0001), whereas CTX-I was unaffected by osteoarthritis status. Strontium ranelate caused a significant decrease from baseline in CTX-II over a 12-month period whatever the osteoarthritis status. Strontium ranelate-treated patients had a significant decrease in CTX-II compared to placebo in both OA+ and OA- groups up to 12 months, the difference remaining still significant at 36 months in patients from the OA- group (p < 0.001). Conclusions The CTX-II profile of changes over 3 years may reflect efficacy of strontium ranelate against cartilage degradation, with an enhanced beneficial effect in subjects with early or mild clinical osteoarthritis, probably exerting its putative chondroprotective influence in early stages of the disease. Carefully controlled studies in targeted populations with early osteoarthritis are warranted to assess the role of strontium ranelate halting osteoarthritis progression. © 2011 International Menopause Society.


Bay-Jensen A.C.,Nordic Bioscience | Platt A.,Roche Holding AG | Byrjalsen I.,Nordic Bioscience | Vergnoud P.,Synarc Laboratories | And 2 more authors.
Seminars in Arthritis and Rheumatism | Year: 2014

Objective: We investigated the effects of tocilizumab (TCZ) on joint tissue remodeling in patients with moderate to severely active RA by measuring tissue-specific biomarker. Methods: The LITHE biomarker study (n = 740) was a phase III study of 4- and 8-mg/kg TCZ in combination with MTX. Early response was evaluated at week 16 as ±20% improvement in swollen/tender joint counts; and ACR50 was evaluated at week 52. Biomarkers (tissue inflammation: C3M, CRPM, and VICM; cartilage degradation: C2M; and bone turnover: CTx and osteocalcin) were tested in serum from baseline, week 4, 16, 24, and 52, and dose-dependent effect was investigated. Patients were divided into the following three groups: early non-responders (ENR), ACR50 responders, and non-responders; their biomarker profiles were compared. Results: At week 52, CRP was inhibited to 4% and 40% of baseline by TCZ8 and TCZ4, respectively. CRPM (63%), C2M (84%), C3M (69%), and VICM (42%) were significantly (p < 0.05) reduced by TCZ8, but not by TCZ4. MMP3 and osteocalcin changed to <58% and >111%, respectively, in response to TCZ. CTx was not changed significantly. ENRs had significantly less inhibition of CRPM (p < 0.05), C2M (p < 0.01), and C3M (p < 0.01) compared to early responders. There was a significant difference in the C2M, C3M, and CRPM profiles of the ENRs, non-responders, and responders. ACR50 responders had significantly inhibited levels (p < 0.001), irrespective of dose. Conclusions: TCZ8 strongly inhibited the biomarkers of joint tissue remodeling suggesting that TCZ actively suppresses key pathobiological processes at the site of inflammation in RA patients. The differences in biomarkers' profiles of responders and non-responders indicate that specific responder profiles exist. © 2014 The Authors.


Genovese F.,Nordic Bioscience | Manresa A.A.,Nordic Bioscience | Leeming D.J.,Nordic Bioscience | Karsdal M.A.,Nordic Bioscience | And 2 more authors.
Fibrogenesis and Tissue Repair | Year: 2014

Interstitial fibrosis is the common endpoint of end-stage chronic kidney disease (CKD) leading to kidney failure. The clinical course of many renal diseases, and thereby of CKD, is highly variable. One of the major challenges in deciding which treatment approach is best suited for a patient but also in the development of new treatments is the lack of markers able to identify and stratify patients with stable versus progressive disease. At the moment renal biopsy is the only means of diagnosing renal interstitial fibrosis. Novel biomarkers should improve diagnosis of a disease, estimate its prognosis and assess the response to treatment, all in a non-invasive manner. Existing markers of CKD do not fully and specifically address these requirements and in particular do not specifically reflect renal fibrosis. The aim of this review is to give an insight of the involvement of the extracellular matrix (ECM) proteins in kidney diseases and as a source of potential novel biomarkers of renal fibrosis. In particular the use of the protein fingerprint technology, that identifies neo-epitopes of ECM proteins generated by proteolytic cleavage by proteases or other post-translational modifications, might identify such novel biomarkers of renal fibrosis. © 2014 Genovese et al.; licensee BioMed Central Ltd.


