WEBVTT
00:00:16.879 --> 00:00:21.039
Hello and welcome back to Better Biopharma, the official podcast of Bioprocess Online.
00:00:21.199 --> 00:00:24.559
I'm your host, Tyler Manichello, and on today's episode, I'm joined by Dr.
00:00:24.640 --> 00:00:34.159
Larry Brown, Chief Scientific Officer at Noviome Biotherapeutics, a Pittsburgh-based biotech company developing ST266 to treat necrotizing and pterocolitis.
00:00:34.399 --> 00:00:40.240
ST266 is a secretome, which I've heard described as a cell therapy without the cells.
00:00:40.399 --> 00:00:42.159
Without further ado, Dr.
00:00:42.240 --> 00:00:45.280
Brown, thank you so much for joining me here on Better Biopharma.
00:00:45.759 --> 00:00:46.960
Thank you very much, Tyler.
00:00:47.200 --> 00:00:52.960
I'm really happy to uh meet with you and talk about our product ST266.
00:00:53.359 --> 00:00:53.920
Likewise.
00:00:54.079 --> 00:01:02.320
And so I want to uh just start off with having you tell our audience about ST266, um, as which is a secretome.
00:01:02.399 --> 00:01:06.959
And for people that aren't familiar, why don't you just give everybody a brief rundown of what that means?
00:01:07.280 --> 00:01:11.599
Well um secretome is actually it's a new class of biologic.
00:01:11.760 --> 00:01:16.000
There are no secretome products yet in the marketplace.
00:01:16.239 --> 00:01:28.560
Uh, we're probably at the leading edge in this field, but if you recall, I don't know, 10, 12 years ago, everyone hoped that stem cells were going to cure every disease.
00:01:29.200 --> 00:01:40.640
And it turns out that stem cells are quite complicated because you have issues such as the potential when injecting cells of obviously rejection.
00:01:40.879 --> 00:01:49.359
Sometimes they just simply can occlude when they're uh the blood vessels when they're injected, we get to narrow capillaries, etc.
00:01:50.000 --> 00:02:01.680
And um there's also the potential that because stem cells we produce sometimes uncontrollably, they could be responsible for the development of tumors.
00:02:02.000 --> 00:02:16.000
So there's been a tremendous amount of uh probably pullback on stem cells, and we haven't seen what uh the potential that was promised, you know, or a lot of people were looking forward to.
00:02:16.319 --> 00:02:35.120
Um the flip side of the story is that more and more research is showing that it's not the cell-to-cell contact necessarily of the stem cells that result in their regenerative or their anti-inflammatory or their um cell survival processes.
00:02:35.360 --> 00:02:39.039
But what it is is what's called paracrine signal signaling.
00:02:39.199 --> 00:02:57.840
That is, these cells actually send out many, many messages, which is called the secretome, what they secrete into the extracellular fluid or into the bloodstream, and they send out messages that tell other cells what to do.
00:02:59.120 --> 00:03:22.800
And so what we do at Noviome, and we've been researching this now for probably 15 years, I've been with a company going on my 14th year now, uh, that we collect a unique set of cells, which are not stem cells, they're stem cell-like, from the placenta amnion cell layer.
00:03:22.960 --> 00:03:51.599
And it's interesting because um the motivation from using these for using these amnion epithelial cells, as they're called from the placenta, is the following is that in the late 1970s, it was first observed that when surgery is done on a fetus in utero for diseases such as spina bifida, where the uh basically the spine is external to the body, or sometimes for heart disease conditions.
00:03:52.000 --> 00:04:01.919
So babies are operated on X um and the uh fetus is then replaced back into the placenta.
00:04:02.080 --> 00:04:08.479
And when those babies are born, sometime later, month or so afterwards, there's no evidence of scarring.
00:04:08.560 --> 00:04:25.600
It's called fetal non-scarring, and it's attributed to all the growth factors and cytokines that are floating around in the amniotic fluid, um, which are important for proper fetal development.
00:04:26.639 --> 00:04:59.839
So Novium took upon this idea, and we decided let us collect those cells, those amnion epithelial cells from the placenta, and we collect them from screen donors who um have passed a variety of other tests and so forth, and they're donated anonymously, so we don't know where the origin of these cells um or placentas are um are coming from.
00:05:00.399 --> 00:05:15.199
And uh we remove the amnion cell layer, the amnion membrane, and then there's a way of harvesting these amnion epithelial cells, and then we take these cells, and I'm skipping literally 2,000 steps.
00:05:16.079 --> 00:05:33.279
We um take these cells, these amnion epithelial cells, and we culture them in a single-use bioreactor, and they produce a variety, over a thousand different uh molecules that are growth factors and cytokines.
00:05:34.079 --> 00:05:56.959
We've taken these growth factors and cytokines, and we've seen that they're anti-inflammatory, they're anti-apoptotic, that is, they strongly promote cell survival, they're neuroprotective, and we've shown that they have regenerative properties in addition.
00:05:58.000 --> 00:06:10.000
And um my involvement in the company came about as a result of um very about 12 or 13 years ago, maybe a little bit longer.
00:06:10.240 --> 00:06:17.120
I was invited to uh a seminar that was given when one of uh Noviome's collaborators.
00:06:17.279 --> 00:06:20.000
In those earlier days, the company was called STEMnion.
00:06:20.240 --> 00:06:22.639
They changed the we changed the name to Noviome.
