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What's Next—Amylin-based Therapies · DOC Updates

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Welcome to the special edition of the American Diabetes Association's Diabetes
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Obesity and Cardiometabolic Podcast,
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where we will be discussing AMLI-based therapies.
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I'm your host, Dr. Neil Skolnick,
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Professor of Family and Community Medicine at the Sidney Kimmel Medical College
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of Thomas Jefferson University.
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This special edition is sponsored by Novo.
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Joining us today to discuss this critically important topic is
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Is one of the most prominent clinical trialists in diabetes and obesity,
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Dr. Juan Pablo Frias.
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Dr. Frias is the medical director and principal investigator at
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the Los Angeles Institute for Metabolic Research and is an adjunct professor
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of medicine at Charles Drew University of Medicine and Science.
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In Los Angeles, California. He has authored numerous publications,
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including first author publications.
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In the boy, there's a long list here:
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New England Journal of Medicine,
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Lancet, Lancet Diabetes and Endocrinology,
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Diabetes, Diabetes, Care and Cell Metabolism.
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If you read the Diabetes, Obesity,
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and Metabolic Literature.
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You know Dr. Frias' name. He's also been involved in research on Amlin
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for over five years and was first author of the phase two trial
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on Cagrissema that was published in The Lancet.
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Juan, I remember the first time that I heard about Amlin was at a meeting where
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you told me about Amlin-based therapies,
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and that was over five years ago.
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And I remember still your excitement about it.
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On welcome back to ADA's podcast.
1:52
Hey, thanks Neil. Great great to be here.
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Appreciate you having me.
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You know, it's interesting. AMLI is not a familiar hormone to many
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of the clinicians in our audience,
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but it's gonna be important to them to become familiar with.
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So today I'd like to first cover the physiology of AMLIN,
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what it is, then some of the clinical trial data with emphasis on trials that will
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soon be relevant to us as practicing clinicians,
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since there is a GLP1 AMLI combination.
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that is currently being evaluated by the FDA.
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We'll talk about those trials in a little bit,
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but first, help us understand AMLIN what it is and what it does.
2:38
Absolutely. So I'll tell you what,
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I mean, it's been actually probably 20 or maybe even 25 years since
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I started studying amylen because there is an amylin analog which
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was actually ~ launched and and commercialized called Pramlintide,
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or the trade name was Simolin,
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in 2005.
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And it is short acting. It's given three times a day,
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but was quite potent and was involved in those clinical trials early on.
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But what we're seeing now are new formulations that are longer acting.
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So cagrillantide, which is an amylene analog we'll be discussing,
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is once weekly. But let's go back to the actual hormone amylene.
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So this is a hormone that's produced and secreted by the pancreatic beta cells.
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So the same cells that
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Produces and secretes insulin.
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So it's co-secreted with insulin by the beta cell when someone eats.
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And it really plays a very important role in nutrient metabolism.
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And three sort of key mechanisms.
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One, it binds to receptors in the brain,
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which reduce appetite and very importantly also increase satiety,
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so the sense of fullness.
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It has effects on gastric emptying.
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So it modulates gastric emptying.
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So it improves or or I would say modulates postprandial glucose,
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so the rate at which glucose empties a stomach.
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And it also has a very important effect on the pancreatic alpha cell,
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which produces and secretes glucagon.
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So in the postprandial state, or after someone eats,
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it reduces glucagon. And that's what you want to see.
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So
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Central effects to improve satiety and reduce appetite,
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effects on gastric emptying, which sort of slow or modulate the release
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of food after a meal, and improvements in postpranial glucagon concentrations,
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which you want to see low after a meal.
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So those are the main actions of the hormone amelin.
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So th that's interesting. So some of those actions seem to overlap with
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the GLP ones, but not all of them.
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~ and I know you were involved in the early clinical trials,
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as you said. So given AMLIN's effects,
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what was the thinking about how it might work in a complementary way with
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the GLP one?
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So that's important. And actually,
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you mentioned something super important is that these are distinct receptors.
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So it's not, when we talk about incretins or GLP1 medicines,
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amylen is a different gut hormone.
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So it's not an incritin, and it does not have the so-called increotin effect,
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which GLP1 based medicines have,
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which is to augment nutrient stimulated insulin secretion.
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So it's secreted along with insulin and has those effects that I mentioned.
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Four. But it does have distinct receptors that are central.
