WEBVTT 00:00:00.000 --> 00:00:02.220 We often hear about these big medical breakthroughs, 00:00:02.279 --> 00:00:04.500 you know, the wonder drugs. But sometimes the 00:00:04.500 --> 00:00:06.919 real story, the interesting part, is the journey 00:00:06.919 --> 00:00:10.859 a drug takes. Absolutely. Twists and turns, unexpected 00:00:10.859 --> 00:00:13.960 discoveries. Exactly. And today we're diving 00:00:13.960 --> 00:00:17.000 into one of those journeys, eggs in a tide. You 00:00:17.000 --> 00:00:19.839 probably know it better as bieta or bidurion. 00:00:20.539 --> 00:00:22.780 And get this, the whole thing kind of started 00:00:22.780 --> 00:00:25.500 with lizard spit. It sounds wild, doesn't it? 00:00:25.739 --> 00:00:28.980 Gila monster saliva, specifically. It really 00:00:28.980 --> 00:00:32.679 shows you how nature can hold these unexpected 00:00:32.679 --> 00:00:35.560 medical answers. Totally unexpected. And understanding 00:00:35.560 --> 00:00:38.240 exonetide, its story. It gives you a great window 00:00:38.240 --> 00:00:40.740 into, well, pharmaceutical innovation for diabetes, 00:00:41.280 --> 00:00:43.560 the hurdles of drug development, regulation. 00:00:44.200 --> 00:00:46.159 All that stuff. Right. And how something that 00:00:46.159 --> 00:00:49.020 starts as like a scientific curiosity actually 00:00:49.020 --> 00:00:51.560 ends up helping people manage their health. Precisely. 00:00:51.560 --> 00:00:53.619 We want to give you that comprehensive view, 00:00:53.619 --> 00:00:55.759 you know, without you having to sift through 00:00:55.759 --> 00:00:59.439 mountains of FDA reports or dense scientific 00:00:59.439 --> 00:01:01.560 papers. Yeah, we've done the sifting. We looked 00:01:01.560 --> 00:01:04.640 at FDA docs, EMA reports over in Europe, clinical 00:01:04.640 --> 00:01:06.939 studies, market analyses, even what patients 00:01:06.939 --> 00:01:09.579 are saying on forums. Volumix of sources. Definitely. 00:01:09.739 --> 00:01:12.400 So our mission here is to pull out the key pieces 00:01:12.400 --> 00:01:15.000 of the exenatide story. where it came from, how 00:01:15.000 --> 00:01:20.219 it works, its impact, and the sometimes bumpy 00:01:20.219 --> 00:01:23.260 road it took. Back to the lizard. Right, the 00:01:23.260 --> 00:01:25.959 Gila monster. So scientists discovered this peptide 00:01:25.959 --> 00:01:28.980 called Xenden -4 in its saliva. OK. And what 00:01:28.980 --> 00:01:31.819 was interesting was how similar it was to a hormone 00:01:31.819 --> 00:01:34.980 we naturally produce called GLP -1, glucagon 00:01:34.980 --> 00:01:38.239 -like peptide 1. Ah, GLP -1. We hear a lot about 00:01:38.239 --> 00:01:41.180 that class of drugs now. We do. And GLP -1 is 00:01:41.180 --> 00:01:43.200 really important for regulating blood sugar. 00:01:43.579 --> 00:01:46.579 So finding the similar compound in all places, 00:01:46.760 --> 00:01:48.939 lizard spit, that was the spark. That's what 00:01:48.939 --> 00:01:51.019 kicked off the development of Xenotides. you 00:01:51.019 --> 00:01:52.780 wonder what else is out there, you know? Doesn't 00:01:52.780 --> 00:01:55.019 it just so much potential in the natural world? 00:01:55.260 --> 00:01:57.439 So the first actual drug people could use, that 00:01:57.439 --> 00:01:59.420 was bieta, wasn't it? That's right. Bieta was 00:01:59.420 --> 00:02:01.579 the first one approved. It's exenatide, but you 00:02:01.579 --> 00:02:03.840 inject it twice a day. Twice a day, OK. It got 00:02:03.840 --> 00:02:06.939 the FDA approval here in the US, let's see, April 00:02:06.939 --> 00:02:10.750 25, 2005. and then Europe followed in November 00:02:10.750 --> 00:02:13.930 2006. And patients took what, like five or 10 00:02:13.930 --> 00:02:16.569 micrograms? Correct, five or 10 micrograms per 00:02:16.569 --> 00:02:19.210 dose. It was a really big step forward at the 00:02:19.210 --> 00:02:22.150 time for a type 2 diabetes treatment. But yeah, 00:02:22.330 --> 00:02:24.009 twice a day. That sounds like quite a commitment. 00:02:24.229 --> 00:02:27.099 I imagine people wanted something. easier. Exactly. 00:02:27.319 --> 00:02:30.259 That was the big push behind developing by Durion. 00:02:30.560 --> 00:02:32.500 That's the once a week version. Okay, once a 00:02:32.500 --> 00:02:34.120 week is much better. How did they manage that? 00:02:34.240 --> 00:02:36.319 It required some clever formulation science. 00:02:36.840 --> 00:02:40.340 They needed an extended release version. So first 00:02:40.340 --> 00:02:43.740 they developed a sort of prolonged release aqueous 00:02:43.740 --> 00:02:45.860 suspension. Aqueous suspension, like a liquid. 