For episode #76 of “The Weekly Bioanalysis”, Dom and John talk about the popular topic of GLP-1 Analogues – these series of recent blockbuster drugs with multiple applications, as well as some of their bioanalytical challenges. First, the guys go over a little bit of the mechanism of action of GLP-1’s, then some of the rules around them and their initial diabetic treatments. They talk about the structures, and a little bit about how they are being used in weight loss (which, of course, is how these drugs have become so popular in mainstream culture now). Finally, they will discuss some of the resulting supply chain issues and even some of the bioanalytical challenges and what the future of these GLP-1 Analogues might be. It’s a jam packed show – really an interesting, fascinating topic the guys enjoy discussing.
“The Weekly Bioanalysis” is a podcast dedicated to discussing bioanalytical news, tools and services related to the pharmaceutical, biopharmaceutical and biomarker industries. Every month, KCAS Bio will bring you another 60 minutes (or so) of friendly banter between our two finest Senior Scientific Advisors as they chat over coffee and discuss what they’ve learned about the bioanalytical world the past couple of weeks. “The Weekly Bioanalysis” is brought to you by KCAS Bio.
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[Music] welcome to the weekly bioanalysis AKC podcast hello and welcome to the 76th episode of the weekly bio analysis the official podcast of kcast Bio kcast bio is a bioanalytical cro serving the pharmaceutical and biopharmaceutical industries for over 40 years my name is John Perkins and I’ve been the bio analytical at lcms space for over 29 years and I’m here with my co-host Dominic warino hello my name is Dominic warino and I’ve been in the LBA and selling gene therapy space for close to 30 years now Dom and I are members of the growing scientific advisory team at K Kass either both of us are available to answer any questions you may have regarding this podcast or any of kass’s services we are thrilled to have you listening to the 76th episode of the podcast which is now available virtually everywhere whatever you choose to find and play your podcast you can now likely find the weekly bioanalysis we welcome all of you whether you are joining us for the first time or if you’re a regular listener today’s podcast will be a review of the latest news and resources and then the focus on a topic of our choosing before discussing any feedback we’ve had from you we’re constantly looking for topics and we’d be happy to discuss something that you want us to cover so again we’re amp to have you here no we’re not going to do it again so again we excited to have you here and we’re look forward to a fun episode today to kick us off for podcast number 76 Dom is going to go over today’s podcast topic a bit before we jump into the news and resources section Dominic John we’re fired up today for gp1 analoges that’s going to be what our main portion is and some of these Blockbuster drugs with multiple applications and the bioanalytical challenges first we’re going to go over a little bit of the mechanism of action of gp1s some of the roles of glp1 analogs and diabetic treatment we’ll talk about the structures maybe we’ll talk a little bit about how they you used in weight loss of course that’s all the rage but then John you know supply chain issues some of the bioanalytical challenges we’ll really dig in there a little bit and also some of the future of glp1 analoges it’s a jam-pack show John really interesting fascinating topic excited to talk to you about it um all right John as always let’s just jump right into the news and notes Here uh got some interesting articles to go over today um tell us a little bit about veritex Farmers is doing yeah so I don’t don’t usually focus on on particular companies so I think I’ve done it a couple of times today but this is this is interesting because um it’s actually well the the headline is vertex pharmer scientist talks about a long road to developing nonadditive painkillers with a supplement to that the vertex inches closer to acute pain Market as FDA accepts VX4 548 and this is basically vertex well it it comes back to comes down to how do we address pain um as the the scientist who was interviewed for this who is vertex’s Chief scientist Dr David uler talked about um vertex’s research and development plans really focusing on this VX 548 um but Al what we have in terms of our tools for paining are things like Tylen oil which are moderately efficient but well tolerated but then the other camp on that are things like your your ID um analgesics which are very effective but of course have the possibility of addiction so vertex have actually taken a completely different approach in terms of how they’re looking at pain um in that in that quest to see if they can figure out to how to develop or if they could figure out how to develop a non-addictive pain medication that was effective um so the really interesting background to this is they’ve been working on it for 20 years um and and the actual Insight that led to the medications developed actually came from studies of people who had a rare condition where they were in sensitive to pain they can feel things sense temperature but don’t do not feel pain and this was actually identified in a family of fir Walkers who could walk on hot Cals so in terms of looking at this family they figur out the condition was due to inherent inherited differences in a particular protein that has a role in pain signaling so if you like this function you don’t feel pain so in his words we and many others have worked for decades to make a medicine that could recapitulate that natur occurring phenomenon you don’t doesn’t article doesn’t say how that’s all addressed but ultimately that’s what so that’s what drove the the direction they went in terms of developing this medication they’ve they’ve had it in I think phase two trials it’s shown that it can definitely reduce pain I think on one phase three study it didn’t match opioids but then I C but then it still has the benefit that it’s non addictive so you know so if it might not be quite as good as opioids but if you’re better than Tylenol Etc but you’re but but you’re um like I say you’re you’re you’re not you don’t have the addictive properties of of opioids maybe you’re in that middle gr or bet to the middle ground that actually makes this a drug that really could have legs and that’s why I wanted to talk about this yeah no John it’s a it’s a fascinating Topic in general just like trying to take any sort of drug that can give you a side effect of getting you high so to speak and then Can it have you know medical purposes like cannabis and things like that so the Opia thing is no different here and this was I I didn’t realize people had started 20 years ago on this that’s great um the the piece that is always interesting is the history around it the I think of it is the anology of it right this came from somebody who was like Hey if I could get these firew Walkers over here and figure out what they’re doing and you know there are people who are asymp I to aspirin right there are people sometimes they get they’re given these drugs and they’re like no I feel fine ouch I can still feel that so that’s still some unlocked things there’s even like for years uh uh not for years for maybe six months of my life I spent trying to look at a unil un um um a uniflow test to look at like a pin prick of the finger to see if you were uh asymptomatic to aspirin John don’t ask yeah so it was it was it was a holy grail of Science and not something that was ever really um probably achievable in that setting and actually we were I was helping out somebody trying to fix something on there so it’s kind of a convoluted story but anyhow um the the reason why I bring all this up is uh there’s a Netflix series called painkillers it’s F fascinating about the whole Purdue Pharma um and that spawned this a lot of it’s generated from that it was a part you know we remember we kind of grew we kind of at least I say grw up through it we lived through it right it wasn’t it’s still it’s still a problem oh absolutely and everything like that but the opad issue I mean they called them drugstore Cowboys right John like it was that’s why you see things locked up so this has been something that um you know they’re they’re breaking through on it because these are powerful things especially as I start to sesse and get older I start thinking about wow what is it like to have some of these things or what what might it be so this is great stuff John I I don’t know um I don’t have much to add I don’t know too too much about like some pain biomarkers we’ve worked at so there are some biomarkers in the space but as I mentioned there’s no real test yeah on firew Walker right you can’t make them walk across fire but there’s no test for this type of stuff so go ahead jump in yeah just just G to add a couple things it’s one of the questions within this why wouldn’t these drugs carry the same addictive properties as opioids and basically they it’s a different mechanism so the opioids are working in the brain whereas he doesn’t talk about the mechanism of action but the mechanism of action here is actually on the periphery of the body um not in the brain so it’s it’s coming from a complete different different process and that’s the way it’s not shouldn’t shouldn’t be an addictive it shouldn’t be an issue of addiction and um in terms of other studies they’re also looking at diabetic peripheral neuropathy so that’s that’s in that’s in phase two and looking forward to phase three and then they also have a a phase two Trail um looking to start um with Lumbo sacral radiculopathy which is called by inflammation or irritation of nerve roots in the lower back um so I mean yeah thinking about a back pain I I I’m I’m hoping