My passion lies in turning great innovative ideas into impact and value, looking forward to collaborating with you in the future.More than 25 years of experience in diverse drug development programs within global pharma, with a focus on translational science, early development and innovation.At Galapagos, I was responsible for strategy and early development projects, including the cystic fibrosis program and various highly innovative assets in the immune-inflammation space. At UCB, I worked as project leader and took responsibility for identifying and assessing innovative solutions-beyond-the-pill with external partners/start-ups and academics. At JNJ, I was exposed to both early and late stage development as clinical pharm leader, project leader and functional line manager. I contributed to multiple drug registration files and to development programs across different therapeutic areas.I've created my own company called "Why2What". The reason for this name is very simple: always ask the "Why-question” first - building your strategy - before moving into the "What" – laying out the actions to achieve your end goal. Why2What Phone: +32473900206 Address: Raymond Delahayelaan 5 2500 Lier Belgium
Neutrophil-activating protein-2 (NAP-2), an NH2-terminally processed form of the platelet-release... more Neutrophil-activating protein-2 (NAP-2), an NH2-terminally processed form of the platelet-release product beta thromboglobulin (beta TG), was purified to homogeneity from stimulated human blood leukocytes. In the presence of a vasodilator substance (PGE2, CGRP) picomolar (pmol/l) amounts of NAP-2 induced neutrophil accumulation and plasma leakage on intradermal injection in rabbit skin, whereas the longer forms, beta TG itself and connective tissue-activating peptide III (CTAP-III), had no such effect. NAP-2-induced increased in microvascular permeability was neutrophil dependent and fast in onset, with a half-life of 65 to 75 minutes, comparable to that previously reported for the structural-related neutrophil-activating protein-1/interleukin-8 (NAP-1/IL-8). However NAP-2 showed a lower potency in that more protein was needed to provoke skin reactivity. Nevertheless the finding that a platelet release product can elicit neutrophil-mediated inflammation further narrows the gap between thrombotic events and inflammatory disorders.
Neutrophil infiltration in synovial fluid is an important step in inflammation characterizing rhe... more Neutrophil infiltration in synovial fluid is an important step in inflammation characterizing rheumatoid arthritis (RA). In this study, the activation and functional state of neutrophils in the blood and synovial fluid of patients with rheumatoid arthritis were compared: mean density of neutrophil activation markers CD11b, CD18 and L-selectin was measured with a flow cytometer, and adhesion to chondrocytes using a fluorimetric assay. No significant differences between control and patient peripheral blood neutrophils were observed. When comparing neutrophils of patient peripheral blood with paired synovial fluid, an increase in CD11b (p = 0.008) and a decrease in L-selectin (p = 0.008) were measured. For neutrophils of control and patient peripheral blood, fMet-Leu-Phe stimulation induced upregulation of CD11b (resp p = 0.007 and p = 0.008) and CD18 (resp p = 0.005 and p = 0.01). In the synovial fluid, no significant increase in CD11b and CD18 could be induced with fMet-Leu-Phe. Percentages of adherent neutrophils were comparable between controls and patients, both in peripheral blood and synovial fluid. Adhesion to chondrocytes of peripheral blood neutrophils of patients was correlated with clinical (Ritchie) and biological (erythrocyte sedimentation rate) parameters (resp r = 0.67, r = 0.73). In conclusion, these results demonstrate that peripheral blood neutrophil adhesion to chondrocytes was correlated with active disease, and that synovial fluid neutrophils were activated in vivo. These findings provide further evidence for the contributing role of neutrophils in articular destruction in RA.
ABSTRACT Paliperidone extended-release tablet (paliperidone ER) is a centrally active dopamine D(... more ABSTRACT Paliperidone extended-release tablet (paliperidone ER) is a centrally active dopamine D(2)- and serotonergic 5-HT(2A)-receptor antagonist that is registered for the treatment of schizophrenia. The controlled rate of release of paliperidone from the ER formulation is designed to have a slower absorption rate, which results in gradual ascending plasma concentrations with observed maximum plasma concentrations occurring at 24 hours after dosing on the first dosing day. On subsequent treatment days, the ER formulation provides minimal fluctuations in plasma concentrations. Paliperidone is eliminated with a terminal half-life of approximately 24 hours. Steady state is achieved after 4 daily doses. Paliperidone ER exhibits time-invariant pharmacokinetics. It shows a 3.5-fold accumulation upon steady state, mainly caused by the controlled release characteristics of the formulation. Paliperidone ER displays dose proportionality over the dose range of 3 to 15 mg; the 90% confidence intervals of the pairwise dose comparisons are all included in the 80% to 125% bioequivalence limits.
