WEBVTT 1 00:00:00.120 --> 00:00:03.560 Welcome to Pharma Talk Radio. This podcast is focused on 2 00:00:03.640 --> 00:00:07.519 achieving oral delivery of peptides to formulation and molecule design 3 00:00:07.519 --> 00:00:11.320 approaches from the twenty twenty four pod Partnership Opportunities in 4 00:00:11.400 --> 00:00:15.720 Drug Delivery Conference. For more information on the pod conference, editorials, 5 00:00:15.759 --> 00:00:19.679 podcasts or webcasts, please visit drug desh Delivery dot org. 6 00:00:20.000 --> 00:00:21.399 Thank you and enjoy the podcast. 7 00:00:21.960 --> 00:00:25.760 I'm le Pasha, I lead the Novel Delivery Technology Steam 8 00:00:25.760 --> 00:00:28.920 at Novatas down the road you're in Cambridge, and I 9 00:00:28.960 --> 00:00:33.079 would like to briefly introduce the panel here today that 10 00:00:33.119 --> 00:00:37.240 will be talking through the oral delivery of peptides via 11 00:00:37.320 --> 00:00:38.960 formulation and molecular designs. 12 00:00:39.039 --> 00:00:41.000 This is the topic that we have for the panel. 13 00:00:41.640 --> 00:00:45.479 So firstly, and it back from Astra Zanika heading the 14 00:00:46.359 --> 00:00:53.200 Advanced Drug Delivery Teams there, Andy Lewis at Quotient Sciences, 15 00:00:53.240 --> 00:00:58.719 the CSO from and Suman Lutra, director at Mark for 16 00:00:58.840 --> 00:01:03.560 the Discover Very Pharmaceutical Science Esteem. So thank you all 17 00:01:03.640 --> 00:01:06.920 for being here. Probably if you could share a bit 18 00:01:07.079 --> 00:01:10.079 on you know, the topic why we have here, so 19 00:01:10.159 --> 00:01:14.760 the purpose of this topic on what makes peptide so 20 00:01:14.920 --> 00:01:18.519 difficult to deliver or really speak to some of your experiences. 21 00:01:19.000 --> 00:01:23.239 If you have an example of two, perhaps each of 22 00:01:23.280 --> 00:01:24.640 you can talk to that a bit. 23 00:01:26.439 --> 00:01:27.920 Okay, I'll go first. 24 00:01:27.959 --> 00:01:32.920 So, yeah, a question science is we're a CDMO, so 25 00:01:33.000 --> 00:01:36.319 we develop manufactured drug products, but we're different in that 26 00:01:36.359 --> 00:01:39.799 we're also a CRO so we've got two clinical trial units, 27 00:01:40.599 --> 00:01:43.680 and we've really pioneered the integration of drug product manufacturing 28 00:01:43.719 --> 00:01:47.359 and clinical testing so that you can optimize drug products 29 00:01:47.840 --> 00:01:48.799 in response. 30 00:01:48.439 --> 00:01:49.280 To clinical data. 31 00:01:49.359 --> 00:01:52.760 And as such, we've we've worked on quite a number 32 00:01:52.760 --> 00:01:54.879 of oral peptide programs. 33 00:01:55.920 --> 00:01:56.799 Somewhere in the region. 34 00:01:56.840 --> 00:01:59.519 Well it's over fourteen programs at the moment, eleven different 35 00:01:59.519 --> 00:02:04.719 peptide All of them have been permeation enhancer programs, so 36 00:02:04.760 --> 00:02:10.680 I think we've evaluated ten different permeation enhancers. It's given 37 00:02:10.719 --> 00:02:14.319 us a really privileged insight into the state of the 38 00:02:14.439 --> 00:02:19.159 art for oral peptides and how different companies are approaching 39 00:02:19.240 --> 00:02:24.240 the clinical development. Obviously we see the pre clinical data 40 00:02:24.319 --> 00:02:27.960 and obviously lucky enough also to see the clinical performance. 41 00:02:28.199 --> 00:02:32.479 And I think for me it's really fascinating because I think, 42 00:02:34.000 --> 00:02:37.199 I mean, there's decades of work been done to try 43 00:02:37.240 --> 00:02:42.360 and understand the biopharmaceutics of oral peptizes. And I think 44 00:02:42.400 --> 00:02:45.000 we do know a lot more than we used to, 45 00:02:45.159 --> 00:02:48.159 but also there's still a lot to learn, and I 46 00:02:48.199 --> 00:02:52.919 think there's been some great advances, but the biopharmaceutics of 47 00:02:53.000 --> 00:02:55.840 oral peptized probably requires a. 48 00:02:55.840 --> 00:02:56.360 Lot more work. 49 00:02:56.400 --> 00:02:59.639 I think someone you want to talk of it. 50 00:03:00.080 --> 00:03:02.960 Thank you, Lipa, and thanks for the invitation to share 51 00:03:03.000 --> 00:03:04.039 my perspectives here. 52 00:03:05.319 --> 00:03:06.360 You know, many years. 