this one gets to the market you know you don’t want to be you don’t want to be chewing Viking in there all morning long like and that’s really interesting because you know as many adults are I’m prone to back back trouble and or and just every so often it can trigger it get triggered and it’s it can be really it can be really debilitating um but I Al I honestly found that when I was was given oxycodon I I saw no effect of it so I actually discontinued it quite quickly because it it it didn’t bother me at all I actually found that actually Advil was more effective for for making me comfortable and keeping my back pain under control whereas my wife wife when she has migraines will do a mix of like Tylenol and Codine to to help with that and then it’s a very short burst of of treatment but yeah it’s it’s it’s like say it’s one of those it’s one of those medicines that we want to watch to see if it makes it to Market and then where it goes from there and it has actually moved from it was started as vx5 R it’s now called suset trogen so it has a has a name and it’s something to to watch out for so yeah yeah so it’s great I I think it’s a really germane topic you’re going to see more and more people living longer so therefore by default that can come with neuropathy not just diabetic right so back pain all of it we’re Body by chemistry and hey I’m a big fan if I could take something that um you know John unlike you you give me an aspirin and I’m wound up like this stuff has a real effect on me I’ve only been prescribed I had my wisdom teeth removed when I was 16 and I think I got some like they were Rock assets or whatever it might be and they I just remember that was a lot and um maybe one other time for another small outpatient surgery where I got prescribed something and my wife’s like you okay I’m like I’m feeling great so this it has an effect on me for sure yes yeah yes it were all different that’s the nice thing any of them all of them like if I have any moderate sometimes like I’ve been running lately I might take a small like I take one ass but it’s a running joke my what even my 18-year-old looks at me he’s like you gonna be okay taking that I’m like yeah shut up you know so because it does it does get to me so uh I don’t know if you want to you kind of covered the veritex thing they’re yeah that’s all all it was two cools covering the same let’s let’s keep the next thing is is it’s just a quick bit I thought it would be interesting again it’s focusing on a particular company but it’s prime prime medicine receives FDA clearance to run a first predicting clinical trial um and so this is the first ever trial first ever human trial of predicting opening the door for testing new technologies that backers hope will widen the array of diseases that can be treated V Gene editing um I think in the past the FDA has been fairly resistant to or has been resistant to this kind of um approach or in terms of clinical studies but um like I said this is first of I I don’t know what so the sorry let let me back up on it the the basically this this therapy is a treatment for chronic granul Gran granulatus disease cjd a rare genetic condition in which fagio sites um don’t work properly typically diagnosed in early childhood it can cause people to get seriously ill from bacteria or fungi that would normally cause few or no SYM symptoms it’s caused by mutations to the genes en coding for a key enzyme called the ND nadph oxidase that white blood cells need to fend off infections and their their treatment is meant to correct the gene mutated in one of the variants of of cgd um so basically the the treatment involves extracting blood stem cells from the patient and sending them to lab where Prim editing would then be used with the goal of correct the mutation cells would then be infused back into the patient hopefully to restore immune functioning um so this is so basically Prime editing is is looking to rewrite short segments of DNA it doesn’t require double spr Stand double strand breaks as with Chris forcast 9 um it’s out of David L Lab at the broad Institute of MIT in Harvard and and there only a recent development um so it’s it the it’s it’s the background to this is the FDA really has been slow or moving in this dire ction or or clearing human studies of new Gene EDI and treatments and this this this was only rolled out in 2019 so this really is a new approach so you can understand their their um conservatism here so it’s just I just thought it’s interesting because it’s first of a kind and again who knows it may go nowhere but it’s that first step and onwards that probably will mean it’s a direction that will will acquire legs in the future if this doesn’t go anywhere um and that you know it’s another medical approach we’ll be watching out for yeah no John it’s it’s a lot unpack here right so we we’re you know for me it’s um I’m back in 1994 where I’m doing my first xvivo autologus therapy and here we are talking about it again right and it’s yeah so far right I’m I’m going the other way it’s actually evolved this is just like another evolution in the in the um xvivo therapy space and you you touched on it about the current crisper Technologies um they have this requirement to break doubl stranded DNA which in and of itself is just it’s just dangerous right that’s a that’s like a that’s what carcinogens do that’s you know that that’s how breaking doubl stranded DNA is how how you kind of kill a cell or mutate the cell so that and but they’re they’re now finding a way and and by the way those initial crisper um Technologies they they did have some side well there was some fear of side effects they’ve engineered them in such ways to prevent them and this is Evolution this is the next engineering so they’ve unpacked a way to rewrite those short segments without having to break it they don’t really talk about it here but that’s their IP right and David Lou I mean we we need to have this we gotta we got to try and get him on the podcast because he’s you know here he is again I mean you couldn’t be a bigger name in this space than him and this Prime medicines looks destined to do some great things but you know these these types of Evolutions are um you know this is this is why we love the field John on because it’s it takes years in the making and this one kind of popped up pretty quickly I’d say I’d say the crisper Technologies themselves have been one of the faster moving and I think the C T Cell space kind of carved the way right because those Technologies I mentioned it we in the early middle part of the 90s started realizing this is powerful stuff how do we you know there’s all sorts of I won’t go over it’s like its own little probably podcast but basically it took decades before the first car T Cell got approved and even now as there still um a bolus of them that were recently approved but now we’ve got oh hey there’s some caution here because this kind of safety thing and they’ll start to we’ve talked about that they’ll mitigate that right so but this is allowed the crisper what we’ve learned from all that that it’s still an Aus they’re both autus ex Vio therapy right yes exactly so that’s the piece that allows this to it’s leveraging that so it’s really it’s made Leaps and Bounds John if when we started this podcast I don’t know what’s it four years ago now I would have said we’re a decade away so they’ve cut it in half you know I really do I’m I this is me you know kind I’d take this if if it came to it that’s what I’m saying that’s how advanced it’s been where if you had asked me five years ago I might have been a little more more like I better really be sick right um but now it’s like hey if I I I think these things have especially as I read this so I’ll stop there John thank this stuff I love John right I love yes so again like I said it was just a highlight of where the where the industry is going and and things to watch out for in the long term the next next piece is this is quite early work but it’s um gut enzymes could make universal donor blood possible so a completely different direction R huge thing to another holy gra of science yeah absolutely yeah it’s it’s really so it’s it’s funny with you know terms of news articles it’s all be it’s actually been quite light but there’s still some real gems in terms of what people are doing well said well said there’s there’s some activity out there but these are some of the things that have come out are hu like they’re like wow this is yeah yeah yeah sure exactly so this is actually a couple of European teams um and an article P published in nature microbiology a team of researchers from the Technical University of Denmark DTU and Lind University in Sweden detailed how they discovered back gut bacteria enzymes that remove not only ANB antigens from red blood cells but other components that have rically hampered progress towards universal donor blood um so this is so the they they say we’re we’re close being able to produce universal blood from Group B donors whereas there still work to be done for the more complex a a group a blood and this was led by mahare Abu haachim I I got bacteria research from one of the study senior authors her Focus now to investigate in detail if there are additional obstacles and how we can improve our enzymes to reach the ultimate goal of universal blood production um so I I’m I’m a non-biologist so I I it it was I actually didn’t know why there was it was called O and B and a so it’s actually this was really interesting to me this is how rudimentary my biology education is well don’t question me John but I know I know a little bit to be dangerous if you know I’m going to read this because is it’s key to the whole thing and actually go ahead go ahead it really leads to the Elegance of it it’s like blood donations must either be matched by type or come from recipient with the only natural occurring universal blood donor type