There is a fast growing interest within pharmaceutical industry in using Physiologically based ph... more There is a fast growing interest within pharmaceutical industry in using Physiologically based pharmacokinetics (PBPK) modeling to predict and mechanistically understand human pharmacokinetics (PK) of potential drug candidates. The scope of this study was to evaluate whether PBPK could positively impact further drug development of a drug candidate with non-linear human PK in function of both dose and time. In vitro experiments were performed to mechanistically characterize the human non-hepatic and hepatic clearance of this BCS Class I compound, which can be further characterized as a basic lipophilic amine with a pKa of 8.2. Hepatic unbound intrinsic clearance, the contribution of several metabolic pathways and enzymes in the hepatic clearance and the interplay between hepatic uptake and metabolism was determined at several concentrations of the compound based on experiments with human hepatocytes, human liver microsomes and recombinant enzymes. The time-dependent CYP inhibition pr...
BACKGROUND Triple combinations of cystic fibrosis (CF) transmembrane conductance regulator (CFTR)... more BACKGROUND Triple combinations of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators demonstrate enhanced clinical efficacy in CF patients with F508del mutation, compared with modest effects of dual combinations. GLPG2737 was developed as a novel corrector for triple combination therapy. METHODS This multicenter, randomized, double-blind, placebo-controlled, phase 2a study evaluated GLPG2737 in F508del homozygous subjects who had been receiving lumacaftor 400mg/ivacaftor 250mg for ≥12weeks. The primary outcome was change from baseline in sweat chloride concentration. Other outcomes included assessment of pulmonary function, respiratory symptoms, safety, tolerability, and pharmacokinetics. RESULTS Between November 2017 and April 2018, 22 subjects were enrolled and randomized to oral GLPG2737 (75mg; n=14) or placebo (n=8) capsules twice daily for 28days. A significant decrease from baseline in mean sweat chloride concentration occurred at day 28 for GLPG2737 versus placebo (least-squares-mean difference-19.6mmol/L [95% confidence interval (CI) -36.0, -3.2], p=.0210). The absolute improvement, as assessed by least-squares-mean difference in change from baseline, in forced expiratory volume in 1s (percent predicted) at day 28 for GLPG2737 versus placebo was 3.4% (95% CI -0.5, 7.3). Respiratory symptoms in both groups remained stable. Mild/moderate adverse events occurred in 10 (71.4%) and 8 (100%) subjects receiving GLPG2737 and placebo, respectively. Lower exposures of GLPG2737 (and active metabolite M4) were observed than would be expected if administered alone (as lumacaftor induces CYP3A4). Lumacaftor and ivacaftor exposures were as expected. CONCLUSIONS GLPG2737 was well tolerated and yielded significant decreases in sweat chloride concentration versus placebo in subjects homozygous for F508del receiving lumacaftor/ivacaftor, demonstrating evidence of increased CFTR activity when added to a potentiator-corrector combination. FUNDING Galapagos NV. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov identifier, NCT03474042.
Neutrophil-activating protein-2 (NAP-2), an NH2-terminally processed form of the platelet-release... more Neutrophil-activating protein-2 (NAP-2), an NH2-terminally processed form of the platelet-release product beta thromboglobulin (beta TG), was purified to homogeneity from stimulated human blood leukocytes. In the presence of a vasodilator substance (PGE2, CGRP) picomolar (pmol/l) amounts of NAP-2 induced neutrophil accumulation and plasma leakage on intradermal injection in rabbit skin, whereas the longer forms, beta TG itself and connective tissue-activating peptide III (CTAP-III), had no such effect. NAP-2-induced increased in microvascular permeability was neutrophil dependent and fast in onset, with a half-life of 65 to 75 minutes, comparable to that previously reported for the structural-related neutrophil-activating protein-1/interleukin-8 (NAP-1/IL-8). However NAP-2 showed a lower potency in that more protein was needed to provoke skin reactivity. Nevertheless the finding that a platelet release product can elicit neutrophil-mediated inflammation further narrows the gap between thrombotic events and inflammatory disorders.
Neutrophil infiltration in synovial fluid is an important step in inflammation characterizing rhe... more Neutrophil infiltration in synovial fluid is an important step in inflammation characterizing rheumatoid arthritis (RA). In this study, the activation and functional state of neutrophils in the blood and synovial fluid of patients with rheumatoid arthritis were compared: mean density of neutrophil activation markers CD11b, CD18 and L-selectin was measured with a flow cytometer, and adhesion to chondrocytes using a fluorimetric assay. No significant differences between control and patient peripheral blood neutrophils were observed. When comparing neutrophils of patient peripheral blood with paired synovial fluid, an increase in CD11b (p = 0.008) and a decrease in L-selectin (p = 0.008) were measured. For neutrophils of control and patient peripheral blood, fMet-Leu-Phe stimulation induced upregulation of CD11b (resp p = 0.007 and p = 0.008) and CD18 (resp p = 0.005 and p = 0.01). In the synovial fluid, no significant increase in CD11b and CD18 could be induced with fMet-Leu-Phe. Percentages of adherent neutrophils were comparable between controls and patients, both in peripheral blood and synovial fluid. Adhesion to chondrocytes of peripheral blood neutrophils of patients was correlated with clinical (Ritchie) and biological (erythrocyte sedimentation rate) parameters (resp r = 0.67, r = 0.73). In conclusion, these results demonstrate that peripheral blood neutrophil adhesion to chondrocytes was correlated with active disease, and that synovial fluid neutrophils were activated in vivo. These findings provide further evidence for the contributing role of neutrophils in articular destruction in RA.
