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Galapagos 2015: de inhoudelijke discussie

3.351 Posts
Pagina: «« 1 ... 144 145 146 147 148 ... 168 »» | Laatste | Omlaag ↓
  1. NielsjeB 21 september 2016 18:51
    NOVEL CORRECTORS AND POTENTIATORS AUGMENT EFFICACY OF TRANSLATIONAL READTHROUGH IN CFTR NONSENSE MUTATIONS

    Mutyam, V.1; Peng, N.1; Sharma, J.1; Xue, X.1; Bedwell, D.M.1; Andrews, M.2; Van der Plas, S.2; Conrath, K.2; Rowe, S.M.1 1. Univ. of Alabama at Birmingham, Birmingham, AL, USA; 2. Galapagos NV, Generaal De Wittelaan L11A3, 2800 Mechelen, Belgium

    Premature termination codons (PTCs) in CFTR result in nonfunc-tional CFTR protein and are the proximate cause of ~11% of CF-causing alleles. Aminoglycosides (AGs; G418, gentamicin), synthetic AGs (NB124, Eloxx), ataluren (PTC124, PTC Therapeutics) and escin have been shown to induce readthrough (RT) of PTCs and partially restore CFTR protein expression and function. To achieve therapeutic levels, we have shown that a combination approach of using the CFTR potentiator ivacaftor (VX-770) with the corrector lumacaftor (VX-809) is beneficial for enhancing RT of premature stop mutations. Using novel correctors and potentiators from Galapagos, we examined if these modulators had synergistic effect with RT agents that could enhance CFTR function to achieve therapeutic levels.Stably transduced Fisher rat thyroid (FRT) G542X, W1282X or R1162X cells were pretreated with G418 (250 µg/mL) or escin (10 µM) to induce RT, with corrector 1 (C1 or early corrector, 0.5 µM) and corrector 2 (C2 or late corrector (complementary to C1), 3 µM) alone or in combina-tion to enhance processing; transepithelial conductance (Gt) was recorded before and after CFTR stimulation with forskolin (10 µM) followed by investigational potentiator (GLPG1837, previously described as GP-5, 10 µM) or ivacaftor (10 µM). Similar studies were also carried out in primary HBE (human bronchial epithelial, G542X/F508del and W1282X/F508del) cells for short-circuit current (Isc) analysis. A cell-surface expression assay with horseradish peroxidase (HRP)-tagged FRT-G542X or W1282X cells was used to examine cell surface expression of CFTR following treatment.GLPG1837 and VX-770 showed dose-dependent increases in CFTR activity (Gt) in all the three FRT CFTR PTC cell lines compared to vehicle control (P<0.05), but only when RT was induced by G418 pretreatment. In FRT W1282X and R1162X, GLPG1837 CFTR activity was significantly greater than VX-770 (P<0.05). In a triple-combination approach, correc-tors alone (C1 or C2) or combined (C1+C2) did not significantly enhance CFTR-dependent Gt compared to G418 alone, indicating the synergy of CFTR modulators with RT agents. In HRP assay, CFTR expression levels were significantly higher in combination of C1+C2 and G418 compared to vehicle. Escin showed significant synergy with C1+C2 and GLPG1837 pre-treatment (Gt: 6.5± 0.3 mS/cm2) as compared to VX-809+GP-5 (Gt: 1.8± 0.1 mS/cm2). In contrast to FRT G542X, in FRT W1282X cells, C1+C2 were significantly efficacious, both alone and in combination with RT agents. In addition, GLPG1837-induced response was significantly higher in the FRT-W1282X mutation compared to G542X and R1162X mutations. Evaluation of CFTR activity in primary cells is in progress.In conclusion, the combination of novel correctors and a potentiator show significant synergy with RT agents. Further, the combination of cor-rectors (C1+C2) exhibited a significant benefit for the W1282X mutation as corrector therapy was efficacious on its own (without RT), especially when combined with GLPG1837. Combination therapy (CFTR modulators + RT agents) may be a useful approach to augment repair of CFTR nonsense mutations.
  2. NielsjeB 21 september 2016 18:52
    DISCOVERY AND CHARACTERIZATION OF ABBV/GLPG-2222, A NOVEL FIRST GENERATION CFTR CORRECTOR

    Singh, A.K.1; Alani, S.1; Balut, C.1; Fan, Y.1; Gao, W.1; Greszler, S.1; Jia, Y.1; Liu, B.1; Manelli, A.1; Searle, X.1; Swensen, A.1; Vortherms, T.1; Yeung, C.1; Conrath, K.2; Wang, X.1; Tse, C.1 1. Abbvie, Inc., North Chicago, IL, USA; 2. Galapagos, Mechelen, Belgium