00:02:46.039 --> 00:02:48.780 Yeah, basically. But then they evolved it further 00:02:48.780 --> 00:02:51.199 into what's called a microsphere formulation. 00:02:51.379 --> 00:02:54.409 Microspheres. Tiny balls, basically. Kind of. 00:02:54.449 --> 00:02:57.469 Think of them as tiny biodegradable capsules 00:02:57.469 --> 00:03:00.409 holding the exenitide. They're designed to dissolve 00:03:00.409 --> 00:03:03.330 slowly over the week, releasing the drug steadily. 00:03:03.550 --> 00:03:05.389 Ah, I see. So that gives you the once weekly 00:03:05.389 --> 00:03:08.250 dosing. Clever. It really is. The goal was convenience, 00:03:08.409 --> 00:03:10.449 you know, helping people stick to their treatment 00:03:10.449 --> 00:03:12.530 plan more easily. And was it just one company 00:03:12.530 --> 00:03:15.139 behind this or? Well, Amalin Pharmaceuticals 00:03:15.139 --> 00:03:17.840 was definitely a key player. Alkermes was also 00:03:17.840 --> 00:03:19.860 involved, particularly with some of the formulation 00:03:19.860 --> 00:03:22.539 technology. Right. And because you had different 00:03:22.539 --> 00:03:24.780 manufacturers, potentially different processes, 00:03:25.000 --> 00:03:26.960 maybe different scales of production, they had 00:03:26.960 --> 00:03:29.340 to do these comparability studies. To make sure 00:03:29.340 --> 00:03:31.379 it was all the same stuff, essentially. Pretty 00:03:31.379 --> 00:03:37.060 much. Studies like BCB 108 and 2993 LAR 105, 00:03:37.400 --> 00:03:39.659 they were designed to show that the drug exposure 00:03:39.659 --> 00:03:42.560 and the patient's response were consistent, regardless 00:03:42.560 --> 00:03:45.520 of the exact manufacturing details. That's super 00:03:45.520 --> 00:03:47.819 important for regulators and for patient safety. 00:03:48.099 --> 00:03:50.580 Makes sense. And later on, they even developed 00:03:50.580 --> 00:03:53.639 the Bidurion Auto Injector Pen, which came with 00:03:53.639 --> 00:03:56.139 a new suspension that didn't need mixing by the 00:03:56.139 --> 00:03:58.240 patient. Just another step towards making it 00:03:58.240 --> 00:04:00.379 easier to use. Yeah, premix is always better. 00:04:00.979 --> 00:04:02.759 Yeah. OK, so we've got the Lizard Spit Origin, 00:04:03.060 --> 00:04:06.560 the Twice Daily, the Once Weekly. What does Xenotide 00:04:06.560 --> 00:04:09.379 actually do for patients? Who is it for? Its 00:04:09.379 --> 00:04:12.000 main job, its indication, is for adults 18 and 00:04:12.000 --> 00:04:14.599 over with type 2 diabetes. The goal is to improve 00:04:14.599 --> 00:04:17.620 their glycemic control. Glycemic control. Basically, 00:04:18.180 --> 00:04:20.740 better blood sugar levels. Exactly, lowering 00:04:20.740 --> 00:04:23.000 and stabilizing blood sugar. And it's not usually 00:04:23.000 --> 00:04:24.500 the only thing they take, right? It's part of 00:04:24.500 --> 00:04:26.819 a bigger picture. That's a key point. It's almost 00:04:26.819 --> 00:04:29.379 always used in combination with other glucose 00:04:29.379 --> 00:04:31.459 -lowering drugs. Like what kind of drugs? Things 00:04:31.459 --> 00:04:33.399 like metformin, which is often the first drug 00:04:33.399 --> 00:04:37.519 people try. Or sulfanolureas, thiazolid and dines, 00:04:38.000 --> 00:04:40.899 even basal insulin sometimes. It fits into a 00:04:40.899 --> 00:04:43.220 broader treatment plan tailored to the individual. 00:04:43.399 --> 00:04:46.040 OK. And does it actually work well? Like, do 00:04:46.040 --> 00:04:49.480 we have proof? I saw mentions of HbA1c. Oh, yes. 00:04:49.560 --> 00:04:52.220 Plenty of evidence. HbA1c, as you probably know, 00:04:52.240 --> 00:04:54.459 gives you that long -term picture of blood sugar 00:04:54.459 --> 00:04:57.420 control over, say, two or three months. Right. 00:04:57.420 --> 00:05:00.040 The average level. Exactly. And numerous clinical 00:05:00.040 --> 00:05:03.019 trials showed Exenetide, especially Bidurion, 00:05:03.420 --> 00:05:07.199 significantly lowers HbA1c. Studies like BCB118 00:05:07.199 --> 00:05:10.439 and BCB120 compared it directly against placebo, 00:05:10.600 --> 00:05:13.540 but also against the twice -daily Bayetta. and 00:05:13.540 --> 00:05:18.240 another drug called Cytogliptin. Definitely. 