Leeming D.J.,Nordic Bioscience | Byrjalsen I.,Nordic Bioscience | Jimenez W.,University of Barcelona | Christiansen C.,Nordic Bioscience | Karsdal M.A.,Nordic Bioscience
Liver International | Year: 2013

Background/Aim: We investigated nine novel biomarkers of extracellular matrix (ECM) remodelling in a rat model of liver fibrosis. Methods: Liver fibrosis was induced in 52 male Wistar rats by inhalation of carbon tetrachloride and the level of hepatic fibrosis was assessed by Sirius red staining compared with controls. The novel serum biochemical markers assessed in the model were type I-(C1M), type III-(C3M), type IV-(C4M) and type VI-(C6M) collagen, citrullinated vimentin (VICM) and biglycan (BGM) all protein fragments generated by matrix metalloproteinases; and formation markers of type III-(P3NP), type VI (P4NP 7S) and type V (P5CP) collagen; hepatic mRNA type I collagen alpha-1 chain levels, serum potassium, sodium, osmolarity, alanine aminotransferase, lactate dehydrogenase, albumin and creatinine. Results: Stratification of the CCl4-treated rats according to total hepatic collagen showed that the degradation markers were significantly elevated in mild to severe fibrosis except for C6M which was also elevated in early fibrosis (P < 0.05). The highest Z-scores in early and moderate fibrosis were provided by P4NP 7S and alanine aminotransferase. All nine markers of ECM remodelling were highly related to the extent of liver fibrosis induced by CCl4. The novel collagen formation marker, P4NP 7S, was reliable for the detection of early fibrosis, while the combination of the two markers, C6M and P5CP provided the best correlation with hepatic fibrosis in all fibrosis levels. Conclusion: As the markers can be used for translational science, these markers may provide valuable information for the evaluation of liver fibrosis in clinical settings. © 2012 John Wiley & Sons A/S.


Bay-Jensen A.C.,Nordic Bioscience | Karsdal M.A.,Nordic Bioscience | Vassiliadis E.,Nordic Bioscience | Wichuk S.,University of Alberta | And 4 more authors.
Arthritis and Rheumatism | Year: 2013

Objective Ankylosing spondylitis (AS) has been considered a seronegative rheumatic disease based on absent or low levels of antibodies against citrullinated proteins. The present study was undertaken to evaluate whether a citrullinated and matrix metalloproteinase-degraded fragment of vimentin (VICM) could be a prognostic biomarker in AS. Methods VICM was measured in serum samples from healthy controls (n = 35), control patients with rheumatoid arthritis (RA) (n = 47), and patients with AS (n = 201). The optimal cutoff for diagnostic sensitivity and specificity was determined by receiver operating characteristic curve analysis. Baseline and 2-year spine radiographs were available from 118 AS patients, and were scored using the modified Stoke AS Spine Score (mSASSS). We assessed correlations with patient demographic characteristics (age, disease duration), disease activity (Bath AS Disease Activity Index [BASDAI], C-reactive protein level), and disease severity (mSASSS) using Spearman's rho. The independent association of VICM with 2-year radiographic progression, defined as a change of >0 in the mSASSS or the development of a new syndesmophyte, was analyzed by multivariate regression. Results Levels of degraded VICM were significantly higher in both RA patients and AS patients than in healthy controls (both P < 0.001). AS patients with the highest levels of VICM had the largest burden of disease (P < 0.01), i.e., highest mSASSS score and BASDAI. VICM levels were significantly and independently associated with radiographic progression after 2 years (β = 0.69, P = 0.0005). Patients with both a high VICM level and a high baseline mSASSS had the highest risk of radiographic progression (odds ratio 13 for mSASSS change, 32 for new syndesmophytes), with progression occurring in 67% of these patients. Conclusion The present findings show that serum VICM may be of prognostic value in AS. The data also suggest that citrullination may be relevant in AS pathogenesis. Copyright © 2013 by the American College of Rheumatology.


SAN FRANCISCO, Nov. 10, 2016 /PRNewswire/ -- Symic Bio, a clinical stage biopharmaceutical company developing a new category of therapeutics focused on extracellular matrix biology, announced today the completion of enrollment for its Phase 1/2a MODIFY­-OA clinical trial of SB-061 in the...


Karstoft K.,Copenhagen University | Christensen C.S.,Copenhagen University | Pedersen B.K.,Nordic Bioscience | Solomon T.P.J.,Copenhagen University
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Context: Glycemic control improves with physical activity, but the optimal exercise mode is unknown. CopyrightObjective: The objective of the study was to determine whether interval-based exercise improves postprandial glucose tolerance and free-living glycemia more than oxygen consumption- and time duration-matched continuous exercise.Design: This was a crossover, controlled study with trials performed in randomized order.Setting: The study was conducted in hospitalized and ambulatory care.Patients: Patients diagnosed with type 2 diabetes mellitus (n=10, no withdrawals) participated in the study.Interventions: Subjects performed three 1-hour interventions: 1) interval walking (IW; repeated cycles of 3 min of slow and fast walking); 2) continuous walking (CW); and 3) control (CON). Oxygen consumption (VO2) was measured continuously to match mean VO2between exercise sessions (∼75% VO2peak).Main Outcome Measures: A mixed-meal tolerance test (MMTT; 450 kcal, 55% carbohydrate) with stable glucose isotopic tracers was provided after each intervention, and glucose kinetics were measured during the following 4 hours. Free-living glycemic control was assessed for approximately 32 hours after the MMTT using continuous glucose monitoring.Results: VO2was well matched between the exercise interventions. IW decreased the mean and maximal incremental plasma glucose during theMMTTwhen compared with the CON (mean 1.2± 0.4 vs 2.0 ± 0.5 mmol/L, P < .001; maximal 3.7 ± 0.6 vs 4.6 ± 0.7 mmol/L, P = .005) and mean when compared withCW(1.7±0.4 mmol/L, P=.02). No differences in the mean or maximal incremental plasma glucose values were seen between the CW and CON. The metabolic clearance rate of glucose during theMMTTwas increased in theIWcompared withCW(P=.049) andCON(P<.001). Continuous glucose monitoring mean glucose was reduced in IW compared with CW for the rest of the intervention day (8.2±0.4 vs 9.3±0.7 mmol/L, P=.03), whereas no differences were found between IW and CW the following day.Conclusions: One interval-based exercise session improves glycemic control in type 2 diabetes mellitus subjects when compared with an oxygen consumption- and time duration-matched continuous exercise session. © 2014 by the Endocrine Society.