53 00:03:06.159 --> 00:03:09.280 Ago there was a lot of innovation that was happening 54 00:03:09.879 --> 00:03:11.719 in the OORO delivery of biologics. 55 00:03:12.879 --> 00:03:14.800 It turned out to be quite challenging. 56 00:03:14.879 --> 00:03:18.520 So the company, you know, the industry as all pivoted 57 00:03:18.599 --> 00:03:23.840 towards patient compliance through improvement and devices and administration, but 58 00:03:23.919 --> 00:03:28.360 there's still interest in taking those established mechanisms and enabling 59 00:03:28.439 --> 00:03:32.599 patient delivery through oral administration. So that's where the peptides 60 00:03:32.639 --> 00:03:34.719 come in. And of course at Mark we have a 61 00:03:34.719 --> 00:03:38.520 lot of interest in immunology and oncology and enabling AORO 62 00:03:38.560 --> 00:03:42.840 delivery or peptides for those patients. So, as Andy mentioned, 63 00:03:45.159 --> 00:03:49.639 the biopharmaceutics principles apply for or delivery and the you know, 64 00:03:49.719 --> 00:03:51.919 the first one comes to mind for a formulator is 65 00:03:51.960 --> 00:03:57.400 what we test is stability, solubility and permeability. Stability is 66 00:03:57.840 --> 00:04:01.919 modulated through early measurements because peptides when they go to 67 00:04:01.960 --> 00:04:05.240 the stomach they see low pH and then they see 68 00:04:05.599 --> 00:04:09.199 various prote ltd enzymes in the GI system. So we 69 00:04:09.360 --> 00:04:13.479 have screens that exist that we can measure and as 70 00:04:13.479 --> 00:04:17.199 a formulator we can you know, make changes to the 71 00:04:17.199 --> 00:04:22.000 formulation to avoid the degradation mechanism as well. Second is solubility, 72 00:04:22.040 --> 00:04:24.600 and as a formulator, again we have a lot of. 73 00:04:24.600 --> 00:04:27.279 Tools to measure and influence solubility. 74 00:04:27.639 --> 00:04:32.319 But the biggest hurdle for biology for the peptide deliveries permeability. 75 00:04:32.879 --> 00:04:34.279 These peptides, on an. 76 00:04:34.199 --> 00:04:38.439 Average twelve to fifteen more amino acids are about two 77 00:04:38.480 --> 00:04:42.319 thousand average daltons and they are high molecular weight as 78 00:04:42.319 --> 00:04:45.079 well as very polar, which makes them beyond role of 79 00:04:45.079 --> 00:04:49.480 five molecules that are not really onally bioavailable. So that's 80 00:04:49.519 --> 00:04:52.279 the biggest challenge we have. And as Andy mentioned, there 81 00:04:52.279 --> 00:04:56.439 are many techniques, formulation interventions and permeation. 82 00:04:56.120 --> 00:04:58.319 Enhancers being the biggest one of them. 83 00:04:58.360 --> 00:05:01.399 That's the chemical approach that's out there, but there is 84 00:05:01.439 --> 00:05:06.399 a ceiling to it. There are approved drop products, there 85 00:05:06.399 --> 00:05:09.240 are many in the clinic that just show us unmentioned 86 00:05:09.319 --> 00:05:12.920 yesterday point five point seven person or by availability. 87 00:05:13.480 --> 00:05:15.639 So that's where the opportunity space. 88 00:05:15.439 --> 00:05:19.920 Is to really lift that ceiling and reduce cost of 89 00:05:19.959 --> 00:05:23.000 goods and improve patient compliance through reducing image size. 90 00:05:23.079 --> 00:05:25.560 So that's the opportunity I see for peptides. 91 00:05:25.959 --> 00:05:28.040 Thanks and it would you like to add to them? 92 00:05:28.160 --> 00:05:31.480 Absolutely? I love over old path sides. 93 00:05:31.600 --> 00:05:34.279 It's the modality I've been at for the longest time 94 00:05:34.319 --> 00:05:37.319 with my career. I did my graduate work on oil 95 00:05:37.439 --> 00:05:41.120 delivery of path sites. I still remember the first time 96 00:05:41.439 --> 00:05:45.319 I did a study where I put panzoma PAP side 97 00:05:45.759 --> 00:05:50.920 in red intestine or homogene it was gone so quickly 98 00:05:51.040 --> 00:05:55.079 that I couldn't measure it. So the prime I agree 99 00:05:55.079 --> 00:06:00.480 with your permeability is an issue God. Before that, we 100 00:06:00.879 --> 00:06:04.240 need to treat modern nature because she sees pap tides 101 00:06:04.279 --> 00:06:08.839 as food and papodi days is pancreatic path todays is, 102 00:06:09.000 --> 00:06:12.319 especially