Eurobench.com

[verwijderd] 19 november 2019 20:47

9

Type 2 diabetes (T2D) is a complex chronic condition characterised by increased blood glucose levels and associated with micro- and macrovascular complications. In 2015, an estimated 415 million people globally had diabetes, with the vast majority (~?90%) having T2D.

Along with lifestyle modifications, current guidelines recommend the use of metformin as the preferred first-line glucose-lowering therapy in patients with T2D. Metformin has a low risk of hypoglycaemia and is weight neutral, with no increased risk of or benefit against adverse cardiovascular events. However, in view of its progressive nature, the majority of patients with T2D require treatment intensification from metformin monotherapy to achieve and maintain recommended HbA1c targets.

Second-line agents approved for dual therapy with metformin in the UK include sulfonylureas (SUs), thiazolidinediones (TZDs), dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium–glucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists and basal insulin analogues.

The National Institute for Health and Care Excellence (NICE) guidelines and the position statement of the American Diabetes Association and the European Association for the Study of Diabetes recommend that initial treatment intensification after failure of metformin monotherapy should consist of dual therapy with one of the following agents: DPP-4 inhibitors, pioglitazone, SUs or SGLT-2 inhibitors.

The choice of second-line agent should be based upon patient-specific considerations to minimise side effects whilst reducing HbA1c levels.

bmcmedicine.biomedcentral.com/article...

Ook deze markt is enorm en Galapagos steekt de nodige energie in stofwisselingsziekten, met als eerste molecule GLPG4059 voor diabetes type 2.

Een lage waarde van HbA1C zonder negatieve zaken als gewichtstoename zijn belangrijk. Wat dat betreft zijn de eerste afbeeldingen in de R&D presentatie veelbelovend.

Voor de liefhebber, meer over HbA1C: Valkuilen bij interpretatie van HbA1c.

www.dnodietist.nl/images/dno-nieuws/D...

fc

[verwijderd] 19 november 2019 20:54

0

dank voor het delen.

[verwijderd] 1 december 2019 18:04

6

Lingus schreef op 11 jun 2019 om 23:16:

Uit het patent, wat meer gedetailleerd:

SIK1 kan een interessante target zijn om type II diabetes en diabetische nefropatie te voorkomen (alinea 0007).
SIK2 en SIK3 zijn recent (2017) geïdentificeerd; ze spelen een rol in ontsteking door de uitscheiding van hoge hoeveelheden anti-ontsteking cytokines, in het bijzonder Interleukine 10 (IL-10) en zeer lage hoeveelheden pro-ontsteking cytokines zoals TNF-alfa (alinea 0008).

Quote Lingus:
Hoog speculatief; maar zou het kunnen zijn dat Galápagos ook met een SIK1 remmer aan de gang is?

De laatste aanname lijkt mij gegrond; Galapagos houdt zich bezig met alle SIK (1/2/3) targets, zoals je zelf eerder beschreef onderhavig het patent en R&D presentatie laatst.
Of SIK1 target specifiek voor diabetes verder wordt doorontwikkeld, is alleen door Galapagos te beantwoorden.

We weten van handicap GLPG3312 (SIK1/2/3). Dit molecuul raakt dus SIK1, en moet als medicijn middels capsule ingenomen moet worden. Een fantastische lokale preklinische werking voor IBD (darmontstekingsziekten) maar kan niet systematisch worden opgenomen (zeg ik dit goed..).

Of dit effect puur met SIK1 te maken heeft, is door ons niet te duiden.

Op basis van waiver aan ziektes is TOLEDO klasse werkzaam in ontstekingsziekten, fibrose en osteoporose.

Wie weet komt er ook een selectieve SIK1 remmer. Maar inzetbaar voor diabetes..=

Voor nu hebben we GLPG4059 als kandidaat medicijn voor diabetes type 2.

[verwijderd] 2 maart 2020 18:57

2

Geneesmiddelenonderzoek naar een nieuw middel dat mogelijk gebruikt kan worden bij de behandeling van type-2 diabetes

Betreft een onderzoek in combinatie met semaglutide (OZEMPIC van Novo Nordisk).

Binnenkort begint een onderzoek met een nieuw middel voor de behandeling van diabetes mellitus type 2. Dit nieuwe middel wordt gegeven in combinatie met het geregistreerde middel semaglutide. Het doel van het onderzoek is om de veiligheid en verdraagbaarheid van het nieuwe middel in combinatie met semaglutide te onderzoeken. Daarnaast wordt onderzocht hoe snel en in hoeverre het nieuwe middel in combinatie met semaglutide wordt opgenomen en uitgescheiden door het lichaam. Er zal ook worden onderzocht wat het effect is van de nieuwe medicatie op het lichaam. In totaal zullen 156 gezonde mannelijke en vrouwelijke vrijwilligers deelnemen aan deze studie, verdeeld over drie delen. De volgende tekst is alleen van toepassing op deel 1, dit deel omvat 60 gezonde mannelijke vrijwilligers.

