DeBeurs.nl

NielsjeB 19 september 2017 20:36

0

quote:
NielsjeB schreef op 19 september 2017 13:28:
Investor Presentation September
www.glpg.com/docs/view/59c0f8005b484-en

Met name slide 48 is interessant. Voor 1690 pivotal/registration study design, dat was tijdens de call ook al de bedoeling, maar nog niet helemaal zeker.
Verder verbaast het me dat Flamingo topline nu ook lijkt uit te lezen in H2 2017. Dat lijkt me niet kloppen met slide 36, waar de study nog loopt tot in Q2 2018.

Nog even de 'oude' versie: www.dropbox.com/s/vu9av1xwa6bws4y/GLP...

[verwijderd] 19 september 2017 20:36

1

quote:
HansGarrincha schreef op 14 september 2017 16:25:
www.fluidda.com/blog-why-spirometry-i...
IPF, FRI, FGN and GLPG

Pagina 29 investor presentation Galapagos » FLUIDDA.

Zelf zal Galapagos kans van slagen GLPG1690 groter achten dan 15%..:).

NielsjeB 19 september 2017 20:47

1

quote:
avantiavanti schreef op 19 september 2017 17:21:
Thanks maar ik doel op post uit begin 2016 mbt lisence met HUB Fnd.

Pagina 84 (20 per pagina), 21 jan 2016 om 08:50.
www.iex.nl/Forum/Topic/1325004/Galapa...

Bizar dat dit forum nog steeds geen rechtstreekse links naar posts aanbiedt.

NielsjeB 19 september 2017 21:20

1

quote:
pe26 schreef op 19 september 2017 20:36:
[...]

Pagina 29 investor presentation Galapagos » FLUIDDA.

Zelf zal Galapagos kans van slagen GLPG1690 groter achten dan 15%..:).

Heel benieuwd of Galapagos een trial design goedgekeurd krijgt waarbij FRI een primary endpoint wordt. En daarnaast natuurlijk of het een placebo-controlled study wordt of, waarschijnlijker, bovenop standard of care Ofev/Esbriet.

holenbeer 19 september 2017 22:03

1

quote:
El buitre schreef op 19 september 2017 00:39:
[...]

Misschien zie ik het wel verkeerd, maar blijkbaar is 5% erbij gelijk aan 19 dollar. Terugrekenen naar 1% * 30, dan kom ik op 114 euro

Dus inderdaad, van 15 naar 30 is 57, de helft van jouw 114. Allebei de berekeningen kloppen.

NielsjeB 20 september 2017 09:37

0

Supplement: The 31st Annual North American Cystic Fibrosis Conference, Indiana Convention Center, Indianapolis, Indiana, November 2–4, 2017

onlinelibrary.wiley.com/doi/10.1002/p...

NielsjeB 20 september 2017 09:38

7

27
MUTATIONS IN THE SECOND CYTOPLASMIC LOOP
OF CFTR SUGGEST DISTINCT MODE OF ACTION
BETWEEN POTENTIATORS VX-770 AND GLPG1837
Mijnders, M.1; Musch, S.2; Peters, F.1; Conrath, K.2;
Braakman, I.1; Kleizen, B.1 1. Cellular Protein Chemistry,
Utrecht University, Utrecht, Netherlands; 2. Galapagos NV,
Mechelen, Belgium
The current therapeutic strategy to repair cystic fibrosis-causing defects
in the chloride channel CFTR is to develop novel and better correctors
(to improve folding) and potentiators (to improve function). Galapagos-
AbbVie identified a novel potentiator GLPG1837 by compound screening
on mutant CFTR. YFP-halide efflux assays and single channel measurements
showed ~2.5-fold improvement in channel activity by GLPG1837
compared to VX-770 (ivacaftor/Kalydeco) on G551D CFTR (1, 2).
GLPG1837 successfully passed the Phase-2 clinical trials and proved to
be the first potentiator after VX-770 to show competitive results on G551D
patients. To identify potential differences in the mode of actions of these
potentiators we studied their effects on CFTR folding and function.
Biochemical radiolabeling experiments showed that mutations in the
intracellular loop 2 (ICL2) disrupt domain assembly between TMD1 and
NBD2, a late folding event in CFTR, but in most cases do not impair CFTR
trafficking towards the cell surface. Protease-susceptibility assays showed
that VX-770 improved late TMD1 folding of many ICL2 mutations, but
GLPG1837 did not.
YFP-halide efflux assays showed that these ICL2 mutants had varying
effect on channel function, ranging from wild-type-like to function-defective
mutants. GLPG1837 restored function of non-CF gating mutant E267K
much better than VX-770. Residue E267 in ICL2 electrostatically interacts
with K1060 in ICL4 to promote channel opening (3). This indicates that
GLPG1837 is more efficient in compensating for this lost interaction.
Altogether, our biochemical and functional data suggests that potentiators
VX-770 and GLPG1837 have a different mode of action.
References:
1. Conrath K, et al. Characterization of novel CFTR potentiators. Pediatr
Pulmonol 2016;51(S45):202.
2. Peters F, et al. Potentiators: How do they impact the fate of CFTR
during biogenesis? Pediatr Pulmonol 2015;50(S41):210.
3. Wang W, et al. An electrostatic interaction at the tetrahelix bundle
promotes phosphorylation-dependent CFTR channel opening. J Biol Chem
2014;289:30364-78.