    To address the most prevalent defects leading to cystic fibrosis, two biomolecular activities are required, namely correctors to increase prop-erly folded F508delCFTR levels at the cell surface, and potentiators to allow the effective opening of the F508delCFTR channel. Combined, these activities allow chloride ion transport leading to improved hydration of the lung surface and subsequent enhancement of mucociliary clearance. Abbvie and Galapagos are collaborating to develop a series of compounds capable of performing each of these activities individually. Orkambi from Ver-tex Pharmaceuticals represents the first disease-modifying therapy for CF patients with homozygous F508del mutation, and was approved based on marginal but statistically significant improvement in lung function (FEV1). However, there still exists a high unmet medical need with F508del CF patients for a more robust therapy.Herein we report the identification and in vitro characterization of ABBV/GLPG-2222, a novel, potent and orally bioavailable corrector currently in clinical trials that exhibits substantial improvements over the existing correctors in the clinic. This includes improvements in potency and drug-drug-interaction (DDI) compared to lumacaftor (VX-809) and improvements in potency and efficacy compared to VX-661. ABBV/GLPG-2222 exhibits potent in vitro functional activity in primary patient cells harboring F508del/F508del CFTR with an EC50 <10nM. In sum, ABBV/GLPG-2222 represents the second component of a three-component combination therapy to treat the most prevalent CFTR mutation, F508del.AS, SA, CB, YF, WG, SG, YJ, BL, AM, XS, AMS, TV, CY, XW and CT are employees of AbbVie. The design, study conduct, and financial support for the research conducted by AbbVie were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.
  3. NielsjeB 21 september 2016 18:59
    CHARACTERIZATION OF NOVEL CFTR POTENTIATORS

    Conrath, K.2; Swensen, A.3; Gees, M.2; Verdonck, K.2; Van der
    Plas, S.2; Andrews, M.2; Hwang, T.1 1. Medical Pharmacology
    and Physiology, University of Missouri, Columbia, MO, USA;
    2. Galapagos, Mechelen, Belgium; 3. AbbVie, Chicago, IL, USA

    Using YFP-based high-throughput screening assay, we identified novel
    compounds that can potentiate cAMP-dependent activity of low temperature-
    rescued F508del CFTR in CFBe41o- cells. A series of reagents was
    developed further, with improvement in the potency of compounds down to
    <10nM for a number of new analogues.
    These compounds were profiled in additional YFP halide assays using
    other class III and IV CFTR mutants. These assays were performed by
    transient transfection of CFTR mutant in HEK293 cells and iodide influx
    was measured after addition of forskolin and potentiator. All compounds
    tested were able to open channels from the different mutants in an efficient
    manner. For several class III mutants, the maximal activity of the mutant
    channel exceeded that of VX-770-treated channel (which was used as
    comparator in the assay) with iodide influx up to 250% of the maximum
    obtained by VX-770. Furthermore, our compounds showed higher potency
    compared to VX-770 in the same assay. A broad set of compounds
    was evaluated in parallel on low temperature-rescued F508del CFTR and
    G551D CFTR and a good correlation between potencies in these two assays
    was observed.
    One of the compounds (GLPG1837) was characterized in detail with
    the patch-clamp technique. In inside-out patches excised from CHO cells
    transiently expressing WT, G551D or F508del CFTR, applications of the
    compound resulted in reversible potentiation of the activity of the channels
    pre-activated with protein kinase A and ATP. For WT CFTR, the Po in the
    presence of 3 mM GLPG1837 is 0.78 ± 0.03 (n = 9) with open time (to) and
    closed time (tc) constants of 1479 ± 387 ms and 292 ± 26 ms respectively, a
    result compatible with those seen with VX-770 (Jih KY, Hwang TC. Proc
    Natl Acad Sci USA. 2013;110:4404-9). However, a 27.5 ± 3.0 fold increase
    of macroscopic G551D CFTR currents was observed (~10 fold for VX-770
    in Jih and Hwang, 2013). For F508del, the Po was dramatically increased to
    0.55 ± 0.05 (n = 9) with to = 3290 ± 819 ms and tc = 2182 ± 516 ms.
    In summary, further characterization of recently identified novel potentiators
    was performed confirming the increased channel opening observed
    in primary cells using patch clamp.
  4. NielsjeB 21 september 2016 19:01
    SAFETY, TOLERABILITY AND PHARMACOKINETICS OF A NOVEL CFTR CORRECTOR MOLECULE GLPG2222 IN HEALTHY VOLUNTEERS

