Oral GLP-1s Are Here Deep Dive on Orforglipron

0:10 Hey everybody, this is Hunter Williams. I hope you're doing amazing wherever you might be in the world. Today's video slash audio podcast is going to be about a new drug called Orforglypron. I don't know how that's actually pronounced, so I'm just going to run with it. Maybe we'll come up with a cool name like we did with Sloop, like Orphe or Orphor. Or for sounds kind of weird. There's not a way to take Orforglypron and make it catchy. But anyway, today I'll be doing an overview of that.

0:41 And we actually just released that as a product called Bio's Appetite. A lot of research companies are going to be getting their hands on it in the following weeks, depending on when you're watching this video and selling it. And maybe they already are at the time of you listening or watching, watching the video. But it is amazing. Basically, I think the headline here is that oral GLPs are here. and they are effective. So I've been using this for around a week now and I will say in terms of the appetite suppression it is as effective if not better than I have experienced

1:14 on Reddit or Church Appetite in term of making you not want to eat food but then also changing your cravings when you do eat and then making get fuller faster to a way where you don't want to overeat. And to me, it actually has less of the sick feeling effect that Terzapotide has. I never really get like a sick-feeling with Reta, but I'm also usually doing lower doses. So it works pretty well. As I usually do continue to sprinkle in my experience as I go through the presentation today, But it worked really well and I would recommend that you

1:48 check it out. What's cool about this is I think you can use it in conjunction with Retatrutide or with Terazapitide. at a lower dose, or you could use it when you are cycling off of those. So I really, really like the appetite suppression I get from this. The fat loss, as you have to be seen, I'm pretty lean right now, but we'll see how it does over time for fatloss. I am going to go over some of that data today that we have from the study so far. Today is going be a fun one. We have it. It is here. You guys probably know, I don't like to, for lack of a better word, blue ball, you guys, meaning that I won't talk about things that you don' have access

2:22 to or at least not on the cusp of having access too, because at that point it just kind of becomes a little bit of mental masturbation of just saying like, oh, there's all these compounds out there we don''t have to access. So we finally have it, it's here, and today we're going to do the deep dive on it. So stay tuned. Before I do that, just check out the peptide cheat sheet down in the description. At the time of this video, my YouTube channel has been deleted, so I don't know where this will be. It might be on YouTube. Hopefully the YouTube Channel comes back up, but if not, you might listen to an audio form or you may be listening just to a Dropbox folder that I send

2:52 out to my email list. But that being said, the email is the most important place to be, not because I'm trying to sell you anything, although I But because you have a direct line of communication with me, so if you do like my videos, you will have access to those videos and to the audio files to be able to do so. So without further ado, I'm going to show my screen. And today we're going talk about Orphoglipron. All right. I am Hunter Williams and today's video is all about orpho-glee-pron, however you want to pronounce it. You know, it's always interesting with these names, where they come from, I don't know.

3:22 Sometimes I feel like they would just be better off putting them in chat and say, come up with a name for this. At least people would be able to pronounce it, but I'm sure someone is sitting around in a marketing meeting somewhere coming up. Let's just walk over the mechanisms first to understand what it is because it's not technically a peptide and that is what actually makes it so good from an oral standpoint. So it a small molecule, it not a Peptide. It binds to the GLP-1 receptor with very high affinity but is a partial agonist rather than a full aganist like injectable GLp-2 medications.

3:54 Basically what that means is that Injectable GLP-1s are so similar to the GLp-2 hormone that for lack of a better way of saying it, they're almost identical to GL1 hormone and so they are binding to it. in a way that the body recognizes that is the same thing. Now they're not that. And so when we look at desensitization, that's why people have to keep upping up the dose because it's not the actual hormone. But this is a small molecule. So it binds to the receptor, but it is not actual peptide itself.

4:27 It is small molecules. Is GS bias. What that means is that it strongly stimulates the GS coupled adenocyclase pathway, which increases cyclic AMP, otherwise known as CAMP, while exhibiting minimal beta arrest and recruitment, which potentially reduces receptor desensitization. I think that's what's going to be interesting is I continue to use this just for my own knowledge and to share with people. But then as we see this, I'm sure some people will have to go up on the doses to get a certain effect.