00:06:23.199 --> 00:06:34.000
Uh and in this collaboration with the Walter Reed Army Institute of Research, they used a penetrating ballistic brain injury model.
00:06:34.160 --> 00:06:44.639
That is, it was supposed to look like if, God forbid, a soldier had sustained a bullet wound to the head, but was surviving.
00:06:45.040 --> 00:06:52.959
Um in this particular animal model, they used uh rat model uh where they put a little probe in.
00:06:53.680 --> 00:07:03.839
Uh, it doesn't matter how they do it, but it it doesn't kill the animals, but it produces basically uh a wound which looks like a bullet wound.
00:07:04.079 --> 00:07:10.319
These animals, as a result of the placement of the particulous part of the brain, lose their motor function.
00:07:10.800 --> 00:07:22.160
So I'm listening to this presentation, and um the way that the ST266 was delivered, it was also called Axe in the old days.
00:07:22.399 --> 00:07:32.399
Amnion derived cellular cytokine solution, ACCS, and uh they infused it into the open wound.
00:07:32.639 --> 00:07:36.319
And within two weeks, these animals regained their motor function.
00:07:36.720 --> 00:07:51.199
And when you look at the histology and a lot of other biomarkers, everything was going toward reversal of this really traumatic brain injury, penetrating brain injury into these animals.
00:07:51.519 --> 00:07:59.439
Um, the group from Walter Reed then said, Well, we tried to give the drug rather than directly into the wound intravenously, but it had no effect.
00:07:59.519 --> 00:08:06.720
And I'm sitting in the audience, and I raised my hand and I asked the question Had you ever considered the intranasal route?
00:08:08.000 --> 00:08:23.439
So it turns out that I had had previous experience with the ability to take um large molecular whey proteins, deliver them through the intranasal route, and you target essentially the olfactory nerves, these nerves that allow us to smell.
00:08:23.600 --> 00:08:32.480
They're the only cells that basically penetrate from the brain into uh outside of the blood-brain barrier.
00:08:33.120 --> 00:08:41.039
And um others had shown that if you can deliver drugs to that area, you can get large moleculate proteins in the brain.
00:08:41.279 --> 00:08:49.519
So um the group from Walter Reed said to us that we've heard of it, but we've never done it.
00:08:49.679 --> 00:08:53.600
Prove to us that you can get ST266 into the brain.
00:08:54.240 --> 00:08:58.879
So um I had ST266 radio labeled.
00:08:59.120 --> 00:09:04.080
We did a study at um uh the Health Partners Institute in St.
00:09:04.240 --> 00:09:07.200
Paul, Minnesota, in the University of Minnesota.
00:09:07.360 --> 00:09:13.679
Uh, there's a leading group there who first investigated intranasal delivery of proteins to the brain.
00:09:13.919 --> 00:09:29.120
Um and they found that when administering ST266 intranasally to rats, indeed we could get the drug throughout the brain, but it turned out that the highest concentration was on the optic nerve.
00:09:29.360 --> 00:09:32.559
So I knew that the drug was anti-inflammatory.
00:09:33.519 --> 00:09:42.320
And uh I looked in the literature for diseases that are show the inflammation of the optic nerve.
00:09:42.480 --> 00:09:51.759
And what pops up when you do a literature search is optic neuritis, which is a presenting symptom of multiple sclerosis in 40 to 60 percent of the cases.
00:09:52.000 --> 00:09:59.679
When a patient shows up to an ophthalmologist with optic neuritis, they are immediately watched to see if they develop MS.
00:10:00.320 --> 00:10:08.720
Um, so I looked through the literature again and I wanted to see if anyone had an animal model of uh optic neuritis.
00:10:08.799 --> 00:10:35.519
And it turned out that Professor Ken Schindler, who's a neuroophthalmologist and has a research lab in addition to being a clinician at the University of Pennsylvania um medical school, he had one, and I called him up and I told him that we had this mixture of hundreds of proteins, have growth factors, and we uh one I wanted to test it in his animal model of optic arritis.
00:10:35.679 --> 00:10:39.440
Um and I said, Oh, yeah, by the way, I want to give it intranasally.
00:10:39.840 --> 00:10:41.120
And he laughed at me.
00:10:41.360 --> 00:10:43.039
And then I said, Well, we'll pay you.
00:10:43.200 --> 00:10:44.399
He says, Okay, I'll do it.
00:10:44.559 --> 00:10:50.639
So he does the studies, and in life, the studies take about 40, over 40 days.
00:10:51.519 --> 00:11:02.639
So after three or four months after we started the project, he calls me and he says, Larry, I've studied the optic nerve my entire career.
00:11:02.799 --> 00:11:14.480
I've tried drugs that I thought might be effective in optic doritis and other drugs that um other pharmaceutical companies thought might be uh effective in optic doritis.
00:11:14.720 --> 00:11:18.960
Nothing comes close to what ST266 reversed.
00:11:19.120 --> 00:11:23.279
Basically, it was able, he he induces the disease.
00:11:23.360 --> 00:11:30.879
It's called the experimental autoimmune encephalamitis model of multiple sclerosis.
00:11:30.960 --> 00:11:32.799
It's a widely accepted model.
00:11:33.279 --> 00:11:37.600
And these animals develop optic neuritis and they actually lose vision.
00:11:37.679 --> 00:11:40.960
So controlled animals were blind in 40 days.