00:05:18.680 --> 00:05:21.079 They provided specific numbers, mean changes 00:05:21.079 --> 00:05:23.399 in HBUNC, and showed these were statistically 00:05:23.399 --> 00:05:26.939 significant. For example, one trial showed Bidurion 00:05:26.939 --> 00:05:31.300 dropping HbA1c by about 1 .44 % compared to Bieta 00:05:31.300 --> 00:05:34.800 at 1 .08%. OK, so a clear improvement with the 00:05:34.800 --> 00:05:37.300 once weekly. Yes. And another study compared 00:05:37.300 --> 00:05:40.980 Bidurion to Cytogliptin and placebo. Bidurion 00:05:40.980 --> 00:05:46.740 lowered HbA1c by 1 .12%, Cytogliptin by 0 .87%, 00:05:46.740 --> 00:05:51.290 and placebo SIBO only 0 .64%. So meaningful improvements 00:05:51.290 --> 00:05:53.529 over other options and definitely overdoing nothing. 00:05:53.670 --> 00:05:55.410 That's pretty clear evidence. So just to recap 00:05:55.410 --> 00:05:58.810 the dosing, Bayetta is? Bayetta is 5 or 10 micrograms 00:05:58.810 --> 00:06:00.970 injected under the skin twice a day, usually 00:06:00.970 --> 00:06:04.490 before meals. And Bidurion? Bidurion is a 2 -milligram 00:06:04.490 --> 00:06:07.069 injection, also subcutaneous, but just once a 00:06:07.069 --> 00:06:09.290 week. OK. And wasn't there something else, a 00:06:09.290 --> 00:06:11.589 side benefit some people get, related to weight? 00:06:11.790 --> 00:06:14.569 Ah, yes. Weight loss. It's not its primary indication, 00:06:14.689 --> 00:06:16.529 but many studies and patient reports show that 00:06:16.529 --> 00:06:18.569 exonetide can lead to some weight reduction in 00:06:18.569 --> 00:06:20.569 quite a few individuals. Which for many people 00:06:20.569 --> 00:06:23.569 with type 2 diabetes is a huge plus, right? Absolutely. 00:06:24.250 --> 00:06:26.730 Managing weight is often a really important part 00:06:26.730 --> 00:06:28.970 of managing their diabetes overall, so it's a 00:06:28.970 --> 00:06:31.129 very welcome potential side effect. Definitely. 00:06:31.449 --> 00:06:35.949 Now, I saw a quick mention, something about Parkinson's 00:06:35.949 --> 00:06:38.660 disease. Was there a connection? That's important 00:06:38.660 --> 00:06:41.420 to clarify. There was some early interest, some 00:06:41.420 --> 00:06:43.980 research looking into whether GLP -1 drugs like 00:06:43.980 --> 00:06:46.740 exenatide might help with conditions like Parkinson's. 00:06:46.759 --> 00:06:49.319 Okay. And Gil. Well, the latest study mentioned 00:06:49.319 --> 00:06:52.060 in our sources actually found no benefit for 00:06:52.060 --> 00:06:55.519 Parkinson's disease. Ah, okay. So that line of 00:06:55.519 --> 00:06:58.100 inquiry didn't pan out for exenatide. It seems 00:06:58.100 --> 00:07:00.360 not. It's a good reminder that drugs can be very 00:07:00.360 --> 00:07:02.540 specific. Just because it works for one thing 00:07:02.540 --> 00:07:04.459 doesn't mean it'll work for something else, even 00:07:04.459 --> 00:07:07.139 if the biology seems related somehow. Good point. 00:07:07.339 --> 00:07:09.579 Let's get into the mechanism. How does it actually 00:07:09.579 --> 00:07:11.720 lower blood sugar? What's the science? OK, so 00:07:11.720 --> 00:07:15.699 exonetide is a GLP -1 receptor agonist. That's 00:07:15.699 --> 00:07:17.879 the key term. Agonist, meaning it activates the 00:07:17.879 --> 00:07:20.720 receptor. Exactly. It basically mimics our natural 00:07:20.720 --> 00:07:23.680 GLP -1 hormone. It fits into the same receptor, 00:07:23.800 --> 00:07:26.000 like a key and a lock, and triggers the same 00:07:26.000 --> 00:07:28.759 downstream effects. What does natural GLP -1 00:07:28.759 --> 00:07:31.480 normally do? Well, a major role is signaling 00:07:31.480 --> 00:07:34.620 the pancreas to release insulin. But, and this 00:07:34.620 --> 00:07:37.310 is crucial, It does this in a glucose -dependent 00:07:37.310 --> 00:07:40.509 way. Meaning only when blood sugar is high. Precisely. 00:07:40.769 --> 00:07:42.810 So when your sugar levels are normal or low, 00:07:43.029 --> 00:07:45.870 it doesn't stimulate much insulin release. This 00:07:45.870 --> 00:07:48.449 drastically lowers the risk of hypoglycemia, 00:07:48.790 --> 00:07:52.129 dangerously low blood sugar, which can be a problem 00:07:52.129 --> 00:07:54.550 with some other diabetes meds. That's a smart 00:07:54.550 --> 00:07:57.209 mechanism. Anything else? Yes, it also helps 00:07:57.209 --> 00:07:59.790 suppress the release of glucagon. Glucagon is 00:07:59.790 --> 00:08:01.610 another hormone, but it does the opposite of 00:08:01.610 --> 00:08:04.269 insulin. It tells the liver to release stored 00:08:04.269 --> 00:08:07.209 sugar, raising blood glucose. So, exonetide hits 00:08:07.209 --> 00:08:10.170 it from both sides. More insulin when needed? 00:08:10.410 --> 00:08:12.990 Less glucagon overall. You got it. Helps bring 00:08:12.990 --> 00:08:15.290 a high blood sugar back down into a better range. 