WEBVTT 1 00:00:00.120 --> 00:00:03.680 Welcome to Farmer Talk Radio. This podcast is focused on 2 00:00:03.720 --> 00:00:07.080 sustained release innovations to reduce patient burden from the twenty 3 00:00:07.120 --> 00:00:11.240 twenty four pod Partnership Opportunities in Drug Delivery Conference. For 4 00:00:11.320 --> 00:00:15.439 more information on the pod conference, editorials, podcasts, or webcasts, 5 00:00:15.759 --> 00:00:18.839 please visit Drug desh Delivery dot org. Thank you and 6 00:00:18.920 --> 00:00:19.839 enjoy the podcast. 7 00:00:20.359 --> 00:00:23.039 We have a pretty exciting topic to walk through and 8 00:00:23.359 --> 00:00:26.079 also a great panel to guide us through that discussion, 9 00:00:26.920 --> 00:00:31.079 and that's on sustained release innovations to reduce patient burden. 10 00:00:31.239 --> 00:00:33.280 And maybe just to kick off a little bit on 11 00:00:33.399 --> 00:00:36.280 sort of why this topic, and I think that really 12 00:00:36.359 --> 00:00:42.159 is around what we would call patient centricity conversations we've 13 00:00:42.159 --> 00:00:44.759 had during the past two days. I think that's a 14 00:00:44.799 --> 00:00:48.840 topic that has emerged and popped up recurrently, and at 15 00:00:48.920 --> 00:00:51.759 least from my perspective, when we talk about patient centricity, 16 00:00:51.759 --> 00:00:58.600 that's really about us as pharmaceutical scientists drug delivery scientists, 17 00:00:59.240 --> 00:01:03.359 putting the patient first and actually recognizing the patient. And 18 00:01:03.399 --> 00:01:07.400 in that context, you know technologies that provide sustained release, 19 00:01:07.640 --> 00:01:12.439 long acting injectables, implantable based systems, these are technologies which 20 00:01:12.519 --> 00:01:17.319 definitely strive to put the patient in the center by 21 00:01:17.359 --> 00:01:22.879 hopefully elevating the convenience experience for that patient also ultimately 22 00:01:22.959 --> 00:01:26.840 hopefully achieving improved compliance and as the title of this 23 00:01:26.840 --> 00:01:31.519 panel discussion also alludes to significantly hopefully reducing the burden 24 00:01:32.359 --> 00:01:36.599 that a patient can experience in taking their medication and 25 00:01:36.640 --> 00:01:41.959 also ultimately improving the therapeutic outcomes. And I think what 26 00:01:42.079 --> 00:01:47.439 will dive into today is different facets of the world 27 00:01:47.480 --> 00:01:53.319 of sustained release technologies, looking into you know, considerations around 28 00:01:53.799 --> 00:01:57.560 the technology space, but also other elements such as you know, 29 00:01:57.959 --> 00:02:03.560 considerations around the payer et cetera. So, without further ado, 30 00:02:04.879 --> 00:02:08.520 I think we'll start out with some self introductions of 31 00:02:09.039 --> 00:02:13.120 the panel that is sitting next to me. So, Adam, 32 00:02:13.159 --> 00:02:14.680 do you want to kick us off. 33 00:02:15.199 --> 00:02:18.159 Yes, thank you Steven, and thank you for having me 34 00:02:18.199 --> 00:02:20.800 as part of this panel. My name is Adam Mendelssohn. 35 00:02:21.080 --> 00:02:23.240 I am one of the co founders and the CEO 36 00:02:23.800 --> 00:02:27.439 of Vivani Medical. At Vivani Medical, we are aiming to 37 00:02:27.479 --> 00:02:31.360 address some of the challenges that Stephen just mentioned with 38 00:02:31.680 --> 00:02:36.560 very long acting subdermal drug implants that can provide steady, 39 00:02:37.280 --> 00:02:41.680 minimally fluctuating levels of medicine over many months. 40 00:02:41.680 --> 00:02:42.240 At a time. 41 00:02:43.039 --> 00:02:47.439 We're utilizing a novel drug delivery technology that's based on 42 00:02:47.560 --> 00:02:51.199 a nanoporus membrane, which is going to be advanced very 43 00:02:51.240 --> 00:02:55.120 soon into a first clinical study with a GLP one 44 00:02:55.199 --> 00:02:59.680 agonist as our lead program. I've been working in this 45 00:02:59.759 --> 00:03:03.960 space drug delivery for many years. In my PhD, I 46 00:03:03.960 --> 00:03:06.520 did work with drug delivery and even before that work 47 00:03:06.639 --> 00:03:11.080 worked on implantable drug delivery systems for interthecled delivery for 48 00:03:11.199 --> 00:03:14.439 pain management. And it's really a pleasure to be here 49 00:03:14.560 --> 00:03:16.520 and participate on this panel with everyone today. 