00:11:41.200 --> 00:11:51.120
The ST266 treated animals were able to reverse loss of vision um with just a daily six microliter drop.
00:11:51.600 --> 00:12:06.240
Uh and by the and at day 40, they the visual acuity was uh equivalent to those of the non-diseased animals.
00:12:06.399 --> 00:12:21.120
So that was one of the in addition to the wound healing stuff, the work that was done with Walter Reed, um, we had two really clear indications that ST266 was neuroprotective.
00:12:21.600 --> 00:12:25.279
The anti-inflammatory component was very, very clear.
00:12:25.519 --> 00:12:43.120
And by doing this intranasal study, we showed that you could get the drug into a larger volume as opposed to just locally, and um we were able to show that the neuroprotective nature also was borne out.
00:12:43.200 --> 00:12:56.320
And so I was always curious what would happen if you gave ST266 systemically, and um ultimately the opportunity came to study in a collaboration with Dr.
00:12:56.399 --> 00:13:02.879
David Hackham at Johns Hopkins Medical School, who's the chief of pediatric surgery.
00:13:03.679 --> 00:13:12.799
Uh, and he has been focusing his research lab's efforts on necrotizing endocolitis animal models.
00:13:12.879 --> 00:13:16.879
So he had an animal model, both a mouse and a piglet model.
00:13:17.279 --> 00:13:18.320
Very interesting.
00:13:18.639 --> 00:13:44.639
And we did multiple studies where when we administered ST266 to premature burn uh cesarean section delivered piglets that weigh about the same weight as babies who were diagnosed with necrotizing anerocolitis, and their GI tracts are very similar to the humans in the in the pig.
00:13:45.120 --> 00:13:53.840
Um it was we were able to prevent um and in the mouse model reverse necrotizing an alkalitis.
00:13:54.399 --> 00:14:19.519
Uh, is his model is very interesting because he's a pediatric surgeon, he's doing surgery on these babies with necrotizing anorcolitis or neck, and he's removing the necrost or the disease parts of the GI tract in this really devastating orphan disease, which has a significant uh mortality still associated with it.
00:14:19.600 --> 00:14:21.200
There's no treatment for the disease.
00:14:21.360 --> 00:14:31.120
All they do is they take the babies off of oral feeding and um they give them antibiotics intravenously and total parental nutrition.
00:14:31.360 --> 00:14:42.320
And we found that our ST266 had some quite remarkable anti-inflammatory GI tract preservation um activities.
00:14:42.559 --> 00:15:04.639
Uh and we went from there basically to take the publication that was printed in the um American Journal of Physiology, and uh we used that data to obtain orphan disease and rare pediatric disease designations for SD266 in the treatment of NEC.
00:15:05.279 --> 00:15:11.519
And then we submitted an IND to bring this drug into the clinic.
00:15:12.240 --> 00:15:23.200
And so I'll pause for a second, see if you have any questions, because I know I just threw a tremendous amount of uh information uh about ST266 at you.
00:15:23.679 --> 00:15:24.240
No, thank you.
00:15:24.399 --> 00:15:25.039
I asked for it.
00:15:25.200 --> 00:15:27.679
I appreciate the rundown for our for our audience.
00:15:27.840 --> 00:15:31.120
And for those at home, um, just to to recap and clarify, Dr.
00:15:31.200 --> 00:15:37.360
Brown, uh necrotizing heterocolitis is or neck is is in premature babies.
00:15:37.440 --> 00:15:48.559
It's as as I remember from the demonstration or like the uh the presentation at at Life Sciences SW, Pittsburgh Life Science Alliance, which is where I first heard about this company.
00:15:48.799 --> 00:16:03.039
Um neck is is in in premature babies, it's pretty much their GI tracks are not fully developed because they are born, they don't have that last couple weeks of gestation when when babies learn to swallow and they swallow the amniotic fluid.
00:16:03.200 --> 00:16:16.399
And in essence, that all the growth growth factors and nutrients in the amnion, amniotic fluid, when they bathe the internal GI tract, it kind of finishes baking the orbit, so to speak.
00:16:17.200 --> 00:16:39.120
Um another way to to to put it is because these premature babies were born roughly though those who develop neck at 22, 23, 24, 25 weeks gestation, um, normal full-term infants swallow 200 mls of amniotic fluid um in the last two months of gestation.
00:16:39.840 --> 00:16:46.320
And we didn't know this either at the beginning when we first started this broad um project.
00:16:46.639 --> 00:17:01.600
But there's a uh surface cell marker molecule called TOL receptor 4 on many cells in the body, but in particular in the GI tract, and it's responsible for innate immunity.
00:17:01.759 --> 00:17:17.119
So when these babies first start getting uh oral feedings, uh and there may be bacteria in the oral feedings, the GI tract's immune system doesn't know how to handle it.
00:17:18.079 --> 00:17:28.960
And um it this disease, when it develops and infects the GI tract, this total receptor 4 remains um unabated.
00:17:30.000 --> 00:17:48.960
And uh normally the amniotic fluid swallowing attenuates that, it lowers the level, and um that allows the normal GI tract to respond to this you know infection.
00:17:49.599 --> 00:17:54.240
So um what we showed, and again, before we did these studies with Dr.
00:17:54.319 --> 00:18:01.759
Hackman, we had no idea that ST266 indeed attenuates toll receptor 4 or TLR4.