4:57 And we're gonna see in the data that people at higher doses obviously lost higher weight. But what will be interesting to see is if that effect will carry through to where they have it long-term with this appetite suppression, whereas with triseptide or trutide, people will go on long term and really the effects completely diminish. So even if you're taking 12 milligrams of Reddit per week, if have been doing that for a year, you are not gonna really feel that much different over time in a long run. We'll see how that ends up happening, but based on the mechanism, it would lead us to believe that that would be the case.

5:29 So it also binds to a unique pocket deep in the receptors transmembrane domain rather than at the native peptide binding site, yet it still activates the receptor effectively. It produces the same key metabolic actions as injectable GLP-1s, which are enhanced glucose-dependent insulin secretion, suppressed glucagon release, slowed gastric emptying, and reduced appetite. So, now let's look at some of the advantages of this. Unlike oral semaglutide, you may have heard of that, it's called Ribelsis.

6:03 was not a good drug when they looked at it, but Orfolipon requires no absorption enhancer, like an oral peptide would, and can be taken without regard to meals, so you don't have to be fasting. So to walk that back a little bit, Ribelsis had these weird requirements, which are not weird if you think about it. But it was an oil version of peptides. And so, you had to take it with a bit of water, You had take with an absorption of enhancers, And you could not take fasted. Whereas this has no requirement. You can take a fast, or you can it take food. It doesn't matter, it has the same effect.

6:33 This is a major practical advantage over the oral GOP1s like Ribelsis. And when we look at it, it has high oral bioavailability without a special formulation, the absorption T max of two to four hours, a long elimination half-life of around 29 to 49 hours as opposed to the six to seven days. But for an oral compound, that's a little bit longer than most oral compounds. It ends up supporting once daily dosing. Because of that, there's no significant accumulation issues and it has predictable dose proportional pharmacokinetics.

7:03 So food intake reduces peak plasma concentration and total exposure by only like 18 to 24%. So if you wanted to do it in the best way, obviously you would do this fasted. However, if he wanted maybe take one serving in a morning, whichever that is, six or 12 milligrams, whatever it ends being for you, and one in an afternoon, you could definitely do that too, to kind of time out that peak dosings. And then also too, if you have to take with food, it's not a problem. It would be better to it faster, but you don't have take it with the food. So although it is not clinically meaningful, It allows patients to to with or without meals.

7:35 And I think that's a huge convenient factor for most people. Let's start going into some of the data here. We have phase one clinical results. So the initial results showed a 1.5 to 1,8% reduction in HbA1c. So, the placebo was only 0.4%, so we're talking about very, very statistical significant reduction. Just to put that in perspective, I know when you think of percentage, 1.,5% doesn't think. When we talk about your A1C, that's taking someone of a 7 A 1c and dropping them down to a 5. 5%. That, I cannot tell you how powerful that is.

8:12 And the reason I'm getting so excited about this is because it's an oral capsule. Yes, injections can do that. We know TERS can that, we know Reddit can to that but this something that when we talk about the barrier to entry, to have something is that powerful. Over 12 weeks, nonetheless, this was 12 week. that powerful in 12 weeks for these people that are not changing life, diet and lifestyle is pretty incredible. So the maximum weight loss was 5.8 kilos, which ends up being around somewhere in the neighborhood of like, I think 12 pounds.

8:44 And up to 6.6% of the baseline weight in just 12 weeks versus 0.5 kilogram gain with the placebo. So again, the max weight loss in 12 week was 5.8 kilos, which again ends up being like somewhere in the neighborhood of 10 pounds, Which is pretty incredible when you talk about three months. The early results demonstrated that it could achieve significant glucose lowering and weight loss within just three months of therapy with a safety profile consistent with other GLP-1s. And because of this in the research, it was concluded that there was a safe and effective once daily oral treatment alternative to injectable GLPs or peptide

9:18 oral formulation. So here is the phase two results. So we can see in this trial, so this was a 26 week phase two trial in type two diabetes patients. They tested Orforgolipron against placebo and weekly injectable Dulaglutide, which I mean, let's be honest, Dulogluteide even compared to Simagglutides is really worth this. And they were doing Dulaguetide 1.5 milligrams, just not like a nothing dose, substantial dose. In 383 adults with type 2 diabetes and the baseline A1C was 8.1%. So when we look at this, we can see the A1C reduction.