50 00:03:17.599 --> 00:03:18.039 Excellent. 51 00:03:18.120 --> 00:03:20.479 Hi everyone, my name is Manishcripta. This is my first 52 00:03:20.599 --> 00:03:26.919 part meeting, enjoying it absolutely. I work at gsk SO 53 00:03:26.960 --> 00:03:30.360 I lead the injectable struct product design and development team. 54 00:03:30.439 --> 00:03:34.319 I team goes across small molecules and biologics. We add 55 00:03:34.360 --> 00:03:38.039 polysorbate to both of those teams. That keeps the interfacial 56 00:03:38.120 --> 00:03:44.400 tension low, keeps us all together. So one of the 57 00:03:44.400 --> 00:03:48.039 things that motivates me in terms of patient centricity is 58 00:03:49.080 --> 00:03:52.280 the work that we've done in terms of HIV and 59 00:03:52.280 --> 00:03:55.840 how we've developed and launched some projects which are long 60 00:03:55.879 --> 00:04:00.280 acting injecticles, more small molecules, but a significant trund position 61 00:04:00.400 --> 00:04:03.960 from multiple tablets a day to six injections per year, 62 00:04:04.080 --> 00:04:06.840 and that makes a huge difference, not just the efficacy, 63 00:04:06.879 --> 00:04:10.479 but safety and the patient adherence aspect of brings one 64 00:04:10.520 --> 00:04:12.879 hundred percent compliance when a person actually goes to the 65 00:04:12.879 --> 00:04:14.280 doctor and gets their injections. 66 00:04:14.280 --> 00:04:16.000 So very glad to be here today. 67 00:04:17.519 --> 00:04:20.720 Ahi, everyone, My name has been I'm the founder of 68 00:04:20.800 --> 00:04:26.040 fast Trax. Fastrax is truct delivery based the CDMO. Over 69 00:04:26.079 --> 00:04:33.120 the last twenty years, fastas has developed various microsphere formulations 70 00:04:33.199 --> 00:04:39.959 for since their release for our partners. So we leveraged formulation, 71 00:04:41.079 --> 00:04:46.560 modify the formulations microsphere formulations to achieve you know, different 72 00:04:46.560 --> 00:04:49.839 type of release profiles ranging from like a week to 73 00:04:51.399 --> 00:04:55.279 as many as six months. And you know, we've developed 74 00:04:55.399 --> 00:05:00.399 these formulations to different stages preclinical and clinical stage is. 75 00:05:03.439 --> 00:05:03.920 Perfect. 76 00:05:04.319 --> 00:05:07.480 But I think we have an eminent panel and certainly 77 00:05:08.240 --> 00:05:13.000 excited to to get the discussion underway. Maybe starting out 78 00:05:13.879 --> 00:05:17.560 rather diverting a bit away from technologies from a starting point, 79 00:05:17.560 --> 00:05:20.439 but maybe zooming out and considering sort of the bigger 80 00:05:20.480 --> 00:05:24.319 picture and ultimately kind of the value proposition that we 81 00:05:24.959 --> 00:05:28.959 perceive with you know, sustained release technologies, things that can 82 00:05:29.000 --> 00:05:32.399 extend the release of our of our drugs. I think, 83 00:05:32.480 --> 00:05:35.839 you know, that's maybe something that intuitively to drug delivery 84 00:05:35.879 --> 00:05:39.000 scientists is very obvious. But you know, we heard, I 85 00:05:39.000 --> 00:05:42.879 think quite compelling, an interesting panel discussion earlier this morning 86 00:05:43.240 --> 00:05:46.199 from a kind of payers perspective and how they perceive, 87 00:05:47.199 --> 00:05:51.399 you know, value proposition of new drug delivery technologies, et cetera. 88 00:05:51.920 --> 00:05:56.480 Curious to hear the panel's perspective on, you know, what 89 00:05:56.720 --> 00:06:00.240 is the value proposition that we're trying to realize with 90 00:06:00.680 --> 00:06:04.040 the types of technologies that each of you are working with. 91 00:06:05.040 --> 00:06:08.120 We'll take a start on that. I think that this 92 00:06:08.279 --> 00:06:12.199 is a very important topic because although there are definitely 93 00:06:12.279 --> 00:06:15.879 people that would prefer the convenience as being the main 94 00:06:15.959 --> 00:06:19.920 reason that they would go with sustained release technologies, there 95 00:06:19.959 --> 00:06:24.959 are also very compelling reasons on health outcomes and pharmacoeconomics 96 00:06:25.560 --> 00:06:29.759 why sustained release technologies can be useful. We heard yesterday 97 00:06:29.759 --> 00:06:33.240 morning our chair Ali Jackson mentioned one hundred and twenty 98 00:06:33.279 --> 00:06:38.240 five thousand patient deaths attributable to non adherence per year, 99 00:06:38.879 --> 00:06:42.920 which is more than correctal different breast and breast cancer combined. 