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So, you know, you have GLP1 hitting GLP1 receptor centrally to reduce appetites.
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You have amylin hitting amylene receptors centrally.
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So sort of some overlapping effects there.
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Both of them actually reduce glucagon concentrations.
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Both GLP1 and AMILINE.
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slow or modulate gastric emptying.
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So again, these are distinct receptors.
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Some of the actions overlap, but some are distinct.
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And and that's why they're they are complementary when when combined.
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And that's what we've shown in the clinical trials,
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both in the phase two and now in phase three.
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So Juan, can you share with us a bit about the early clinical data and
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how you felt about it as the data emerged for for both obesity and diabetes?
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Yeah, absolutely. So we conducted,
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and I was the the lead investigator on on a phase two study,
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and this was in people with type two diabetes.
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And as I recall, they were treated with with mecformin,
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SGLT2 inhibitors, with or without a sulfonyl urea as well.
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A1C a little over eight percent of baseline.
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But the bottom line is that we studied the combination of cagrillantite,
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so the long acting amylen analog and semaglutide.
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well-known GLP1 receptor Agnes,
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both at a dose of 2.4 milligrams once weekly.
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So we slowly escalated to that,
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those doses. But importantly we compared it to the so-called monocomponents.
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So there was one arm which was CAGRECEMA,
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one arm which was just semaglutide,
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and then one arm that was just cagrillentide.
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So now we were comparing the combination to the individual components.
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And it was double blind
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not placebo controlled, it was the these were all active medications.
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And we studied these patients for 32 weeks.
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And again, this was injected once weekly,
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subcutaneously. And we actually saw greater A1C reduction.
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This was numerically greater with CAGRISEMA.
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I mean, very robust A1C reduction from 8.2,
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there was a 2.2% ~ reduction in hemoglobin A1C.
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As I recall, it was 1.8% with semaglutide.
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And close to 1% with cagrillantide alone.
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But we got better effect with the combination compared to the individual components.
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And particularly for weight loss,
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I mean the weight loss was quite impressive.
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For 32 weeks, we saw with CAGRI SEMA,
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the combination, 16% average weight reduction with
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the combination compared to 5% with semaglutide and 8%.
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With cagrillentide. And at 32 weeks,
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I mean, in in actually in all of the arms,
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it was still reductions that were ongoing in in body weight,
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because usually that plateaus at about a year on average.
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So again, these were, you know,
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it was about 90 or so participants.
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So some you know, smallish phase two study,
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but gave us a very good indication that the combination,
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again, because of these complementary actions,
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was likely better.
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with respect to weight and maybe to glucose lowering than the individual components,
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a semaglutide alone or cagrillantite alone.
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So I think they sort of helped prove this this hy or beginning
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to prove the hypothesis. And certainly it was it was evidence that we should move
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on to to phase three and look at this both for diabetes and for weight management.
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Yeah, that that must have been very exciting.
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How'd you feel when you saw those results?
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'Cause those are impressive results.
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You know, I I wouldn't say I was shocked,
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but I was, you know, pleasantly surprised.
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~ I have to say that I was somewhat surprised that the sumaglutide
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did not do better. And that happens sometimes in small studies
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and because we've seen in people with diabetes greater weight loss with semaglutide
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alone at 2.4 milligrams, somewhere in the 10% range.
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But again, it was only 32 weeks.
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You don't know what happens beyond that.
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And in each of the three arms,
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there was still reduction ongoing.
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I I thought the results with cagrillantite alone were very impressive
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to have an eight percent weight reduction on average of 32 weeks.
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So I I think that was very good sort of proof of concept that an amelin analog,
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even on its own, could have some very nice effects.
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And I and I would say something else about the phase two studies,
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it was really well tolerated.
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~ so the typical effects, side effects that you see with with increin-based
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therapies, ~ you see with amylin as well.
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So GI side effects are the most common.
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But there were ~ and they tend to occur during escalation and then most mild
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or moderate in severity and tend to dissipate or reduce over time.
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So you need to start low and go slow with the escalation.
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But I recall that with CAGRICEMA,
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there were
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No patients that discontinued the trial due to GI side effects during
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the entire 32 weeks, which was,
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I think, a very good signal that it was it was being tolerated well.
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So you weren't getting sort of an additive effect of potential side effects.
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So I think that's we we always have to balance obviously the tolerability with
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the efficacy.
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Yeah, that that's a really good point.