9:55 That's this first little bar right here. Dulaglutide had more than that. So with A 1 C reduction of 0.43% in the placebo, Dulaguetide, had 1.1% reduction, so not nothing substantial. And then the Orforaglipron at 45 milligrams, which is going to be a pretty high dose, had a A1C reduction of 2.1%. And the average weight loss was 10.10 kilos. The average weigh loss in the Dulaguthide was 3.9 kilos, so what is that in pounds? That ends up being 7 times 2 point 2, like 17 pounds.

10:31 of extra fat or extra body mass, excuse me, not fat, but extra-body mass that was lost. And then the weight loss in the placebo group was 2.2 kilos. So the highest Orforaglopron dose improved A1C 1% more than weekly doula glutide and produced nearly three-fold greater weight-loss over six months. Over 80% of patients on sufficient doses reached an A-1c under 7% and again the average starting was 8.1% which was significantly more than placebo or doula glutide. So you can see there this is pretty compelling data that is now out on our formula product.

11:08 There was another 36 week trial, it enrolled 272 adults and this looked at obesity. It wasn't looking at diabetes, was looking to obesity so the mean weight was 108 kilos. Body mass was averaged around 37.9. And we had 14.7% maximum weight loss in the highest dose of 45 milligrams after 36 weeks versus 2.3% with placebo. 75% of the patients achieved greater than 10% percent of their body mass loss. So just think if you had someone that was 250 pounds.

11:39 75% of the people of this 272 people achieved at least 25 pounds lost or more. It's pretty cool. Over nine months on a oral compound, which we know that people are not changing their diet or lifestyle. First is 9% on placebo. meaning that only 9% compared to 75% lost greater than 10%. And then there was an average weight loss, the highest dose of around 15 to 16 kilograms,

12:11 which again ends up being somewhere in the ballpark of like 35 to 40 pounds on average. So that was the average we lost at the 45 milligram dose. Now I'm going to recommend, and we'll get to this in dosing, you do not start at 45 milligrams. All pre-specified secondary measures of adiposity and metabolic health. So we do have some data from the phase three achieve one trial. So this is a 40 week randomized double blind trial in 559 adults with type two diabetes.

12:44 Inadequately controlled by diet exercise alone confirmed or for gloprons efficacy. So when we look at glycemic control, which this one was the primary endpoint because it was in diabetes patients, the mean A1c reductions were significant across all doses. Three milligram dose down to 1.3% A 1c, pretty substantial. 12 milligram doses, spoiler alert, I think is going to be end up being the sweet spot for a lot of people at least starting out. 1.6% reduction in A1C, 36mg dose, 1,5% percent reduction A-1c.

13:18 What do we see here? We see that 8mgs of RETTA beats 12mms of REDTA. We the 12 mg of O4-4L is beating 36 mg. So very interesting. At least when it comes to A 1C it'll be a little bit different with the weight. Now when we have placebo, only a 0.1% improvement in A1C makes sense. So over 65% of patients on the 36 milligram dose achieved an A 1C under 6.5% by week 40. Now they're gonna call that the non-diabetic range. I think it needs to be under 5. 5%, but at least it's trending in the right direction.

13:49 Let's look at the weight loss. Significant weight reduction accompanied the improvement A-1c. The three milligram does, people lost 4.7% of their body weight, which is not nothing. 12 milligram dose, 6.1% percent of the bodyweight. The 36 milligram loss, 7.9% bodyweights. So that's where the higher dose is gonna really stand out, not so much from a blood sugar improvement perspective, but from weight loss perspective. That's an extra basically 2%, 1.8% improvement in the weight. If someone was 200 pounds, they would have lost what would that be, 16 pounds instead of 12 pounds, which is pretty impressive.

14:29 And then placebo, only 1.6% of their body weight was lost. So, notably weight loss had not yet plateaued by 40 weeks, suggesting longer treatment might yield even greater losses. Let's look at the safety profile. Like other GLP-1s, the most common side effects involve the GI system occurring primarily during dose escalation. Notice dose escalation is when people are titrating up. So common GI side effects, nausea, 13 to 18% of the patients had nause, diarrhea, 19 to 26%, which is kind of on par with semaglutide and trisapidide,

15:03 if you look at the data. There was rare cases vomiting. It was actually pretty rare to find that, and they actually didn't have a percentage on that. Dyspeptia, which was indigestion, 10 to 20%, and then constipation, eight to 17%. So kind part for the course. Now I personally, at 12 milligrams per day, I haven't gone higher than that so far. have not had any of those things whatsoever. And even I would say like 2.5 milligrams of triseptide starting out, I'd have probably a little bit of that. So the characteristics of the GIFX were dose dependent, they were typically transient and occur primarily during the titration.