Per 14 november 2019 duidelijk gemeld dat in jaar 2020 het fase 1 onderzoek van GLPG4059 zal starten voor Diabetes type-2.
Het is twijfelachtig of de door mij aangehaalde studie dit fase 1 onderzoek omvat, aangezien in presentatie door Piet Wiegerinck (CSO Galapagos) met name de combinatie met Metformine werd aangehaald.

www.geneesmiddelenonderzoek.nl/meedoe...

Lama Daila 5 september 2020 09:23

2

www.glpg.com/docs/view/5dfa3a5d93d37-en

Let me start now with a view on a completely novel activity. This is a metabolic area. GLPG4059 is a small molecule. It is being orally dosed, and it hits a complete novel mechanism of action, which is more focused around how the body handles lipids. So it has nothing to do with STLG-2s, nothing with PD4s or whatever, is completely something coming out of the lipid area. But my scientists really came to me and said Piet this is really a target for type-2 diabetes. It has every promise we need to make it successful. So we believe we are the only company working currently on this target. I'm not going to disclose this. So we've been working for years first in rodents. And our rodent models are, in fact, completely normal mice we use. We put them for 12-week on what we call a western diet, which is high fats and high sugar intake. And then after 6 weeks, we start to dose the mice with the drug for 6 weeks.
So here, you see the outcome at the end of the 6 weeks, at the end of the 12 week of the experiments and 6 weeks of dosing. So what you can see is that the effect on the lipids, we always see a very clear drop of lipids circulating in the plasma. That's what we have observed. That -- the compound is given the dark green bars. We've included that to the reference just to give you an idea, is this marginal activity?
Or is this decent activity, metformin. The gray are the healthy mice which are keep on the normal diet. The orange bars are the ones that have been fed as well for 12 weeks.
But you have as well picked up quite early is a sustained decrease of body weight. So really, those mice lose a lot of fat and they lose body weight because they have much less fat in their body, similar to metformin here as well. Then as well finally, those mice, which is mice only, I agree with you, they handle much better all of the sugar content that they're getting. So they're fasting plasma glucose, that's what we measure in mice. It's much lower than in disease states. So really, by blocking this novel mechanim-of-action, we see a number of parameters, which we believe are important for type 2 diabetes, moving into the right direction.
Having been working for 3 years almost on, I said guys, It is time we confirm this as well in monkeys. So that's what we recently did. So now we are looking here to diabetic monkeys, they are older monkeys, and they have all of the symptoms of type 2 diabetes. So there are no healthy controls in this experiment, but we've added in yellow a box, where we combine our drug '4059 with metformin. The idea is if you move in type 2 diabetes, all patients will be on metformin and we want to illustrate that we don't block that activity. So it's not the idea really that with a single dose you see an increase in activity, it's just showing the principle when you combine them, patients will do well.
So again, on the left, the lipids there, a nice drop of lipids compared to the disease. In the middle of the body weight change again as well in monkey we see a nice drop the combo seems to be -- do a bit better in that, indeed in metformin. And here, we can measure HbA1c. So the glucose bond to hemoglobin. And as well, there, we see a nice effect. So that's one of the novel and the first projects in our metabolic program, which all in all is limited. But that has reached the stage where we currently are doing tox studies with it. Hope to move it into Phase I next year and then quickly move to type 2 diabetes patients, both as a monotherapy and on top of metformin. But just to give you a glimpse that we do more than just in inflammation and fibrosis only.

Lama Daila 5 september 2020 09:26

2

Het nieuwe patent dat Paté ontdekt had en WST ook al op het Toledo-draadje had vermeld is vermoedelijk gelinkt aan GLPG4049.
patentscope.wipo.int/search/docs2/pct...

PASK = Per-Arnt-Sim Kinase
Lingus gaf op dat Toledo-draadje ook al de link naar volgend document:
www.ncbi.nlm.nih.gov/pmc/articles/PMC...

Lama Daila 5 september 2020 09:45

2

europepmc.org/grantfinder/grantdetail...

Is PASK a therapeutic target for diabetes?