100 00:06:43.600 --> 00:06:46.639 It's really a tremendous figure. But in addition, to that 101 00:06:46.759 --> 00:06:50.800 there are about five hundred billion dollars in avoidable healthcare 102 00:06:50.839 --> 00:06:55.319 costs in the US per year attributable to adherents. There 103 00:06:55.360 --> 00:06:58.480 have been studies that have looked at the difference in 104 00:06:59.240 --> 00:07:02.720 as an example, clinical trial results where patients are more 105 00:07:02.839 --> 00:07:06.839 likely to take their medicine and real world outcomes. One 106 00:07:06.879 --> 00:07:09.480 study in the GLP one space a number of years 107 00:07:09.480 --> 00:07:13.639 ago showed that a very big delta between clinical trial 108 00:07:13.680 --> 00:07:17.040 and real world results that three quarters of that could 109 00:07:17.040 --> 00:07:21.680 be attributed specifically to medication adherents. There have been other 110 00:07:21.720 --> 00:07:25.800 studies that have shown in the diabetes field that five 111 00:07:25.920 --> 00:07:29.480 hundred dollars per non adherent patient per year can be 112 00:07:29.519 --> 00:07:33.920 attributed to non adherence because of hospitalization visits that could 113 00:07:33.920 --> 00:07:36.920 have been avoided, acute care visits which could have been avoided. 114 00:07:37.519 --> 00:07:42.279 So having options that all of the people in the 115 00:07:42.319 --> 00:07:46.360 ecosystem of a patient's care can feel assured that that 116 00:07:46.439 --> 00:07:50.360 patient is getting the medicine that their physician prescribes can 117 00:07:50.399 --> 00:07:54.480 have tremendous health outcomes from economic, etc. Advantages, and I 118 00:07:54.480 --> 00:07:57.519 think provides real motivation for all of us to do 119 00:07:57.600 --> 00:07:59.800 what we can to improve that outcome. 120 00:08:02.120 --> 00:08:05.040 Maybe the other thing I'll add is sometimes it's treatment 121 00:08:05.199 --> 00:08:08.839 and it's prevention as well. So if there are aspects 122 00:08:08.879 --> 00:08:11.439 of adherence that come into play for patients, they may 123 00:08:11.480 --> 00:08:14.160 still take a medicine for treatment, but if it's for prevention, 124 00:08:14.279 --> 00:08:17.519 they may not unless some of these options become available, 125 00:08:17.519 --> 00:08:18.879 which is a huge factor as well. 126 00:08:19.040 --> 00:08:20.560 Yeah. 127 00:08:20.759 --> 00:08:24.399 Yeah, over the twenty last twenty twenty five years, I 128 00:08:24.399 --> 00:08:30.120 think there have been suscetainay release products commune to the market, right, 129 00:08:30.319 --> 00:08:33.840 like a lupront depot respital conster, right, and they are 130 00:08:33.879 --> 00:08:39.960 about twenty close to twenty sustain release products in the marketplace. 131 00:08:42.200 --> 00:08:46.120 So I think, you know, these these products products proven, 132 00:08:46.519 --> 00:08:50.360 have proven their their safety safety, good safety profile, and 133 00:08:50.519 --> 00:08:54.919 also they're really helping patients in terms of the compliance 134 00:08:55.159 --> 00:08:57.399 right in a use so you don't have to take 135 00:08:57.480 --> 00:08:59.799 paills like you know, three times a day, but you 136 00:08:59.840 --> 00:09:03.480 can just get it when you know, subke injection every 137 00:09:03.639 --> 00:09:06.360 every month or every three months. So so I think 138 00:09:06.480 --> 00:09:11.440 that's really valuable. I think we will continue I see 139 00:09:11.440 --> 00:09:16.360 the continuation in that direction developing sustainiy release, but over 140 00:09:16.480 --> 00:09:19.039 the you know, again over the last twenty five years, 141 00:09:19.039 --> 00:09:22.639 but most efforts have been focused on developing sustained release 142 00:09:22.720 --> 00:09:27.960 formulations for small molecules, peptides made to some degree proteins. 