15:38 Once after the first week or two when the titeration occurs, people tend to improve and the side effects plateau out or go away. That's why gradual dose titration is critical, so we don't need to titrate the dose every week or every two weeks. Slower titrations mitigate symptoms, and the discontinuation rates due to GIFX were only 4 to 8%. So again, for people that dropped out, we're looking at only four to eight percent, not bad. And 90 to 95 percent of patients were able to continue therapy. So, again these are in line with other injectable GLP-1s.

16:10 So we look at other potential side effects. So as expected of a GLP-1, it does not cause hypoglycemia by itself because it augments insulin secretion in a glucose dependent manner. Sulfonylureas or insulin. And I want to make this a point here is a lot of times people think like, oh, it's semitourbs red if they're going to cause me to have low blood sugar. That's not the mechanism of how they work. They help you bring down your blood Sugar when it is higher, but they don't drop your Blood Sugar just like injecting insulin would.

16:43 So when we look at hepatic safety, unlike some other small molecule GLP-1 candidates, aka Pfizer's Danuclepron and Lotiglipron, which were discontinued due to liver toxicity, or Forglifron has not shown any significant hepatics safety signals to date in the Achieve 1 Phase 3 trials explicitly stated no hepactic safety symbols were observed. No cases of adjudicated pancreatitis have been reported with Orforaglopron and published data.

17:13 And rates of elevated pancreatic enzymes did not differ from placebo totally. So very interesting to note, there's no going to be pancretitis or gallbladder issues, at least that we've seen so far. Then we look at immunogenicity. I did want to put this in here. As a small molecule, Orfogloperon does not cause quote, does not cause anti-drug antibodies avoiding the issue of immunogenic reactions that can occur with a lot of other peptide and protein drugs. So I wanted to put that in because when we look at the desensitization to this, again, am I saying that you could sell it on 12 milligrams for the rest

17:47 of your life and have the same effect? No, without cycling off, no. But I think compared to staying on like two milligrams of turzaphtide, which usually after like eight weeks, almost feels like nothing there's going to be a huge difference with this so very very important to know that as a small molecule it does not cause anti-drug antibodies the way that peptides do because of the mechanisms of peptide so overall it appears very safe and well tolerated with the safety profile consistent with other GLP ones so When we look at clinical significant outcomes, just to sum those up, by lowering A1C by in the range of 1.5 to 1,7% and bringing a large fraction of patients

18:23 to non-diabetic glycemic ranges, it addresses diabetes. Then we looked at transformative weight loss. So ability to produce greater than 10% weight-loss in over 75% of the people is very, very meaningful. We also are going to look at secondary analysis that showed improvements in biomarkers of cardiovascular risk, including decreases in triglycerides, inflammatory markers, blood pressure, and lipid levels alongside weight reduction. And again, will this be the thing that kills statins? Probably not because they're such a cash cow, but we could use this in the same way and for the intended effect of normalizing lip profiles instead of

18:59 wholesale ripping lipids and destroying lipides in a way that causes damage to the system long term. And so by promoting weight loss and glycemic control without injections and without strict dosing restrictions, this may improve patient satisfaction and adherence over time and ultimately lead to better patient health. So here is my dosage strategy. You can begin with one milligram daily. That would be the pharmaceutical recommendation. However, the capsule started six milligrams. I think everybody could start at six milligram and then it go in six-milligram increments.

19:30 We go to six to 12 and 18 and 24 as needed at intervals of one to four weeks, I would recommend at least four week. So the final therapeutic dose for most people is going to probably be in 12 to 36 milligrams for someone like me. probably 12 milligrams for someone that needs to lose 70 pounds, probably 36 or even the size of the 45 milligrams that we saw. So that would be my recommendation. Again, the cool thing about this, no reconstitution needed. No need to do math in your head. You can take one six milligram capsule and then kind of go from there and adjust as needed, so I always say go low and go slow when it comes to the titration.