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Let's move on to the more recent clinical trial data.
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There's the redefined studies and the reimagined trials.
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Can you go over some of the phase three data that we now have?
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Yeah, absolutely. So very robust phase three.
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So after the phase two study, the decision was made by NOVA to move into phase
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three, both for weight management and specifically for type two diabetes.
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So the reimagined program is a large program in type two diabetes.
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And then the redefined program,
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a program with the primary endpoint being body weight.
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And most of these studies are in people without diabetes.
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But from a regulatory perspective,
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and certainly from what we want to see as clinicians,
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it was also a study. It was ~ it was redefined two,
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which was specifically in patients with type two diabetes with
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the primary endpoint of weight loss.
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So these were longer-term studies,
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68 weeks in general. So now you're getting,
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you know, is there where does the the weight loss or the A1C reduction plateau?
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And ~ in redefined one.
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was this this was in people with obesity without type two diabetes
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was was ~ it was an important study it compared cagrillantite
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to ~ to to cagricema and semaglutide so quite similar to what we
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did in phase two but this was in people without diabetes now we were looking
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at the combination versus the individual components and here again
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You know, we saw very impressive weight loss with the combination,
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which was greater than the individual components.
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I mean, depending on which estimate was looked at with the hypothetical
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or efficacy estimate, it was approximately 23% weight reduction with
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the combination compared to around 16% with semaglutide,
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which is what we'd seen in semaglutide in people without diabetes in the past,
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and about 12% with cagrillantite,
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so very good weight.
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With cadrillantite as well, and kind of a similar side effect profile.
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I think, I think quite manageable,
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but again, we don't want to minimize this with GI side effects being
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the most important, but both mild to moderate and severity.
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So I think we sort of, you know,
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although the phase two study was in people with type two diabetes,
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and this study, which is redefined one,
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was in people without diabetes,
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we saw sort of similar, directionally similar results with quite impressive weight
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reduction.
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The combination, you know, as high as twenty three percent on average
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in the efficacy estimate.
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Interesting. And ~ you just never know until you study it whether these individual
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components are gonna have a greater effect together or are gonna have greater side
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effects and it's fortunate they don't have greater side effects together.
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No, that's a good point. I mean,
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you don't know till you study,
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even though you see, you know,
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you've got the mechanism of action,
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you certainly have, you know, a breadth of data for many years with semaglutide,
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and you think based on the mechanisms in earlier trials that these are
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the types of results you get, you don't know until you do it.
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And you mentioned, I mean, I think very importantly,
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you don't know what the side effect profile is going to be.
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And thankfully, you know, it was it was something that
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That I think, and this is my opinion,
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once this is launched and in clinical practice will be will be very manageable just
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as we manage GLP one medicines today.
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Yeah, and can you also ~ talk about the diabetes trials with Cagri Semin?
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Yeah, so the diabetes trials were the the so-called reimagined trials,
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and there are a number of these of these studies.
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So in reimagined one versus placebo,
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there was significantly greater A1C reduction with CAGRECEMA you you would expect.
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I mean, almost a 2% point reduction in hemoglobin A1C,
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and also very robust weight loss.
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Though in these type two diabetes trials,
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the primary end point is A1C. We saw somewhere around 15% weight loss.
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In people with type 2 diabetes,
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which is very, very robust for that population.
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But then Reimagine 2 actually looked at people already
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on anti-hyperglycemic agents, so metformin with or without SGLT2 inhibitor.
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And as with the phase two study,
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looked at CAGRICEMA versus semaglutide alone,
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2.4 milligrams versus cagrillentide.
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And we saw
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greater reduction in body weight and hemoglobin A one C with
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the combination compared to the individual components.
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So it looks like and and again,
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similar from a safety perspective,
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quite comparable safety profile as well.
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So I think very encouraging data.
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Yeah, for both diabetes and obesity.
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Now, whenever we treat either one of these,
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it's not just about weight, it's not just about blood sugar,
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it's also about the broader set of cardiometabolic parameters.
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Can you touch on that? 'Cause I saw a recent trial on blood pressure with CAGRECEMA.
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Yeah, no, no, absolutely. And that's so critical.
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I mean, we're we're treating, you know,
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we're not treating just to reduce weight.
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I mean, we want to improve health.