00:08:15.430 --> 00:08:17.089 What about digestion? I think I read something 00:08:17.089 --> 00:08:18.910 about that. Yeah, especially the shorter -acting 00:08:18.910 --> 00:08:21.790 biota formulation. It's known to slow down gastric 00:08:21.790 --> 00:08:24.189 emptying. So food moves out of the stomach more 00:08:24.189 --> 00:08:27.029 slowly. Right. Which means glucose from your 00:08:27.029 --> 00:08:29.269 meal gets absorbed more gradually, potentially 00:08:29.269 --> 00:08:32.090 blunting those big post -meal blood sugar spikes. 00:08:32.450 --> 00:08:34.960 Does the once -weekly bidurion do that too? It 00:08:34.960 --> 00:08:37.820 might, but possibly less so over the long term. 00:08:38.100 --> 00:08:40.539 There's this phenomenon called tachyphylaxis. 00:08:40.659 --> 00:08:43.220 Tachy what? Tachyphylaxis. It basically means 00:08:43.220 --> 00:08:45.799 the body's response to a specific effect of a 00:08:45.799 --> 00:08:48.919 drug can lessen with continuous exposure. So 00:08:48.919 --> 00:08:51.960 that slowing of gastric emptying might not be 00:08:51.960 --> 00:08:54.919 as pronounced with long -term bidurion use compared 00:08:54.919 --> 00:08:57.460 to bieta. Interesting. And does it affect appetite? 00:08:57.559 --> 00:09:00.269 You mentioned weight loss earlier. It can. GLP 00:09:00.269 --> 00:09:03.190 -1 receptor agonists generally seem to increase 00:09:03.190 --> 00:09:06.450 feelings of satiety or fullness. That could definitely 00:09:06.450 --> 00:09:08.590 contribute to the weight loss effect by helping 00:09:08.590 --> 00:09:11.539 people feel satisfied with less food. Okay, that 00:09:11.539 --> 00:09:13.600 whole mechanism makes a lot of sense. Now, what 00:09:13.600 --> 00:09:16.000 about how the body handles it? Once it's injected, 00:09:16.360 --> 00:09:17.980 how quickly is it absorbed? How long does it 00:09:17.980 --> 00:09:20.120 stick around? Pharmacokinetics, right. Right, 00:09:20.299 --> 00:09:22.980 pharmacokinetics and pharmacodynamics PKPD. So 00:09:22.980 --> 00:09:24.860 it's injected so cutaneously under the skin. 00:09:25.399 --> 00:09:27.940 For Bidurion, the once weekly one, it takes a 00:09:27.940 --> 00:09:29.500 little while to see the full effect on blood 00:09:29.500 --> 00:09:32.399 sugar. Maximum HbA1c reduction usually happens 00:09:32.399 --> 00:09:35.440 around week 14 or so. 14 weeks? Wow, okay. Yeah, 00:09:35.600 --> 00:09:38.159 it reflects that slow, sustained release from 00:09:38.159 --> 00:09:40.679 the microspheres and the time it takes to reach 00:09:40.679 --> 00:09:43.159 what we call steady state concentration in the 00:09:43.159 --> 00:09:45.159 blood. Steady state. Yeah. Like a consistent 00:09:45.159 --> 00:09:47.940 level. Exactly. With the weekly bidurion shots, 00:09:48.080 --> 00:09:51.320 the level stays around 300 picograms per milliliter, 00:09:51.519 --> 00:09:53.600 maintained over the week. And what about half 00:09:53.600 --> 00:09:55.960 -life? How quickly does the body clear it? For 00:09:55.960 --> 00:09:58.320 bieta, the twice -daily one, it's quite short, 00:09:58.460 --> 00:10:00.379 about two hours. That's why you need two doses 00:10:00.379 --> 00:10:03.299 a day. Makes sense. And Bidurion? Bidurion is 00:10:03.299 --> 00:10:05.259 different because of the slow release. It doesn't 00:10:05.259 --> 00:10:08.220 have a simple half -life like Biata, but it takes 00:10:08.220 --> 00:10:10.940 about six to seven weeks of weekly injections 00:10:10.940 --> 00:10:13.720 to reach that stable, steady state level in the 00:10:13.720 --> 00:10:16.500 body. OK. And you mentioned different manufacturers 00:10:16.500 --> 00:10:19.379 earlier. Did the drug behave the same way regardless 00:10:19.379 --> 00:10:21.539 of who made it? That was checked carefully in 00:10:21.539 --> 00:10:24.179 those comparability studies. They looked at the 00:10:24.179 --> 00:10:26.679 exposure -response relationship, basically, how 00:10:26.679 --> 00:10:29.080 much drug in the blood leads to how much effect 00:10:29.080 --> 00:10:32.120 on HbA1c. And they found it was comparable between 00:10:32.120 --> 00:10:34.500 the different manufacturers, like Amalin and 00:10:34.500 --> 00:10:37.679 Alkermes. The potency seemed consistent. They 00:10:37.679 --> 00:10:41.059 even calculated the EC50. Yeah, the concentration 00:10:41.059 --> 00:10:44.820 needed to get half the maximum effect. For Bidurian's 00:10:44.820 --> 00:10:48.120 effect on HbA1C, it was around 83 .5 picograms 00:10:48.120 --> 00:10:50.759 per milliliter. And that number held up across 00:10:50.759 --> 00:10:53.139 the different manufacturing sources. Consistency 00:10:53.139 --> 00:10:55.860 is key. Definitely. Now, this next part sounds 00:10:55.860 --> 00:10:59.690 really interesting. Antibodies. the body can 00:10:59.690 --> 00:11:02.809 fight the drug. Yes, this is a fascinating and 00:11:02.809 --> 00:11:05.590 important aspect. Some patients develop antibodies 00:11:05.590 --> 00:11:08.049 to exenitide. Their immune system recognizes 00:11:08.049 --> 00:11:10.330 it as foreign and creates antibodies against 00:11:10.330 --> 00:11:13.169 it. Does that matter? Does it stop the drug working? 