    Van de Steen, O.1; Namour, F.2; Kanters, D.1; Geller, D.E.3;
    de Kock, H.1; Vanhoutte, F.P.1 1. Galapagos NV, Mechelen,
    Belgium; 2. Galapagos SASU, Romainville, France; 3. AbbVie
    Inc, North Chicago, IL, USA

    Background: GLPG2222 (GLPG2222/ABBV-2222) is a novel cystic
    fibrosis transmembrane conductance regulator (CFTR) corrector in clinical
    development for the treatment of cystic fibrosis (CF). In cellular assays,
    GLPG2222 was shown to be a potent corrector, partially restoring F508del
    CFTR cell surface expression when using a CFBe41o- cell line harbouring
    HRP-tagged F508del CFTR. In primary bronchial epithelial cells derived
    from patients homozygous for F508del, the combination of GLPG2222 and
    a CFTR potentiator restores the function of F508del CFTR and exhibits
    potent activity with an EC50<10nM. GLPG2222 represents one component
    of a future potentiator/corrector(s) combination therapy targeting a broad
    CF patient population.
    Methods and Objectives: This randomized, double-blind, placebo-
    controlled first-in-human study was designed to assess the safety, tolerability
    and pharmacokinetic properties of GLPG2222 in healthy volunteers.
    The study consisted of two parts: the first part assessed single ascending
    doses (SAD) of 50 mg qd to 800 mg qd administered in two alternating
    cohorts of 8 subjects. The second part assessed multiple ascending doses
    (MAD) of 150 mg qd to 600 mg qd in three sequential cohorts of 8 subjects
    whereby doses are administered for 14 days. Subjects were randomized in
    a 3:1 ratio (active versus placebo). 40 healthy subjects were included. The
    safety and tolerability evaluation consisted of adverse events, clinical laboratory
    parameters, physical examination, vital signs and ECGs. Plasma and
    urine pharmacokinetics of GLPG2222 were determined.
    Results: We report preliminary results of this phase I study (follow-up
    of the last cohort in the MAD part was still ongoing at the time of submission).
    Over the dose ranges tested, GLPG2222 was not associated with any
    serious adverse events (SAEs) or premature discontinuation due to adverse
    events. Based upon blind data, the following adverse events (AEs) were
    reported to be at least possibly related to GLPG2222: headache, flushing,
    asthenia, fatigue, gastroenteritis, diarrhoea, abdominal pain, thirst, abdominal
    discomfort and pruritus; all were considered mild. Clinical laboratory
    parameters, physical examinations, vital signs and ECGs did not show any
    clinically relevant findings. GLPG2222 given as oral liquid formulation in
    fed state was rapidly absorbed (median tmax = 1-3.5h) and eliminated with
    a mean apparent t1/2 of about 15h. GLPG2222 exposure (Cmax and AUC)
    increased dose proportionally between 150 and 300 mg and slightly more
    than dose proportionally between 300 and 600 mg. Steady state was reached
    within 2 days.
    Conclusions: The preliminary results of this first-in-human study
    demonstrate GLPG2222 to be safe and well tolerated administered for 14
    days up to 600 mg qd in healthy subjects. Full safety and PK data will be
    presented at the conference. These findings support GLPG2222 to be further
    developed for the treatment of subjects with CF.
  5. NielsjeB 21 september 2016 19:02
    GLPG1837 IN SUBJECTS WITH CYSTIC FIBROSIS (CF) AND THE S1251N MUTATION: RESULTS FROM A PHASE IIA STUDY (SAPHIRA2)

    De Boeck, C.1; Van Braeckel, E.2; van der Ent, C.K.3;
    Verhulst, S.4; Weersink, E.J.5; Conrath, K.6; Kanters, D.6;
    Namour, F.7; de Kock, H.6; Van de Steen, O.6 1. Department
    of Pediatrics, University of Leuven, Leuven, Belgium;
    2. Department of Respiratory Medicine, Ghent University
    and Hospital, Ghent, Belgium; 3. Cystic Fibrosis Center and
    Department of Pediatric Respiratory Medicine, Wilhelmina
    Children’s Hospital, University Medical Center Utrecht, Utrecht,
    Netherlands; 4. Cystic Fibrosis Center, University Hospital
    Antwerp, Antwerpen, Belgium; 5. Department of Respiratory
    Medicine, Academic Medical Center, Amsterdam, Belgium;
    6. Galapagos NV, Mechelen, Belgium; 7. Galapagos SASU,
    Romainville, France