in the GI track, will chew them off faster 103 00:06:12.439 --> 00:06:16.319 than you can say peptide. So there's a design effort 104 00:06:17.199 --> 00:06:21.839 up front where we need to design metabolic liability out 105 00:06:21.839 --> 00:06:25.680 of pap tides, and we will discuss that here today, 106 00:06:25.920 --> 00:06:29.000 and then I absolutely agree we have an issue after 107 00:06:29.079 --> 00:06:34.839 that that's permeability as well. And I've seen every time 108 00:06:34.959 --> 00:06:38.879 I've encountered an old path tie getting at the path 109 00:06:38.920 --> 00:06:42.720 today's issue before you can do your first PK studies. 110 00:06:42.759 --> 00:06:45.879 Even IVY, it's an issue, but getting at the path 111 00:06:45.879 --> 00:06:50.360 today's issue is the paramount to. 112 00:06:50.439 --> 00:06:55.160 Teg Thanks for starting off with some of these challenges 113 00:06:55.199 --> 00:06:59.040 but also opportunities like you rightly mentioned things. So what 114 00:06:59.079 --> 00:07:01.480 we have heard in the last two days at this 115 00:07:01.600 --> 00:07:06.720 conference is also achieving this patient adherence but also being 116 00:07:06.759 --> 00:07:10.480 competitive in this field. It definitely needs drug delivery approaches 117 00:07:10.560 --> 00:07:15.480 beyond probably permation and answers like we do today. If 118 00:07:15.519 --> 00:07:20.240 Anatan Suman, based on your early discovery and drug delivery experience, 119 00:07:20.279 --> 00:07:23.879 you can share a bit of insights on how an 120 00:07:23.920 --> 00:07:28.279 early molecular design approaches could look like. And perhaps also 121 00:07:28.279 --> 00:07:32.560 if you want to look at different delivery targets for 122 00:07:32.680 --> 00:07:35.480 a given peptide, if you can add a bit on 123 00:07:35.560 --> 00:07:37.480 that and share with the audience. 124 00:07:37.040 --> 00:07:41.920 Here sold you one, Okay, go ahead. I mean this 125 00:07:42.240 --> 00:07:46.839 first the issue around how to design the molecule, and 126 00:07:46.879 --> 00:07:50.279 then there's the second question what to design it for. 127 00:07:51.040 --> 00:07:54.399 If you look at molecular design first and foremost right, 128 00:07:55.720 --> 00:08:03.279 there's two approaches to overcome both pats bases and permation. Right, 129 00:08:03.720 --> 00:08:09.000 you can insert non natural amino acids, you can libidate 130 00:08:09.079 --> 00:08:14.079 it to make it more hydrophobic, and you can cyclize. 131 00:08:14.639 --> 00:08:18.560 These are the sort of three key standard approaches to 132 00:08:18.680 --> 00:08:24.160 molecular design. Right Now, there's the pros and cons. Right, 133 00:08:24.279 --> 00:08:28.839 you can actually design quite by available path sites. But 134 00:08:28.920 --> 00:08:30.920 then can you make a product out of it? 135 00:08:31.160 --> 00:08:31.360 Right? 136 00:08:31.480 --> 00:08:35.399 If you have ten non natural amino acids and cycles 137 00:08:35.399 --> 00:08:40.759 and stables, and you know they may become especially for 138 00:08:40.879 --> 00:08:46.000 more common diseases, they may become too expensive to produce. 139 00:08:46.639 --> 00:08:50.799 So it is really threading a needle between you know, 140 00:08:50.879 --> 00:08:54.480 the low buyo availability of linear liberated path sites and 141 00:08:54.519 --> 00:08:59.360 the higher bioavailable ability you can get with highly designed 142 00:08:59.360 --> 00:09:03.360 path sides versus your cost of goods. The linear path tize. 143 00:09:03.440 --> 00:09:05.919 You can also make the cells the other ones you 144 00:09:06.000 --> 00:09:07.879 need to synthesize. 145 00:09:07.159 --> 00:09:10.200 Which is more expensive and nonetheless. 146 00:09:09.840 --> 00:09:14.480 Of course what you wanted to sign for. We have 147 00:09:14.679 --> 00:09:20.960 touched about path today stability and permeability, but you can 148 00:09:21.000 --> 00:09:24.679 also design for maybe absorption and different paths of the 149 00:09:24.759 --> 00:09:29.799 GI tract. Right, You can get, for example, you have 150 00:09:29.919 --> 00:09:35.039 less pathadases in the barka maculsa. It's a route that 151 00:09:35.080 --> 00:09:39.840 we don't explore that often. You can use nanoparticles etcata. 