143 00:09:28.279 --> 00:09:32.120 But nowadays we are in a nuclear nuclear asset, you know, error, 144 00:09:32.559 --> 00:09:36.720 So how do we I think there's a I think 145 00:09:36.840 --> 00:09:39.759 the new direction is, uh, at least it's one of 146 00:09:39.840 --> 00:09:43.720 the directions is to develop sustainary release formulations for m 147 00:09:43.799 --> 00:09:45.559 r n as s r n AS. 148 00:09:47.159 --> 00:09:49.360 I think that's a that's a good segue to maybe 149 00:09:49.399 --> 00:09:53.840 the natural next topic. We're mostly scientists or a lot 150 00:09:53.879 --> 00:09:55.639 of scientists in the in the audience, and of course 151 00:09:55.679 --> 00:10:00.639 also the panel members themselves. You know, from a technology perspective, 152 00:10:01.840 --> 00:10:07.080 there are different technology possibilities and domains within sort of 153 00:10:07.200 --> 00:10:12.039 sustained release and also implantable systems. Curious just to hear 154 00:10:12.080 --> 00:10:17.399 the panel's perspectives on how they see the technology landscape 155 00:10:18.159 --> 00:10:20.559 today and also recognizing that, you know, some of the 156 00:10:20.559 --> 00:10:24.200 mainstays of this space, you know, such as PLGA, have 157 00:10:24.320 --> 00:10:29.360 been around for actually quite some decades, and maybe there 158 00:10:29.440 --> 00:10:31.720 is you know, an opportunity and also a need for 159 00:10:31.840 --> 00:10:36.080 introducing you know, new materials and bringing those to the 160 00:10:36.120 --> 00:10:40.600 four in terms of realizing you know, potential or possibilities 161 00:10:40.600 --> 00:10:44.080 that we can currently achieve with those formulation concepts that 162 00:10:44.080 --> 00:10:46.279 we find in marketed products. 163 00:10:48.120 --> 00:10:48.600 Thoughts. 164 00:10:49.960 --> 00:10:54.080 Maybe I can start so the one that, yeah, you're right. 165 00:10:54.120 --> 00:10:56.320 I mean, when you look at the history of say, 166 00:10:56.519 --> 00:11:01.240 long acting injectibles, there's all kinds of formulations plg is, microspheres, 167 00:11:01.279 --> 00:11:05.279 We had injectables which were designed in oil vehicles. The 168 00:11:05.320 --> 00:11:08.840 ones that comes to mind is just simple long acting 169 00:11:08.879 --> 00:11:12.039 injectibles which don't have much in terms of polymers, but 170 00:11:12.480 --> 00:11:15.039 they rely on the drug substance itself makes our jobs 171 00:11:15.159 --> 00:11:20.240 much easier in terms of unlike oral drug delivery, where 172 00:11:20.279 --> 00:11:23.279 you want the solubility of the compound to be really high, 173 00:11:23.720 --> 00:11:26.840 you now try to design and optimal solubility such that 174 00:11:26.879 --> 00:11:31.080 the release is to keep the concentration below the cmax, 175 00:11:31.200 --> 00:11:32.440 avoid the side effects but. 176 00:11:32.480 --> 00:11:34.759 Above the CEMN, which. 177 00:11:34.519 --> 00:11:37.360 Then goes back to design for developability and trying to 178 00:11:37.639 --> 00:11:40.279 get the right solubility built. 179 00:11:40.080 --> 00:11:41.399 Into the compound itself. 180 00:11:42.159 --> 00:11:44.279 I think that, combined with the fact that if you 181 00:11:44.320 --> 00:11:49.440 can understand the immunogenicity of some of those compounds because 182 00:11:49.879 --> 00:11:52.399 the way the deeper forms, there's all kinds of fascinating 183 00:11:52.440 --> 00:11:56.360 biology that happens underlying. So I think combining those two 184 00:11:56.919 --> 00:12:00.480 into the drug substance itself, you can then design long 185 00:12:00.519 --> 00:12:01.559 acting inspectable. 186 00:12:01.919 --> 00:12:07.679 Yeah, I think to bring in the patient centricity aspect 187 00:12:07.799 --> 00:12:11.720 to this, I think it will also be important to 188 00:12:11.720 --> 00:12:15.000 see how is the patient going to interface with the 189 00:12:15.039 --> 00:12:20.279 delivery mechanism for the compound. As an example PLGA who 190 00:12:21.039 --> 00:12:24.919 can often require a larger payload and a larger needle gauge. 191 00:12:25.080 --> 00:12:29.120 And in the history of GLP ones by Durian, which 192 00:12:29.200 --> 00:12:31.960 was the once weekly exenotide, suffered in part by a 193 00:12:32.039 --> 00:12:34.440 larger needle gauge. And when Trulicity came on the market, 194 00:12:34.440 --> 00:12:38.200 which was the first easy to use version, it quickly, 195 00:12:38.399 --> 00:12:41.320 you know, outpaced the adoption. So I think it's not 196 00:12:41.519 --> 00:12:44.559 just the technical considerations that need to be achieved, but 197 00:12:44.600 --> 00:12:48.279 also yeah, challenges and how we couple those with delivery 198 00:12:48.279 --> 00:12:50.600 technologies that will make it easier for people. 