The Story of GLP-1 Receptor Agonists

00:00:01: Hello

00:00:07: and welcome back to EASD TV.

00:00:10: This morning we've been privileged to hear from Jens Holst who was awarded the Lilly Global Impact Award.

00:00:18: So, Jens Holst what a pleasure it is have you in this studio with us. Given the prize of course because involvement in GLP ones.

00:00:30: And I wanted to ask you how this all started, take us back to the young Jens Holst growing up in Copenhagen and Denmark?

00:00:39: Yeah so i am an MD and was just qualified as a doctor and training at surgery those days... ...and got together with group of people who were also interested in new field gastrointestinal hormones.

00:00:55: Hormones from gut that they could play a role in insulin secretion and that was our particular focus.

00:01:02: And we had some patients at the department there who developed hypoglycemia, so I was interested to find out whether this new work we were doing with the so-called Incrutin hormones could explain their hypoglycemia.

00:01:16: if what factor or you know...what would be done about it?

00:01:19: Actually its interesting because those stories turned out completely true!

00:01:23: It was GLP one which is responsible for these things.

00:01:27: the hypoglycemia with an antagonist against you'll be one of such and antagonists as being developed clinically in these days.

00:01:34: So I mean that story is very nicely rounded off but it was an extremely exciting time because everything we did, completely new and untried so were having enormous fun doing this work.

00:01:51: This started in the seventies really.

00:01:56: The groundwork for all of this was done started in the early seventies actually.

00:02:01: The, uh... Actually demonstration or with the isolation and sequence on that of GLP-One was in eighty six.

00:02:10: Everybody immediately thought this might be a fantastic therapy, but there was a problem wasn't there?

00:02:17: because it wasn't stable.

00:02:19: So in fact the interest was very small and people working with the incursion hormones were usually put up at very very small halls of the diabetes conferences where you know just a handful of people met and discussed very eagerly their findings.

00:02:35: But uh...the general interest was not there.

00:02:38: And this is because nobody really believed that you could treat diabetes with any of these hormones, and there were good reasons for not believing about clinical experience telling them they would never be done.

00:02:51: So it was actually quite a surprise when eventually, we, together with Michael Nauck in Germany were able to infuse GLP-I to people with diabetes.

00:03:01: And show that we could completely normalise their blood glucose levels within the infusions of this hormone.

00:03:06: This was a whole difference!

00:03:09: That's what changed everybody opinion about us.

00:03:12: Was that your moment of great excitement?

00:03:14: Yes

00:03:15: it was In fact yes absolutely.

00:03:17: Now tell me where a Gila monster comes into all of this

00:03:21: as a joke.

00:03:23: No, no I mean so this was uh...this is completely a parallel but completely different story.

00:03:31: So researchers in New York were interested their real basic researches.

00:03:36: you know they're interested in strange peptides from strange animals.

00:03:40: There are still quite a lot of people interested in strange peptides from strange animals.

00:03:44: Yes, and

00:03:44: I also think it's a huge wonderful idea And i've kept working with that you know for a long time Cold snails and things like almost our most recent contributions to this but nevertheless.

00:03:55: So what they found was?

00:03:57: That they were isolating some interesting principle in principal Interesting peptides, From the venom over Some Of These Lizards from Arizona particularly This one The Gila monster And they thought it was a completely different substance.

00:04:13: They saw that it was working on the exocrine pancreas, and how this was isolated really... ...and then there were more or less certain depictions where people just put in preparation to have GLP-I receptors which showed full agonists for the GLP one receptor.

00:04:30: In fact, this animal. the Gila monster, has its own GLP One which is very similar to mammalian GLP ONE.

00:04:36: It's hugely conserved in biology.

00:04:40: So nobody really knows what the idea about extending for us, but it was a full and stable

00:04:46: happiness.

00:04:47: That's key point!

00:04:49: It

00:04:49: was stable.

00:04:50: And so that enabled the people, particularly John Ing who was the main figure here interested in this to look at it

00:05:01: in people with diabetes, which was interesting given the fact they were isolated from the venom of these creatures.

00:05:05: but... That also caused a lot problems when the pancreatitis business came up where even officers from the WHO said that this was published in New England Journal of Medicine,

00:05:21: That it is completely conceivable, that injections of this compound excenotide would cause pancreatitis because they experienced one had with bites on the Gila monster.

00:05:33: and it was completely false!

00:05:34: It had never been observed.

00:05:36: but what's the sentiment these days?

00:05:38: Ah well you got them... It causes pancreatritis.