O mismatched donations can lead to what’s known as an acute hemolytic reaction where the immun system attacks the transfused breed blood cells um they this to this was all figured out about 40 years ago um scientists discovered a set of gut enzymes capable removing antigens that characterize type B blood cells a different set of antigens characterize a blood cells cells with both A and B antigens are type A B while those without with with those without neither of them that without either of them are type O um so what the team then focused on is if they could remove the the antigens then then they could make the blood similar to to T typo um and so um let’s see yeah I I’ll pass it back to you then I I’ll come well it’s there’s a couple things where red blood cells are non-nuclear Leed cells they’re tiny now you’re going to treat them with some enzyme to knock this antigen type off of it to make them less immunogenic that’s basically what they’re doing so you you kind of described it if you’re type A type B type A or type O if you type a you have a if you type B you have B if you’re type A and B you have both antigens you type O you lack them right so that there’s uh um there’s there’s a clear path to removing one of them they kind of talk about I think it’s the A to B path but all of this is um it just get it’s just fascinating how they continue to like take like um parts that are in us all and figuring out how to repurpose them to do therapies that’s what I’m hearing right that’s kind of cool right I say part you know enzymes and if you don’t mind me jumping in but and and still things that we think we know about they’re still finding new new information about them because what LEDs to this is one of the researchers at L called Jennifer Richie Hagman identified a previously undiscovered extension of the type being antigen and and so I mean this is this is recent stuff but we’ve been talk about this stuff like originally from 40 years ago it’s it’s how it’s fascinating how we have these bodies but we’re still learning about them you know the the thing see that’s why I said I know enough to be dangerous I know this is dense but they teach it to you like oh it’s a it’s B it’s oh it’s really easy like I described it right but you know they just in even in this article 24 different types of a so it’s it’s pretty and like they said the the finding of that extension on B then LED them to look back at a and found there similar extensions to that and and they think and which and similar extensions which despite knowledge of their existence hadn’t been thought a play thought to play a role in blood type compatibility so that’s when the labs collaborated to to sort of to use a bacteria to then take off not just the antigens but the extensions and that’s where your hopefully your path to Universal good luck to them John it just seems s like a red blood cell so fragile that you’re doing I if they still contain their you know efficacy I guess I can’t you know what I mean I guess it does obviously I’m not quite you know I’m not I’m no like red blood cell transfusion expert right I’m obviously I’m I’m more interested in what the tea cells might do when they get in you I’ve never uh been too involved in just straight up blood transfusions or but you know there’s and most blood products that we use you’re just throwing away the righted blood cells are licing them getting them out of there getting them out of there so but you know there there’s something that obviously I’ve studied enough about but um these these types of uh Therapeutics just continue to uh fascinate me around how they um sure in the the where I was going is De one of the best things I had some great mentors and one of them said hey if you really want to know Immunology go study developmental biology and I was like what are you talking about I’m like why but if you can unlock how a mother allows the fetus to grow joh a lot of the here if you could unlock those keys and man that’s something that is if if someone said what there’s an not an understudied area but there’s there’s that’s probably an area that has a lot of like value to try to unlock the keys of Immunology any immune privileged areas are some of the best things to study and your eye is one the brain is one and then of course the you know the mother’s womb is one so anyway John that that go it makes my mind go there it makes me think about these things and just any young scientist or scientists in general often times the keys just sitting right in front of you John right a lot of the everything almost every drug we talk about has some uh form of it in nature that we’re just trying to replicate or or isolate and I I don’t I think the sky is the limit I still don’t think we know all the receptors on cells let alone red blood cells as evident by her you know this you said it 40 years we discovered these a antigens and now even within the last year someone discovered a new one it’s just it’s mind-blowing right and then like everything we study somewhat static and when I say static like the surface of a cell is like you know that that’s like it’s just constantly up and down up and down moving very Dynamic and then the gene area I’m going to go deep on you John we still haven’t unlocked all of the information we got from there and how it translates into proteins and Sur sure yeah absolutely yeah yeah so yeah so be it’s interesting these like say these enzymes are from a bacteria which lives off bacteria’s acrania mucin ailia which lives off the mucus lining of the surface of the gut and it could break down carbohydrate extensions of the both type A and type B antigens and that’s where 24 comes in there’s different seven 24 different types of these um enzymes from this bacterium bacteria and then they found that seven were actually possibly capable of of taken off sufficient to to to move to this more what they’re calling universal blood um that they’re actually now they patented the enzymes um and the protocol for converting them and the hope is that this will no long term be available for you know get to get to the clinic and and be useful so yeah yeah John I’ll close up one thing I’ve worked on some platelet like synthetic platelets synthetic red blood cells great stuff a lot of Department of Defense work incredibly powerful stuff yeah so I I I thought it was like I say fascinating I learned a lot just in that one small article um let’s move on to the main topic seems there’s a fair amount to talk on that um so I think I put so basically called I called this go1 analoges Blockbuster drugs with multiple applications and the bioanalytical challenge um we we the gop1 analoges uh and the the sort of tension between diabetes treatment and obesity treatment have been in the news for a long time and and it’s it’s sort of driven by you know celebrity endorsements and all sorts of stuff and we’ve sort of just been watching this space without necessarily um feeling it was a time to talk about it we have worked on a number of these um and you know our nonp team have have supported some work and we we hope to have them in in one of our near future podcasts and maybe we’ll we’ll discuss this with them um but it just seemed that you know there was enough going on with the the glp1 analoges to sort of dig in a bit into the background um you know why they’re effective um just some of the yeah and and actually it was also brought to the four because um there’s there’s an article and I think the American Association for the advancement of science which is a really good review artic cool um which so it said innovators who fought to unlock glp1 drugs for obesity awarded the man L Bic breakthrough of the Year award um and like I said it’s a great article and it just it just seemed like a good time for us to to touch on this particular you know the bioanalysis their non routine is the is the best way to put it they they’re they’re sort of they I I would say bio analytically they’re they’re probably fun things to work with but they’re not really really because it’s like instrumental instrumentally they a pain in the neck but um we’ll touch on that later in the in the um in the topic so yeah that that’s that’s that’s the main topic let’s let’s let’s get going I know John that’s a good intro I’ll just jump in real faster maybe um you you’re talking about oligos right and that’s what makes them no no no no no no no no no these are peptides ah well my mistake so pepti should I give a should I give a little bit of the history before we I was that’s I I don’t know why my brain slipped into oligos my mistake peptides peptides because we spend so much time talking about oligos at the moment let’s take a moment and they’re glp1 peptides right and you can you can give us a big bolus of it and I’ll let you go in a second here but they’re these are bioanalytical uh challenges because of their size right they fall into that tweener space right yeah yeah so you have to do things and you can drill into it you can do things on the mass speec side that the mass speec doesn’t always like and then for us on the LBA side the piece of real estate’s so small right to begin with and the part is there’s a lot of homologies between these like sometimes it’s just a single amino acid difference right you might drill into that a little bit but like there’s a lot of like it’s tough to get an antibody that’s very specific against say the drug or the endogenous version of it or you know even in general to capture all of it it it has all sorts of challenges to it so that that’s my little bioanalytical piece but John I’m gonna put myself on mute and you tell us all about this you love this okay go ahead well it’s it’s like I say it’s it’s it’s fascinating I’ll give a little bit about mechanism of action again as the non-biologist but I think it’s relative it’s basically glp1 is glucagon like peptide it’s a hormone that stimulates insulin