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And most of these patients have obesity-related complications or will develop these
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complications, whether they're metabolic complications like prediabetes
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or diabetes or hypertension or dyslipidemia,
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~ or biomechanical complications like osteoarthritis or obstructive sleep apnea,
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and we can't
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you know, discount the the psychological complications as well.
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But if we look specifically at the cardiovascular risk factors,
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and there was a a recent analysis or or additional data from redefined one.
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So redefined one again was ~ these were were patients without diabetes that were
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treated ~ with CAGRECEMA or cagrillentide.
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But the bottom the bottom line is we saw very robust improvement
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improvements in in blood pressure in in that trial.
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So up to in systolic blood pressure,
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up to an average of slightly over 10 millimeters of mercury,
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with about 40% of the patients that were treated with antihypertensive agents
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actually stopping those antihypertensives.
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So from a clinical perspective is something that with these medications
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and with weight loss
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You know, it's important to know that we may need to make adjustments,
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particularly in blood pressure medications,
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as we're escalating these and patients are are losing weight.
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Mm-hmm. That that's important.
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And effect on lipids.
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Yeah, improvements in in lipid parameters as well,
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primarily triglycerides, but also increases in in HDL,
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cholesterol. I would say improvements also.
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I mean, very large. I I think it was somewhere around,
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you know, 65-ish percent, maybe slightly more improvements in
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in highly sensitive CRP. So ~ improvements in inflammatory markers as well.
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And then there have been, you know,
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looks also at body composition.
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So
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A real improvement, not only just in in sort of a more kind of
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I wouldn't say primitive gross measure of body composition,
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which would be waist circumference,
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but you're getting it looks like most of this fat is being lost,
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or the weight is being lost as fat from visceral adiposity,
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which is where we want to lose it.
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But this has been shown also with with MRI stub studies as well.
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So I think you know the the weight loss seems to be coming from the right place.
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And then we're getting these improvements that have been shown in these studies
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in cardiometabolic or cardiovascular risk factors as well.
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So we talk primarily about CAGRI SEMA because that is the one that is closest
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to FDA approval, but it's not the only Amlin agonist out there.
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Can you just touch on some of the others?
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Because there there are some others that are in the pipeline,
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is that correct?
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Yeah, no, no, no, absolutely. LR alantite is an in also a long acting amylin
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analog that's it's in clinical development now in phase three.
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And ~ and that is it's a lily drug,
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again, investigational and and being studied along coglantide as well,
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being studied sort of as monotherapy as well for for weight management.
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So there's petrolantide, which is another one that's that now just recently
19:56
in Milan, actually at the EASD,
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the European Diabetes Meeting,
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there was phase two data and people looking at weight management
20:04
and people without diabetes. And this is a Roche drug,
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and they've completed a trial now,
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Roche in Zealand, I should say,
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completed a trial of phase two and type two diabetes as well.
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That hasn't been
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Published yet, but it's been, you know,
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released. The top line data have been released.
20:21
So the bottom line is that there are other long-acting ambient analogs that are,
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and there are others as well, but ~ that are in either phase two
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or now several starting phase three clinical trials ~ and and look look quite
20:37
promising.
20:38
Particularly from a tolerability perspective.
20:42
It looks and we'll need to see the data obviously,
20:44
you know, in greater detail in the phase three trials,
20:47
but certainly looks like it may be better tolerated than GLP
20:52
one medicines in general.
20:54
that's interesting and that it's so important clinically because ~ one,
20:58
these are challenging medicines for a lot of patients and there also
21:03
are patients who are just unable to dose escalate.
21:06
We've all ~ seen that and a ~ more easily tolerated medicine certainly would
21:12
be very attractive.
21:15
I agree. And I and it gives you at the end of the day that that,
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you know, theoretically could give you better persistence.
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And you know, even if and and I would say,
21:23
you know, in general, when we look at the degree of weight loss,
21:26
and we've seen this in the CAGRI sema versus cagrillantite alone,
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and we've seen this with some of the the other long-acting amylin,
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the the weight reduction is not on the order of what you get with semaglutide
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or trzepatite you know retrotrutide,
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but not everyone needs.
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twenty, thirty percent weight loss.
21:45
I mean, people may need less or may not tolerate other medications
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and and persistence may end up improving ~ effectiveness in the real world as well.
21:56
So I think it's nice to have these options.
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I I agree with you. I think that ~ one of the things we've learned
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is that obesity is in a way the soil out of which all these other cardiometabolic
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problems, hypertension, cholesterol,
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mash, ~ HEFPEF grow.