00:05:42: so

00:05:43: When was the first therapy developed?

00:05:47: Therapy. Therapy with GLP ones.

00:05:48: The first one that was approved, was Extentin-IV, Accenotide, approved in two thousand and five.

00:05:55: John Ing had been working with this little company Amelon Pharmaceuticals or something like that And they were able to... With a bit of help from Lilly demonstrating that their two daily injections could improve glycemic profiles, and also actually eventually cause a small weight loss of a couple of kilograms.

00:06:20: So that was the first clinical evidence.

00:06:22: but you know at the same time other groups particularly in Novo Nordisk were working with natural peptide trying to see what can be done to

00:06:31: rescue that and discovered the fixing was to attach fatty acid to the molecule, make it bind to albumin in circulation, avoid illumination of the kidneys.

00:06:43: And then also stabilize towards DPP-IV enzyme we had demonstrated completely deleterious to the hormone.

00:06:53: And that was then, it wasn't ready for a long time but there was an approved in two thousand

00:06:58: nine and two thousand ten.

00:07:00: So all through those early naughties It kind of puttered along didn't?

00:07:08: People thought it might be good But they weren't great.

00:07:13: Then what happened?

00:07:14: in 2009

00:07:17: It was clear, I think from pretty early days that lyraclutitis which is the big compound in those days.

00:07:26: Was a fairly good anti-diabetic agent also compared to existing therapies and particularly in combination with insulin.

00:07:35: actually it's really powerful so that in itself was as a good and stable

00:07:40: observation. no problem in that. The weight losses was not great.

00:07:46: So at Novo Nordisk, they finally decided to engage in this and they did a new dose response study with the experience that you had to go slowly with increasing the doses and found out that three milligrams rather than one point

00:08:02: eight were more effective on bodyweight as we have published already long time ago.

00:08:10: and then that was led to the registration trials, the scale trials for three milligrams of lyraclutide, the saccente which worked giving six-to eight percent weight losses in people.

00:08:25: And it was approved for weight loss.

00:08:27: so this is really a new development.

00:08:31: we had at GLP One.

00:08:32: that was approved for treatment of obesity but it wasn't a sensation and why? because If you weigh a hundred and twenty kilograms, I mean six to eight percent is not enough.

00:08:43: It's the Christmas lunch?

00:08:45: Exactly!

00:08:46: No no... You're right.. I mean absolutely. So

00:08:48: then semaglutide was developed which is long-acting and better.

00:08:53: it's more powerful molecule also in terms of reduction on appetite.

00:08:58: And again it caused that weight loss now of six two eight percent just like three milligrams of saxenda.

00:09:05: And again, some people felt that maybe something more could be obtained.

00:09:10: So they did another dose response study and sure enough with careful optitiation you can actually obtain much larger weight losses of up to eighteen percent with semaglutide.

00:09:25: and that changed the whole picture because now all a sudden. The weight loss was sufficient to satisfy peoples expectations which is really different.

00:09:35: And at that moment, it just exploded.

00:09:37: Yes!

00:09:38: That is the decisive moment

00:09:41: and The way that GLP ones have kind of taken over the world has been utterly extraordinary.

00:09:48: I mean we had a conversation Some time ago on EASD TV.

00:09:52: an I said I thought there would be very soon counterfeit medicines in this because... ...the weight loss was so successful and people wouldn't necessarily want to go and beg for weight loss treatment.

00:10:05: They'd want to quietly do it, so they would kind of behind the back door for it... And that's what happened!

00:10:15: It became extraordinarily successful drug.

00:10:18: So how did you feel Jens when you saw GLP-I on every front page?

00:10:29: Whatever feelings I might have had, I suppressed them.

00:10:32: Because this was on...I couldn't handle that.

00:10:34: so forget it!

00:10:35: So this is just something that is happening and now you have to live with us right?

00:10:39: But but its also fantastic as well fun And i was present at the American... the conference on obesity, Jema Conference in Chicago and in May.

00:10:53: Discussing the global obesity and what should we do about it?

00:10:57: And where is kind of materialized for first time really that one of solutions to a global problem is the GLP1 agonist!

00:11:04: The problem is just how can we, How do we make these huge amounts of it?

00:11:10: How do you make them at a price that is affordable and what should it be like, or should they be injectable.

00:11:20: I mean how can we make sure this principle can be used for the global treatment of obesity?

00:11:28: That's an exciting problem.

00:11:32: What we're seeing right now is that Semaglutide has obviously gone off patent in a number of countries and large numbers of providers are now producing it.