152 00:09:39.919 --> 00:09:42.679 To get to the lower GI tract as well, so 153 00:09:42.840 --> 00:09:44.320 those are options as well. 154 00:09:46.399 --> 00:09:48.200 So then you would like to add someone. 155 00:09:48.360 --> 00:09:51.840 Yes, thank you for bringing up the point about you know, 156 00:09:51.879 --> 00:09:56.360 what are the molecular handles for designing the peptides. And 157 00:09:56.600 --> 00:09:59.039 I just want to add, you know, cyclization have life 158 00:09:59.120 --> 00:10:02.480 extensions non natural amino asseys methylation. 159 00:10:03.039 --> 00:10:04.080 These are very you know. 160 00:10:04.120 --> 00:10:09.639 Established tools in our medicinal chemistry tool set to to 161 00:10:09.799 --> 00:10:15.279 designs you know, stable and well we can call them permeable, 162 00:10:15.360 --> 00:10:18.559 but you know, as best as they can be in 163 00:10:18.720 --> 00:10:22.759 our chemical you know design process. But then there's also 164 00:10:22.919 --> 00:10:27.039 designing the molecule for the delivery system, making sure that 165 00:10:27.120 --> 00:10:27.639 you have the. 166 00:10:27.679 --> 00:10:30.720 Right pH solubility profile and if. 167 00:10:30.519 --> 00:10:33.200 You do need to modulate it, say for example through 168 00:10:34.440 --> 00:10:37.399 self emultifying drug delivery systems and making sure you know, 169 00:10:37.480 --> 00:10:42.000 those properties that make it enabled for that delivery system 170 00:10:42.120 --> 00:10:44.399 are also died in into the molecule design. 171 00:10:45.120 --> 00:10:46.120 We also as. 172 00:10:45.960 --> 00:10:49.320 Formulators, we layer in formulation engineering on top of the 173 00:10:49.360 --> 00:10:52.039 molecule design. And this is where you know, and I 174 00:10:52.080 --> 00:10:57.440 can curve with a net that our standard approved products 175 00:10:57.440 --> 00:11:00.480 in the market for peptides are you know, immediate released 176 00:11:00.519 --> 00:11:01.399 rug deglorary. 177 00:11:01.080 --> 00:11:03.879 System with premation enhancers. But then there is an. 178 00:11:03.840 --> 00:11:08.080 Opportunity that if we need to avoid the you know, 179 00:11:08.120 --> 00:11:14.759 either the stomach degradation or peptidase driven metabolic pathways in 180 00:11:14.840 --> 00:11:19.120 certain parts of the GI, what is that regional area 181 00:11:19.200 --> 00:11:21.399 in the small interest tine where you want to deliver it. 182 00:11:21.720 --> 00:11:23.879 And it's not a simple delivery or just. 183 00:11:23.799 --> 00:11:27.799 A peptide, because permation enhancer is a functional recipient, we 184 00:11:27.919 --> 00:11:31.120 need to make sure that we are targeting to deliver 185 00:11:31.279 --> 00:11:34.720 both the pe as well as the peptide at a 186 00:11:34.799 --> 00:11:37.519 defined region of the GI. So that's where the formulation 187 00:11:37.639 --> 00:11:41.639 engineering comes in where the opportunity space is. One more 188 00:11:41.679 --> 00:11:43.320 thing I want to add here is we are talking 189 00:11:43.399 --> 00:11:47.320 about the molecule design and in the discovery space, and 190 00:11:47.399 --> 00:11:50.360 one important aspect of there is sitting in the discovery 191 00:11:50.360 --> 00:11:54.320 space where we are influencing the discovery of the molecules, 192 00:11:54.360 --> 00:11:58.200 we need to have an appropriate in vitro in vivo correlation, 193 00:11:58.399 --> 00:12:02.200 which is missing for these large molecules. And not only that, 194 00:12:02.519 --> 00:12:06.480 the pre clinical to clinical translation is also missing, which 195 00:12:06.519 --> 00:12:11.039 makes a discovery engine of peptides very slow. So if 196 00:12:11.039 --> 00:12:14.200 there are opportunities for GUT on the chip based models 197 00:12:14.240 --> 00:12:17.840 to really expedite and be able to you know, screen 198 00:12:17.919 --> 00:12:22.200 molecules faster, that would help the field overall. 199 00:12:24.240 --> 00:12:28.679 And one more common great point on the first camp propitcies. 