secretion after you eat it helps you feel full and regulates your blood blood sugar and this is where the initial interest came for it was for people with type two diabetes um where um where you know they they’re obviously um their hormone release and response can be ineffective or absence um and that’s why you know diabetes leads to to higher blood sugar levels so these drugs are Bas they’re really called they’re really glp1 agonists and they work by activating the glp1 receptor they slow gastric empty and inhibit the release of glucagon and stimulate insulin production therefore reducing hypoglycemia and people would type to diabetes they they also reduce feed intake and therefore body weight making them an effective treatment for obesity um gp1 events its main effect by stimulating glucose dependent insulin release from pan pancreatic eyelets has also been SL shown to slog gastric empty and inhibit inhibit inappropriate postmeal glucagon release and reduce it food intake so a lot of that is the reason why it it works in multiple areas and really the the like I say the focus for these was very much diabetes um but you know it’s it’s similar to similar to Viagra you know that that was developed um that that was developed in terms of it was for a cardiac indication but then they not to side effects and and they they I don’t think those side effects were expected but then they could see a market for it whereas where these it’s actually in inent part of the mechanism is the fact that you know it it it it curbs your appetite so therefore there is there’s almost immediately a a secondary Market because Beyond diabetes um the the big deal with these the the first one on the market um was it was ex I think it was it was exenatide but was marketed as bieta and I think the company was amalin who are a California based company and um it was actually it the the beta was um structurally similar to a A prot or peptide that was found in the saliva of the helila monster so I I love the like the the learning from nature piece um the the big challenge though with with glp1 or these a the the natural glp1 is that it doesn’t hang around long in the body and so it has an effect but it’s gone so if you’re trying to design a medication um then is actually they something has to be done to actually help them hang around longer and this is where a lot of this a article comes in it’s talking to Lotty be be or talking about loty bear nudson who who I think she was um she was a key scientist at um Nova Nordisk and nov ordis we’ll talk about a lot some because some agde and then um the other other person who Name Escapes me right now um was was affiliated with Lily um but actually it was it was um ly be nudson who postulated that by adding um fatty acid chains to these peptides you could extend the halflife and and the first one that she um I think it was gelati was the first example of this and I’ll keep throwing all these these different names out but it it it basically it showed the concept of the the halflife could be extended by adding the fatty acid chain onto the peptide um this is at the root of all these drugs so stide has a different length of fatty acid gen tpde which is m G which is the Lily version has a completely has another different you know again non-polar chain added to the added to the basic peptide and and you’re right there is a lot of um commonality between the um the the peptide at the root of it all um and so that that actually could play into some analytical approaches because we we talked to do da and the hybrid team about that um but so that was that was the root of of the of of basically developing drugs that could then be successfully um administered um into humans because they’re useful halflife um and and and they obviously had a good clinical effect yeah I think the half-life piece is really the key yes um you know the um what am I I trying to say the these come in many flavors right the delivery of the glp1 is some technology too John correct me if I’m so maybe I don’t know where you want to go but like when you kept talking about those chains I thought what does he mean by that like I think I know what you mean but maybe elaborate a little bit on so the a fatty acid is um I’m supposedly a chemist um well it’s really so a fatty acid is so when you think of a fat it’s it’s basically it’s a a a long non positive end negative end right it’s got no it does well the a fat wouldn’t well when you say a fatty acid that is basically a long it’s a long non-polar chain so it’s long when we talk about non-polar it’s it’s groups that aren’t yeah they’re um they’re sort of they’re I’m trying to think how to describe it and they’re sort of it’s it’s sort of neutral to to it’s it’s neither acidic nor basic it’s uh it’s sort of neutral to what’s going on with the fact you got this long neutral chain but you have a acid group at the end of it um and so that’s that’s that’s going to be your your roote of attachment onto the peptide so then what the net effect is you have then the peptide okay they’re link through the polar group and then you got this long non polar chain um it’s you know it’s like like soap is basically like a long grease but with a polar piece that’s how you yeah and I think of fatty acids and you know everything I’ve learned about what you’re talking about is through like the cell layer right so I’m kind of yeah yeah and like fatty acids have a a wide array you know one of the lower number within the lipid Bayer right so this but they those things and play a role and stuff so anyhow so you’re basically just throwing a fatty acid chain onto a pepti right that’s you’re attaching it it’s chemically bled it be so completely they wrap them into lmps and stuff or am I mistaken I don’t some of no I think I think it’s I think it’s mainly just infusion okay they just they just put this fatty ass chain peptide it’s a hormone right let’s call it what it is yes so then it then it just and that stabilizes it in the periphery increases its half life but certainly certainly they they’re not well there is actually some work been done on an oral um okay oral oral dose of of smaglo um so I remember reading about that a little back up a b let me the first one that ly be nudson up with was actually LTI we’ve worked on LTI um it not the and there’s so then we go and OIC that is um stide and and I think wovi I think is that wovi will be the diabetic medication OIC will be the the antiobesity okay so they are slightly different from each other right no I I think they’re just different dose branding yeah okay so they’re that’s often what happens dosage it’s different different dosages they give them these crazy names who knows who invent these names yes and and then the Lily one has two different names too so I think the Lily tep tide is obviously it chemical name then it was as released as a diabetic medication as Manjaro and then it now is that bound and that’s it’s a it’s a b um a b form and and so so this so those those are the main drugs currently driving the market are are basically stide and then um tepati but obviously as with any drug company they’ve all got things in in the pipeline and we will talk on new therapies and and other things later on in this this discussion um if we talk about application as weight loss drugs obviously this all comes down to that um that you know that constraint of appetite um I I read a article in the guardian must been like a year ago when I was first really reading up more on on this stuff and it sort of said you know one of the it you lose you lose um weight by obviously it reducing your appetite actually the person that was writing said it completely removed their interest in food I’m like I don’t want to anything to do with a drug anybody yeah anybody that knows our podcast has to know this is not something for us I don’t because that’s it it’s I think yes it obviously there’s a lot of people this is really beneficial for but it’s it’s not something that you you enter lightly because yeah it it impacts how you how you think about food and things like that so um yeah I know some friends that are on it it it has significantly hindered what they’re they they they’re very happy with the health benefit sure absolutely and you know I jokingly say it’s not for us but we’re we’re fortunate enough that we don’t need it although looking at me you wouldn’t be no I’m just kidding John right so but but if you have something that says hey you need to do this to help and doctors kind of indicating you’d be maybe better serve taking this or helping yourself long term then yeah but it it it definitely has um you know there’s been a noticeable decrease in that a friend of mine’s just sure as appetite but in general when he’s eating it’s like yeah it just doesn’t taste the same I mean you can still taste it but it’s not the same and that but you know I don’t know how that outweighs things but I hope I don’t ever really have to make that decision right John yeah exactly I hope I hope not too I mean you said some interesting thing around like Viagra and these that’s like a lot of medicines have this isn’t new right so yeah but but but like those types of drugs there’s some studies out there that say taking uh those cardiac medicines they John you and I should be on them right now like it’ll cut your rate of having a heart attack by like 70% the numbers are staggering so like it is something that I will start to evaluate as I get a little bit older and it’s not for I I don’t want to make it into a joke because it’s like oh you’re on this but like anything that could cut my rate of having something like that happen to me you should be interested and the numbers are staggering John with that so this is this is the same category right and um potentially potentially we have it’s been proven it’s been proven that these cardiac medications they say they don’t have side effects but we know there