32
EVALUATION OF NOVEL CFTR POTENTIATORS IN A
FERRET MODEL OF COPD
Kaza, N.1; Tang, L.1; Rasmussen, L.W.1; Mutyam, V.1;
Sammeta, V.1; Monjardet, A.3; Borgonovi, M.3; Corveleyn, S.2;
Conrath, K.2; Rowe, S.M.1 1. Medicine, University of Alabama
at Birmingham, Birmingham, AL, USA; 2. Galapagos NV,
Mechelen, Belgium; 3. Galapagos SASU, Paris, France
Chronic obstructive pulmonary disease (COPD) is the third leading
cause of death in the US and is a major contributor of disease and death
worldwide. We have previously demonstrated the role of acquired (non-genetic)
CFTR dysfunction in the pathogenesis of COPD. Here, we evaluated
novel and potent CFTR potentiators to reverse acquired CFTR dysfunction
in COPD and chronic bronchitis using a novel ferret model established by
our laboratory. While previous data has demonstrated ivacaftor can rescue
wild-type (WT) hCFTR dysfunction in smoking, it does not activate WT
ferret CFTR. Therefore, we evaluated GLPG2196 and GLPG1837, two
novel CFTR potentiators under clinical development. A YFP assay showed
GLPG2196 and GLPG1837 were potent in activating both human and ferret
WT CFTR with an EC50 of 30, 100 and 38, 113 nM, respectively. In
vitro studies on ferret bronchial epithelial cells showed that GLPG1837
and GLPG2196 elicit a concentration dependent increase in short circuit
current (Isc) that achieved 9.6 ± 1.9 µA/cm2 and 2.4 ± 0.96 µA/cm2 with an
EC50 of 1.08 µM and 0.32 µM, respectively. Ex vivo testing on WT ferret
trachea, GLPG1837 and GLPG2196 showed significant improvement in
?Isc (70.5 ± 14.4 µA/cm2) and (60.2 ± 22.1 µA/cm2) respectively, when
compared to vehicle (10.9 ± 6.1 µA/cm2, P<0.02). Next, we confirmed
whether GLPG1837 would be similarly effective ex vivo in smoke exposed
trachea in which CFTR was rendered dysfunctional. As observed in air-exposed
ferret trachea (50.7 ± 23.1 µA/cm2), GLPG1837 stimulated CFTR in
chronic smoke-exposed ferret trachea (47 ± 8.3 µA/cm2) when compared
to their respective vehicle controls (2.4 ± 1.2 µA/cm2 and 4.1 ± 0.7 µA/
cm2, P<0.03), establishing that GLPG1837 could be used to rescue smoke
induced CFTR dysfunction. To establish the efficacy of GLPG2196 on ferret
CFTR, we tested GLPG2196 in vivo in ferrets via nasal transepithelial
potential difference measurements. We found that single-dose GLPG2196
perfusion induced an increase in nasal ?PD in smoke-exposed ferrets (-2.8
± 1.6 mV) as well as matched air-controls (-3.4 ± 1.5 mV). To assess the
oral bioavailability of GLPG2196 in ferrets, we performed a single dose
pharmacokinetic study that showed that high and sustained plasma concentrations
(Cmax of 4,100 ng/mL at 5-6 hours) can be reached in ferrets
of both genders. These preliminary findings establish that GLPG2196 is
efficacious in activating wild-type CFTR in smoke-exposed ferrets and can
be used in vivo to test its ability to treat COPD-related chronic bronchitis in
a ferret model of the disease.

NielsjeB 20 september 2017 09:38

4

36
SAFETY, TOLERABILITY AND PHARMACOKINETICS
OF A NOVEL CFTR POTENTIATOR GLPG3067 IN
HEALTHY VOLUNTEERS
Petkova, M.1; Gesson, C.1; Notebaert, S.1; Conrath, K.1;
Corveleyn, S.1; Geller, D.2; Van de Steen, O.1; De Kock, H.1
1. Galapagos NV, Mechelen, Belgium; 2. AbbVie Inc, Chicago,
IL, USA
Background: GLPG3067 is a novel cystic fibrosis transmembrane
conductance regulator (CFTR) potentiator in clinical development for the
treatment of cystic fibrosis (CF) and represents one of the components of
a future potentiator/corrector combination therapy targeting the F508del
CF population. We report the results of a Phase 1 study of GLPG3067 in
healthy volunteers (HV).
Methods and Objectives: This randomized, double-blind, placebo-
controlled first-in-human study is designed to assess the safety, tolerability
and pharmacokinetic properties of GLPG3067 in HV. The study
consists of four parts: the first part assesses single ascending doses (SAD),
administered in two alternating cohorts of 8 subjects. The second part of
the trial assesses relative bioavailability of a tablet compared to the oral
suspension of GLPG3067 as well as the effect of food on the exposure of
GLPG3067. The third part assesses multiple ascending doses (MAD) in
three sequential cohorts of 8 subjects whereby doses are administered for 14
days. Part 4 assesses multiple doses of the combination of GLPG3067 and
GLPG2222 administered for 14 days in two sequential cohorts of 8 subjects.
Subjects are randomized in a 3:1 ratio (active versus placebo). This part is
conducted through an open label design that includes 9 healthy subjects.
The safety and tolerability evaluation consists of adverse events, clinical
laboratory parameters, physical examination, vital signs and ECGs. Plasma
and urine pharmacokinetics of GLPG3067 and GLPG2222 are determined.
Results: We report preliminary results of this phase I study. The SAD
doses GLPG3067 which have been tested at the time of abstract submission
were not associated with any serious adverse events (SAEs) or discontinuation
due to adverse events. Based upon blind data, headache and stomach
discomfort were adverse events (AEs) reported to be at least possibly related
to GLPG3067. Clinical laboratory parameters, physical examinations,
vital signs and ECGs did not show any clinically relevant changes.
Conclusions: The preliminary blind results of this first-in-human study
demonstrate GLPG3067 to be safe and well tolerated administered for 14
days in healthy subjects. Full safety and PK data as well as bioavailability
data for the solid formulation will be presented at the conference.