200 00:12:29.120 --> 00:12:32.240 One thing that I've also seen that's quite important when 201 00:12:32.279 --> 00:12:36.720 you design molecules is to keep if you use excipients 202 00:12:36.759 --> 00:12:41.559 such as permation enhances to produce some early studies around 203 00:12:41.879 --> 00:12:46.120 how the molecule interacts with the permation and hands. But 204 00:12:46.279 --> 00:12:51.480 otherwise great outliner and the first camp propies I can. 205 00:12:51.360 --> 00:12:52.600 Just add add to it as well. 206 00:12:52.639 --> 00:12:55.759 I actually see in recent years, I think there's been 207 00:12:55.759 --> 00:13:00.799 a convergence of drug drug discovery and engineering and drug delivery. 208 00:13:02.320 --> 00:13:06.000 I think a third of the most recent programs that 209 00:13:06.039 --> 00:13:09.519 we've done the peptides have been specifically designed for oral 210 00:13:09.559 --> 00:13:11.159 delivery using some of these. 211 00:13:13.120 --> 00:13:13.840 Strategies. 212 00:13:14.320 --> 00:13:18.480 But you know, there's technologies such as phage display where 213 00:13:18.519 --> 00:13:21.720 you can create huge libraries of peptides and screen them 214 00:13:21.799 --> 00:13:25.879 for properties of interest. You know quite often that will 215 00:13:25.879 --> 00:13:31.440 be receptor binding, but you can also screen for stability 216 00:13:31.480 --> 00:13:32.679 to peptidases, etc. 217 00:13:33.759 --> 00:13:35.720 Great thanks for sharing these insights. 218 00:13:36.039 --> 00:13:37.919 I believe one of the point that you mentioned about 219 00:13:37.960 --> 00:13:41.159 this in vitro in we will connect or disconnect in 220 00:13:41.320 --> 00:13:45.720 the WABC it this is also an apportionatefy nicely highlight 221 00:13:45.759 --> 00:13:49.840 and probably speaks to some of these collaboration potential we're having. 222 00:13:50.080 --> 00:13:54.799 Building models specifically to address this kind of issue would 223 00:13:54.879 --> 00:13:57.000 be quite helpful in the industry. 224 00:13:57.720 --> 00:13:59.840 And you rightly introduced. 225 00:13:59.320 --> 00:14:02.679 A course sciences and also the rich experience that has 226 00:14:02.720 --> 00:14:07.000 come through with actually testing into clinic some of the 227 00:14:07.279 --> 00:14:11.480 peptides with permission and answers and other tools and techniques. 228 00:14:11.519 --> 00:14:14.639 If you can share, based on your experience what has 229 00:14:14.679 --> 00:14:18.360 worked well perhaps and also where you see things need 230 00:14:18.399 --> 00:14:20.240 to further improve, that'll be great. 231 00:14:21.399 --> 00:14:23.679 Yeah, wells worked well well as a CDMO. I'm not 232 00:14:23.720 --> 00:14:26.360 allowed to tell you what the best permeation enhancer is, 233 00:14:26.399 --> 00:14:28.919 but I think what I can say is the answer is, 234 00:14:30.159 --> 00:14:34.200 and people have published this that some permeation enhancers seem 235 00:14:34.240 --> 00:14:36.919 to work well with some peptides and not others. And 236 00:14:36.919 --> 00:14:39.399 I think it's probably to the point and that was 237 00:14:39.440 --> 00:14:43.320 making in terms of the interaction between the permeation enhancer 238 00:14:43.360 --> 00:14:51.480 and the peptide, but potentially also you know how it's delivered. 239 00:14:51.759 --> 00:14:55.919 You know again people, many people have published we need 240 00:14:55.919 --> 00:14:59.639 to deliver the permeation enhancer to the epithelium at the 241 00:14:59.679 --> 00:15:04.080 same time time as the peptide, so that that's a 242 00:15:04.120 --> 00:15:10.799 really really important consideration when when we're advancing or a 243 00:15:10.879 --> 00:15:14.639 peptides into the clinic. You know, bearing in mind we've 244 00:15:14.639 --> 00:15:17.320 got this functional and excipient, we need to deliver them 245 00:15:17.399 --> 00:15:21.679 at the to the epithelium at the same time. Compared 246 00:15:21.679 --> 00:15:25.080 to normal first in human study, we tend to use 247 00:15:25.120 --> 00:15:29.519 more complex dosage forms. So for a small molecule first 248 00:15:29.519 --> 00:15:32.039 in human quite often people will use a drug in capsule, 249 00:15:32.200 --> 00:15:38.480 maybe enabled intermediate, but quite often the first in human 250 00:15:38.519 --> 00:15:42.919 study will be a tablet formulation. Many of these permeation 251 00:15:43.080 --> 00:15:46.080 enhancers need to be in the tablets in really high amounts, 252 00:15:46.200 --> 00:15:49.799 