199 00:12:52.120 --> 00:12:55.879 Absolutely, and maybe just an extension maniche of what you 200 00:12:55.960 --> 00:12:58.399 were talking about in terms of, of course, you know, 201 00:12:58.440 --> 00:13:02.399 we cannot look at these drug delivery technologies in isolation. 202 00:13:03.360 --> 00:13:06.279 There's kind of an intimate relationship between the formulation and 203 00:13:06.679 --> 00:13:11.799 the drug, and just also maybe people's panel members thoughts 204 00:13:11.799 --> 00:13:15.159 reflections in terms of you know what and to what 205 00:13:15.240 --> 00:13:18.559 extent we can achieve with you know, innovation on the 206 00:13:18.639 --> 00:13:23.039 molecule versus what we can actually do with a formulation 207 00:13:23.879 --> 00:13:27.159 and delivery innovation. I mean, I'm thinking, you know, of course, 208 00:13:27.480 --> 00:13:31.559 we have established chemistry principles that can actually extend the 209 00:13:31.600 --> 00:13:34.000 half life of you know, many of our compounds for 210 00:13:34.200 --> 00:13:35.759 you know, multiple days, maybe up. 211 00:13:35.679 --> 00:13:36.159 To a week. 212 00:13:37.559 --> 00:13:41.039 Do we believe drug delivery technologies can can win the 213 00:13:41.039 --> 00:13:45.279 battle of how far you can extend half life or 214 00:13:45.320 --> 00:13:49.200 is that something that our friends in chemistry are better 215 00:13:49.320 --> 00:13:51.799 or best equipped to achieve. 216 00:13:51.960 --> 00:13:56.039 I think it's a combination absolutely, because I mean people 217 00:13:57.000 --> 00:14:00.759 now for oral delivery design molecules to maximize the solubility 218 00:14:00.759 --> 00:14:03.879 and simulated intestinal fluid. Now, I think we need to 219 00:14:03.919 --> 00:14:07.799 start to look at interstitial fluids for subcutaneous intramuscular delivery 220 00:14:07.840 --> 00:14:10.639 and then design the sweet spot in terms of solubility. 221 00:14:10.639 --> 00:14:12.919 And then to your points, see if if you can. 222 00:14:12.799 --> 00:14:17.080 Start to build in vitro and then in silico tools 223 00:14:17.080 --> 00:14:20.399 to be able to build these in vitro in vivo 224 00:14:20.519 --> 00:14:24.519 relationships and then design the right molecules, then it will 225 00:14:24.559 --> 00:14:28.120 become much easier to get to the right drug substance 226 00:14:28.440 --> 00:14:29.799 and then the right product. 227 00:14:32.879 --> 00:14:36.159 I think I agree with the manage it it's an atom. 228 00:14:36.240 --> 00:14:38.440 It's a combination, right, you know, it's a combination. And 229 00:14:38.559 --> 00:14:42.159 there's a device side, there's a formulation side, and there's 230 00:14:42.279 --> 00:14:46.600 also you know, different technology modalities where we noticed that 231 00:14:47.320 --> 00:14:51.679 have evolved and also emerging. Right, So like for example, 232 00:14:52.360 --> 00:14:55.759 in addition to PHG in micro sladers, there's also you 233 00:14:55.759 --> 00:14:59.600 know in situ forming jails, right, you know technology, and ah, 234 00:14:59.639 --> 00:15:04.960 there's a also implants, right, there's a so so all 235 00:15:05.000 --> 00:15:09.440 these these technologies can provide a different release profile and 236 00:15:09.440 --> 00:15:12.559 and uh and so that that's good. But but another 237 00:15:12.559 --> 00:15:14.720 thing I want to mention is from the formulation stamp 238 00:15:14.799 --> 00:15:19.440 on a side, I noticed the people numerous companies are developing, uh, 239 00:15:20.039 --> 00:15:28.279 synthesizing more new polymers, new barty gradeable materials. They can facilitate, 240 00:15:28.759 --> 00:15:32.080 can you know, create like a precise uh you know 241 00:15:32.120 --> 00:15:36.039 release profile like very you know, precisely desired to release 242 00:15:36.120 --> 00:15:40.080 profile like a reduced further reduced you know burst release 243 00:15:40.279 --> 00:15:45.360 and and and and maintain a very yeah flat release 244 00:15:46.039 --> 00:15:47.320 release file. 245 00:15:48.960 --> 00:15:53.879 Yeah. I'll just add I think that once the molecule 246 00:15:54.080 --> 00:15:58.120 is in systemic circulation, then its circulation half life plays 247 00:15:58.120 --> 00:16:00.840 a role in how long it's going to last. But 248 