MSD NV Organon

Oss, Netherlands

MSD NV Organon

Oss, Netherlands
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Van Koppen C.J.,MSD NV Organon | De Gooyer M.E.,MSD NV Organon | Plate R.,MSD NV Organon | Conti P.,MSD NV Organon | And 4 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

TheTSH receptor (TSHR) on orbital fibroblasts (OF) is a proposed target of the autoimmune attack in Graves' ophthalmopathy. In the present study, we tested whether the novel low-molecularweight (LMW) TSHR antagonist Org-274179-0 inhibits cAMP production induced by rhTSH, Graves' disease IgG (GD-IgG), or M22 (a potent human monoclonal TSHRstimulating antibody) in cultured and differentiated OF from Graves' ophthalmopathy patients. cAMP production significantly increased after incubation either with 10 mU/ml rhTSH (3-fold; P≤ 0.05), 1 mg/ml GD-IgG (2-fold; P≤ 0.05), or 500 ng/ml M22 (5-fold; P ≤ 0.05). Incubation with the LMW TSHR antagonist dose dependently inhibited rhTSH, GD-IgG as well as the M22-induced cAMP production at nanomolar concentrations; complete blockade was affected at 10-6 m. Our results suggest that GD-IgG- and M22-induced cAMP production in differentiated OF is exclusively mediated via the TSHR because it can be completely blocked by the LMWTSHR antagonist, Org 274179-0. Copyright © 2012 by The Endocrine Society.


Miltenburg A.M.M.,MSD NV Organon | Prohn M.,MSD NV Organon | van Kuijk J.H.M.,MSD NV Organon | Tiessen R.G.,PRA International | And 2 more authors.
British Journal of Clinical Pharmacology | Year: 2013

Aim: Conjugation to antithrombin III ATIII-binding pentasaccharides has been proposed as a novel method to extend the half-life of therapeutic proteins. We aim to validate this technological concept in man by performing a first-in-human study using CarboCarrier® insulin (SCH 900948) as an example. A rising single dose phase 1 study was performed assessing safety, tolerability, pharmacokinetics and relative bioactivity of CarboCarrier® insulin. Safety, tolerability and pharmacokinetics (PK) of single doses of CarboCarrier® insulin in healthy volunteers were explored, and the dose-response relationship and relative bioactivity of CarboCarrier® insulin in subjects with type 2 diabetes were investigated. Methods: After an overnight fast, subjects were randomized to a treatment sequence. PK and pharmacodynamic (glucose, insulin and C-peptide) samples were obtained for up to 72h post-dose. Effects of CarboCarrier® insulin were compared with those of NPH-insulin. Results: CarboCarrier® insulin was safe and well-tolerated and no consistent pattern of adverse events occurred. CarboCarrier® insulin exposure (Cmax and AUC) increased proportionally with dose. The mean terminal elimination half-life ranged between 3.11 and 5.28h. All CarboCarrier® insulin dose groups showed decreases in the mean change from baseline of plasma glucose concentrations compared with the placebo group. Conclusions: CarboCarrier® insulin is pharmacologically active showing features of insulin action in man. The elimination half-life of the molecule was clearly extended compared with endogenous insulin, indicating that conjugation to ATIII-binding pentasaccharides is a viable approach to extend the half-life of therapeutic proteins in humans. This is an important step towards validation of the CarboCarrier® technology by making use of CarboCarrier® insulin as an example. © 2012 The British Pharmacological Society.


PubMed | MSD NV Organon
Type: Clinical Trial, Phase I | Journal: British journal of clinical pharmacology | Year: 2013

Conjugation to antithrombin III ATIII-binding pentasaccharides has been proposed as a novel method to extend the half-life of therapeutic proteins. We aim to validate this technological concept in man by performing a first-in-human study using CarboCarrier insulin (SCH 900948) as an example. A rising single dose phase 1 study was performed assessing safety, tolerability, pharmacokinetics and relative bioactivity of CarboCarrier insulin. Safety, tolerability and pharmacokinetics (PK) of single doses of CarboCarrier insulin in healthy volunteers were explored, and the dose-response relationship and relative bioactivity of CarboCarrier insulin in subjects with type 2 diabetes were investigated.After an overnight fast, subjects were randomized to a treatment sequence. PK and pharmacodynamic (glucose, insulin and C-peptide) samples were obtained for up to 72h post-dose. Effects of CarboCarrier insulin were compared with those of NPH-insulin.CarboCarrier insulin was safe and well-tolerated and no consistent pattern of adverse events occurred. CarboCarrier insulin exposure (Cmax and AUC) increased proportionally with dose. The mean terminal elimination half-life ranged between 3.11 and 5.28h. All CarboCarrier insulin dose groups showed decreases in the mean change from baseline of plasma glucose concentrations compared with the placebo group.CarboCarrier insulin is pharmacologically active showing features of insulin action in man. The elimination half-life of the molecule was clearly extended compared with endogenous insulin, indicating that conjugation to ATIII-binding pentasaccharides is a viable approach to extend the half-life of therapeutic proteins in humans. This is an important step towards validation of the CarboCarrier technology by making use of CarboCarrier insulin as an example.

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