Miss J Meng | Imperial College London

Abstract

Existing data indicates that PAS domain containing protein kinase (PASK) may be a new component in the GLP-1 signalling pathway and may be a novel drug target for the treatment of obesity and diabetes. GLP-1 has numerous beneficial effects and does not induce hypoglycaemic episodes, making it an ideal therapeutic target. The goal of this research project is to investigate whether the global activation of PASK improves control of food intake, glucose homeostasis, and the response to GLP-1 and its long-acting analogues. The research aims to determine whether more effort is warranted in the development of small molecules that modulate PASK activity. Recent work has suggested that PASK may act on multiple tissues (including the brain) as a central regulator of food intake and to control the circadian rhythm of the pancreas. Transgenic mice will be generated (using doxicyclin) which over-express a human variant of PASK, PASK (G1117E). The key goal of this research is to assess whether increased PASK activity will reduce appetite and/or improve glucose tolerance, in mice that are maintained on a normal chow or high (60%) fat diet (HFD).

Lay abstract

The key goal of this research is to investigate a potential new therapy for diabetes. When we eat, our body releases a substance called insulin, which removes sugar (glucose) from the blood and stores it in our cells. Diabetes arises when the body fails to produce insulin or the effect of insulin is lost. Therefore the sugar remains in the bloodstream and the constantly elevated blood sugar level is referred to as diabetes. Too much sugar in the blood can damage blood vessels in our body. In the management of diabetes, the goal is to keep blood sugar level within a certain range. In this research, we are investigating a molecule called PASK (PAS domain-containing serine/threonine-protein kinase) to determine whether it could have a role in controlling how much we eat and maintaining the level of sugar in our blood. PASK may work in a pathway that does not cause blood sugar levels to become too low (which can lead to coma), which is a complication of some current drugs available.

Lingus 5 september 2020 09:59

0

Met dank aan Lama, mijn tekst uit het Toledodraadje nog even hier geplaatst:

Het patent hierboven behandelt 168 compounds die als PASK-remmers ingezet kunnen worden. PASK staat voor Per-Arnt-Sim Kinase, zie onder meer www.ncbi.nlm.nih.gov/pmc/articles/PMC... .
Uitgaande van de aannames in dit draadje zijn het geen Toledo-moleculen.

Het patent pakt een brede indicatiescope: het voorkomen of behandelen van endocriene, nutritionele, metabole en/of cardiovasculaire ziektes.

De toepassing waar Galápagos onderzoek naar doet is volgens het patent Type 2 diabetes mellitus (T2DM), de meest voorkomende vorm (90%) van suikerziekte.

Onderzoek suggereert dat PASK-remming zorgt voor een hoge mate van ongevoeligheid voor een vetrijk dieet en daarmee een hoge mate van ongevoeligheid voor obesitas, het gebruikelijke voortraject van T2DM en ook bijvoorbeeld NASH.

Veel korter kan ik het niet samenvatten. Interessante en grote markt! 168 compounds, hopelijk levert dat enkele klinische kandidaatmedicijnen op.

Wall Street Trader 5 september 2020 10:16

5

@Lingus & Lama Daila

Indeed it's probably GLPG4059 Novel MOA for Type 2 diabetes

GLPG4059 product candidate: We have one pending UK patent applications claiming GLPG4059 compositions of matter and methods of treatment using GLPG4059. Patents, if any, that issue based on these pending patent applications are estimated to expire in 2040, not including any potential extensions for the marketed product that may be available via supplementary protection certificates or patent term extensions.

Piet Wigerinck Galapagos NV - Chief Scientific Officer

GLPG4059 is a small molecule. It is being orally dosed, and it hits a complete novel mechanism of action, which is more focused around how the body handles lipids. So it has nothing to do with STLG-2s, nothing with PD4s or whatever, is completely something coming out of the lipid area. But my scientists really came to me and said Piet this is really a target for type-2 diabetes. It has every promise we need to make it successful. So we believe we are the
only company working currently on this target. I'm not going to disclose this. So we've been working for years first in rodents. And our
rodent models are, in fact, completely normal mice we use. We put them for 12-week on what we call a western diet, which is high fats
and high sugar intake. And then after 6 weeks, we start to dose the mice with the drug for 6 weeks.

So here, you see the outcome at the end of the 6 weeks, at the end of the 12 week of the experiments and 6 weeks of dosing. So what you
can see is that the effect on the lipids, we always see a very clear drop of lipids circulating in the plasma. That's what we have observed.
That -- the compound is given the dark green bars. We've included that to the reference just to give you an idea, is this marginal activity?