00:16:00.879 --> 00:16:05.200 where delivery technologies can play a role is in delaying 249 00:16:05.399 --> 00:16:09.480 when that molecule gets into systemic circulation after administration of 250 00:16:09.519 --> 00:16:13.879 the product. So whether that's kind of an intuchu forming 251 00:16:13.960 --> 00:16:18.120 gel or an implant, you know, as an example, with 252 00:16:18.159 --> 00:16:20.679 our implant, our lead program is delivering a jug with 253 00:16:20.720 --> 00:16:23.919 a very very short half life, but the plasma levels 254 00:16:23.919 --> 00:16:27.480 are maintained at therapeutic levels because as it gets cleared, 255 00:16:27.840 --> 00:16:31.240 it's continuously being replenished by the device. So as we 256 00:16:31.240 --> 00:16:34.080 think about a product profile that's going to be attractive, 257 00:16:35.200 --> 00:16:38.440 having a long half life may not be necessary as 258 00:16:38.480 --> 00:16:41.360 long as it's coupled with the right delivery technology, But 259 00:16:41.919 --> 00:16:43.759 either way can achieve a similar outcome. 260 00:16:43.879 --> 00:16:45.080 Absolutely absolutely. 261 00:16:45.720 --> 00:16:48.279 And maybe another topic that you know, I think many 262 00:16:48.279 --> 00:16:50.720 of you were scratching the surface of in some of 263 00:16:50.759 --> 00:16:54.000 your comments just a moment ago. That's the kind of 264 00:16:54.200 --> 00:16:58.399 the development and the optimization process of you know, whatever 265 00:16:58.440 --> 00:17:03.039 drug delivery or drug every system one is developing. In 266 00:17:03.080 --> 00:17:06.720 my experience, there still remains a lot to be done 267 00:17:06.759 --> 00:17:10.799 in terms of providing a suite of tools that can 268 00:17:10.839 --> 00:17:15.319 actually guide the scientists in you know, refining and improving 269 00:17:16.160 --> 00:17:21.039 be it release profile or whatnot. And that's something where 270 00:17:21.079 --> 00:17:24.480 we still haven't got as far as I believe we 271 00:17:24.519 --> 00:17:27.920 need to in terms of having robust in vitro tools 272 00:17:27.960 --> 00:17:31.200 to be predictive of what we can then anticipate to 273 00:17:31.240 --> 00:17:36.920 see in vivo curious to hear the perspectives of the 274 00:17:37.079 --> 00:17:39.000 of the panel on that and and sort. 275 00:17:38.759 --> 00:17:42.519 Of where where where are we moving and are we moving? 276 00:17:42.880 --> 00:17:43.839 And is it forward? 277 00:17:44.759 --> 00:17:44.960 Yeah. 278 00:17:45.079 --> 00:17:46.920 The one thing that comes to mind, I think is 279 00:17:47.519 --> 00:17:51.359 the understanding that we've built with tools like the artificial 280 00:17:51.440 --> 00:17:54.079 cut for oral delivery, where we have those tools in 281 00:17:54.119 --> 00:17:56.880 the place, and I think that's mostly because we have 282 00:17:57.000 --> 00:18:00.559 good mechanistic understanding of what really happens in the human gut. 283 00:18:00.799 --> 00:18:04.519 If we understand what happens upon injection to the implant 284 00:18:04.680 --> 00:18:07.920 or the microsphere or the long acting injectable, and I 285 00:18:07.960 --> 00:18:10.640 think that kind of an understanding we can build based 286 00:18:10.680 --> 00:18:13.799 on imaging studies, So if you can actually image the material, 287 00:18:14.319 --> 00:18:16.720 then you can understand what's really going on in terms 288 00:18:16.720 --> 00:18:19.680 of release. And that is one of the things that 289 00:18:19.720 --> 00:18:23.960 we're working on to build a physiologically based pharmacokinetic model 290 00:18:24.000 --> 00:18:27.240 to then predict what the release of the material. 291 00:18:26.839 --> 00:18:28.319 Will be from a depot. 292 00:18:28.400 --> 00:18:30.759 But that I think goes back to the point of 293 00:18:31.160 --> 00:18:34.279 cross functional partnerships and collaborations to actually now work with 294 00:18:34.359 --> 00:18:37.160 imaging scientists to understand what's really going on. 295 00:18:40.920 --> 00:18:45.240 And in that regard to you, I mean, are there 296 00:18:45.279 --> 00:18:48.599 are tools out there and there are publications where people 297 00:18:48.720 --> 00:18:51.279 are suggesting and claiming that you know, this is a 298 00:18:51.319 --> 00:18:57.200 tool which can predict forecasts. You know what we expect 299 00:18:57.200 --> 00:19:00.440 to see in vivo you mentioned Maniche, you know what 300 00:19:00.599 --> 00:19:04.440 is available in the world of oral drug delivery. Is 301 00:19:04.440 --> 00:19:08.039 it realistic for us to you know, advance the science 302 00:19:08.160 --> 00:19:11.000 in the sub Q space so that we actually can 303 00:19:11.680 --> 00:19:15.880 reach a level of you know, predictivity that our colleagues 304 00:19:15.960 --> 00:19:20.759 doing oral small molecule drug delivery can can do today? 