00:11:43: And the prices are falling, and you can buy at very low prices in India.

00:11:48: I mentioned in my talk that somebody said they could sell it for eight dollars per month which is affordable.

00:11:55: Yes!

00:11:56: It's affordable.

00:11:57: and suddenly You're looking...I mean..you look at drug people perceive to be about weight loss but actually it's so much more in terms of its impact on diabetes and now we know you know, of all the impacts on cardiovascular disease and other things.

00:12:15: Yeah

00:12:16: that to me for a while was perhaps most important.

00:12:20: this ability of it... ...to solve the problems of the metabolic syndrome, and the complication rates associated with this.

00:12:31: For long time I thought this is fantastic!

00:12:33: Let's make sure that all of the Globe you can have GLP1s for this.

00:12:38: But I also now realize that it's going to be much further than that, because people want it.

00:12:43: And...I don't see why we should prevent people from getting it somehow if they really really wanted.

00:12:53: It is a kind of ethical moral issue which is normally not my business.

00:12:58: I have to say, i am a doctor!

00:13:03: We already know that people don't care about the legislation and all that.

00:13:08: That you can half of what the semaglutide is being used in United States is counterfeit or

00:13:15: off-label

00:13:16: compounded?

00:13:17: Yes!

00:13:18: And not provided by companies...and they're selling a retatrutide now in large amounts, it's not even approved yet so sources probably who knows.

00:13:33: And

00:13:34: shed out to the back of a garage?

00:13:36: Precisely, and apparently this is possible which tells you that it's possible to produce sufficient amounts of this product absolutely!

00:13:43: And its impossible do at affordable prices.

00:13:47: so your in a situation where And what then should prevent people from doing it?

00:13:53: I don't know.

00:13:54: But isn't

00:13:55: this extraordinary to go from six percent weight loss, we're talking about twenty-five percent weight

00:14:01: lost.

00:14:01: It's utterly extraordinary.

00:14:03: and also the thing that really intrigues me is at the very beginning everybody said all these effects beyond simply glucose were all about weightloss.

00:14:16: But actually there's something else, isn't that?

00:14:18: Yes.

00:14:18: I think so!

00:14:20: One of the best indications for this is really the study with a compound called albiglutide which was produced by GSK and large molecule GLP-I agonist And it had very nice effects on cardiovascular risk.

00:14:35: The same kind of twenty percent production as all others but no weight loss.

00:14:40: So how is possible? It's possible if you dive into data that you can find something.

00:14:46: But that's nevertheless the truth, a good illustration of something else I think.

00:14:52: So you've had very long and productive life.

00:14:58: If you have another thirty or forty years.

00:15:02: what would be investigating?

00:15:03: What are key research questions You'd like to look

00:15:08: at?

00:15:08: As briefly mentioned i started as surgeon And somehow i loved surgery.

00:15:15: The only alternative I can imagine was that it's continuing in surgery, which would have been fun.

00:15:21: My hands somehow were put on the right position so... ...I really enjoyed it!

00:15:28: But looking at my colleagues and age who became surgeons they've retired long ago most of them actually dead.

00:15:36: It is a hard life.

00:15:39: So you know i'm really lucky that i was diverted into research at an early age and I am still able to work in my laboratory, we're doing research every day.

00:15:53: What do you think has propelled you all the time?

00:15:55: Is it about curiosity...

00:15:58: fun and curiosity, as long as you know, not all results are good of course.

00:16:04: And encouraging but there is always something that keeps you in the good spirit.

00:16:10: Then what it's all about?

00:16:13: Is that you open your laboratory to young people, the PhD students and all that.

00:16:19: You get to know a wonderful number of wonderful people.

00:16:24: so its such an inspiring life flow of younger people in your laboratory for so many years.

00:16:33: It's really fun!

00:16:33: And actually, what is wonderful about science?

00:16:36: Is that you open one door and then fifty other doors open in front of you because every question creates new questions.

00:16:45: it also like crime novels the closed or the secluded room.

00:16:50: I mean find a solution but find out what goes on there.

00:16:53: the detective is at work here.

00:16:57: It's been an extraordinary career.

00:17:00: This award, the Global Impact Award is so well-deserved because the impact of what you've done has truly been global.

00:17:08: it affects the entire world and not many people can say that as a result their work.

00:17:15: So thank you so much for talking to us yet.

00:17:16: Thank you.

00:17:17: Wonderful.

00:17:19: Well such a pleasure to talk to Jens Holst there And they'll be more from EASD very shortly.

00:17:26: Diabetes, Insights Breakthroughs and Innovators.

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