20:08 Now let's look at this in comparison with some of injectables. So, injectable GLP1s are peptides that act as full or nearly full agonists at the GLp1 receptor like we were talking about before, so they engage both G-protein signaling and beta-arrestin pathways, and orforaglopron is a partial aganist with GS-bias signaling. So despite the lower intrinsic efficacy in recruiting cellular pathways it achieves similar downstream metabolic effects due to high receptor affinity and sufficient exposure. So when we look at it in comparison, A1C in type 2 diabetes patients, when you use 36 to 45 milligrams of orafoglipron, we had a 1.7 to 2.1% reduction.

20:48 1 milligram of semaglutide had 1,5 to 1.,8. So orofogluepron beats semogglutides there. Weight loss, eight to 10 kilograms versus four to five kilograms for one milligram of semen glutide. So again, doubling the amount of weight loss from sema-glutide and then for obesity or for glupron at 45 milligrams gave around 15% weight-loss at 36 weeks compared to 2.4 percent or excuse me, 2 .4 milligrams of Sema Glutid. They had a 15 percent weight lost at 68 weeks.

21:18 Almost in double the time, or excuse me, in half the time, or for glupron had the same fat loss as semaglutide. That's pretty cool. And I think for something that's an oral is pretty. Now when we look, so when you look at the maximal efficacy, it seems in the ballpark is injectable semoglucide though, perhaps a bit less than Lilly's dual agonist triseptide, which gave around 20% weight loss in 72 weeks in obesity. But it is definitely like trending in that direction to be on par with trizeptides in terms of fatloss.

21:48 Also too, like I talked about, we have the no fasting requirement, obviously no refrigeration needed. So you can take this when you travel. You don't have to worry about insulin coolers or anything like that. And it's very simple to prescribe oral capsules. ruling over this one. I also think I wanted to throw this to just a manufacturing scalability and potential cost benefits. Because of the nature of what this is, is going to be able to get into the hands of so many more people, which is a huge,

22:19 huge win. And then we can obviously use it as GLP-1 therapy, but When we look at combination therapy, I wanted to talk about potentially using this with RETA. I think using something like a metformin and a Jardiance, an SGLT2 inhibitor with this is a no-brainer. But the question now is like, okay, well, could I use this, with a little bit of Reta, or could use when I cycle off-Reta? And I the answer is yes, absolutely. Am using a microdose of Reta, like one milligram per week total, right now alongside of it. To which that does, I really don't get any appetite suppression, but I get all of like the inflammation, systemic benefits of RETTA.

22:54 And so I'm doing that right now. So using like 12 milligrams of or four glopron per day, and then one milligram of retta per week. That seems to work really, really well. I think you could use both of these together because they're doing different things. But I thing more importantly, it allows someone to either reduce the amount of Retta that they would need to use or then have something to keep the momentum going if they want to cycle off and not have to go. So just to sum up the timeline, so this actually was first started in 2018 as was originally discovered, first human studies in 19 and 20, phase one B

23:27 completion was in 21, 22, base two results came in 23, face three launched late 23 and the first phase three results in April of 25. So that's what we're seeing now. It is on track to hopefully be approved next year or not hopefully depending on who you are. So again, it remains an investigational drug. Right now we have a few different phase three trials. So the achieve program has seven phase two trials and type two diabetes. There were 6,000 patients using it right now.

23:58 The attain program, has multiple phase 3 trials for chronic weight management and obesity. And if it gets approved next year, It would be the first. Here's what they're doing in the Achieve One. They're three milligram, 12 milligram and 36 milligram versus placebo. I always think about like those people that get a placebo or even if you get like three milligrams versus 36 milligrams and you're thinking like, man, I'm taking this thing that's gonna help me lose weight and then you are getting a placebo or you getting Dulagutide, which... Anyway, if Dulaguetide is injectable, then wouldn't you know that it's a Placebo?