46
DECIPHERING THE MODE OF ACTION OF
CLINICALLY RELEVANT NEXT GENERATION C2
CORRECTOR COMPOUNDS GLPG2737 AND GLPG3221
Peters, F.1; Sahasrabudhe, P.1; De Wilde, G.2; Kleizen, B.1;
Conrath, K.2; Braakman, I.1 1. Cellular Protein Chemistry,
Utrecht University, Utrecht, Netherlands; 2. Galapagos N.V.,
Mechelen, Belgium
The current therapeutic strategy to repair cystic fibrosis-causing defects
in the chloride channel CFTR is to develop novel and better correctors
(to improve folding) and potentiators (to improve function). Galapagos-
AbbVie identified C2 correctors by high-throughput compound screening
and Med Chem optimization for cell surface rescue of F508del-CFTR.
These C2 correctors are acting synergistically with a type I corrector such
as ABBV/GLPG2222. Two C2 correctors, ABBV/GLPG2737 and ABBV/
GLPG3221 were optimized for drug like properties and are in clinical and
pre-clinical evaluation, respectively.
From both the functional halide efflux assays and pulse chase analysis
we showed that the rescue efficiency of F508del-CFTR after combination
treatment (C1 + C2) is markedly higher (=50% of wild-type levels) than
the sum of C1 and C2 correction. These strong synergistic effects show not
only that C1 and C2 have a different mode of action, but also highlight the
benefit of the triple-combination treatment with addition of a potentiator.
To investigate how, when and where these C2 correctors act on CFTR
we use radiolabeling approaches in combination with protease susceptibility
assays. We first evaluated C1 corrector ABBV/GLPG2222 using in vitro
translation and translocation assays in the presence of semi-intact HEK293
cells as source for endoplasmic reticulum (ER) membranes. We found that
ABBV/GLPG2222, but not the C2 correctors, acted on transmembrane
domain 1 (TMD1) in an identical fashion as lumacaftor by promoting its
cytoplasmic loop packing important for domain folding.
Varying the time of drug addition in pulse chase experiments showed
that, like C1 corrector, both C2 correctors reached maximal rescue efficiency
when present during, and shortly after the 15-minute pulse labelling. The
C2 correctors acted additively with all F508del suppressors (I539T, G550E
and R1070W) and did not restore nucleotide binding domain 1 (NBD1)
folding in the F508del-CFTR background. Although we did not identify yet
where the C2 correctors act, these compounds restored trafficking of the
NBD2-less F508del-CFTR (F508del-1219X) construct very well.
Our results show that the C2 correctors promote the earliest folding
events of the ER-export competent CFTR molecule lacking NBD2, ruling
out all possible NBD2 inter-domain assembly events (TMD1/NBD2;
NBD1/NBD2; TMD2/NBD2) as target candidate. The triple-combination
treatment that includes these C2 correctors significantly raises the
F508del-CFTR rescue ceiling, with the aim to reach sufficient clinical
benefit for most CF patients in the near future.

NielsjeB 20 september 2017 09:39

3

198w
DEVELOPMENT AND CHARACTERIZATION OF NEXTGENERATION
CORRECTORS AS PART OF A TRIPLE
CF THERAPY
Balut, C.1; Akkari, R.3; Alani, S.1; Bock, X.3; Claes, P.2;
Cowart, M.1; Desroy, N.3; De Wilde, G.2; Fan, Y.1; Gao, W.1;
Gees, M.2; Jia, Y.1; Liu, B.1; Manelli, A.1; Musch, S.2;
Pizzonero, M.2; Scanio, M.1; Searle, X.1; Singh, A.K.1;
Swensen, A.1; Van Der Plas, S.2; Vortherms, T.1; Wang, X.1;
Tse, C.1; Conrath, K.2 1. Abbvie Inc, North Chicago, IL, USA;
2. Galapagos, Mechelen, Belgium; 3. Galapagos, Romainville,
France
Cystic fibrosis (CF) is a life-threatening, genetic disease caused by
mutations in the gene encoding the cystic fibrosis transmembrane conductance
regulator (CFTR) protein. This results in abnormal transport of
chloride across epithelial cells, leading to dehydration of airway surface
liquid and impaired mucociliary clearance. The F508 deletion in CFTR
is the most prevalent mutation present on at least one allele in 85% of CF
patients. Maximal restoration of F508delCFTR is expected to require at
least two corrector molecules with complementary mechanisms, type 1
(C1) and type 2 (C2), to increase CFTR at cell surface, in combination
with a potentiator (P) to increase channel activity. To this end, AbbVie and
Galapagos have been developing multiple CFTR modulators to develop a
triple combination therapy.
Our lead C1 corrector, ABBV/GLPG-2222 exhibits significant
improvements over existing type 1 correctors, lumacaftor and tezacaftor
and is continuing progression in clinical studies. Multiple novel potentiators
(P) are also in clinical studies.
To complete the triple combination, herein we report the identification
and in vitro characterization of type 2 correctors. Two lead C2 compounds
from different chemical series, ABBV/GLPG-2737 and ABBV/GLPG-
3221 exhibit desirable pharmacologic properties and are currently in late
preclinical development to early clinical trials. Our C2 leads have consistently
shown a substantial increase in cellular protein processing and in
combination with the other assets in our portfolio have shown a significant
increase in CFTR function in human bronchial epithelial (HBE) cells with
the homozygous and heterozygous F508del CFTR mutations.
CMB, SA, MDC, YF, WG, YJ, BL, AM, MS, XS, AKS, AS, TAV, 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.