00:18:02.319 --> 00:18:29.920
And that's probably one of the key mechanisms for this particular disease on the anti-inflammatory and in the immunology point of view that this multi-targeted secretome is able to address a disease both at the innate immunity level and at the anti-inflammatory level uh and in the restorative level.
00:18:30.160 --> 00:18:46.720
When we did these studies, we also showed in mice that were induced with necrotizing and endocalitis that the what's called the RNA transcriptome, the genes that are upregulated for the maturation of the GI tract were all upregulated.
00:18:47.440 --> 00:18:56.000
So it was further proof now of the regenerative um capability of the ST266 secretome.
00:18:56.240 --> 00:19:00.319
And it speaks to basically how cells talk to each other.
00:19:00.559 --> 00:19:21.039
We're just providing what results in both the cell homeostasis, the cell survival, and the ability to uh basically survive and treat hopefully a devastating disease that uh that again has no treatment.
00:19:21.680 --> 00:19:23.599
Yeah, thank you for the explanation.
00:19:23.759 --> 00:19:25.039
I just think it's so cool.
00:19:25.119 --> 00:19:28.240
I it was a couple of weeks ago when I heard about Novium for the first time.
00:19:28.319 --> 00:19:32.799
I was at uh Pittsburgh Life Science Alliance show, uh Life Sciences Future Southwest.
00:19:33.599 --> 00:19:38.160
And uh I watched the presentation, it blew my mind away because I'd never really heard of it.
00:19:38.240 --> 00:19:47.599
I mean, correct me if I'm wrong, I kind of think about it as like a um um extracellular vesicle full of signaling molecules and proteins and nutrients.
00:19:47.759 --> 00:19:51.200
Is it would you can would you call it and classify it as a vesicle?
00:19:51.359 --> 00:19:52.640
Is it a lipid in nature?
00:19:52.720 --> 00:19:54.640
Like how would you describe the sacrotome itself?
00:19:54.799 --> 00:19:55.440
I won't get into that.
00:19:55.920 --> 00:20:05.519
Yeah, so this is interesting because now we're getting into the manufacturing by so extracellular vesicles contain many of the same um growth vectors and cytokines.
00:20:06.240 --> 00:20:19.440
Um our product is a solution, so it doesn't have any extracellular uh vesicles, so we've actually we actually filter that, ultra-filter them out as part of the manufacturing process.
00:20:19.920 --> 00:20:26.960
Okay, so it's not necessarily a bunch of you know little pockets of there's not necessarily no contents in a solution.
00:20:27.279 --> 00:20:47.359
No, it's it's not, it's it's actually a solution, you know, a large array of molecules from you know small molecules all the way up to peptides um and large molecular weight glycoproteins with um molecular weights, you know, close to or over a million.
00:20:47.839 --> 00:20:54.880
Um and but they're in solution, they're not vesicles floating around um in the product.
00:20:55.519 --> 00:20:55.920
Got it.
00:20:56.000 --> 00:20:56.240
Okay.
00:20:56.319 --> 00:20:57.599
Well, that was a misconception on my part.
00:20:57.680 --> 00:20:58.240
Thank you for talking about it.
00:20:58.559 --> 00:21:00.480
But they're very they both have similar activities.
00:21:00.640 --> 00:21:06.720
Um to be sure, you know, we may be cheating ourselves of some activity.
00:21:06.880 --> 00:21:31.440
I mean, I I don't I shouldn't say it that way, but um the but we we're doing it in order from from a safety manufacturing perspective to have better control on the drug product by knowing uh that uh we have no undefined particulates in the in the product, although they're quite small, you know, extracellular vesicles.
00:21:31.599 --> 00:21:35.519
So yeah, I think sometimes called exosomes, also, you know.
00:21:35.839 --> 00:21:36.880
Exosomes, gotcha.
00:21:37.359 --> 00:21:44.880
Yeah, I wanted to dig into the the whole manufacturing regulatory aspect of this first of its kind secretome therapy.
00:21:45.039 --> 00:21:52.079
So um what what would you say are the unique challenges in manufacturing this ST266?
00:21:52.240 --> 00:22:03.279
And then also kind of piggybacking off that, what would you say are the most critical elements of the CMC package that you had to put together for something that I think it's safe to say regulators have not seen before necessarily.
00:22:03.359 --> 00:22:04.240
Is that correct?
00:22:04.720 --> 00:22:09.599
So, um, first of all, as you mentioned early on, this is cell therapy without the cell.
00:22:09.759 --> 00:22:12.400
So this is a first of its kind biologic.
00:22:13.039 --> 00:22:14.880
It's it's it's new.
00:22:15.519 --> 00:22:27.680
There are m there are others clinical trials that have been done primarily throughout the world by academic institutions as opposed to companies.
00:22:27.839 --> 00:22:38.400
I'm pretty certain we're as far down the quote-unquote regulatory pathway as anybody in the industry, you know, to move such technology forward.
00:22:38.640 --> 00:22:53.839
Um and uh some of the key challenges, obviously, are defining the specifications so that we are able to produce a very reproducible product.
00:22:54.160 --> 00:23:11.440
Batch-to-batch comparability, reproducibility on everything from the contents to biopotency assays or bioassays to show that we're actually delivering an active product are critical.
00:23:12.079 --> 00:23:17.359
And obviously, maintaining the safety uh and quality of the product are.