    Background: GLPG1837 is a novel cystic fibrosis transmembrane
    conductance regulator (CFTR) potentiator in clinical development for the
    treatment of cystic fibrosis. GLPG1837 has shown to be safe and well
    tolerated after 2 weeks of dosing up to 800 mg orally twice daily in healthy
    subjects. In vitro assays on S1251N CFTR showed GLPG1837 to open this
    dysfunctional channel with a high potency. Together, these results suggest
    GLPG1837 could be beneficial to CF patients harbouring the S1251N
    mutation.
    Methods and Objectives: SAPHIRA2 is a phase IIa, open-label, multicentre
    study designed to evaluate two doses of GLPG1837 (two weeks
    of dose 1, followed by two weeks of dose 2). Primary study objective is
    to evaluate safety and tolerability. Secondary outcome parameters include
    sweat chloride concentration as pharmacodynamic biomarker and pulmonary
    function. In addition, we explore the correlation of biomarker change
    and GLPG1837 plasma exposure. Main study inclusion criteria are: CF and
    S1251N mutation on one allele; age = 18 years; FEV1 = 40% of predicted
    normal. For subjects treated with ivacaftor, a 7-day washout prior to start
    of first dose of GLPG1837 is required. At least 6 subjects will be included
    in the study.
    Results: At the time of submission of the abstract, the study is still
    ongoing: 7 subjects have been screened, 5 subjects have been enrolled and
    4 subjects have completed the study. To date, no unexpected safety signals
    have been detected and the study is continuing as planned. The current
    projection is to complete enrolment by end of June 2016. Consequently, we
    expect top-line results to become available by September 2016.
    Conclusions: Pending results.
  6. [verwijderd] 21 september 2016 20:20
    quote:

    NielsjeB schreef op 21 september 2016 19:02:

    GLPG1837 IN SUBJECTS WITH CYSTIC FIBROSIS (CF) AND THE S1251N MUTATION: RESULTS FROM A PHASE IIA STUDY (SAPHIRA2)

    De Boeck, C.1; Van Braeckel, E.2; van der Ent, C.K.3;
    Verhulst, S.4; Weersink, E.J.5; Conrath, K.6; Kanters, D.6;
    Namour, F.7; de Kock, H.6; Van de Steen, O.6 1. Department
    of Pediatrics, University of Leuven, Leuven, Belgium;
    2. Department of Respiratory Medicine, Ghent University
    and Hospital, Ghent, Belgium; 3. Cystic Fibrosis Center and
    Department of Pediatric Respiratory Medicine, Wilhelmina
    Children’s Hospital, University Medical Center Utrecht, Utrecht,
    Netherlands; 4. Cystic Fibrosis Center, University Hospital
    Antwerp, Antwerpen, Belgium; 5. Department of Respiratory
    Medicine, Academic Medical Center, Amsterdam, Belgium;
    6. Galapagos NV, Mechelen, Belgium; 7. Galapagos SASU,
    Romainville, France

    Background: GLPG1837 is a novel cystic fibrosis transmembrane
    conductance regulator (CFTR) potentiator in clinical development for the
    treatment of cystic fibrosis. GLPG1837 has shown to be safe and well
    tolerated after 2 weeks of dosing up to 800 mg orally twice daily in healthy
    subjects. In vitro assays on S1251N CFTR showed GLPG1837 to open this
    dysfunctional channel with a high potency. Together, these results suggest
    GLPG1837 could be beneficial to CF patients harbouring the S1251N
    mutation.
    Methods and Objectives: SAPHIRA2 is a phase IIa, open-label, multicentre
    study designed to evaluate two doses of GLPG1837 (two weeks
    of dose 1, followed by two weeks of dose 2). Primary study objective is
    to evaluate safety and tolerability. Secondary outcome parameters include
    sweat chloride concentration as pharmacodynamic biomarker and pulmonary
    function. In addition, we explore the correlation of biomarker change
    and GLPG1837 plasma exposure. Main study inclusion criteria are: CF and
    S1251N mutation on one allele; age = 18 years; FEV1 = 40% of predicted
    normal. For subjects treated with ivacaftor, a 7-day washout prior to start
    of first dose of GLPG1837 is required. At least 6 subjects will be included
    in the study.
    Results: At the time of submission of the abstract, the study is still
    ongoing: 7 subjects have been screened, 5 subjects have been enrolled and
    4 subjects have completed the study. To date, no unexpected safety signals
    have been detected and the study is continuing as planned. The current
    projection is to complete enrolment by end of June 2016. Consequently, we
    expect top-line results to become available by September 2016.
    Conclusions: Pending results.