ABSTRACT Paliperidone extended-release tablet (paliperidone ER) is a centrally active dopamine D(... more ABSTRACT Paliperidone extended-release tablet (paliperidone ER) is a centrally active dopamine D(2)- and serotonergic 5-HT(2A)-receptor antagonist that is registered for the treatment of schizophrenia. The controlled rate of release of paliperidone from the ER formulation is designed to have a slower absorption rate, which results in gradual ascending plasma concentrations with observed maximum plasma concentrations occurring at 24 hours after dosing on the first dosing day. On subsequent treatment days, the ER formulation provides minimal fluctuations in plasma concentrations. Paliperidone is eliminated with a terminal half-life of approximately 24 hours. Steady state is achieved after 4 daily doses. Paliperidone ER exhibits time-invariant pharmacokinetics. It shows a 3.5-fold accumulation upon steady state, mainly caused by the controlled release characteristics of the formulation. Paliperidone ER displays dose proportionality over the dose range of 3 to 15 mg; the 90% confidence intervals of the pairwise dose comparisons are all included in the 80% to 125% bioequivalence limits.
There is a fast growing interest within pharmaceutical industry in using Physiologically based ph... more There is a fast growing interest within pharmaceutical industry in using Physiologically based pharmacokinetics (PBPK) modeling to predict and mechanistically understand human pharmacokinetics (PK) of potential drug candidates. The scope of this study was to evaluate whether PBPK could positively impact further drug development of a drug candidate with non-linear human PK in function of both dose and time. In vitro experiments were performed to mechanistically characterize the human non-hepatic and hepatic clearance of this BCS Class I compound, which can be further characterized as a basic lipophilic amine with a pKa of 8.2. Hepatic unbound intrinsic clearance, the contribution of several metabolic pathways and enzymes in the hepatic clearance and the interplay between hepatic uptake and metabolism was determined at several concentrations of the compound based on experiments with human hepatocytes, human liver microsomes and recombinant enzymes. The time-dependent CYP inhibition pr...
BACKGROUND Triple combinations of cystic fibrosis (CF) transmembrane conductance regulator (CFTR)... more BACKGROUND Triple combinations of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators demonstrate enhanced clinical efficacy in CF patients with F508del mutation, compared with modest effects of dual combinations. GLPG2737 was developed as a novel corrector for triple combination therapy. METHODS This multicenter, randomized, double-blind, placebo-controlled, phase 2a study evaluated GLPG2737 in F508del homozygous subjects who had been receiving lumacaftor 400mg/ivacaftor 250mg for ≥12weeks. The primary outcome was change from baseline in sweat chloride concentration. Other outcomes included assessment of pulmonary function, respiratory symptoms, safety, tolerability, and pharmacokinetics. RESULTS Between November 2017 and April 2018, 22 subjects were enrolled and randomized to oral GLPG2737 (75mg; n=14) or placebo (n=8) capsules twice daily for 28days. A significant decrease from baseline in mean sweat chloride concentration occurred at day 28 for GLPG2737 versus placebo (least-squares-mean difference-19.6mmol/L [95% confidence interval (CI) -36.0, -3.2], p=.0210). The absolute improvement, as assessed by least-squares-mean difference in change from baseline, in forced expiratory volume in 1s (percent predicted) at day 28 for GLPG2737 versus placebo was 3.4% (95% CI -0.5, 7.3). Respiratory symptoms in both groups remained stable. Mild/moderate adverse events occurred in 10 (71.4%) and 8 (100%) subjects receiving GLPG2737 and placebo, respectively. Lower exposures of GLPG2737 (and active metabolite M4) were observed than would be expected if administered alone (as lumacaftor induces CYP3A4). Lumacaftor and ivacaftor exposures were as expected. CONCLUSIONS GLPG2737 was well tolerated and yielded significant decreases in sweat chloride concentration versus placebo in subjects homozygous for F508del receiving lumacaftor/ivacaftor, demonstrating evidence of increased CFTR activity when added to a potentiator-corrector combination. FUNDING Galapagos NV. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov identifier, NCT03474042.
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