are and you wonder but L what they’re starting to find out over years of researching them is that they are very safe have huge benefits not just with heart attacks they may be preventing Strokes in elderly men and they’re actually thinking about giving it to women this is like this Crossroad with these weight loss drugs can you can talk about the I don’t know if the Optics on it is what I want to say but like there’s a lot of noticeable people in Hollywood taking it the the scarcity of it the people who really need it driving the cost up there’s some things here and then there is some like hey what is the long-term effects of these you know it’s still a peptide you’re injected into yourself right yeah I mean I I come up with all I think all drugs have side effects yeah well so but but yeah do the benefits outweigh the side effects that’s clearly they do here in some you know for it’s it’s the healthy people taking it that you kind of wonder about that’s what I me so so the other guy who whose name I’ve now found is a guy called Rich who’s the other Prize winner along with ly beer nudson is a guy called Richard deari who’s now a professor of biochemistry and Guild chair in biomolecular Sciences Indiana University and like I say he was at Lily and the so we we we lump um tepati in with STI simply because it’s the two drugs both going at the same market and both showing effect and uh obviously beneficial effect for people the tpde is different it’s actually a a what they call a jip glip because it actually um if I can find chip it’s a it’s a it’s another different approach again he was working to try and make a a different synthetic glucagon to help patients recover faster during hypoglycemic attacks um and he was collaborating with a with someone called let me no can’t find his name but he they were they were looking at into these different glucagons one went into obese animals and mouse lost weight but it was by a different mechanism um and they they sort of thought this glue could going to be used to generate a futile cycle that decreased body weight by increasing energy use he wanted to know if this weight loss effect from the stimulating glucagon receptors could be integrated with the appetite suppressing effect of glp1 a single safe molecule for unprecedented work loss weight loss sorry not work loss um working with grad students he found that they could in fact design a single hormone that could stimulate both the glucagon and glp1 receptors and so it’s so basically cut a long story short um they they focused on gluc glucose dependent insulinotropic polypeptide or Gip is is is it’s another hormone and and like gp1 jip is a gut hormone that triggers insulin secretion um so by they tpde actually combines the Gip and glp one mechanism and it’s a jip glip I think Gip glip inhibitor something like that um so that’s that’s the the Lily drug is is slightly different it’s not a pure glp1 because it’s Al got this Gip activity too and so that’s that’s the root of of that as the as the alternative drug yeah no it’s it’s definitely a um an interesting story John one that’s taken it’s this isn’t an overnight success a lot of what you just describes going way back into the 90s right some of the earlier uh type of 90s stuff that you’re I think you’re kind of talking about there like well um but yes yes yes and not just that like this is dense the the biology behind this is pretty fascinating but I I I um I I think it’s important to note a couple you know again we’re back into like finding things from the gut right we just T touched on that in our news and notes earlier right um and and all of this stuff uh has bloodb brain barrier implications to it I don’t know if you want to talk about that a little bit yes I just read just looking at that that is it’s another fascinating these These are fascinating drugs that becomes a techn so now that like when you think about it it’s it starts to click as to why there are so many out there and how you know you just think aren’t they all the same or aren’t they all just treating diabetes no there’s so many different things that like we’re kind of eliciting and yeah there’s a lot of crossover right you I mean that I’ll touch on the blood so basically it’s still according to this article how the drugs achieve weight loss has been the subject of discussion and debate um but there was part of it was can they cross the could the glp1 cross the bloodb brain barrier and so the team at novonordisk looked at ltid in the bodies of mice and while the blood brain barrier kept lorag from moving into the the brain it was able to access small structures that line the brain’s fluid filled cavities and from there bind to neurons and hypothalamus um a part of the brain involving in involved in regulating food intake at the same time the drug binds to neurons in the hind brain her research showed and activates other circuits through these combined effects the drug affects both Cate C Sati and hunger Pathways effectively stop something called food noise the Relentless desire to keep eating so it it’s yeah it’s it’s fting I mean it is fascinating but you can imagine what they just said there is is it’s just I’m not saying it’s easy to elicateam Mouse but it’s virtually impossible to do it yeah it just is and it’s great that it’s come this far and it’s John I I I think it’s some with with a with some uh continued research and continued evolution in biotech and Pharma this might be something that’s like in the water like fluoride for all we you know what I mean like I don’t know Al my son asked like oh fluoride I’m like it’s good he’s like it is I’m like yeah why wouldn’t you want fluoride in the water but you know what do I know so so yeah so that’s the backround to the drugs absolutely fascinating in terms of the physiology Etc um obviously there there’s there’s there’s they were developed for type 2 diabetes they had then the benefits for obesity that has set up something of a conflict and also it’s it’s it’s we I think we touched on this a long time ago there is sort of some some Med medical practitioners don’t necessarily view obesity as a as a genuine a genuine Condition it’s like well yourself yeah that’s important and so so I think there was like the the looking at drugs for obesity is almost fed with suspicion and and it does touch on it again this article that Nova Nordisk they weren’t sure they really want to go in that direction because is it is it a real thing however let’s let’s move on from that because you’ve got the two camps who both want and need this medication um it’s these These are obviously fairly complex chemical structures I don’t know how long it takes to to make a significant amount of any of these drugs but right now Supply is out no demand is outstrip in Supply so although the these drugs are are are already generating billions of dollars worth of revenue for the for the companies that sell them they can’t make enough to um to actually sell as much as people want crazy so we touched on the purchase of Calum by Nova Nordisk um a few podcasts ago because that was like totally out the blue and seemed like just a very um bizar strange very out you know what’s the out there kind of purchase but brilliant right like not I I say bizar until you like because normally Farm companies or biotechs aren’t buying CR right but or G facilities so it was weird but then like when you dug into it it’s like oh this is brilliant but this is this is done to help alleviate their their constraints in terms of their um their their supply for you know some agites basically I think if you’re paying attention I feel like some other cdmos or GMP facilities are getting purchased by other Giants in this space dominoes right that’s what’s happening and and Lily have announced that they’re they’re increasing their production capacity but right now they their their supply constrained up with manaro Etc and so it was just in the news this week they they’ve increased their their guidance for the year in terms of the revenue they expect from inj but it’s still it’s still really the supply issue is the biggest challenge for for for these companies it’s not it’s not it’s not trying to sell the drug because people want it it’s um it’s it’s actually making the drug so I think maybe we’ll go go ahead I suddenly I thought is there challenges to making it but that let’s don’t answer that there probably are I we’ll stick to our agenda but go ahead I I would say I don’t know enough about it but I mean I think I mean yeah we’re not GMP G for I think I think the making the peptide is fairly routine but then be it’s that yeah mean structure stability all that stff yeah I I don’t know I I I would be I would love to know actually but I don’t like anything else after you do it a few times it might get easier but I’m sure there’s nothing easy about this yeah but it’s also who who knows I don’t know what the starter material is and how many steps it takes and that’s obviously that’s part of it because even even some simple drugs going to be an incredible number of steps to get to the end product I just don’t know I mean you know natural I wonder if I can get like a natural version of glp1 huh I wonder if that’s well that’s that’s where this all started that’s I know but like everything now is you know it’s engine it’s a Rec coment or however you want to think it’s it’s strictly chemistry it’s all synthetic that’s the word I’m looking for so we yeah so we can step on we can should we a good it’s a good segue into the bioanalytical challenges that’s exactly John and we and I I’m talking over you go ahead you turn so yeah if if we if we look at it from the from the the manufact from the drug company’s point of view their challenge is the supply issue but obviously as part of a development of these and new similar drugs they’re still going to be doing PK studies that are going to use um Labs like Kass um and