    So that is any day now?
  7. [verwijderd] 22 september 2016 08:02
    quote:

    Nash equilibrium schreef op 22 september 2016 06:58:

    Gilead nixes clinical development of GS-5745 for ulcerative colitis
    Te lezen op SA
    Thanxs.
    even de link

    www.gilead.com/news/press-releases/20...

    en twee kleine voor ons relevante stukjes tekst.
    ...
    No safety concerns were noted in this interim analysis
    ...
    Separately, a Phase 3 study of GS-5745 is ongoing in patients with gastric cancer, as well as a Phase 2 study in patients with gastric cancer in combination with nivolumab and additional Phase 2 studies in moderately to severely active Crohn’s disease, rheumatoid arthritis and cystic fibrosis. These studies will continue as planned.
  8. Loureiro 22 september 2016 09:28
    quote:

    pe26 schreef op 22 september 2016 09:16:

    Goed nieuws voor Galagagos.
    Filgotinib meer en meer het speerpunt van Gilead.

    In RA, Crohn's en UC nu het leidende onderzoek.
    Inderdaad, crohn van GLPG wordt het eerste doel voor Gilead. Naast het goede aankomende nieuws van de potentiator GLPG1837 gaat de start van de aankondiging fase in crohn niet lang uitblijven... en dan gaat de koers definitief over de 60 euro.
  9. Loureiro 22 september 2016 09:39
    quote:

    de tuinman schreef op 22 september 2016 09:34:

    Wanneer kunnen we de 1e milestone-betalingen verwachten?
    Zoals reeds geopperd werd door GLPG zelf, verwacht ik belangrijke milestones in het 4de kwartaal.
  10. [verwijderd] 22 september 2016 12:21
    quote:

    winx08 schreef op 22 september 2016 08:02:

    [...]

    Thanxs.
    even de link

    www.gilead.com/news/press-releases/20...

    en twee kleine voor ons relevante stukjes tekst.
    ...
    No safety concerns were noted in this interim analysis
    ...
    Separately, a Phase 3 study of GS-5745 is ongoing in patients with gastric cancer, as well as a Phase 2 study in patients with gastric cancer in combination with nivolumab and additional Phase 2 studies in moderately to severely active Crohn’s disease, rheumatoid arthritis and cystic fibrosis. These studies will continue as planned.

    Wat verder relevant is: 1e deel fase 2b/3 studie bij onderzoek GS-5745 in Ulcerative Colitis (UC) betrof 150 patiënten.
    Binnen 1 jaar geworven, start dosing en resultaten opgemaakt van Fase 2b.

    Studie van Gilead stopgezet en zodoende gaat alle concentratie volledig naar Filgotinib binnen UC.
    Reeds heeft Gilead de klinieken al gecontracteerd van de eerdere UC-studie
    en dus moet Filgotinib Fase 2b UC snel kunnen verlopen (sneller dan 12 maanden, waarna fase 3 kan aanvangen).

    Galagagos heeft in een eerder vrijgekomen abstract omtrent filgotinib onderzoek Crohn al gemeld dat werkzaamheid binnen UC is aangetoond (dierlijke studie in muis wat mij bijstaat.

    Filgotinib studie UC (fase 2b/3) is orale dosering wat concurreert met Receptos molecuul van Celgene wat ruim jaar voorsprong heeft, doch kan Celgene
    nog niet buigen op veel succes in IBD, zeker door twijfels die zijn ontstaan in Mongersen studie van Celgene.

    Filgotinib wordt toch zeker GOUD.

  11. avantiavanti 22 september 2016 12:51
    Janney rep. 22/9

    GLPG: Filgotinib is now more important to Gilead
    Flash Takeaways
    Gilead (GILD - No rating) halted its phase 2/3 study of GS-5745, in patients with
    moderate to severe active ulcerative colitis (UC) due to futility, implying filgotinib is potentially more important to Gilead's intermediate- to long-term growth prospects.
    Recall, three phase 3 studies (FINCH program) in RA were initiated last month; A
    Crohn's phase 3 program is anticipated during 4Q16; and A phase 2/3 study in UC
    is also expected to commence during 4Q16. Note, UC is currently not reflected in ourmodel. Upcoming 4Q16 clinical catalysts include: Crohn's endoscopy data from the
    FITZROY phase 2 program at the UEG Week, October 15-19; SAPHIRA 1 & 2 (Cystic
    Fibrosis) study readout at the NACFC, October 25-27. Despite GLPG stock being up
    ~25% over the past three weeks, (up 7.4% YTD vs. XBI down 2.7%), the stock is
    relatively under-owned (51 holders), and the upcoming data events could provide
    meaningful upside from current level, in our view.


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