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NielsjeB 21 september 2016 18:51

5

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.

NielsjeB 21 september 2016 18:52

3

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.

NielsjeB 21 september 2016 18:59

3

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.

NielsjeB 21 september 2016 19:01

3

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.

NielsjeB 21 september 2016 19:02

4

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.

NielsjeB 21 september 2016 19:13

16

PDF met de abstracts hier (zoeken op Galapagos): onlinelibrary.wiley.com/doi/10.1002/p...

Ruud Rubbers 21 september 2016 20:17

1

Dankjewel Nielsje + AB's

Maycon 21 september 2016 20:18

0

quote:
NielsjeB schreef op 21 september 2016 19:13:
PDF met de abstracts hier (zoeken op Galapagos): onlinelibrary.wiley.com/doi/10.1002/p...

Update rondom voortgang CF kan niet lang meer uitblijven lijkt

[verwijderd] 21 september 2016 20:20

1

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?

NielsjeB 21 september 2016 20:23

0

En de abstracts netjes uitgeknipt door BiotechRadar: twitter.com/BiotechRadar

jeroen85 21 september 2016 20:41

0

Bedankt Nielsje B,
Ook een ab van mij voor al je zoekwerk.
Met vr.groet,Jeroen

Nash equilibrium 22 september 2016 06:58

2

Gilead nixes clinical development of GS-5745 for ulcerative colitis
Te lezen op SA

avantiavanti 22 september 2016 07:05

5

Vooruitblik Morgan Stanley op UEGW

Bijlage:

[verwijderd] 22 september 2016 08:02

0

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.

[verwijderd] 22 september 2016 09:16

0

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

In RA, Crohn's en UC nu het leidende onderzoek.

Loureiro 22 september 2016 09:28

0

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.

de tuinman 22 september 2016 09:34

0

Wanneer kunnen we de 1e milestone-betalingen verwachten?

Loureiro 22 september 2016 09:39

0

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.

[verwijderd] 22 september 2016 12:21

3

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.

avantiavanti 22 september 2016 12:51

7

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.

Bijlage:

Vertraagd	24 apr 2024 17:35
Koers	27,120
Verschil	-0,440 (-1,60%)
Hoog	27,760
Laag	27,100
Volume	86.317
Volume gemiddeld	80.773
Volume gisteren	52.063

12 apr	KBC Securities verlaagt koersdoel Gal...
05 apr	Galapagos toont innovatieve aanpak in...
23 feb	AEX op de waakvlam het weekend in, ko...	2
23 feb	Beursblik: gebrek aan opwaarts potent...
23 feb	Gaat AEX op recordjacht of gaat de be...
23 feb	Update : Galapagos voldoet aan verwac...
19 feb	Beursblik: cashburn belangrijk voor G...
15 feb	Galapagos presenteert nieuwe onderzoe...
01 feb	Galapagos rondt Jyseleca-transactie af
04 jan	Galapagos in zee met Thermo Fisher

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