so that these are not your normal tablet formulations and 253 00:15:49.840 --> 00:15:55.879 that can present analytical and manufacturing challenges. But also if 254 00:15:55.879 --> 00:16:00.960 you look at the published you know, phase one clinical 255 00:16:01.000 --> 00:16:04.519 studies on oral peptides, so the ribelsa swan and the 256 00:16:04.600 --> 00:16:12.639 merks PSK nine inhibita, you'll see that the formulations need 257 00:16:12.679 --> 00:16:16.159 to be optimized, you know, because of you know, what 258 00:16:16.240 --> 00:16:20.480 we don't know is what the best performing formulation is 259 00:16:20.519 --> 00:16:23.080 in humans, and so generally there needs to be an 260 00:16:23.159 --> 00:16:29.039 expanded singlear sending dose phase where people is fairly exploratory 261 00:16:29.120 --> 00:16:33.440 exploring what is the best performing formulation for that peptide. 262 00:16:33.519 --> 00:16:37.759 And typically people will evaluate the dose of the peptide, 263 00:16:38.600 --> 00:16:43.720 the levels of the permeation enhancer, the ratio between the two. 264 00:16:45.039 --> 00:16:46.840 Inter subject variability. 265 00:16:46.879 --> 00:16:50.120 In intras subject variability is something that's really important to 266 00:16:50.639 --> 00:16:54.879 get a good handle on, potentially the site of delivery, 267 00:16:55.360 --> 00:16:59.480 so in terrat coating with and without terror coating. 268 00:17:01.440 --> 00:17:02.840 Amongst amongst other things. 269 00:17:03.480 --> 00:17:07.240 And I recently reviewed all of our oral peptide programs 270 00:17:07.240 --> 00:17:11.200 that we've done for a number of clients, and I 271 00:17:11.319 --> 00:17:14.519 compared to the pre clinical by availability to the. 272 00:17:14.359 --> 00:17:17.640 What we achieved in humans, and. 273 00:17:19.160 --> 00:17:22.799 What it certainly showed was which might be pleasing as 274 00:17:22.839 --> 00:17:26.079 a formulator. When you change the formulation, you change performance, right, 275 00:17:28.319 --> 00:17:31.480 And if you look at them as a hole, there 276 00:17:31.519 --> 00:17:38.640 isn't a great correlation. However, interestingly, dog by dog by 277 00:17:38.680 --> 00:17:44.640 availability seems to correlate fairly well with humans. So yeah, 278 00:17:44.960 --> 00:17:48.599 the data that we've got relatively small data maybe, but 279 00:17:48.759 --> 00:17:53.440 fourteen clinical studies seems to show that or dog if 280 00:17:53.480 --> 00:17:56.599 you can what you can achieve in a. 281 00:17:56.640 --> 00:17:58.200 Dog, you can achieve in humans. 282 00:17:58.240 --> 00:18:01.279 However, the best performing formulation is different. 283 00:18:03.079 --> 00:18:04.319 So that's what we've found. 284 00:18:04.640 --> 00:18:09.160 Yeah, that's a really good point pre clinical species because 285 00:18:09.559 --> 00:18:15.279 the delivery of peptides using chemical permation enhances is a 286 00:18:15.319 --> 00:18:20.000 functional mechanism which depends on the physiology, and the physiology 287 00:18:20.039 --> 00:18:23.400 between humans and preclinical species is different. Yes, I think 288 00:18:23.480 --> 00:18:27.200 as a formulator we need to pay close attention towards 289 00:18:27.240 --> 00:18:32.920 the castric volume, the pH the upper GI, the mucus, 290 00:18:34.480 --> 00:18:39.200 castric motility, transit time. All of those aspects pay play 291 00:18:39.240 --> 00:18:42.559 a very big role as we are screening molecules and formulations. 292 00:18:42.559 --> 00:18:44.079 But yeah, I agree with you. 293 00:18:43.519 --> 00:18:49.440 You know, I think categorically dog may correlate better, but 294 00:18:49.480 --> 00:18:51.160 then humans are still humans. 295 00:18:51.920 --> 00:18:54.519 Can I just start of coming here? I think it 296 00:18:54.559 --> 00:18:57.960 becomes even more important to have that knowledge as we 297 00:18:58.119 --> 00:19:01.119 think outside the permation and here. So if you look 298 00:19:01.160 --> 00:19:06.039 across this conference, there's been many sort of innovative devices, etc. 299 00:19:07.039 --> 00:19:11.119 To get at all delivery of biologics, and having that 300 00:19:11.359 --> 00:19:16.839 understanding of the physiology and the biopharmaceutics becomes even more 301 00:19:16.880 --> 00:19:17.720 paramount there. 