Karsdal M.A.,Nordic Bioscience | Christiansen C.,Nordic Bioscience | Ladel C.,Merck KGaA | Henriksen K.,Nordic Bioscience | And 2 more authors.
Osteoarthritis and Cartilage | Year: 2014

For both economic and ethical reasons, identification of the optimal treatment for each individual patient is a pressing concern, not only for the patients and their physician, but also health care payers and the pharmaceutical industry. In the field of osteoarthritis (OA) this is of particular relevance, due to the heterogeneity of the disease and the very large number of affected individuals. There is a need to pair theright patients with the right therapeutic modes of action. At present, the clinical trial failures in OA may be a consequence of both bona fide treatment failures and trial failures due to clinical design deficiencies. Tools are needed for characterization and segregation of patients with OA. Key lessons may be learned from advances with another form of arthritis, namely rheumatoid arthritis (RA).Personalized health care (PHC) may be more advantageous for a number of specific indications which are characterized by costly therapy, low response rates and significant problems associated with trial and error prescription, including the risk of serious side effects. We discuss the use of diagnostic practices guiding RA treatment, which may serve as a source of key insights for diagnostic practices in OA. We discuss the emerging concept of PHC, and outline the opportunities and current successes and failures across the RA field, as the OA field collects further data to support the hypothesis. We attempt to outline a possible path forward to assist patients, physicians, payers and the pharmaceutical industry in assuring the 'right' patients are treated with the 'right drug' in OA. Finally we highlight methods for possible segregation of OA patients that would allow identification of patient subtypes, such as OA driven by inflammation that may be ideally suited for PHC and for targeted therapies. © 2013 Osteoarthritis Research Society International.


Nedergaard A.,Nordic Bioscience | Karsdal M.A.,Nordic Bioscience | Sun S.,Nordic Bioscience | Henriksen K.,Nordic Bioscience
Journal of Cachexia, Sarcopenia and Muscle | Year: 2013

Background: The skeletal muscle mass is the largest organ in the healthy body, comprising 30-40 % of the body weight of an adult man. It confers protection from trauma, locomotion, ventilation, and it represents a "sink" in glucose metabolism and a reservoir of amino acids to other tissues such as the brain and blood cells. Naturally, loss of muscle has dire consequences for health as well as functionality. Muscle loss is a natural consequence of especially aging, inactivity, and their associated metabolic dysfunction, but it is strongly accelerated in critical illness such as organ failure, sepsis, or cancer. Whether this muscle loss is considered a primary or secondary condition, it is known that muscle loss is a symptom that predicts morbidity and mortality and one that is known to impact quality of life and independence. Therefore, monitoring of muscle mass is relevant in a number of pathologies as well as in clinical trials as measures of efficacy as well as safety. Methods and results: Existing biomarkers of muscle mass or muscle loss have shown to be either too unreliable or too impractical in relation to the perceived clinical benefit to reach regular clinical research or use. We suggest serological neoepitope biomarkers as a possible technology to address some of these problems. Blood biomarkers of this kind have previously been shown to respond with high sensitivity and shorter time to minimum significant change than available biomarkers of muscle mass. We provide brief reviews of existing muscle mass or function biomarker technologies, muscle protein biology, and existing neoepitope biomarkers and proceed to present tentative recommendations on how to select and detect neoepitope biomarkers. Conclusion: We suggest that serological peptide biomarkers whose tissue and pathology specificity are derived from post-translational modification of proteins in tissues of interest, presenting so-called neoepitopes, represents an exciting candidate technology to fill out an empty niche in biomarker technology. © 2012 Springer-Verlag.

Loading Nordic Bioscience collaborators
Loading Nordic Bioscience collaborators