305 00:19:21.200 --> 00:19:24.279 Or what I think with the cross functional collaboration, I 306 00:19:24.359 --> 00:19:27.480 think we can. I hear subcutaneous consortium, I hear the 307 00:19:27.480 --> 00:19:31.400 Innovation and Quality Consortium, and how Caesar is being used 308 00:19:31.440 --> 00:19:35.039 successfully for the biologics in terms of absorption. So I think, yes, 309 00:19:35.119 --> 00:19:36.440 we can get there. 310 00:19:37.200 --> 00:19:46.200 Yeah, excellent, but that's good to be optimistic. Maybe Another consideration, 311 00:19:46.279 --> 00:19:49.720 of course, as it relates to long acting or sustained 312 00:19:49.759 --> 00:19:53.359 release is of course, when you then do get in vivo, 313 00:19:54.839 --> 00:19:57.279 you have to be very patient because these studies are 314 00:19:57.359 --> 00:20:01.839 running for typically a very long time, and that I 315 00:20:01.839 --> 00:20:07.319 think complicates the drug development process at every stage. Curious 316 00:20:07.359 --> 00:20:11.319 to hear the panels sort of thoughts reflections on are 317 00:20:11.319 --> 00:20:16.799 there smart ways where we can you know, cut corners? 318 00:20:16.839 --> 00:20:18.799 And by cutting corners, I mean that in a in 319 00:20:18.839 --> 00:20:20.680 a in a positive way that we can actually be 320 00:20:20.880 --> 00:20:27.480 more efficient in performing conducting in vivo studies. Is that 321 00:20:28.079 --> 00:20:31.359 is there a way to do that? Better be good? 322 00:20:33.000 --> 00:20:37.880 So I remember, we we we we created some some 323 00:20:38.000 --> 00:20:42.400 systems that where we just uh, you know, we we 324 00:20:42.400 --> 00:20:45.680 we we can divide the study, the entire we study 325 00:20:45.680 --> 00:20:49.559 into stages right and and and fusted and so we 326 00:20:49.880 --> 00:20:53.319 if it's a city day release and then we would 327 00:20:53.640 --> 00:20:55.359 this is in virtual if we were started with the 328 00:20:55.480 --> 00:20:59.559 mutual and then we and look at that. We we 329 00:20:59.640 --> 00:21:02.319 look at the first you know stage maybe first ten days, 330 00:21:02.400 --> 00:21:04.319 and then we see we can see a trend, right 331 00:21:04.680 --> 00:21:07.799 and and after many if we do this repeatedly, you know, 332 00:21:07.839 --> 00:21:10.759 we create we can kind of predict, right, you know 333 00:21:10.880 --> 00:21:13.759 that the system you know what's gonna, what's gonna what's 334 00:21:13.799 --> 00:21:16.000 the second phase and the third phase is going to 335 00:21:16.079 --> 00:21:19.559 look like? Right, and and then we can apply this 336 00:21:19.680 --> 00:21:23.480 in vivo and and maybe in the first to seven 337 00:21:23.519 --> 00:21:26.279 days you can have a very good idea whether your 338 00:21:26.359 --> 00:21:28.920 your formination is going to be it's going to work, 339 00:21:29.039 --> 00:21:31.440 you know, it's going to give you the profile you need. 340 00:21:31.920 --> 00:21:35.480 So that's just the one that approaches we we adapted. 341 00:21:36.839 --> 00:21:39.960 Yeah, I mean, we try to be very strategic with 342 00:21:40.160 --> 00:21:43.839 how we intertwine in vitro and in vivo studies to 343 00:21:44.000 --> 00:21:48.319 try to get the most useful information as a total 344 00:21:48.359 --> 00:21:52.279 as quickly as possible, recognizing the costs of proceeding in 345 00:21:52.319 --> 00:21:56.200 each way. And we've definitely found having early in vivo 346 00:21:56.279 --> 00:21:59.400 studies to make sure there isn't something very surprising that 347 00:21:59.400 --> 00:22:03.039 we're going to find it can be helpful in the development. 