00:23:17.519 --> 00:23:26.559
So, from the safety, one of the biggest concerns since most biologics, you cannot terminally sterilize the product as you can do with many others.
00:23:26.720 --> 00:23:28.960
So everything has to be done aseptically.
00:23:29.039 --> 00:23:34.480
That is, the through the use of um ultrafiltration to remove any viruses.
00:23:34.799 --> 00:23:45.200
So one of the things that we clearly do is there's a whole array of viruses that um are screened in the final product to make certain they're not there.
00:23:45.759 --> 00:23:58.480
But what we do is using these ultra filtration techniques and making certain that there's no endotoxins available in in the product is ensure the ultimate quality.
00:23:58.640 --> 00:24:03.759
Um, we use single-use bioreactors that are commercially available.
00:24:03.839 --> 00:24:11.359
Um, we've had a tweak to be sure how we feed the cells.
00:24:11.519 --> 00:24:16.160
So we have our own proprietary media which is serum-free.
00:24:16.319 --> 00:24:20.319
Most people who grow cells use fetal calf serum, for example.
00:24:20.400 --> 00:24:27.519
And then that has to be removed because there's obviously photo uh foreign proteins um there.
00:24:28.079 --> 00:24:42.960
We have our own proprietary media that we would develop specifically for these amnion epithelial cells to make them grow um over the time period of culturing in the single-use bioreactors.
00:24:43.279 --> 00:24:54.960
Um the secretome is collected continuously during the production, and uh then the cells at the end are ultra-filtered out.
00:24:55.119 --> 00:24:58.400
So we have just a solution of all these growth factors.
00:24:58.640 --> 00:25:10.319
What's really interesting is that if you look at the individual concentrations of any one of these growth factors in cytokines, they're in the picogram per ml concentration or lower.
00:25:10.720 --> 00:25:21.039
So if you took very often we get the asked the question which growth factor in cytokine is responsible for the activity that you observe?
00:25:21.440 --> 00:25:23.119
And it's not just one.
00:25:23.920 --> 00:25:35.519
In fact, we and what we've done is we've actually taken recombinant proteins, uh, like for five or six of them, and put them in some of our bioassays, and they don't work.
00:25:36.000 --> 00:25:39.839
Partially because their concentrations individually are so low.
00:25:40.880 --> 00:25:56.559
Um, and the other is that you need more than just those five or six you know, growth factors and cytokines that are implicated in, for example, in wound healing or anti-inflammatory activities that are from the literature.
00:25:56.799 --> 00:26:02.400
Um, when we were working, or when we work with uh Dr.
00:26:02.720 --> 00:26:12.640
Ken Schindler at the University of Pennsylvania Medical School in the optic neuritis work, we fractionated the SD266.
00:26:12.720 --> 00:26:22.960
As I mentioned, it there's a wide ver array of molecular weights that are composed that the the uh SD266 product.
00:26:23.119 --> 00:26:31.279
So we fractionated them by molecular weight and say, is there any activity that's associated with one particular fraction?
00:26:31.440 --> 00:26:50.160
And it turned out that indeed there's certain activities that are uh seem to be primarily associated with a certain fraction, and others where there isn't any of that same bioassay activity, but nothing works as well as the entire uh secretone.
00:26:50.880 --> 00:27:12.319
So um we have the challenge now from a regulatory and CMC point of view of again showing the batch-to-batch reproducibility for so many of these drug uh components, and um in addition, making certain that we can make this reproducibly.
00:27:12.480 --> 00:27:17.519
So we have a variety of assays, everything from immunoassays.
00:27:18.000 --> 00:27:28.480
We have one of the most powerful uh LC mass specs to basically characterize the proteome of the product.
00:27:28.960 --> 00:27:41.200
And um we're uh a wide array of of bioassays, which we're adding to all the time that address the specific activities um of the product.
00:27:41.599 --> 00:27:46.160
So we've done a lot and it's not over till it's over, right?
00:27:46.400 --> 00:27:46.960
Yeah, right.
00:27:47.200 --> 00:28:08.559
And and to be sure, the biggest challenge I think um you know will be um we've recently moved into uh a new facility and built out uh uh a uh clean room that is um at the highest standard for the production of biologics.
00:28:08.880 --> 00:28:23.039
Um ultimately the FDA will have to come in up um and and and inspect us to show that uh so that we can show that we comply to all required regulatory um requirements.
00:28:24.640 --> 00:28:30.559
Yeah, and I I was gonna ask you kind of, and I think you kind of just answered the question about what what is the biggest challenge.
00:28:30.640 --> 00:28:40.319
Would it be that aseptic piece, or would it be kind of cobbling together this um almost Frankensteinian uh manufacturing process for you know something like that?
00:28:40.559 --> 00:28:44.319
Well, it's not it may sound Frankensteinian, that's a good word.
00:28:44.720 --> 00:28:55.920
Um but it in fact the aseptic part is is is is is we have a great deal of control in in we've never had a contaminated batch ever, even through development.
00:28:56.160 --> 00:29:02.319
Oh wow um showing the effectiveness of the you know the aseptic filtrate ultra filtration process.
00:29:02.559 --> 00:29:20.480
We've we've never so the aseptic part, I think, is well established in the you know in the biologics industry because they're all I mean uh that done uh using um these you know uh particular filters.
00:29:20.799 --> 00:29:26.160
Um the biggest challenge is all the time is documentation.