231
EFFICACY OF NEXT GENERATION CFTRMODULATORS
OF GALAPAGOS-ABBVIE IN RECTAL
ORGANOIDS
de Poel, E.2,1; van Mourik, P.2; Vonk, A.M.2,1; Oppelaar, H.2,1;
Hagemeijer, M.C.2,1; Berkers, G.2; Heida-Michel, S.2;
Geerdink, M.2; van der Ent, C.K.2; Musch, S.3; Conrath, K.3;
Beekman, J.M.2,1 1. Regenerative Medicine Center, University
Medical Centre, Utrecht, Utrecht, Netherlands; 2. Pediatric
Pulmonology, University Medical Center Utrecht, Utrecht,
Utrecht, Netherlands; 3. Galapagos, Mechelen, Belgium
The primary drug target for novel CFTR modulators is the most dominant
F508del (p.Phe508del) CFTR mutation that is carried by ~85% of
people with CF on at least one allele. Treatment of F508del CFTR by the
first generation CFTR modulators (ivacaftor (VX-770) and Lumacaftor
(VX-809)) have yielded significant clinical improvements. However,
VX-809/VX-770 (Orkambi) treatment is suboptimal, highlighting the need
for a more effective F508del therapy that enables treatment of the majority
(>85%) of people with CF. Galapagos (GLPG) and AbbVie (ABBV) have
developed two distinct sets of correctors (ABBV/GLPG C1: ’2222, C2:
‘2737 and ’3221) with complementary mechanisms and different potentiators
(ABBV/GLPG P: ’1837, ’2451) that can synergistically restore CFTR
function in primary human bronchial epithelial cells. Here, we assessed the
CFTR restoring capacity of these compounds using a forskolin-induced
swelling (FIS) assay in patient-derived rectal F508del/F508delCFTR organoids.
Various compound combinations (C1 or C2 + P and C1 + C2 + P)
were assessed using three different forskolin concentrations to study maximal
restoration and potential synergy of compound combinations. Combination
therapy (C1 or C2 + P) resulted in a significant increase of organoid
swelling indicating restoration of CFTR function. The C1+P combination
also showed a higher efficacy than the first generation CFTR modulating
compounds (VX-809/VX-770). Synergy was observed when additional
correctors of the second set (C2) were added to the combination treatment
containing a corrector of the first set (C1 + P). This synergistic effect was
present, but limited as compared to the synergistic effects of these compounds
in Ussing chamber settings using the identical rectal cells. Future
experiments will include the setup of additional swelling phenotypes in
organoids to optimally assess synergistic CFTR repair, as well as studies
focusing on the mode of action of these CFTR modulators on F508delCFTR
and other non-F508delCFTR mutations.