00:11:13.389 --> 00:11:16.350 It can. If the antibody levels or titers get 00:11:16.350 --> 00:11:18.289 high enough the threshold mentioned was a titer 00:11:18.289 --> 00:11:21.690 of 625 or more, they can actually interfere with 00:11:21.690 --> 00:11:24.190 measuring the drug in the blood and, more importantly, 00:11:24.490 --> 00:11:26.350 potentially reduce its effectiveness. So your 00:11:26.350 --> 00:11:28.889 own body could make the diabetes drug less effective? 00:11:29.210 --> 00:11:31.789 Potentially, yes, at those higher antibody levels. 00:11:32.230 --> 00:11:34.230 The pharmacokinetic models even predict that 00:11:34.230 --> 00:11:36.669 the drug concentration might increase if antibody 00:11:36.669 --> 00:11:39.029 titers go up or if kidney function goes down. 00:11:39.250 --> 00:11:41.519 It's complex. Wow. Doctors need to be aware of 00:11:41.519 --> 00:11:43.720 that possibility. They do. Although it's worth 00:11:43.720 --> 00:11:45.779 noting, the studies didn't find a clear link 00:11:45.779 --> 00:11:48.179 between having antibodies and having more side 00:11:48.179 --> 00:11:50.600 effects, just potentially less effect at high 00:11:50.600 --> 00:11:53.179 titers. Okay. And you mentioned kidneys just 00:11:53.179 --> 00:11:56.240 now. How does kidney function affect xenotide? 00:11:56.620 --> 00:11:59.600 For patients with mild or moderate kidney problems, 00:11:59.860 --> 00:12:02.240 exposure to the drug seems pretty similar to 00:12:02.240 --> 00:12:04.740 people with normal function. But what about severe 00:12:04.740 --> 00:12:07.659 kidney issues? Ah, well, for Bayetta, the twice 00:12:07.659 --> 00:12:09.860 -daily one, it's specifically not recommended 00:12:09.860 --> 00:12:12.720 for people with severe renal impairment or end 00:12:12.720 --> 00:12:15.480 -stage kidney disease. The risk of side effects 00:12:15.480 --> 00:12:17.679 might be higher because the kidneys play a role 00:12:17.679 --> 00:12:19.980 in clearing the drug. Got it. Okay, let's shift 00:12:19.980 --> 00:12:22.750 to the physical product itself. Bidurion. with 00:12:22.750 --> 00:12:25.529 the microspheres. How is it actually made and 00:12:25.529 --> 00:12:27.570 put together? It's not just a simple liquid, 00:12:27.769 --> 00:12:30.049 right? No, definitely not. It uses that sustain 00:12:30.049 --> 00:12:33.009 -release microsphere technology. The egg -zenotide 00:12:33.009 --> 00:12:36.250 drug is encapsulated inside these tiny biodegradable 00:12:36.250 --> 00:12:38.610 polymerspheres. So the product usually comes 00:12:38.610 --> 00:12:41.149 as a kit. You get a vial with the dry microsphere 00:12:41.149 --> 00:12:43.450 powder, a syringe pre -filled with the liquid 00:12:43.450 --> 00:12:46.149 diluent to mix it with, plus needles and a connector 00:12:46.149 --> 00:12:48.669 piece. So the patient has to mix it? Traditionally, 00:12:49.070 --> 00:12:52.029 yes, for the original vial formulation. You have 00:12:52.029 --> 00:12:54.350 to carefully transfer the diluent into the powder 00:12:54.350 --> 00:12:56.990 vial, mix it gently to create a suspension. It 00:12:56.990 --> 00:12:59.210 looks kind of cloudy. And then draw it up and 00:12:59.210 --> 00:13:02.009 inject it. It's a bit of a process. Each kit 00:13:02.009 --> 00:13:04.629 delivers that two milligram dose. Sounds like 00:13:04.629 --> 00:13:06.289 something you wouldn't want to mess up. Precision 00:13:06.289 --> 00:13:08.509 is definitely required. That's why the pre -filled 00:13:08.509 --> 00:13:11.610 pen, the Biodurion B -Cise, was a welcome development, 00:13:11.789 --> 00:13:14.610 no mixing needed. Right. And what else is in 00:13:14.610 --> 00:13:17.350 there besides the drug and the polymer? Any key... 00:13:17.450 --> 00:13:20.389 inactive ingredients. Yes, excipients are crucial. 