It’s an interesting phenomenon that, so far, the weight-lowering effects that have been observed with drugs that are on the market is markedly lower in people who not only suffer from obesity but also type 2 diabetes. And some of these combinations between amylin and GLP-1 analogues, they seem to achieve better weight reduction in people who also suffer from type 2 diabetes. So there seems to be a relatively big potential. My name is Thomas Lutz. I’m a professor of veterinary physiology at the University of Zurich and I have been doing research on the control of appetite for the last 35 years. And my main interest over this entire period was the effect of gut hormones and gut hormone analogues for the control of eating, with my special interest in the pancreatic hormone amylin. Amylin is a pancreatic beta cell hormone. It’s co-released with insulin in a specific molecular ratio between amylin and insulin. And for this reason, blood concentrations of amylin basically reflect changes in insulin in response to eating. About twenty years ago, the first amylin analogue, which was called pramlintide, was released on the market and was licensed by the FDA for the treatment of type 1 and type 2 diabetes together with insulin, not as a monotherapy, but together with insulin, and because of amylin’s effect on eating. So, amylin physiologically reduces meal size, and it reduces eating and eventually also leads to a decrease in body weight. Pramlintide has also been studied in this respect. Now it’s true that the effect of pramlintide on body weight reduction was rather limited. It was only about two to three kilos compared to the respective control groups. The reason for that is probably that the biological half-life of pramlintide is very, very short. It also had to be injected three times a day, before every single meal, and the effect was limited to the subsequent meal. So, there was no long-term efficacy by this molecule. And for that reason, probably the reduction in body weight that was seen with pramlintide was really minor compared to the newer compounds that are in clinical development at the moment. Amylin as I just said, comes from the pancreatic beta cells. Its physiological function, as we believe, is control of the meal size. So, it acts as a satiation hormone, and glucagon-like peptide-1, GLP-1, is also released in response to meals, and GLP-1 physiologically also has meal size effects. So, biologically, they seem to have similar behavioural consequences if you inject them to experimental animals or also given to humans, of course, so both reduce eating. The reason why it’s an interesting option to combine amylin and GLP-1 analogues is that they most likely act on similar areas in the brain, but they seem to trigger different neuronal populations. So, the primary neurons that are activated by amylin or GLP-1 analogues are probably different. And for that reason, it’s a very interesting possibility and also plausible possibility that by combining these two peptides you will actually achieve a bigger decrease in eating and eventually a bigger decrease in body weight. There’s a large number of amylin analogues that are currently being tested. They differ in various aspects, and I must put perhaps very briefly explain the receptors that mediate the effect of amylin. This seems to be a rather complex receptor system. There is a specific core receptor and there are amylin receptors. And the core receptor is actually a calcitonin receptor. So, calcitonin receptors and amylin receptors are very much related. And some of these compounds that are in development are more specific towards the amylin receptors and some are less specific. That means they activate the amylin receptors and the calcitonin receptor. In that respect, there’s quite some difference between the different compounds which may perhaps, but we don’t know the answer yet, also lead to different efficacy profiles in patients. But we don’t know exactly yet what type of receptor would be the best one to be activated. At the moment, I think the most promising approach is the combination of amylin and GLP-1 analogues for the treatment of obesity, in particular in people with diabetes. Because it’s an interesting phenomenon that, so far, the weight lowering effects that have been observed with drugs that are on the market is markedly lower in people who not only suffer from obesity but also type 2 diabetes. And some of these combinations between amylin and GLP-1 analogues, they seem to achieve better weight reduction in people who also suffer from type 2 diabetes. So there seems to be a relatively big potential at the moment. Obesity and diabetes, type 2 diabetes, I think, are the most promising indications for the use of these combinations. The number of patients that have been included in clinical trials is really very large. So, at the moment there’s no concern at all that the activation of the calcitonin receptor might have negative side effects. Actually, the activation of the calcitonin receptor may also be the reason for some beneficial potential of the addition of amylin to GLP-1. Because during weight loss, we typically also see a reduction in bone mass. And this reduction in bone mass can also lead to higher fracture rates. And by activating the calcitonin receptor, this effect can potentially be counteracted. So, at the moment, it’s rather seen as a positive phenomenon, rather than a negative phenomenon that would be a reason for concern. It’s really important to understand that gut hormone analogues have a very, very high potential for being successful weight loss and anti-diabetes drugs. And we should not only focus on the ones that are already registered like GLP-1 or GIP agonists. The addition of other targets like amylin, but potentially also other targets, offers the possibility to basically increase the number of available therapies, because not every patient may react in the same way to any of these therapies. So, I think it’s important to realize that there are other hormones out that can be used as a target. Amylin, at the moment, is one of the very prominent ones. The side effects, the safety profile of all of these newer approaches to treat obesity and diabetes so far, has not brought any new surprises. We know, for example, that GLP-1 agonists have a high potential to induce nausea and also vomiting in some patients. There’s nothing new when you combine GLP-1 analogues with amylin analogues, for example, but it doesn’t seem to make the side effects much more serious, even though the body weight loss is actually superior to single therapy. So, the safety profile seems to be predictable at the moment. And the possibility to combine different drugs and to adapt the treatment regimen of individual patients to whatever they react best to, is a very promising option.