NielsjeB 20 september 2017 09:39

4

259
GLPG1837 IN SUBJECTS WITH CYSTIC FIBROSIS AND
THE S1251N OR G551D MUTATION: RESULTS FROM
PHASE 2A STUDIES (SAPHIRA 1 AND 2)
Conrath, K.1; Gesson, C.1; Allamassey, L.1; Van de Steen, O.1;
Kanters, D.1; De Kock, H.1; De Boeck, C.2; Davies, J.C.3
1. Galapagos, Mechelen, Belgium; 2. KUL, Leuven, Belgium;
3. Imperial College London, London, United Kingdom
Background: GLPG1837 is a novel cystic fibrosis transmembrane
conductance regulator (CFTR) potentiator in clinical development for
the treatment of cystic fibrosis. In vitro assays on S1251N and G551D
CFTR showed GLPG1837 to open this dysfunctional channel and suggest
GLPG1837 could be beneficial to CF patients harbouring these mutations.
Methods and Objectives: SAPHIRA1 and 2 are phase 2a, open label,
multi-centre studies designed to evaluate ascending doses of orally administered
GLPG1837 for 4 weeks (125, 250 and 500 mg b.i.d. in SAPHIRA1
and 62.5 and 125 mg b.i.d. in SAPHIRA2). Here, we present the analysis of
the pharmacokinetics (PK) and pharmacodynamic (PD) results in relation
to in vitro based predictions for activity.
Results: 26 and 7 subjects for SAPHIRA 1 or 2, respectively were
included in the studies. Overall, GLPG1837 was generally well tolerated
and results from the individual studies have been presented at NACFC 2016
(Van de Steen O, et al. Pediatr Pulmonol. 2016;51(S45):287) and ECFS
2017 (Davies J, et al. J Cyst Fibros. 2017;16:S24-5), respectively.
Intestinal organoids and primary bronchial epithelial cells were used
to project efficacious exposures in patients. Due to differences in potency
of GLPG1837 on S1251N and G551D CFTR, different dose ranges were
selected for the two clinical studies.
In SAPHIRA1 (G551D), no marked deviation in dose-proportionality
in plasma levels of GLPG1837 was observed but high variability in pre-
dose levels was seen. A clear dose-dependent activity of GLPG1837 was
observed as demonstrated by an association between increasing GLPG1837
plasma exposures and decreasing sweat chloride concentration (SwCl).
At the high dose (500 mg b.i.d.), an overall decrease in SwCl from 98
mmol/L at baseline to 66 mmol/L at D22 was observed. Patients exceeding
the predicted target concentration at 500 mg b.i.d., showed a more pronounced
decrease in SwCl going from 94 mmol/L to 52 mmol/L. Patients
with GLPG1837 plasma exposures below the predicted efficacious target
concentration, showed smaller SwCl changes. Overall, these data show
a compelling PK/PD relationship. Furthermore, the observed changes in
SwCl are independent of the CFTR mutation present on the second allele
(69% of patients carrying an F508del mutation).
In SAPHIRA2 (S1251N), the small sample size and the lower than
expected exposures of GLPG1837 make it more difficult to draw clear
conclusions in terms of PK/PD correlation. Nevertheless, the study results
indicate a trend for a PK/PD correlation similar to what is observed in
SAPHIRA1.
Conclusions: GLPG1837 shows a clear dose-dependent effect in
reducing SwCl as seen in the SAPHIRA1 study. The data support the validity
of our in vitro models used to translate in vitro CFTR activity to sweat
chloride changes in patients. SwCl is a rapid biomarker to measure CFTR
activity in patients.

262
SAFETY, TOLERABILITY AND PHARMACOKINETICS
OF SINGLE AND MULTIPLE DOSES OF GLPG2737, A
NOVEL CFTR CORRECTOR MOLECULE, IN HEALTHY
VOLUNTEERS
Brearley, C.1; Gesson, C.3; Kanters, D.1; Conrath, K.1;
Corveleyn, S.1; Geller, D.2; De Kock, H.1; Van de Steen, O.1
1. Clinical Development, Galapagos, Mechelen, Belgium;
2. Clinical Development, AbbVie Inc, Chicago, IL, USA;
3. Galapagos SASU, Romainville, France
Background: GLPG2737 is a novel cystic fibrosis transmembrane
conductance regulator (CFTR) corrector in clinical development for the
treatment of cystic fibrosis (CF). GLPG2737 exhibits potent in vitro activity
in primary patient cells harbouring F508del/F508del. GLPG2737 represents
one component of a future potentiator/correctors combination therapy targeting
a broad CF patient population.
Methods and Objectives: This is a 2-part, randomized, double-blind,
placebo-controlled, dose-escalation, first-in-human study designed to assess
the safety, tolerability and pharmacokinetic (PK) properties of GLPG2737
in healthy, male volunteers (HV). Part 1 investigated escalating single doses
of GLPG2737/placebo, whilst in part 2 escalating multiple doses given once
daily for 14 days are investigated. Each cohort has 8 subjects randomized.
Safety and tolerability are evaluated by adverse events, clinical laboratory
parameters, physical examinations, vital signs and ECGs. Plasma pharmacokinetics
of GLPG2737 is determined.
Results: We report blinded, preliminary results of this phase I study
(follow-up of the last cohort of subjects is still ongoing at time of submission).
47 and 32 male volunteers were included in Parts 1 and 2 of the study,
respectively. Following single doses of GLPG2737/placebo, the most common
adverse events reported by 2 or more subjects were apathy, common
cold, cough, headache and irritation at site of ECG electrodes. Following
the administration of GLPG2737/placebo once daily for 14 days, the most
common adverse events reported by 2 or more subjects were dry mouth or
throat or skin, common cold, acne, sore throat, tiredness, skin irritation at
site of ECG electrodes, cannula site reaction and headache. Clinical laboratory
parameters, physical examinations, vital signs and ECGs did not show
any clinically relevant findings in either part of the study.
Conclusions: The preliminary results of this first-in-human study
demonstrate that repeated doses of CTFR corrector GLPG2737 administered
for 14 days were generally well tolerated in healthy subjects and the
PK of GLPG2737 support a once daily dosing regimen. Full safety and PK
data will be presented at the conference. These preliminary findings support
the further development of the CTFR corrector GLPG2737 for the treatment
of subjects with CF.