like like I mentioned earlier on we have worked on stide and we’ looked at lorag tide um dagati we’ve worked on these these these drugs are all they all have you know that they have that peptide chain they have a lipid addition to it but the lip size lip Edition it can be can really have a a huge effect on how they behave so let’s so basically on these drugs you’ve got the peptide which is really what I we would consider a a polar um a polar piece you had this this lipid this fatty acid add this lipid chain that now you’re adding this big non-polar chunks you completely change the property of of the um of the of the drug in in a in a bioanalytic IAL setting you know if if you’re looking at a peptide it’s predictable how you your chromatography is going to be predictable you you know how it’s it we you got a good handle on what it’s going to do in terms of chromatography Mass speec Etc um these these become chemically more challenged because of that that nonpolar chain it you no longer you just dealing with a pure um a pure peptide you’re dealing with this this this this m Ule that has two very different regions that want to behave very different differently from each other um and so for us we we we found that yes we can we can come up with asss that’s that’s that’s fine um but what we found it even even though with these changes in length of FTI acid chain the one a one acid to the next doesn’t necessarily translate because it because I think the I think toti has isn’t just a pure fatty acid there’s other pieces in it that so it will it will behave differently from others it’s just a pure fatty acid addition the length of the fatty acid will change how how they how they act within an extraction so much to unpack with what you’re saying so the first question I keep great it’s great you’re you’re trying your best but I’m gonna ask the first one right um the um you’re saying that all the drugs on the market themselves even though you there’s no I guess the way I think there’s no Universal assay for GL glp1 peptides right because of the way the or is that a fair statement or is there like a off-the-shelf method that we could use we have well certainly with lcms we found that one set of conditions that would run ideally for one won’t don’t really translate to another that’s not surprising right if fat acid chain is different on each of them exactly my next question change you know not a mass spec expert but you know I hang out with people that are right and so there’s there’s peptides it makes sense that a peptid straightforward because it’s got kind of like a like a um a sequence to it that is a weight to it that you know and then maybe it’s down AEP an amino acid here or there so you kind of get a good understanding of where it’s supposed to be right you put these chains on it how is it is each of the chains different are there more than one chain right how does that the the current drugs at the moment all have one chain yeah that’s what I figured because of the real estate I know that but within that sorry John because I think of it I kind of think of like pegal of stuff right each fatty acid chain have a like a different I might be now is my a density to it or whatever the the size that the spec is looking at you know on the reader is that so does there a profile to or is it kind of a solid line with like a just think of like like the analytical method for it versus the bioanalytical method talk a little bit about that so so the way I would look at it is that the one set of conditions that you have for one um will give you you’re aiming for particular sensitivity that may be good for that one but if you then apply those same conditions to the next with a diff maybe a longer fatty acid chain that actually your sensitivity may be garbage in comparon you really lot a lot that’s good to know right so like because just because you got a functioning method for one of these ones doesn’t mean you’re just going to plug and play and it’s easy to adapt to it might right it might be but you know there is some development and you still got to revalidate well you’re going to have to revalidate analy but it may give you it may give you the direction to go in but you you don’t go into this exp if if I was going with a simple um say uh series of analoges of a of a small molecule you’d expect that one set of conditions will work for most of them you know there may be something with an outlandish bit more outlandish side polar or side chain that affects it but these doesn’t really translate one to ask I’m going to take a left turn on you what about lot to lot variation within the drug the same drug I’m I’m not concerned about that that pretty consistent so so even back to that one question I don’t if you actually answered it I probably talked right through you but is is the within the drug products themselves is the consistency of that fatty acid chain pretty good or is it or is there variability in like the size of that that chain I I I think as it’s a as it’s made as a chemical I think it has to be consistent I kind like Peg right pegs are messy right this is yeah it’s this this is be I think well pegs but you’re pegs you’re talking you know tens of thousands yeah I guess they’re not even comparable right so even what I’m saying even if this is 10% different you’re not the mass Spec’s not going to see that right yeah I the these are ones where you’ve basically got the peptide won’t differ from lot to lot and you you’re adding another group and I again I don’t know all the steps to go through all this to make the actual compound but it’s going to it’s it’s it’s going to be the same batch to batch if it isn’t you got if it isn’t you got a problem you know kind of I’m losing track of time we’re this is I’ve suddenly become very interested in glp1 bioanalysis right so we got one more item to go over this yeah yeah this GP this isn’t actually the biggest issue with them the biggest issue is actually they’re a pain in the neck to to so so for us OB lcms is a sequential process so it’s like if you have a b batch of 96 samples say a 96 well plate you inject sample one anal then inject two Analyze That injects well three analyze that and you go through it the ideal ideal assay um if you have one going from one sample to the next you see no effect from one sample to the next it’s what we call carryover you want to see no carryover that’s the ideal methodology these things or these analytes because of that that non-polar chain are sticky and so what we would call a sticky compound and so carryover is actually the biggest analytical challenge that sort of that piece of you know changing one assd going from one to next that’s less of an issue um it’s you know you expect maybe moving from one analy to another you’re going to change conditions that that we can live with but carry that that carryover it’s how we Define it is if going from one high concentration to sample to low concentration sample if you’ve got a significant amount of carryover your your readout of that low concentration sample is going to be off because there’s a proportion that’s come from that high concentration sample that’s artificially boosting it because these things hang around the system and so I don’t I think it’s I think it it’s not just there’s there’s various places in the lcms path where you see carryover mainly in the injector and then the head of the column and then sometimes in the tubing between um but the so injectors usually e easier to address because you change solvents cleaning Cycles etc etc in carry over in the head of the column is is can be awful to deal with so these these compounds are sticky and they they both they basically are an issue in terms of the inject to that can you address but they also we get carryover from the head of the column so that actually that adds a lot of um run how do you remedy that John run time and and really convoluted approaches to address carry over to get that under control so because what we needed to when you say convoluted is that like having to clean the column with something in between yeah you can either do you can go the approach of doing blank blank samples between each sample which you wouldn’t want to do cuz that doubles your run time or what we’ve we’ve done is actually do like uh if you’re running a gradient you get to the end you then do like a dummy injection that runs through the gradient again so effectively washes the column so it’s but it’s all adding cycle time that you don’t you don’t want to be using because you want to get on to the next sample to analyze but because of the nature of these compounds then you have to do it you know that is that’s probably the overwhelming thing you have to deal with and we could like say hopefully with with the the nonp team we can touch on that and they can they can talk more about this what John’s alluding to is we’re going to we’re we’re maybe this is a good segue we’re gonna have our GP you know the people who do this come on and talk a little bit more about it because we find this to be incredibly exciting okay John uh this is I’m I’m done grilling you right I felt like I put you on the hot seat because you can tell I I I find top the topic fascinating one thing I would like to touch on because I talked I’m this isn’t I talked about these really talking about the non-gp teams work on these these glp1 analoges um at the ebf in 2022 um and one thing we did very quickly um was because he’s a these have a peptide route we also asked the hybrid team to look at how what what kind of sensitivity could we get if we digested these and went for a smaller piece of the amino acid um cuz you you one thing I haven’t touched on these are around 4,000 molecular weight so it’s like there’s a I can’t remember how long the peptide chain is but then obviously the the the fatty acid on top of that and but if we could digest the uh peptide portion of that then