302 00:19:19.000 --> 00:19:21.200 Great, that's a very nice segue because one of the 303 00:19:21.240 --> 00:19:24.000 aspects that I'm sure just as I'm curious about in 304 00:19:24.039 --> 00:19:26.839 this room others as well. So we talk about them 305 00:19:26.880 --> 00:19:30.240 now probably the near future. But when it comes to 306 00:19:31.160 --> 00:19:34.000 making a breakthrough in oral delivery of peptides, and coming 307 00:19:34.039 --> 00:19:36.599 back to your points and where probably we are doing 308 00:19:36.640 --> 00:19:40.839 smaller increments information enhancers and yet not there to do 309 00:19:40.920 --> 00:19:45.519 a justice to delivering peptides orally and with a higher biovailability. 310 00:19:46.119 --> 00:19:47.799 If you, each of you have to think of a 311 00:19:47.799 --> 00:19:53.160 blue sky aspiration for delivering peptides orally, what is that 312 00:19:53.319 --> 00:19:57.279 technology which probably is out there yet not developed, but 313 00:19:57.359 --> 00:20:00.240 also something that is not out there. What you wish 314 00:20:00.359 --> 00:20:02.920 that it is available? What would that be for each 315 00:20:02.960 --> 00:20:05.920 of you? So know soonne if you want to get status. 316 00:20:07.359 --> 00:20:11.960 So if you guys heard the keynote from Bob Linger yesterday, right, 317 00:20:12.799 --> 00:20:17.519 he has brought from his you know lab spuns the 318 00:20:17.519 --> 00:20:20.839 com various companies have spun off that brought the Runnie pill, 319 00:20:21.039 --> 00:20:23.720 the biograil, and there are a couple other options like that. 320 00:20:25.000 --> 00:20:29.920 I just want to be cautiously optimistic of that delivery 321 00:20:29.960 --> 00:20:33.519 system because that's so far I think it's been in 322 00:20:33.519 --> 00:20:36.720 the clinic just as an empty pill to test the 323 00:20:37.000 --> 00:20:41.839 mechanism safety, not so much the delivery, and it's been 324 00:20:41.880 --> 00:20:45.160 claimed in pre clinical species that that gives about sub 325 00:20:45.240 --> 00:20:49.200 Q like biovailability. So double digits anywhere between twenty to 326 00:20:49.200 --> 00:20:52.880 forty percent has been reported, which is great because as 327 00:20:53.000 --> 00:20:57.240 as I mentioned right, the current standard threshold is less 328 00:20:57.240 --> 00:20:58.000 than one percent. 329 00:20:58.119 --> 00:21:00.519 So I think that is a blue sky idea. We 330 00:21:00.680 --> 00:21:04.039 just have to be really you know, working towards that. 331 00:21:04.200 --> 00:21:07.440 What is our patient population that we are trying to 332 00:21:07.799 --> 00:21:11.400 make it a better delivery system for over injectables and 333 00:21:11.559 --> 00:21:14.599 these are mostly chronic indications. So if we move from 334 00:21:14.680 --> 00:21:20.640 weekly monthly injections to daily pills and they are working 335 00:21:20.880 --> 00:21:25.759 through lack of a better work, you know, injecting into 336 00:21:25.839 --> 00:21:28.319 the GI on a daily basis, I think there are 337 00:21:28.440 --> 00:21:32.640 CMC regulatory hurdles that we need to demonstrate that these 338 00:21:32.680 --> 00:21:34.440 are safe for chronic indications. 339 00:21:34.519 --> 00:21:36.640 So that's the blue sky right now. 340 00:21:36.640 --> 00:21:40.559 As we see, there are other options that we haven't 341 00:21:40.599 --> 00:21:42.640 looked into, and I would be very curious to hear 342 00:21:42.880 --> 00:21:45.880 I know and had mentioned in trabuccal intrant nasal. 343 00:21:45.920 --> 00:21:48.920 Are there other roots of administration that are not. 344 00:21:49.079 --> 00:21:51.720 As invasive and can get us to better than one 345 00:21:51.720 --> 00:21:53.720 person by availability of captides. 