NielsjeB 20 september 2017 09:39

3

263
PHARMACOKINETICS AND SAFETY OF A NOVEL
CFTR CORRECTOR MOLECULE GLPG2222 IN
HEALTHY SUBJECTS AND IN SUBJECTS WITH CYSTIC
FIBROSIS: RESULTS FROM TWO PHASE I STUDIES
Van de Steen, O.1; Gesson, C.2; Conrath, K.1; Kanters, D.1; De
Boeck, C.3; Corveleyn, S.1; Geller, D.4; De Kock, H.1 1. Clinical
Development, Galapagos, Mechelen, Belgium; 2. Galapagos
SASU, Romainville, France; 3. Pediatrics, Pediatric
Pulmonology, Leuven, Belgium; 4. Clinical Development, AbbVie
Inc, Chicago, IL, USA
Objectives: GLPG2222 (GLPG2222/ABBV-2222) is a novel 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. We present results from
two phase I clinical studies: a phase I first-in-human (FIH) study in healthy
subjects and a phase Ib study in adult subjects with CF.
Methods: The FIH study was a randomized, double-blind, placebo-controlled
study designed to assess the safety, tolerability and pharmacokinetic
(PK) properties of GLPG2222 in healthy subjects. The study consisted of
two parts: the first part assessed single ascending doses of 50 mg to 800
mg administered in two alternating cohorts of 8 subjects. The second part
assessed multiple ascending doses ranging from 150 mg q.d. to 600 mg q.d.
administered for 14 days in three sequential cohorts of 8 subjects each. The
phase Ib study in CF patients was an open-label, single-centre, 2-treatment
period study designed to evaluate the PK and safety of 2 single oral doses
of GLPG2222 (150 and 300 mg) in adults with CF. All subjects received
the 2 doses in a paired design. The higher dose was administered = 7 days
apart from the lower dose.
Results: Forty subjects participated in the FIH study. GLPG2222
was generally well tolerated when dosed up to 600 mg q.d. for 14 days in
healthy subjects. All adverse events (AEs) were mild in intensity, no clinically
significant changes in vital signs, safety laboratory tests, ECGs and
spirometry results were observed. GLPG2222 was rapidly absorbed, the
elimination half-life was 12 hours and steady state was attained within two
days of dosing. Six pancreatic insufficient CF subjects were included in the
phase Ib study. GLPG2222 was rapidly absorbed with a median tmax of 1.0
to 1.5 h. No marked deviation from dose-proportionality was observed. In
general, PK profiles from this study were similar to those of healthy subjects.
Three transient treatment emergent AEs were reported, 2 were mild
(cough and productive cough) and 1 was moderate (headache).
Conclusions: In adult healthy subjects and in adult subjects with CF,
GLPG2222 was generally well tolerated. The GLPG2222 PK profile was
similar across both phase I studies. These findings support further development
of GLPG2222 for the treatment of CF: two phase II studies with
GLPG2222 have been initiated and are ongoing (ALBATROSS study:
NCT03045523 and FLAMINGO study: NCT03119649).

264
SAFETY, TOLERABILITY AND PHARMACOKINETICS
OF CFTR POTENTIATOR GLPG2451 WITH AND
WITHOUT CFTR CORRECTOR GLPG2222 IN HEALTHY
VOLUNTEERS
van ’t Klooster, G.A.; Brearley, C.; Gesson, C.; Kanters, D.;
Conrath, K.; Corveleyn, S.; Van de Steen, O.; De Kock, H.
Galapagos, Mechelen, Belgium
Background: GLPG2451 is a novel cystic fibrosis transmembrane
conductance regulator (CFTR) potentiator in clinical development for the
treatment of cystic fibrosis (CF). In cellular assays, GLPG2451 exhibits
potent in vitro activity in primary patient cells harbouring the CFTR
F508del/F508del mutation. GLPG2222 is a novel CFTR corrector in clinical
development for the treatment of CF. In cellular assays, GLPG2222
exhibits potent in vitro activity, partially restoring F508del CFTR cell surface
expression. GLPG2451 and GLPG2222 represent two components of
a potential future potentiator/corrector(s) combination therapy targeting CF
patients harboring at least one F508del mutation.
Methods and Objectives: This is a 2-part, randomized, double-blind,
placebo-controlled first-in-human study designed to assess the safety, tolerability
and pharmacokinetic properties of GLPG2451 in healthy volunteers
(Part 1) and the combination of GLPG2451 and GLPG2222 when given
for 14 days (Part 2). Safety and tolerability evaluation consists of adverse
events (AEs), clinical laboratory parameters, physical examination, vital
signs and ECGs. Plasma pharmacokinetics of GLPG2451 and GLPG2222
(Part 2 only) are determined.
Results: We report preliminary results of this phase I study (follow-up
of the last cohort of subjects was still ongoing at the time of submission).
23 and 24 healthy volunteers were included in the study in Part 1 and Part 2
respectively. All AEs were self-limited and mild/moderate in severity. AEs
reported by =2 subjects included common cold, headache, loose stools, dry
skin, sore throat and migraine headache, neck or muscle stiffness and flu
like/upper respiratory tract symptoms in Part 1, and headache, diarrhea/
loose stools, rash and sore throat in Part 2. Most AEs were considered not
or possibly related to study drug. Clinical laboratory parameters, physical
examinations, vital signs and ECGs did not show any clinically relevant
findings in either part of the study.
Pharmacokinetic data demonstrate that GLPG2451 is relatively rapidly
absorbed and slowly eliminated.
Conclusions: Preliminary results of this 14-day study in heathy male
volunteers demonstrate that repeated doses of GLPG2451 with and without
the CFTR corrector GLPG2222 were generally well tolerated in healthy
subjects. The pharmacokinetics of GLPG241 is consistent with once-daily
dosing.
Full safety and PK data will be presented at the conference.
These preliminary findings support the further development of the
CTFR potentiator GLPG2451 for the treatment of subjects with CF.