24:32 But anyway, always wonder stuff like that. They're going to do additional trials and then they're also going look at cardiovascular outcomes. So that's something that we have to stay tuned and look forward to, which is how it improves cardiovascular parameters. And again, they are still recruiting and doing these phase three trials. I did want to look it versus Ribelsis. Oral semaglutide, or otherwise known as Ribalsis, is a peptide GLP-1 receptor agonist with an SNAC absorption enhancer that must be taken fasting with

25:02 a small sip of water. kind of similar results to regular stemaglutide with it, but again, it made a lot of people sick and that is approved for type 2 diabetes. Whereas orforgopron is a small molecule, It can be taken with or without food. It obviously hands down beats stemoglutaride oral or injectable when we look at the weight loss. and the phase three completed for type two diabetes is done and we're looking at some sort of approval probably late next year.

25:32 So there's those discontinued ones from Pfizer that we talked about and there are other candidates. There's also several ones that are trying to be developed right now I'm sure too. make them enhanced and even better. So we also, I wanted to talk about this is like some of the other candidates, the problem with them was that they had liver toxicity. And this raised questions about whether liver toxic might be an inherent class effect of small molecules, but or for the product to date through all of these trials and we're going back four to five years has not shown that whatsoever.

26:04 Again, this going to be something that I want to question You know, if, Lily owns both of these, will they release Reddit True Tide and or 4Glipron at the same time? Or will at least Reddit true tide first? Will they released or four Glyphron first and end up doing it because you know maybe they'll cannibalize sales. I don't know. Some people would say yes. Somebody wouldn't say no to that, but I do think it's an interesting thought to see which one they will release first or if they're released both them or they like scale out and titrate out the release of both of those.

26:38 So we have, you know, fixed dose combinations. I think we could obviously combine it with metformin and Giardian. And so I would advise people do that. There's going to be a lot of potential for this and fatty liver disease and PCOS and other conditions where GLP-1 therapy have shown province. But I do think there's gonna be lots of data that comes out on the cardiovascular benefits and also the renal benefits for people with diabetic kidney disease. at least because of the difference that it's not an injection, that's an oral, see to be taken globally at scale very, very fast.

27:12 So again, just to sum up, we have or for the front, it is a small molecule, not a peptide. There is tons of data that we reviewed today to show that is going to efficacious. I would recommend if you can get your hands on it, you try it. It has a very good safety profile for what we've seen so far and we're looking at it for coming out to be approved probably sometime in quarter three or quarter four of next year and it would be the first ever oral GLP-1 approved for obesity. So that is it for the slides.

27:42 And that, is everything you need to know about Orforgopron. I'm surprised I didn't butcher saying Orforgopon multiple times. Maybe that's not even the right way to say it, but it's the way I say based on how I read the letters when it comes out. Anyway, I am really excited about it so far as I have used it. It has been amazing just for appetite suppression. We'll see how the fat loss goes for myself. Again, I'm not trying to lose a ton of fat right now, but I think it will be pretty powerful for people to do it. And I this is one, if you're watching this, you are probably on the fringe anyway of being in the peptide world.

28:13 But I think this is one, like obviously all of us that are into this stuff, we want to tell our moms, dads, aunts, uncles, brothers, sisters that you could say, Hey, I know you're not going to order anything off the internet and then mix it with backwater and inject it into yourself, but try this capsule and they'll kind of get to see the benefits of the whole entire peptide slash small molecule space and what real power they have to change people's lives. So that's why I'm excited. This is also one of many things that we're coming out right now. We were kind in this biotech explosion era.

28:44 And hopefully we have the runway to continue to bring these products to market and do so and to do it in a way that gives people access to amazing revolutionary agents that serve as a true catalyst for change in their life and allow them to improve their health and ultimately improve everything about their lives. Again, just to sum up, thank you guys so much from the bottom of my heart. You know, YouTube channel or not, Deletion or the fact that I get to do what I do and bring this information to you, guys, and bringing products to guys and just bring whatever I can to help improve your guys' life.

29:14 That is my mission. And so thank guys. So much. I have an amazing base of people that support me. Whether it's liking, commenting, sharing the videos, assuming the channel is up or, not and then also just sharing and Another thing too I forget to mention all the time is that everything is always on Spotify or iTunes in the podcast So even videos from my old old channel that have been deleted. It's it's repository to on there So you can check those out So whether the channel is down or not You can always go to Spotify and that's a good place if you want to listen to audio and I'm gonna be more conscious now I've knowing that there's probably more people listening on the audio format That are

29:49 driving around or working out or whatever. So thank you guys so much from the bottom of my heart. I can't stress how much I love each and every one of you for listening. And without anything else to say, that'll be it for this one.