22:15
And to have something where we can feel more comfortable treating people
22:21
at lower levels of obesity. I believe now the average
22:27
BMI at which people are treated is somewhere above 35.
22:30
And and that's not what we should need to wait for.
22:35
Yeah, I would agree. I mean we need to be we need to be treating this earlier
22:39
if we're seeing the trajectory going we're really preventing,
22:42
preventing at the end of the day and preventing these obesity related complications.
22:48
So CAGRICEME is the ~ amlin agonist combined with
22:54
s semiglutide that is most advanced now.
22:58
It's at the FDA, it it they will ~ declare whatever they declare probably
23:05
by the end of the year. Where do you see this fitting in
23:10
to our now more expansive set of choices?
23:15
That is a great question. I think,
23:18
you know, based on the degree of weight loss,
23:21
I mean, I would start with saying people that need to lose significant weight.
23:26
I mean, if someone, you know, just needs a little weight loss,
23:30
there may be other options for them.
23:32
There may be oral options, there may be,
23:34
you know, less potent medications,
23:36
or maybe this at a lower dose.
23:39
But I think someone who really would benefit from significant weight loss.
23:44
I would also say that, you know,
23:45
it it could be someone who's who's transitioning already on a medication
23:51
and maybe has plateaued and is,
23:54
you know, would like additional weight loss and is at the highest dose
23:58
of whatever weight management medication they're on.
24:01
This could be sort of a a a step up,
24:04
if you will.
24:05
also for for patients. So that's sort of you know big picture where I would
24:09
see this this being used. But certainly I think there's utility with a
24:13
lot of these very potent medications,
24:15
potentially at lower doses.
24:18
That's interesting. Yeah. Yeah.
24:20
We don't we often don't think about that,
24:21
but I I think you're right. We'll at some point be talking about other potent
24:26
medicines, ~ where, you know, we now have an option of lower doses which might
24:31
be better tolerated. Right.
24:34
and i it's gonna be this balance.
24:37
We like choices, but choices can also lead to ~ inertia when
24:43
you can't decide among
24:45
The choices. And I think that particularly for our broad group
24:49
of primary care clinicians out there,
24:51
we are entering an era of choice with regard to medicines
24:57
for treating obesity, GLP 1 based medicines for treating diabetes.
25:03
And choice is always good and bad,
25:05
right? You you you need to know your science.
25:09
You need to know the medicines to not be impeded by an overwhelming
25:15
Amount of choices. Juan, we're about out of time.
25:18
Any final thoughts you want to share for our listeners?
25:22
Yeah, well, I you made a great point.
25:23
I think at the end of the day,
25:25
you know, we need to, to the extent possible,
25:28
avoid clinical inertia, realize that this is a disease that has many,
25:33
many very important complications that we need to either improve or prevent.
25:39
So we need to get comfortable with these medications and and use them.
25:43
And you know, quite frankly, I think it's nice to have all of these choices.
25:48
This is such a complex disease.
25:50
That for people to have different sort of pathways,
25:54
if you will, that are mitigated or that are addressed,
25:58
I think will be important for many,
25:59
many people to have both the GLP1 with the AMLIN,
26:03
for example. So that's really where we're headed with this.
26:05
And the last thing I would say is,
26:07
you know, the weight reduction is clearly important.
26:09
Patients need to be patient and they need to realize that at the lower doses,
26:14
they may not lose that much, but we start low to improve tolerability,
26:19
but at the end of the day.
26:20
I like to show my patients, look what your lipids are doing,
26:23
look what your ALT and AST is doing.
26:26
Even if you don't have, you know,
26:27
significant metabolic liver disease.
26:29
We're seeing improvements in so many markers that I think that helps patients stay
26:35
on the medications as well. They they really can see that their entire sort
26:39
of their health is improving.
26:41
Well, those are such good points,
26:43
Juan. This has been a great discussion.
26:45
Doctor Juan Pablofrias, thank you so much for joining us.
26:49
Thank you. Thanks for having me,
26:50
Neil.
26:51
And to our listeners, thank you for joining us on this special edition
26:55
of ADA's Diabetes, Obesity, and Cardiometabolic Podcast.
26:59
This special edition is sponsored by Novo for the American Diabetes Association.
27:05
I'm Dr. Neil Skolnick. Till next time,
27:08
stay safe and keep learning.