NielsjeB 20 september 2017 09:42

5

5w
ACTIVITY OF HUMAN CFTR MODULATORS ON CFTR
FROM DIFFERENT SPECIES
Musch, S.; Segers, C.; Verdonck, K.; Christophe, T.; Conrath, K.
Galapagos, Mechelen, Belgium
In order to improve the folding/maturation and functional properties of
the cystic fibrosis transmembrane conductance regulator (CFTR) and thus
address the main defects leading to cystic fibrosis (CF), we are developing
different compound series. Each of these series contains either correctors
that increase CFTR levels at the cell surface, or potentiators that allow the
effective opening of the CFTR channel. Combined, these compounds are
able to restore chloride ion transport yielding improved hydration of the
lung surface and subsequent restoration of mucociliary clearance.
Understanding where and how the compounds act on CFTR is of high
interest. Several methodologies can be applied to get insights into the mechanism
of action of CFTR modulators.
Here we present the effect of CFTR modulators on wild-type (WT)
CFTR from different species, measured using a YFP-halide assay. For this,
HEK293 cells were transfected with a plasmid encoding for YFP (H148Q/
I152L/F47L) and a vector containing WT CFTR from one of the following
species: human, mouse, rat, dog, clawed frog, zebrafish and ferret. For each
species’ CFTR, the optimal forskolin concentration to activate the channel
was determined. After this optimization step, cells were incubated with
different concentrations of CFTR modulators (either potentiators or correctors)
and CFTR function was measured after activation of the channel using
forskolin. Activity of potentiators on WT CFTR from different species
could be measured and it was observed that the potency of the potentiators
can differ from species to species. For example, most potentiators seem to
activate rat CFTR with much lower potency than human CFTR. Since certain
types of correctors were shown to impact WT CFTR channel activity,
also corrector effects were compared across species.
By combining information on similarities and differences between the
CFTR protein sequences from the different species and on the effects of
compounds on the different species’ CFTR function, insight into potential
areas of binding of different CFTR modulators can be gained. In addition,
knowing whether the CFTR modulators act on other species than human
can help to understand which in vivo animal models might be useful for the
evaluation of certain CFTR modulators.

HansGarrincha 20 september 2017 11:47

0

Dank je Niels, voor de lawine aan info. Hoewel veel mij iets boven de pet gaat, vond ik het opvallend te lezen dat men ook kijkt naar potentiele behandeling van COPD gerelateerde aandoeningen zoals chronische bronchitis. Dat vergroot het bereik en mogelijke markt als de CF triples de eindstreep gaan halen.

[verwijderd] 20 september 2017 15:17

1

Thanks Niels voor de Abstracts.

Opvallend ja de passage over GLPG2196 als potentiator.

These preliminary findings establish that GLPG2196 is
efficacious in activating wild-type CFTR in smoke-exposed ferrets and can be used in vivo to test its ability to treat COPD-related chronic bronchitis in
a ferret model of the disease.

Persbericht Galapagos 16-12-2014:
Galapagos will regain full and unencumbered rights to the entire GPR84 program going forward, which includes the inhibitor GLPG1205 and its backup compound GLPG2196.

globenewswire.com/news-release/2014/1...

[verwijderd] 20 september 2017 15:23

2

Deze info zeker belangrijk:

We report preliminary results of this phase I study. The SAD
doses GLPG3067 which have been tested at the time of abstract submission
were not associated with any serious adverse events (SAEs) or discontinuation
due to adverse events. Based upon blind data, headache and stomach
discomfort were adverse events (AEs) reported to be at least possibly related
to GLPG3067. Clinical laboratory parameters, physical examinations,
vital signs and ECGs did not show any clinically relevant changes.
Conclusions: The preliminary blind results of this first-in-human study
demonstrate GLPG3067 to be safe and well tolerated administered for 14
days in healthy subjects. Full safety and PK data as well as bioavailability
data for the solid formulation will be presented at the conference.

Ofwel: milde bijwerkingen GLPG3067 bij gezonde vrijwilligers met SAD dose.
Hoofdpijn is een zeer geaccepteerde bijwerking.

HansGarrincha 20 september 2017 15:30

1

En de concurrent:
BOSTON--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (VRTX) (Nasdaq: VRTX) today announced that 11 abstracts from its cystic fibrosis (CF) research and development program will be presented at the annual North American Cystic Fibrosis Conference (NACFC) in Indianapolis, November 2 to 4, 2017. Previously announced data from the Phase 3 EVOLVE and EXPAND studies of the investigational tezacaftor/ivacaftor combination in people with CF ages 12 and older who have certain mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene will be presented for the first time. Additionally, data from the Phase 3 extension study of ORKAMBI® (lumacaftor/ivacaftor) in children with CF ages 6 to 11 who have two copies of the F508del mutation and real-world KALYDECO® (ivacaftor) data will be presented. The company also submitted an abstract for the late-breaking poster session with previously announced Phase 1 and Phase 2 data for three different next-generation correctors (VX-440, VX-152 and VX-659) in triple combination regimens with tezacaftor and ivacaftor in people with CF who have one F508del mutation and one minimal function mutation and in people with two copies of the F508del mutation.

[verwijderd] 20 september 2017 15:43

1

Omtrent GLPG2451 voorlopige Fase 1 scores, als monotherapie part 1 of dual-dosering met GLPG2222 part 2, een positieve afsluiting,
al was follow-up van 1 groep (cohort: dual met GLPG2222..) nog gaande op moment van indiening abstract.