346 00:21:55.599 --> 00:21:57.319 Great to add more to that. 347 00:21:58.240 --> 00:22:03.200 Sure, absolutely, I mean I think for the barcal route 348 00:22:03.240 --> 00:22:06.319 what you get away where is the enzymes. You still 349 00:22:06.359 --> 00:22:11.400 have the permeability issue, but muco adhesive patches for baccle 350 00:22:11.519 --> 00:22:16.160 delivery can still in some peptides be an advantage. We 351 00:22:16.200 --> 00:22:20.839 don't see any on the market though right Other things 352 00:22:20.880 --> 00:22:25.440 that have been explored pre clinical is nanoparticles, muke adhesive 353 00:22:25.519 --> 00:22:29.400 to the lower GI tract as well. Again less enzymes 354 00:22:30.599 --> 00:22:36.759 more but again still a permation issue. The item that 355 00:22:36.839 --> 00:22:40.920 I wanted to bring up we had earlier today we 356 00:22:41.079 --> 00:22:45.319 had a session of novel exhibients. You know, we are 357 00:22:45.400 --> 00:22:50.279 still using them, I'm sorry, same old permation enhances. You know, 358 00:22:50.400 --> 00:22:54.680 there's a lot of exhibient innovation that potentially could be 359 00:22:54.759 --> 00:22:58.119 done there as well. So but the excipient chemist out there, 360 00:22:58.519 --> 00:23:01.720 that's an option as well, if you want me to 361 00:23:01.839 --> 00:23:06.240 go really blue sky. I've heard about this for quite 362 00:23:06.279 --> 00:23:11.440 a number of years now, like microbial drug systems that 363 00:23:11.559 --> 00:23:16.599 actually produce the pathtide of the biologic institute in the intestine. 364 00:23:17.559 --> 00:23:20.519 I met a first time about seven or eight years ago. 365 00:23:20.680 --> 00:23:21.559 I've not seen it. 366 00:23:21.640 --> 00:23:26.240 Progress, but it seems like conceptually a really good idea, 367 00:23:26.319 --> 00:23:29.400 but that's very much out in the blue sky. 368 00:23:30.200 --> 00:23:32.680 Thanks for sharing that. Anatids reminds a bit of this 369 00:23:32.880 --> 00:23:35.319 enviable you know, cell generating. 370 00:23:34.759 --> 00:23:42.359 Systems don't get many bacterial toxins can transverse gut epithelia 371 00:23:42.400 --> 00:23:44.519 as well, So yeah, it's quite the idea, I think. 372 00:23:44.640 --> 00:23:48.440 Ken. So, whoever can crack that nut, you know, will 373 00:23:48.480 --> 00:23:50.079 crack that market. I think. 374 00:23:51.480 --> 00:23:51.759 Great. 375 00:23:51.799 --> 00:23:54.160 Any anything that you would like to add to what 376 00:23:54.200 --> 00:23:58.119 you would wish to see running some clinical trials from 377 00:23:58.119 --> 00:23:59.480 say ten years from now. 378 00:24:00.200 --> 00:24:05.240 Yeah, Well, the first time I saw the ingustible devices, 379 00:24:05.279 --> 00:24:06.839 I was kind of blown away, But then I was 380 00:24:06.880 --> 00:24:12.240 also I also kind of became a little bit It 381 00:24:12.319 --> 00:24:15.319 was kind of skeptical in that there's obviously going to 382 00:24:15.319 --> 00:24:19.480 be cost associated with manufacturing of them and how much 383 00:24:19.599 --> 00:24:23.599 patients would accept them. So they're getting great by availabilities, 384 00:24:23.599 --> 00:24:26.839 and it comes to that kind of cost benefit analysis, 385 00:24:26.880 --> 00:24:32.839 particular patient groups, particular indications, et cetera. I think, you know, 386 00:24:32.880 --> 00:24:39.319 the premation enhancers they do suffer from from food effects, 387 00:24:40.400 --> 00:24:44.720 which are you know, quite significant. I think technologies that 388 00:24:44.799 --> 00:24:48.519 can address that, and I think in fact, there was 389 00:24:48.599 --> 00:24:52.319 there was a talk earlier on a device that was 390 00:24:52.400 --> 00:24:56.200 that was there's been developed that again just kind of 391 00:24:56.559 --> 00:25:02.519 effectively controlling the location of the peptide as it's being 392 00:25:02.559 --> 00:25:07.039 delivered with permeation enhancers and also allows you know, these 393 00:25:07.119 --> 00:25:11.000 kind of patches that biodesi patches as well, I think 394 00:25:11.319 --> 00:25:15.079 are really really interesting developments that could address many of 395 00:25:15.119 --> 00:25:16.279 the issues we've discussed. 396 00:25:17.319 --> 00:25:20.519 Great now, thanks thanks a lot for sharing these insights. 397 00:25:21.000 --> 00:25:23.839 I think so given the promise and also given that 398 00:25:24.200 --> 00:25:28.079 there are immense of portunities in this field into where 399 00:25:28.119 --> 00:25:31.720 we all strive for delivering peptides differently in this case orally, 400 00:25:32.519 --> 00:25:35.599 it is important, really important to look at patenting opportunities, 401 00:25:35.640 --> 00:25:41.440