we would get a we could get a specific peptide or a peptide that’s common to multiples but the nice thing about that approach is you actually have you’re back to that route of having a an analyte that behaves predictably it also takes away from the carry overpiece so we did we just did a very quick test as a proof of concept we never took it into Matrix but if we found that with if if we were asked to work on these where someone really needed ultimate sensitivity maybe this this maybe this would be a route we’d go down rather than trying to measure them intact actually go for the smaller piece to see how low we can go and hopefully then get away from a lot of the analytical issues that we we face with these these these drugs so you talked subtly you mentioned control and that’s a big yeah so even if there is some um level of noise right as long as it’s controllable that’s that’s how we tackle bioanalytical problems right um so so this was great John I I feel like uh we want to touch on the future of GOP analoges or new this because I think it’s it’s really really a future it’s future days and then where antiobesity is going um because yeah obviously the the the the pharmaceutical industry is there to make money and so not only are Lily and Lily and Nova Nordisk are out there by themselves at the moment there’s a lot of people snapping at their heels um but so but it’s interesting because you have researchers looking at where can well L and Nova Oris are looking where these drugs are going independent researchers looking where they can go but then you’ve also got a number of different approaches to T tackle obesity so if we just talk on let’s let’s wrap up some agti and toti in terms of new the new therapeutic areas these are just these are just news items within the last you know few months um we have seen that hold on a tick yeah are you talking about a presentation from October 4th right or what what no no no I’m actually just soorry I’m just saying here’s some of the news articles about these two drugs um so Lily plans for zet bound label expansion into sleep apnea in mid 2024 and the back of a phase three win so there’s sleep Happ there there’s a different indication OIC and movi have taken over have taken over obesity treatment can of help with cancer too um so as study found that they appear to reverse the impairment in cancer fighting natural killer cells seen in people with ob obesity this is like say this is all investigative this is where we I that that’s this is some good stuff John so so then um some magti um we go shown cardiovascular benefit again this time in the phase three step um HF PF Trail on top the expected weight loss so there’s possible cardiovascular benefits um there’s possible Dash yeah Ash is another one and then smoking and and drinking wow John they’re smoking they’re smoking drinking sorry so John as we get a little bit older all we need is Viagra all we need is some Viagra and a few shots of GOI right we’re good so yeah the there’s there’s question can they can GOP 1es help you quit smoking or drinking that’s the mo that was the most out there in terms of these articles I mean think about it it’s it’s got It’s got legs right imagine if you could design one that makes you the smoke not like disgust to you or the drinking not tastes good right that that could really do it right because that seems it seems to play on the senses a little bit which does make me a little bit I don’t know about nervous is the right way but like it’s it’s just it’s just a little bit kind of somewhat mysterious still right well I think I think it comes down to that that piece of the study with mice where it went into the pock pockets of the brain that help with you know feeling s got in there right so so John you actually the the myth of the bloodb brain barrier right we’re all we’re all out to say nothing got through there well we know that’s not true just is there another area that a differently designed one could go to that would affect other things I I don’t know but I mean it does tell you what what is out there um so just just to move on to obesity itself there are currently 116 assets in Phase 1 to three it tells you how much attention is been paid to obate at the moment and and obviously Lily and Nova Nordisk have their follow-up drugs um some of them are6 trials is that it 116 no 100 116 assets assets wow so just that’s like so assets being you that that’s compounds however you want to think of it’s 116 different potential drug candidates yes yes exactly w wow and and in terms of of you know the some new modalities one that was in the news was was fractile have a glp1 obesity gene therapy which outd does stide for weight loss in m so very early work but now Gene therapy’s looking at this and then you’ve got youve got oral drugs where Lily and fizer have both got oral drugs that are designed for this approach you know I know it certainly there’s a oral form of smaglo I’m not sure how that’s that that has I’m not sure how that’s been administered or what’s there to help it be delivered as a oral drug as as opposed to the usual injection but there are oral drugs in the way in terms of actually anti-obesity drugs in phase three there are this is all according to Nikia survey there’s there’s seven in phase three um boring ingleheim have got a a Gip GP glucagon receptor Agonist Eli Lily have two Gip glip or three Gip glip glucagon receptor Agonist so assuming that they’ll be either better or complimentary to tpde and then different indications um eurofarma labor trees have a a combination two small molecules that’s an Oro Nova orisk have atide combination with another another similar compound um it’s called krinti um schwind who I’ve never heard of of another Gip glip glucagon receptor Agonist teada have a gastric and pan pancreatic lias inhibitor so it’s another oral drug so and people are always interested in the oral simply because of ease of ease of administration y Li C too I think too right yes so it just tells you how much interest there is out there and like I said that’s why I thought it was a good time to to talk about the G I think one of the biggest surprises just all the indications that it has John right so it’s really cool yeah um exactly and yeah CU it’s well I think I found a little a little little figure that’s pulled off the web that just showed the number of number of organs that seem to be impacted by by glp1 yeah it’s all the food we eat too right yeah yes yes so John uh I think we’re we’re we’re good uh this has been a a very fun uh episode one that uh you’re you’re obviously well versed in a little bit more than I am I I hope I was able to contribute a little bit today I felt on the sidelines but that’s okay John no um where I’m going is uh let’s talk about our weekend maybe I don’t know about you but I got some exciting stuff going on I yeah absolutely we’ll do it I just want to wrap up because yeah I think it was it it was good but also it’s a counterbalance to some of the other no I know I was that’s where I was going and I no and say yeah yeah yeah no I know what you mean like hon you know say when you say well vers honestly a lot this I I’ve been paying attent being paying half an eye to it but I really learned a lot in the last couple of days just sort of looking at it and then sort of piecing things together in my mind and and is it’s it is I’ve obviously known about the drugs and the as a bioanalytical person think about the bio bio analysis of them that’s why right this is both yeah actual most of the time you see oh a new indication oh okay that’s nice type of thing but it’s but bio analytically these are really interesting drugs yeah’ been they’ve been over the last few years you you’ve just learned about it so much because we’re doing it right like yeah and that that’s part of the why it’s so great to work here you you know you can we’re Mo almost all the things that are coming to us are like the innovator you know Innovation wise and not necessarily what’s behind us so that’s that’s why we’re this is so near and dear to you now it’s because you’re kind of getting into it and we’re learning more and more about it I think the the entire bioanalytical Community is learning a lot about it right not just us we all everybody is because it’s become it’s just exploded right yeah so yeah as a as a cro it’s it’s funny you’re in two minds you you actually you want all your asses to go smoothly you want all the easy compounds But ultimately you don’t really cuz you actually really like things like these that are the analytical challenges CU they’re the ones you learn from they’re the ones that you actually grow with and you know they’re the ones that save lives too or benefit mankind too right yeah yeah yeah so it it’s the the they they’re fascinating be because like I say it’s sometimes it’s really nice to have a drug that just runs day in day out you know if you get the samples there’s going to be no issues from our perspective there’s carryover sensitivity is fine called generics John right have some some drugs that I’ve worked on in the past you know like every run run you did you knew it was going to pass it was going to look really clean all the standards in qc’s be really tight and you like those once in a while but ultimately how do you you that’s not very interesting to talk to other people about the interesting ones are the are the nightmare drugs yeah nightmare the nightmares from from bi the flesh methods huh John is you’re saying bio analy you know we didn’t even talk about immunogenicity there is that’s still something that’s a little bit TBD here I do think people do have to some immunogenicity against it but I I think it’s pretty um to me a lot of this is uh peptides are in a strange class um you know you’ll know they’re neutralizing because it just Drug’s just going to stop working uh it’s already hard enough to try to measure these things I