Conclusie voor GLPG2451 (in 1e triple CF-patiënten Galapagos studie Q4 ) op basis van dit abstract is duidelijk: doorgaan met ontwikkeling.

Plasma pharmacokinetics of GLPG2451 and GLPG2222
(Part 2 only) are determined.
Results: We report preliminary results of this phase I study (follow-up
of the last cohort of subjects was still ongoing at the time of submission).
23 and 24 healthy volunteers were included in the study in Part 1 and Part 2
respectively. All AEs were self-limited and mild/moderate in severity. AEs
reported by =2 subjects included common cold, headache, loose stools, dry
skin, sore throat and migraine headache, neck or muscle stiffness and flu
like/upper respiratory tract symptoms in Part 1, and headache, diarrhea/
loose stools, rash and sore throat in Part 2. Most AEs were considered not
or possibly related to study drug. Clinical laboratory parameters, physical
examinations, vital signs and ECGs did not show any clinically relevant
findings in either part of the study.
Pharmacokinetic data demonstrate that GLPG2451 is relatively rapidly
absorbed and slowly eliminated.
Conclusions: Preliminary results of this 14-day study in heathy male
volunteers demonstrate that repeated doses of GLPG2451 with and without
the CFTR corrector GLPG2222 were generally well tolerated in healthy
subjects. The pharmacokinetics of GLPG241 is consistent with once-daily
dosing.
Full safety and PK data will be presented at the conference.
These preliminary findings support the further development of the
CTFR potentiator GLPG2451 for the treatment of subjects with CF.

[verwijderd] 20 september 2017 15:53

4

In Q4 2017 zal Galapagos starten met 1e Fase 1b studie in CF-patiënten.

GLPG2451+2222+2737

Bovenstaand abstract GLPG2451, voltooiing Fase 1 d.d. 12-9, en bevestiging Investor presentation september maken duidelijk dat Fase 1b gaat starten in 2017.

Go Galapagos!

Beurskingpin 20 september 2017 19:37

0

quote:
pe26 schreef op 20 september 2017 15:53:
In Q4 2017 zal Galapagos starten met 1e Fase 1b studie in CF-patiënten.

GLPG2451+2222+2737

Bovenstaand abstract GLPG2451, voltooiing Fase 1 d.d. 12-9, en bevestiging Investor presentation september maken duidelijk dat Fase 1b gaat starten in 2017.

Go Galapagos!

Was dit geen fase 2 studie triple combo die startte in Q4 2017? Of is deze fase 1b bijna een volwaardige fase2?

[verwijderd] 20 september 2017 22:37

4

quote:
Beurskingpin schreef op 20 september 2017 19:37:
[...]

Was dit geen fase 2 studie triple combo die startte in Q4 2017? Of is deze fase 1b bijna een volwaardige fase2?

Zie pagina 40 investor presentation Galapagos Juli (Ofwel open dropbox Niels).

Galapagos kiest meer en meer voor Fase 1b studies.
Zie o.a. MOR106/GLPG1972 en dus de CF triple combi studies.

Met mijn bescheiden kennis van inhoud studies zeg ik dat Fase 1b vooral gekend is wegens de effectieve en flexibele opzet:

»Doel is optimale dosis te bepalen.
Combinaties van verschillende (interne) moleculen met of zonder (externe) moleculen mogelijk.

Populatie Fase 1b studie relatief klein van omvang, wat het aantal te openen klinieken beperkt.

Het betreft patiënten en geen vrijwilligers en daarom verkrijgt men in relatief korte tijd een goed inzicht in safety-, verdraagzaamheid-
en effectiviteitsscores van behandeling.

Doel: snel naar Fase 3 of fase 2b/3 met CF triple combi therapie Galapagos/AbbVie.
Is dit te bewerkstelligen zonder afzonderlijke fase 2(b) studie..?

»»Is een studie-opzet Fase 1b met grotere populatie (+80) en/of met langere behandelingsduur (4-weeks primary scores + verlenging naar 12-weeks endscore) realistisch gezien de grote secuurheid die wordt gevraagd en verscheidenheid CF-patiënten (homozygous en heterozygous).

Daarbij belang tijdige indiening en inwilliging IND's (2737/2451/3067) bij/door FDA een uitdaging, wil je ook studies (fase 1b) starten in USA.

Dit kan bijv. niet opgaan voor triple 2451/2222/2737, maar wel voor 2e triple 3067/2222/2737 waarvan start Q1 2018 is voorzien.

Design 3 triples Vertex is fase 2 met 4-weeks behandeling, (uitgezonderd VX-440) en mogelijk goed vergelijkbaar met Fase 1b die Galapagos zal starten.

Komende 12-15 maanden wordt een hoop duidelijk of aparte fase 2(b) voor de geselecteede triple combi therapie(ën) Galapagos/AbbVie die worden doorontwikkeld noodzakelijk is.
Dit is al ruim een jaar het strijdplan Galapagos (1b » 2b » 3), echter geeft studie-opzet Vertex' triples wellicht kans voor Galapagos/AbbVie om ook versneld combi fase 2b/3 op te starten.

Veel hangt af van scores Fase 1b Galapagos onderzoeken, en hoe en waar ze worden vormgegeven/opgestart.

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