00:29:26.319 --> 00:29:29.599
Show that you have complete control over the process.
00:29:29.680 --> 00:29:31.920
It's it's it's a complex process.
00:29:32.240 --> 00:29:36.000
You know, and it's you know it's it's a complicated process.
00:29:36.240 --> 00:30:03.279
So making certain that the cells, you know, remain uh viable throughout the culturing period and they're producing the uh expected secretome at the end because we have specifications for the concentrations of um a subset of these uh molecules that we check for every very every batch, and we're able to um keep them within a very, very tight range.
00:30:03.440 --> 00:30:12.400
Our goal is to keep every cytokine that we measure within two standard deviations of the mean, and we've been able to do that uh very nicely.
00:30:12.799 --> 00:30:13.039
Yeah.
00:30:13.359 --> 00:30:14.240
That that's the key.
00:30:14.400 --> 00:30:19.200
And the FDA comes in and they look at your documentation and say, yes, they've been able to do that.
00:30:19.599 --> 00:30:31.279
It's part of the uh the FDA approval process from a CMC point of view, is that one has to produce three batches of the product and show comparability between each one.
00:30:31.680 --> 00:30:32.000
Yeah.
00:30:32.480 --> 00:30:34.240
For all these assays.
00:30:35.599 --> 00:30:48.400
And when you when you kind of emphasize the importance of control and the way you're describing the quality and um that just that the tight control across batches, what would your advice to folks in our audience be?
00:30:48.559 --> 00:30:58.559
And maybe to frame that a different way, like what have you learned in in this development process, like growing alongside ST266, putting that process together?
00:30:58.720 --> 00:31:07.839
Um, what have been the biggest learnings for you uh in your career as far as it, you know, as it relates to this this CMC aspect of control and quality?
00:31:09.200 --> 00:31:11.119
It's a great question because there's there's two sides of it.
00:31:11.200 --> 00:31:14.720
Is showing the efficacy in the clinic is number one, right?
00:31:15.359 --> 00:31:15.839
It works.
00:31:15.920 --> 00:31:21.759
And then number two, making certain that you can dot the I's and cross the T's when it comes to manufacturing.
00:31:22.000 --> 00:31:29.440
So I think what we've learned is that um attention to detail is critical.
00:31:29.680 --> 00:31:35.839
And as I mentioned a moment ago, the documentation of everything that is done is is critical.
00:31:36.480 --> 00:32:03.200
Um, more and more uh people are relying on uh hopefully we're able to do so with such a complicated product uh with AI to help uh keep control of the of the process and um make certain that during manufacture um we produce what we expect.
00:32:03.680 --> 00:32:06.640
Uh that I think is the is is the key.
00:32:06.880 --> 00:32:08.960
Um it's a long road.
00:32:09.039 --> 00:32:17.519
It's it's I can't overemphasize with a new product such as this, because we're inventing the wheel from a CMC point of view.
00:32:18.000 --> 00:32:18.559
Yeah.
00:32:18.960 --> 00:32:36.000
And literally a couple of things that you know that are important to us is that we make it such that uh we have complete control and that uh the process can pass any inspection by the FDA.
00:32:36.880 --> 00:32:46.960
You know, it's product safety, uh, efficacy uh and uh quality are are the key.
00:32:48.000 --> 00:32:48.160
Yeah.
00:32:48.319 --> 00:32:53.359
And how have how has your interaction with regulators, how has that gone for you?
00:32:53.440 --> 00:32:57.279
How how are you engaging with them throughout the progress?
00:32:58.240 --> 00:33:12.880
So it's interesting because necrotizing endocolitis is this orphan disease with no treatment, significant mortality, um, no advances in 40 years, right, in in treatment.
00:33:13.200 --> 00:33:28.240
The the orphan disease division of the Center for Biologics um has been very helpful because they're as interested in helping uh these babies as as as anyone.
00:33:28.559 --> 00:33:57.599
Um so it's not just from a compassion point of view, but they recognize that A very few companies because of the risks, this obviously this is high risk, um involved get into developing to try to commercialize their first drug for pediatrics, never the you know, and and and in our case for neonates that are just usually a few days old or a couple of weeks old.
00:33:57.839 --> 00:34:08.400
This disease presents primarily from what like one, you know, a couple of weeks after birth to maybe up to you know a month or two after birth.
00:34:08.639 --> 00:34:21.440
Um and uh so so you know there's a lot of there's a lot of boxes to check off to move forward, but the FDA has been helping us, to be sure.
00:34:21.679 --> 00:34:32.000
You know, at the same time, I think when it comes to the drug product, they're going to put us at the same standard as any other biologic.
00:34:32.320 --> 00:34:36.079
And I we know that, and that's what we're preparing for.
00:34:37.440 --> 00:34:38.320
Yeah, that's great.
00:34:38.400 --> 00:34:41.199
I'm glad that they're uh they're helping you guys.
00:34:41.760 --> 00:35:02.880
And what would your advice be to, again, those those listening in our audience who are in a similar position of developing a novel therapeutic uh that probably folks have never even heard of or seen before, modality-wise, or some some ambitious new type of biologic, like in your experience, what would you would be one piece of advice you should offer to them?
00:35:03.119 --> 00:35:10.159
You know, to be sure, um interacting with the FDA, you know, when you have a question, ask them.