00:13:20.649 --> 00:13:23.509 They often use medium chain triglycerides, MCTs, 00:13:23.590 --> 00:13:26.070 which help control how the exanatide gets released 00:13:26.070 --> 00:13:28.830 over the week. And sucrose, basically sugar, 00:13:29.029 --> 00:13:31.570 is used in the newer formulation as a stabilizer 00:13:31.570 --> 00:13:33.750 to keep the product stable over its shelf life. 00:13:33.990 --> 00:13:35.950 And I assume there's rigorous testing to make 00:13:35.950 --> 00:13:38.450 sure every batch is right. Oh, absolutely. A 00:13:38.450 --> 00:13:41.409 quality control is intense. They test everything. 00:13:41.730 --> 00:13:44.309 The exact amount of drug, its purity, the size 00:13:44.309 --> 00:13:46.370 of the microsphere particles because size affects 00:13:46.370 --> 00:13:49.009 release rate, how much drug bursts out initially, 00:13:49.470 --> 00:13:52.129 the release rate over time, and lab tests, moisture 00:13:52.129 --> 00:13:55.009 content, any leftover solvents. You name it. 00:13:55.169 --> 00:13:57.990 Sounds thorough. It has to be. These comparability 00:13:57.990 --> 00:14:00.529 tests ensure consistency and quality from batch 00:14:00.529 --> 00:14:03.490 to batch. OK, complex manufacturing. Now let's 00:14:03.490 --> 00:14:05.929 talk regulations. Getting these drugs approved. 00:14:06.169 --> 00:14:09.269 Was it smooth sailing for eggs in a tide? Uh, 00:14:09.429 --> 00:14:12.190 not entirely, especially for Bidurian, the once 00:14:12.190 --> 00:14:14.649 weekly version. The first application, the NDA 00:14:14.649 --> 00:14:18.070 was submitted to the FDA back in 2009. Approved. 00:14:18.230 --> 00:14:20.309 Nope. They got what's called a complete response 00:14:20.309 --> 00:14:23.309 letter. Basically, the FDA said not yet. Oof, 00:14:23.409 --> 00:14:25.730 why? What were the issues? The FDA wanted more 00:14:25.730 --> 00:14:28.070 information. Specifically, they had concerns 00:14:28.070 --> 00:14:30.090 about the drug's potential effect on the heart's 00:14:30.090 --> 00:14:32.450 rhythm, the QT interval, and they wanted more 00:14:32.450 --> 00:14:34.549 safety and efficacy data from one of the key 00:14:34.549 --> 00:14:38.470 clinical trials, study 2993LAR105. So back to 00:14:38.470 --> 00:14:40.730 the drawing board essentially. Pretty much. The 00:14:40.730 --> 00:14:43.210 company had to gather the extra data, address 00:14:43.210 --> 00:14:45.909 the concerns, and then resubmit the application. 00:14:46.269 --> 00:14:49.330 And eventually got approved. Yes, Bidurion did 00:14:49.330 --> 00:14:51.389 eventually get the green light from the FDA. 00:14:51.789 --> 00:14:54.970 Bayetta, the twice -daily one, had its own process 00:14:54.970 --> 00:14:57.870 and was approved earlier, back in 2005, as we 00:14:57.870 --> 00:15:00.149 mentioned. What about after approval? Does the 00:15:00.149 --> 00:15:03.429 monitoring stop? No way. Post -marketing surveillance 00:15:03.429 --> 00:15:07.049 is crucial. And with Bayetta, after it launched, 00:15:07.690 --> 00:15:09.529 reports started coming in about some potentially 00:15:09.529 --> 00:15:12.350 serious issues. Like what? Things like acute 00:15:12.350 --> 00:15:15.250 pancreatitis, some cases of acute kidney failure, 00:15:15.370 --> 00:15:18.090 and even some concerns about thyroid growths, 00:15:18.269 --> 00:15:21.120 specifically thyroid C -cell neoplasms. Wow, 00:15:21.200 --> 00:15:23.460 okay. So what did the regulators do? Well, these 00:15:23.460 --> 00:15:26.740 reports led the FDO to require a REM for Beata. 00:15:26.899 --> 00:15:29.480 A REMS risk evaluation and mitigation strategy. 00:15:29.639 --> 00:15:31.720 Exactly. It's a safety program to make sure the 00:15:31.720 --> 00:15:33.779 drug's benefits still outweigh its risk, given 00:15:33.779 --> 00:15:36.259 the new information. It could involve extra patient 00:15:36.259 --> 00:15:38.320 education, special guides, things like that. 00:15:38.440 --> 00:15:40.980 Any other requirements? Yes. There was also a 00:15:40.980 --> 00:15:44.120 deferred pediatric study required under PREA, 00:15:44.159 --> 00:15:46.519 the Pediatric Research Equity Act, to look at 00:15:46.519 --> 00:15:48.960 its use in kids, though it was initially approved 00:15:48.960 --> 00:15:51.539 only for adults. And how did things go in Europe 00:15:51.539 --> 00:15:55.179 with the EMA? Similar process, different timeline. 00:15:55.600 --> 00:15:58.259 The EMA authorized Bayetta in the EU in June 00:15:58.259 --> 00:16:01.779 2009, and Bidurion followed in June 2011 based 00:16:01.779 --> 00:16:04.940 on their own review of the data. OK. Shifting 00:16:04.940 --> 00:16:08.299 from regulators to lawyers. What about patents? 