348 00:22:04.319 --> 00:22:07.400 And we definitely see there are things that in vitro 349 00:22:08.160 --> 00:22:11.960 kind of assays or are not predictive of you know. 350 00:22:12.319 --> 00:22:16.599 So it's I hope you're right that we're going to 351 00:22:16.680 --> 00:22:20.079 have very predictive in vitro tools that we can use, 352 00:22:21.319 --> 00:22:24.200 but for now we can't completely rely on that. So 353 00:22:24.359 --> 00:22:26.720 it has to just based on what it is that 354 00:22:26.759 --> 00:22:30.640 you're developing, makes good strategic choices as you proceed. 355 00:22:31.599 --> 00:22:33.839 Yeah, the other thing that comes to mind is if 356 00:22:33.880 --> 00:22:36.480 it's not in vitrol, can you then translate from pre 357 00:22:36.519 --> 00:22:39.240 clinical to clinical? And I think that's another way to 358 00:22:39.279 --> 00:22:42.039 look at it is you introduce a few variables into 359 00:22:42.039 --> 00:22:45.319 the pre clinical study, then you can start to deconvolute 360 00:22:45.359 --> 00:22:49.400 stuff into clinical translation, and then the third variable that 361 00:22:49.440 --> 00:22:52.119 you then introduce, you can actually predict what the clinical 362 00:22:52.200 --> 00:22:52.920 impact would be. 363 00:22:52.920 --> 00:22:54.839 So that's another way to look at it. If the 364 00:22:54.920 --> 00:22:56.240 in vitrol part doesn't work out. 365 00:22:56.480 --> 00:23:02.039 Yeah, so if we if we imagine we succeed in 366 00:23:02.079 --> 00:23:05.680 our early pre clinical research and are actually progressing something 367 00:23:05.720 --> 00:23:08.079 into the clinic and it's starting to look good, then 368 00:23:08.119 --> 00:23:10.400 of course we need to start thinking a bit more 369 00:23:10.960 --> 00:23:16.319 deeply on you know, scaling and manufacturing and of course 370 00:23:16.839 --> 00:23:21.200 you know the complexity of the formulation or the delivery 371 00:23:21.279 --> 00:23:26.160 system can have a profound effect or impact on you know, 372 00:23:26.240 --> 00:23:31.599 how scalable and easy it is to manufacture a final 373 00:23:31.680 --> 00:23:36.000 drug product for whatever therapeutic indication one might have in mind. 374 00:23:37.279 --> 00:23:41.160 I'm curious just to hear Panels reflection on you know, 375 00:23:41.240 --> 00:23:46.319 how we see with current and also emerging opportunities in 376 00:23:46.400 --> 00:23:52.039 this technology space, are they can we envisage them to 377 00:23:52.079 --> 00:23:58.960 be scalable and how can we achieve that perhaps also 378 00:23:59.039 --> 00:24:02.640 with the prospect of you know, treating even more prevalent diseases. 379 00:24:02.680 --> 00:24:06.960 I think today, you know, much of the technologies in 380 00:24:07.000 --> 00:24:12.240 this space are are you could say, focused in certain indications, 381 00:24:12.279 --> 00:24:18.319 whether it's within the kind of CNS antipsychotic, anti schizophrenia 382 00:24:18.799 --> 00:24:22.240 or anti virals as as you mentioned. Also, can we 383 00:24:22.400 --> 00:24:27.960 envisage into the future that these technologies being also scale 384 00:24:27.960 --> 00:24:30.799 to a level that could treat more prevalent diseases. 385 00:24:32.680 --> 00:24:35.559 I think you can have some benchmarks, right, you know, 386 00:24:35.599 --> 00:24:39.480 for example, the existing products they have a certain really 387 00:24:39.640 --> 00:24:43.319 profile and certainly establish the manufacturing. 388 00:24:44.920 --> 00:24:46.000 Processes, right. 389 00:24:46.079 --> 00:24:51.079 And then so when approach is that you can use 390 00:24:51.200 --> 00:24:54.359 like if it like it really depends on a compound, 391 00:24:54.640 --> 00:24:57.279 right it's a very hydrophobic or it's some of them 392 00:24:57.279 --> 00:25:00.200 maybe more hydrophilic. Right, So you know, if you you 393 00:25:00.240 --> 00:25:04.799 divide you have like an establish some kind of template 394 00:25:05.319 --> 00:25:08.240 for like a hydrophobic a compound, then you will see 395 00:25:08.279 --> 00:25:11.359 more like a consistency, right. And then for like a 396 00:25:11.440 --> 00:25:14.880 very hydrophilic or you know what a soluble compound, then 397 00:25:14.920 --> 00:25:19.319 there will be a different type of process processes and 398 00:25:19.359 --> 00:25:23.200 then enough formulation as well. And so based on our experience, 399 00:25:23.279 --> 00:25:25.440 and then we found that you know, if we have 400 00:25:25.559 --> 00:25:32.480 like a very too similar, like two compounds worth similar hydrophobicity, 401 00:25:32.599 --> 00:25:35.359