don’t know measure and antibodies against them is I do think there’s um I don’t think it’s mandatory though John right it’s it’s in a a class that doesn’t make it I don’t think they have to do it but I I I could be mistaken I know we yeah I I don’t I don’t know because I I don’t think about I feel like it has to do with um so it’s low risk and if the risk assessment of the immun of of it comes pops up somewhere then you you’re going to have to take a look at it um I I um you know I feel like have not a feel I know we’ve looked at anti- GPL glp1 uh antibodies for sure and I know there are like you know you can purchase them right that’s how some of the IP steps yeah and that was actually going to be one of my questions in terms of the you know the the LBA approach to these because I did it’s just it’s tough I I approach these purely as an LCS person that’s my background and so I know that we we can obviously do them they they they obviously you know the successful asses out there they fragment they do they do what needs to be done so we can measure them um it’s really interesting I mean I I’d love to know what Novo Nordisk did with these in the early days because I know for example when it comes to insulin that’s a little bit bigger but and when we’ve done we’ve done anti-insulin some of the that’s what I was referring to but like John I think it falls into like one of those categories where often times you got to do do it maybe early and then it can stop right there’s some there and then like immunogenicity is just evolving so much John we probably need to have a podcast in and of itself the whole the preclinical non-clinical space is definitely changing and then there are some recent uh things within the community where they they you know they want to really move away from the the bridging format that we do often and the positive control you know that we rely on you’ve heard me talk about this a little bit they want to move away from that and just do signals so like put put the drug down like a real serological immunogenicity acid kind of like what you would do for seeing if someone a vaccine efficacy kind of using that approach but that that’s a whole another podcast and uh it’s a it’s a really um I think it’s going to happen right as soon as this is a train that’s getting out of the station and but more importantly it’s not a cost thing or or an ease thing this is just better science so that’s that’s the piece that becomes really important but it is a significantly less you know we’re doing three tiers for immunogenicity and there’s some approaches that could be less so John like uh thanks great REM before I tell you about my to quickly wrap up this on the insulin piece because it would be fascinating to know how how Novo looked at this in the early days because I’ve you know obviously there’s this sort of peptides and proteins there’s that sort of you know we look we can look at them both with the LBA and LCS and there’s sort of some there’s a there a there’s a point at which he becomes you know up to a point it’s LCS only and then or mostly LCS and then there’s a a middle ground where it becomes both involved and and then you go large molecule is still it’s like LBA is more accepted than lcms and this is not me trying to top one technology over the other I visited Nova Nordisk years ago um and like I said that it was really to talk about insulin but insulin’s what 5700 molecular weight whereas these are 4,000 molecular weight and I that’s a big part of it right so yeah I I presented actually some of our LC M’s data from the like they did inulin Gage and in and inulin the quicker you know the the different acting time frames on insulins presented to a noval group and the data was Immaculate from an lcms perspective but their take at that point was you know we have a really good group for generating antibodies we don’t really feel the need to look at lcms and even though the data that I was presenting totally matched the the the levels you needed to be at Via LBA they that was very much their approach so I want I’d love to know knowing that group’s mentality how did they measure sagla being that little bit smaller but being very much an LBA group in terms of how they thought obviously I’m not gonna have that conversation right but it would I hope at some point maybe I do noville who can tell me all about it but is it’s it was just really interesting as a mass spec person walking in it and and really I was never going to get anywhere with them because they had a way that worked and I’m totally fine with that it was just it was very interesting for me as a as a as more of a a chemist and a biologist to sort of you know be be greeted with that kind of reaction despite the data anyway let’s move on we’re done no I John thanks for sharing some of that uh for me this is graduation season John right so I’ve got a son that uh the next time we have a podcast he will I think pretend it depends on how soon it is but he’s a couple weeks away from graduating high school so John this is eye popping to me never have I been so popular in my life you should see the number of graduation potties they started last weekend out here John I got like four or five I got I got I need like a event ATA for my weekends the next few weekends and even like the day we’re having his graduation potty we’re going to be running all over the place I got family coming in town from Boston from Colorado from Nebraska it’s going to be a whirlwind for me but this weekend it kicks off I think there are like I said about four of them we got to go to we still got some things to plan for but this is this has suddenly become the month of May will be dedicated to uh my uh son’s senior year graduation parties and actually I don’t mind them John I get to hang out with a lot of parents that I like so anyhow that that’s what I’ll be doing and I boy is it a great year to be I’ve been landscaping and cooking and gotta mention got to make some pasta sauce I might pull out my piece of machine but my you know all life’s going good and uh you know it’s it’s it’s a beautiful time of the year out here but um I’ll be I’ll be tied up with that stuff what say you so when’s When’s graduation it is the 19th of May Sunday oh nice okay yeah so so for us I was lucky that was this is an after recording rather in the morning cuz we’re in the middle of having our our front porch um so the our house is 1872 built um the front porch we used to use a lot but then we noticed it was quite spongy at the front so the wood wasn’t as good as it could be and we we’d been trying to get builders in to to do something about it and just for whatever reason never never succeeded so we actually have been able to engage uh um what they called morning du Builders or morning de as you would call them um it’s actually it’s a it’s a young guy who’s actually a best friend of my daughter and her husband he set up his own business and he he does really top quality work he’s done some stuff inside so to this this week has basically been the removal of the front portch that we had so we we’ve been in demolition mode and then he’s got the the house patched stop ready to in terms of cuz we’re expecting rain this weekend and then he’ll go into building mode and we have a completely new front porch on the house so it’s it’s actually it’s really interesting to a watch how it all comes apart and and and and then getting an insight into like how the house was built um and you know we bought the house it’s got it had like vinyl siding on it and so we knew what was under the vyl siding there’s always that concern was the vyl siding there to hide stuff actually just cuz it was the fashion at the time I think it’s been I think he’s found it it was the fashion at the time yeah good deal said what he’s seeing is pretty sound underneath so it’s actually it’s that’s that’s been dominating the week so he like say C the afternoons are usually gone because they’re just disposing of all the stuff they’ve broken down this weekend is actually first weekend my wife has been back in a couple of weeks cuz she’s been in the UK for brother’s 60th birthday so we’ll actually get get to spend some time together um yeah and and then obviously you know that that’s been really nice because we we did the trip to Venice Etc which was fantastic but then I think she she she was back a day went off to to New York City to to do some work there and then she was back for like another day and then gone so we we barely had any time to to connect so that that’s going to be our our our weekend you just reminded me that I’ve had been trying to get the house ready I mentioned people coming in and like I got sink issues that have been taking up my Sunday evenings a neighbor has been helping me I should have just called the plumber one of those moments where yes or I might have saved some money but it’s been you know oh three trips to Menards and still don’t have the damn right piece for the sake you know Menards is like a Home Depot John out here yeah so yeah you’re making me cring cringe a little bit and I I threw 60 bags of mulch down uh over the last say three weekends as well this will be the first weekend I’m not throwing 20 bags of mulch on my and I laid 200 yards of the bug you know the repelling of the weeds it’s all my body killing me but I’m sure our audience is like hey why don’t you wrap this up so John um I’m I’m good John I I’m going to say goodbye to our audience it’s been a pleasure doing this podcast with you I’m looking forward to number 77 we’re going to be up to right with our uh Discovery Mass Spec team done so y yes thank you very much it’s been I hope I’m sorry I got a little bit carried away talking but you know that’s what that’s this this the what fora and bioanalysis is what excites us so you got to be Unapologetic about your passion take care bye [Music] [Music] [Music] [Music] [Music] [Music] [Music]