00:35:10.480 --> 00:35:25.119
Um what's generally done, there are a lot of uh people with significant FDA experience, and they have these consulting companies, they're a wealth of information.
00:35:25.280 --> 00:35:46.400
So that a lot of this, when as I mentioned before, documentation, you have to write it everything in FDA language, and so having those uh uh advisors is is critical because they can help you say this is what the FDA reviewers are looking for.
00:35:46.639 --> 00:35:54.960
And sometimes you think something else is important to emphasize, and they said no, they'll accept that you can make the drug aseptically, right?
00:35:55.360 --> 00:35:55.760
Yeah.
00:35:56.400 --> 00:35:57.840
We're doing something new here.
00:35:57.920 --> 00:36:04.719
We want to know about other aspects of the chemistry manufacturing controls that they haven't seen before.
00:36:05.039 --> 00:36:10.000
So um they're very, very helpful in in advising this.
00:36:10.159 --> 00:36:26.800
And and I that was going to tell someone to go out, if they were developing a similar cutting edge biologic, um, you know, the utilization of experienced FDA, uh, you know, ex-fDA consultants is is is very valuable.
00:36:27.920 --> 00:36:28.400
That's great.
00:36:28.559 --> 00:36:29.119
Great advice.
00:36:29.199 --> 00:36:29.840
Thank you.
00:36:30.079 --> 00:36:31.679
Um I had one more question.
00:36:31.760 --> 00:36:35.840
I had one more question on the manufacturing front, another question on the product itself.
00:36:36.000 --> 00:36:37.840
Um first on the manufacturing.
00:36:37.920 --> 00:36:45.760
I know you said that you had to kind of develop your own feed media for your for your um amniotic cell lines.
00:36:46.079 --> 00:37:00.960
And I was curious if the rest of the process, the manufacturing process, was that built on existing GMP technology and infrastructure, or was there other necessary invention along the way that you just you needed a solution that just didn't exist yet?
00:37:01.119 --> 00:37:02.800
And um in this in the sake of the case.
00:37:02.960 --> 00:37:10.159
Yeah, so I mean, you know, again, as I mentioned before, um no one's taken this type of product forward.
00:37:10.639 --> 00:37:17.840
Uh so we had a we're using commercially available bioreactor single-use bioreactor.
00:37:18.239 --> 00:37:32.239
See um and there are others that uh one one key is that these are you have controllers that feed the cells and stir the cells, etc., and pump the media around and so forth.
00:37:32.480 --> 00:37:48.400
Um, and uh these controllers and the software associated with them, you know, is areas where you have to optimize for your particular, you know, product after you we've determined what the ideal growth conditions are for the cells.
00:37:48.639 --> 00:37:53.119
Um so you can get these, but it takes a lot of optimization.
00:37:53.920 --> 00:38:12.000
There's a lot of optimization um when you feed the cells, uh, how often you test them during culture to make sure certain that the cells are viable, as I mentioned earlier, and that they're producing the product as expected.
00:38:13.360 --> 00:38:14.719
Yeah, that makes sense.
00:38:14.880 --> 00:38:15.360
Thank you.
00:38:15.519 --> 00:38:17.599
Uh, and on the product side, I'm curious.
00:38:17.760 --> 00:38:21.440
This is more so just out of my own biological curiosity here.
00:38:21.760 --> 00:38:33.679
You you were talking before about control and and making sure that any given um any given cytokine ratio is is is within what you said two standard deviations.
00:38:33.760 --> 00:38:40.239
So you try to keep tight control on the ratio of all these these growth factors and cytokines and molecules in the solution.
00:38:40.400 --> 00:38:59.199
I'm curious if, and you know, I don't want you to give away the secret recipe or anything, but is that is that ratio of cytokines and and nutrients, we'll call it just the good stuff, is that is that was that the default output of the cell lines, or did that take some trial and error to come up with the golden ratio, so to speak, for the product?
00:38:59.519 --> 00:39:00.239
It definitely, yeah.
00:39:00.559 --> 00:39:11.440
Early on it took trial and error because we have other forms um based on adjustments in the media that yield a different secret tone.
00:39:11.840 --> 00:39:12.559
Oh wow.
00:39:12.719 --> 00:39:24.480
Yeah, so is it is it a matter of the ingredients in the feed, or is it a matter of like upregulating certain or downregulating certain um genes in in the cell lines or it it's feeding the cells and so forth.
00:39:24.639 --> 00:39:28.800
Um, it's a large number of factors that that are involved.
00:39:28.960 --> 00:39:31.280
But you can change what the secret home looks like.
00:39:31.440 --> 00:39:32.960
I'll give you one example.
00:39:33.199 --> 00:39:49.760
There's a if you look in the literature and the secret tomes, if you look at clinicaltrials.gov, you'll find other clinical trials, again, as I mentioned, primarily in academic institutions, using mesenchymal stem cells as this uh to secrete the product.
00:39:50.000 --> 00:40:02.559
It turns out that the secretome that comes from our proprietary cells is significantly different from mesenchymal stem cells, secretone.
00:40:02.880 --> 00:40:06.000
Even they're both, you know, we're stem cell-like.
00:40:06.480 --> 00:40:11.440
Mesenchymal stem cells are in some ways are more mature, right?
00:40:11.920 --> 00:40:42.480
Um and uh there's some published evidence that suggests that the uh activity and perhaps the um the regenerative capability of uh secretomes that come from quote unquote younger cells, of which these anion epithelial cells are you know coming from the placenter, they're as as young as they get, right?