00:16:08.480 --> 00:16:10.799 Are these drugs heavily protected? Oh, definitely. 00:16:11.240 --> 00:16:13.700 The patent landscape for GLP -1 agonists like 00:16:13.700 --> 00:16:16.500 exenatide is really complex. Sources suggest 00:16:16.500 --> 00:16:18.559 companies often get a lot of patents for each 00:16:18.559 --> 00:16:20.419 drug. How many are we talking? Like an average 00:16:20.419 --> 00:16:23.019 of maybe 19 or 20 patents per product in this 00:16:23.019 --> 00:16:25.100 class. 20 patents for one drug. What are they 00:16:25.100 --> 00:16:27.740 all for? Interestingly, a big chunk, often more 00:16:27.740 --> 00:16:29.700 than half, aren't just for the drug molecule 00:16:29.700 --> 00:16:31.899 itself, but for the delivery device, the pens, 00:16:32.059 --> 00:16:34.440 the microsphere technology. Why? How you get 00:16:34.440 --> 00:16:37.139 the drug into the body. Ah, so protecting the 00:16:37.139 --> 00:16:39.299 pen. is as important as protecting the pill, 00:16:39.419 --> 00:16:42.039 so to speak. Exactly. And on top of patents, 00:16:42.240 --> 00:16:45.840 they get regulatory exclusivities, like NCE, 00:16:46.259 --> 00:16:48.480 new chemical entity exclusivity for the first 00:16:48.480 --> 00:16:51.299 approval of a totally new drug, or sometimes 00:16:51.299 --> 00:16:54.000 NPP, new patient population exclusivity if it 00:16:54.000 --> 00:16:56.240 gets approved for a new group. Do generics ever 00:16:56.240 --> 00:16:58.809 challenge these? They can try under the Hatch 00:16:58.809 --> 00:17:01.769 Wax Men Act, but our sources indicate that so 00:17:01.769 --> 00:17:04.529 far no generic company has successfully challenged 00:17:04.529 --> 00:17:07.910 the patents and gotten a generic GLP -1 agonist 00:17:07.910 --> 00:17:10.349 approved by the FDA. Which means? Which means 00:17:10.349 --> 00:17:13.029 these drugs stay branded and generally quite 00:17:13.029 --> 00:17:15.990 expensive for a long time. Lack of generic competition 00:17:15.990 --> 00:17:18.069 is a big factor in the cost. Right, the cost. 00:17:18.269 --> 00:17:20.289 Let's talk economics. How big is the market for 00:17:20.289 --> 00:17:22.910 exenatide? It's pretty substantial. For 2024, 00:17:23.230 --> 00:17:25.650 the global market for exenatide injections is 00:17:25.650 --> 00:17:29.740 estimated around $2 .97 billion. Yearly $3 billion. 00:17:30.079 --> 00:17:32.400 And is it growing? Oh, yeah. It's projected to 00:17:32.400 --> 00:17:34.500 grow at a rate of over 8 % per year, hitting 00:17:34.500 --> 00:17:38.029 something like $5 .6 billion by 2032. significant 00:17:38.029 --> 00:17:39.890 growth. What's driving that growth? More people 00:17:39.890 --> 00:17:42.250 getting diabetes. That's a huge part of it. Yes. 00:17:42.849 --> 00:17:45.410 The rising prevalence of diabetes globally is 00:17:45.410 --> 00:17:48.769 a key driver, plus greater acceptance of injectable 00:17:48.769 --> 00:17:50.349 therapies. You know, people getting more comfortable 00:17:50.349 --> 00:17:52.410 with them. And the technology helps, right? Better 00:17:52.410 --> 00:17:55.329 pens and stuff. Absolutely. Advancements in drug 00:17:55.329 --> 00:17:58.170 delivery like the easier to use auto injectors 00:17:58.170 --> 00:18:00.349 make a difference. And sometimes government initiatives 00:18:00.349 --> 00:18:03.130 supporting diabetes care play a role, too. Where's 00:18:03.130 --> 00:18:06.130 the biggest market geographically? Still North 00:18:06.130 --> 00:18:09.000 America. Yes, North America is dominant currently. 00:18:09.200 --> 00:18:11.599 Strong pharma presence, high diabetes rates, 00:18:12.019 --> 00:18:14.500 established healthcare systems. Europe is second. 00:18:14.779 --> 00:18:17.380 Any regions growing particularly fast? The Asia 00:18:17.380 --> 00:18:19.480 -Pacific region is projected to have the fastest 00:18:19.480 --> 00:18:22.299 growth. Think rising healthcare spending, more 00:18:22.299 --> 00:18:24.940 disposable income, greater awareness about diabetes 00:18:24.940 --> 00:18:27.359 treatment options in countries there. With all 00:18:27.359 --> 00:18:29.720 this growth, are the drugs actually affordable? 00:18:29.779 --> 00:18:31.740 You mentioned they're expensive. That remains 00:18:31.740 --> 00:18:35.039 a major issue. GLP -1s, including exenitide, 00:18:35.140 --> 00:18:37.910 are costly. Net prices have generally been rising, 00:18:38.210 --> 00:18:40.430 and that translates into significant out -of 00:18:40.430 --> 00:18:42.569 -pocket costs for many patients, which can be 00:18:42.569 --> 00:18:45.289 a real barrier to access. Yeah, that's the tough 00:18:45.289 --> 00:18:48.369 part. Effective, but potentially hard to afford. 