Or is this decent activity, metformin. The gray are the healthy mice which are keep on the normal diet. The orange bars are the ones that
have been fed as well for 12 weeks.
But you have as well picked up quite early is a sustained decrease of body weight. So really, those mice lose a lot of fat and they lose
body weight because they have much less fat in their body, similar to metformin here as well. Then as well finally, those mice, which is
mice only, I agree with you, they handle much better all of the sugar content that they're getting. So they're fasting plasma glucose,
that's what we measure in mice. It's much lower than in disease states. So really, by blocking this novel mechanim-of-action, we see a
number of parameters, which we believe are important for type 2 diabetes, moving into the right direction.
Having been working for 3 years almost on, I said guys, It is time we confirm this as well in monkeys. So that's what we recently did. So
now we are looking here to diabetic monkeys, they are older monkeys, and they have all of the symptoms of type 2 diabetes. So there are
no healthy controls in this experiment, but we've added in yellow a box, where we combine our drug '4059 with metformin. The idea is if
you move in type 2 diabetes, all patients will be on metformin and we want to illustrate that we don't block that activity. So it's not the
idea really that with a single dose you see an increase in activity, it's just showing the principle when you combine them, patients will do
well.

So again, on the left, the lipids there, a nice drop of lipids compared to the disease. In the middle of the body weight change again as
well in monkey we see a nice drop the combo seems to be -- do a bit better in that, indeed in metformin. And here, we can measure
HbA1c. So the glucose bond to hemoglobin. And as well, there, we see a nice effect. So that's one of the novel and the first projects in our
metabolic program, which all in all is limited. But that has reached the stage where we currently are doing tox studies with it. Hope to
move it into Phase I next year and then quickly move to type 2 diabetes patients, both as a monotherapy and on top of metformin. But
just to give you a glipse that we do more than just in inflammation and fibrosis only.

For more information See PDF:

www.glpg.com/docs/view/5de1211042ad2-en

Lama Daila 5 september 2020 22:54

3

Het patent verwijst helemaal onderaan naar BioEnergenix.
Recent artikel waarbij ook verwezen wordt naar BioE-1115, a selective and potent oral PASK inhibitor:
aasldpubs.onlinelibrary.wiley.com/doi...
En een artikel van 2014:
www.researchgate.net/publication/2637...
Hier het patent van BioEnergenix waar vanuit het patent van Galapagos verwezen wordt:
patentscope.wipo.int/search/en/detail...
ISR: patentscope.wipo.int/search/docs2/pct...

Lama Daila 5 oktober 2020 20:19

7

Fase1 GLPG4059 gestart (Recruiting in Groningen):
clinicaltrials.gov/ct2/show/NCT04575818

Lama Daila 5 oktober 2020 21:14

5

De studie bevat dus 4 arms:
SAD (Single Ascending Dose) en de Placebo-SAD
FE (Food Effect) Fasted en FE Fed

Hier de definitie van Fasted en Fed volgens de FDA:
www.fda.gov/media/70945/download

Fasted Treatments: Following an overnight fast of at least 10 hours, subjects should be administered the drug product with 240 mL (8 fluid ounces) of water. No food should be allowed for at least 4 hours post-dose. Water can be allowed as desired except for one hour before and after drug administration. Subjects should receive standardized meals scheduled at the same time in each period of the study.

Fed Treatments: Following an overnight fast of at least 10 hours, subjects should start the recommended meal 30 minutes prior to administration of the drug product. Study subjects should eat this meal in 30 minutes or less; however, the drug product should be administered 30 minutes after start of the meal. The drug product should be administered with 240 mL (8 fluid ounces) of water. No food should be allowed for at least 4 hours post-dose. Water can be allowed as desired except for one hour before and after drug administration. Subjects should receive standardized meals scheduled at the same time in each period of the study.

Lama Daila 19 maart 2021 12:19

1

Er is een 5e arm toegevoegd:

clinicaltrials.gov/ct2/history/NCT045...

Experimental: GLPG4059 rBA/FE tablet fasted
Single dose of GLPG4059 in fasted state

Study Completion: April 2021 [Anticipated ] —> June 2021 [Anticipated ]

Lama Daila 6 mei 2021 22:20

1

Q1 2021: We stopped further work on ‘4059 for metabolic disease, given that this is not a core therapeutic area

winx09 6 mei 2021 22:51

0

Had ik persoonlijk veel van gehoopt. Is de afgelopen jaren heel veel R&D in gegaan. Meende dat Onno op de Ava 2 jaar geleden opmerkte "... resulaten kome erg traag, mij te traag, maar te beloftevol om te schrappen.." . Dit na aanleiding van mijn opmerking dat een goede veredelaar heel goed kan weggooien.

jammer.

Lingus 6 mei 2021 22:57

1

Misschien kan dit programma verkocht worden aan een ander bedrijf. Gebeurt wel vaker.

Lama Daila 11 mei 2021 14:55

2

Terminated:
clinicaltrials.gov/ct2/show/NCT04575818

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