00:18:49.130 --> 00:18:52.269 OK, lastly, what about the sort of cultural side? 00:18:53.329 --> 00:18:56.670 Patient experiences, public awareness. Looking 00:18:56.670 --> 00:18:58.569 at patient forums and discussions online, you 00:18:58.569 --> 00:19:00.930 see a mix, as you'd expect. Many people report 00:19:00.930 --> 00:19:03.230 good results, better blood sugar. The weight 00:19:03.230 --> 00:19:06.059 loss benefit is often mentioned. But downsides, 00:19:06.299 --> 00:19:08.480 too. Yes, side effects are definitely discussed. 00:19:08.920 --> 00:19:11.220 Gastrointestinal issues like nausea seem pretty 00:19:11.220 --> 00:19:14.140 common, especially initially. And injection site 00:19:14.140 --> 00:19:17.680 reactions, redness, itching. It highlights that 00:19:17.680 --> 00:19:20.640 individual experiences really vary. And does 00:19:20.640 --> 00:19:22.660 exenatide get caught up in all the recent buzz 00:19:22.660 --> 00:19:26.180 about GLP -1s for weight loss generally? Well, 00:19:26.279 --> 00:19:28.920 while the newer drugs like semaglutide and terzepotide 00:19:28.920 --> 00:19:30.559 are getting most of the headlines for weight 00:19:30.559 --> 00:19:33.779 management specifically, exenatide, as one of 00:19:33.779 --> 00:19:36.140 the pioneers in the GLP -1 class for diabetes, 00:19:36.519 --> 00:19:38.420 certainly helped pave the way. So it laid some 00:19:38.420 --> 00:19:40.460 groundwork for public understanding. I think 00:19:40.460 --> 00:19:43.079 so. It helps introduce the concept of GLP -1 00:19:43.079 --> 00:19:45.380 agonists for diabetes treatment, even if newer 00:19:45.380 --> 00:19:47.359 agents are more in the spotlight right now. It's 00:19:47.359 --> 00:19:49.960 part of that evolving story. Okay, so as we kind 00:19:49.960 --> 00:19:52.880 of wrap up this deep dive, what are the absolute 00:19:52.880 --> 00:19:55.940 key takeaways people should remember about eggs 00:19:55.940 --> 00:19:58.630 in a tide? Well, first, that amazing origin from 00:19:58.630 --> 00:20:01.630 Gila monster saliva showing where science can 00:20:01.630 --> 00:20:04.990 find inspiration. Then it's evolution, you know, 00:20:05.130 --> 00:20:08.069 from twice daily biota to the more convenient 00:20:08.069 --> 00:20:10.630 once weekly by durian using that microsphere 00:20:10.630 --> 00:20:13.200 tech. Right. It's important role in managing 00:20:13.200 --> 00:20:16.440 type 2 diabetes by mimicking GLP -1, improving 00:20:16.440 --> 00:20:18.660 blood sugar, often with that weight loss kicker, 00:20:18.660 --> 00:20:22.279 but also the complexities how it works, the potential 00:20:22.279 --> 00:20:25.619 for antibodies to affect it, the careful manufacturing. 00:20:25.819 --> 00:20:27.900 And the journey it took. Exactly. The regulatory 00:20:27.900 --> 00:20:30.220 hurdles, the safety monitoring that led to the 00:20:30.220 --> 00:20:33.039 REM -S, the whole patent situation, keeping generics 00:20:33.039 --> 00:20:35.819 at bay, and ultimately the significant economic 00:20:35.819 --> 00:20:38.119 impact, but also the challenge of cost and access 00:20:38.119 --> 00:20:40.099 for patients. It's a really packed story. It 00:20:40.099 --> 00:20:42.539 absolutely is. molecule with quite the biography. 00:20:43.019 --> 00:20:44.940 So maybe a final thought for you, our listener, 00:20:45.140 --> 00:20:47.160 to chew on. Considering this whole journey, the 00:20:47.160 --> 00:20:50.180 innovation, the careful regulation, but also 00:20:50.180 --> 00:20:52.720 the high cost and patent walls we see with drugs 00:20:52.720 --> 00:20:56.359 like Xenotide. How do we strike the right balance? 00:20:56.859 --> 00:21:00.140 How can we keep encouraging these kinds of breakthroughs 00:21:00.140 --> 00:21:02.500 while making sure the resulting treatments are 00:21:02.500 --> 00:21:05.099 actually affordable and accessible for everyone 00:21:05.099 --> 00:21:07.859 who stands to benefit? That is the multi -billion 00:21:07.859 --> 00:21:10.140 dollar question, isn't it? Something critical 00:21:10.140 --> 00:21:12.279 for us all to think about. And hey, if this dive 00:21:12.279 --> 00:21:15.299 into XNHAD got you interested, definitely dig 00:21:15.299 --> 00:21:17.519 deeper into the sources or related research. 00:21:17.579 --> 00:21:19.839 For sure. There's always more to uncover. Thanks 00:21:19.839 --> 00:21:21.599 so much for joining us on this deep dive. See 00:21:21.599 --> 00:21:22.099 you next time.