00:40:42.880 --> 00:40:50.559
Right um may be more advantageous, but but we know that the secretome is different.
00:40:51.199 --> 00:40:52.559
We know it's different.
00:40:53.199 --> 00:40:54.079
Interesting.
00:40:54.400 --> 00:40:56.719
Thank you for indulging my curiosity there.
00:40:57.519 --> 00:40:58.559
Um well, Dr.
00:40:58.719 --> 00:41:00.719
Brown, just a couple last questions here.
00:41:00.880 --> 00:41:06.960
Uh first and foremost, I want to know what's next for Novio and what are you looking forward to this year and next year?
00:41:07.039 --> 00:41:14.320
Uh, what are the biggest benchmarks or hurdles in front of you as the as both chief scientific officer and just as for the company overall?
00:41:15.119 --> 00:41:22.800
I think that's a great question because you know we've looked at a number of other potential indications.
00:41:23.840 --> 00:41:34.880
Um one of the unique opportunities of NEC is because it's an orphan disease and there's no treatment, and there's a need, uh, an unmet need.
00:41:35.199 --> 00:41:52.239
Um, from a regulatory point of view, it made the most sense for our company to uh get hopefully approval on the uh biological license applications for this for this particular disease.
00:41:52.480 --> 00:41:57.280
For other conditions, we we've looked at a variety of wound healing applications.
00:41:57.519 --> 00:42:04.239
Um we did studies with a condition called uh persistent epithelial defects.
00:42:04.320 --> 00:42:08.880
They're actually infected holes in the cornea that don't heal.
00:42:09.119 --> 00:42:13.599
And we had some very interesting results there that have been published also.
00:42:14.079 --> 00:42:18.400
But those have to go through the regular long regulatory pathway.
00:42:18.559 --> 00:42:28.400
So the advantage of this orphan indication is that there's an accelerated path of approval.
00:42:29.199 --> 00:42:36.559
Um, there's no doubt that when you're doing work with an orphan disease, patient recruitment is a bigger challenge, also.
00:42:36.960 --> 00:42:40.079
Um, but we think this is the right pathway.
00:42:40.239 --> 00:42:49.519
Um, I described earlier uh our observations of the work from the nose-to-brain delivery and through the intranasal route.
00:42:49.760 --> 00:43:05.599
Um, we'd like to investigate that particular opportunity is real because of the neuroprotective capabilities that we've seen in a variety of animal models.
00:43:05.920 --> 00:43:17.440
Um, and we actually did a phase one safety trial um with the intranasal delivery and showed that ST266 by the intranasal route was safe.
00:43:17.840 --> 00:43:22.719
And we had an anecdotal safety uh observation.
00:43:23.280 --> 00:43:34.480
Um, it turned out that the last subject in the trial, we were testing ST266 intranasally in glaucoma suspects.
00:43:34.559 --> 00:43:52.239
That is, those are people or patients that have um high intraocular pressure, which is one of the etiologies of uh glaucoma, uh, or they had a strong family history.
00:43:52.480 --> 00:44:10.159
So it turned out that the last subject in our intranasal phase one safety trial uh At her first follow-up visit, disclosed that 13 months before she was in the trial, she had COVID.
00:44:10.480 --> 00:44:13.360
I mean, she didn't have it at the time that she was in the clinical trial.
00:44:13.679 --> 00:44:17.679
And she had completely lost from that over those 13 months.
00:44:17.840 --> 00:44:22.000
She hadn't been able to her sense of smell was gone, anosmia.
00:44:22.320 --> 00:44:23.760
And she had discousia.
00:44:24.719 --> 00:44:27.519
Her sense of taste was all messed up.
00:44:28.559 --> 00:44:35.360
Um so she reported to the investigator that uh her sense of smell came back 100%.
00:44:35.920 --> 00:44:45.519
And she was actually a little bit upset because over the past 13 months, she was able to eat spicy food that she had never been able to eat before, and her sense of taste came back normally.
00:44:45.920 --> 00:44:58.239
So, you know, I I think that perhaps people with long COVID um may benefit from the intranasal delivery of SD266.
00:44:58.639 --> 00:45:10.559
Um I think that other diseases that are uh could be treated would be things such as Alzheimer's and uh or Parkinson's disease, etc.
00:45:11.119 --> 00:45:12.880
Maybe ALS.
00:45:13.199 --> 00:45:20.639
Um, and we'd like to, you know, when we have the resources, investigate those additional indications also.
00:45:22.159 --> 00:45:23.199
Yeah, that's great.
00:45:23.280 --> 00:45:25.519
I mean, a lot to look forward to, a lot of the horizon.
00:45:25.599 --> 00:45:33.280
And it sounds like if I remember from that presentation, it was um, and maybe we talked about this in the pre-call too, where it's just like you can't get it to fail, right?
00:45:33.440 --> 00:45:35.840
Like everything that you've well, you mean or less tried it.
00:45:38.719 --> 00:45:50.559
But it it's interesting too when we every time we've done a new animal model, um, and we turns out that there's a certain biochemical pathway that's known to be involved.
00:45:50.719 --> 00:45:54.159
And again, we didn't go into, oh, we know that we upregulate this pathway or that point.
00:45:54.320 --> 00:46:02.480
You know, we just know that it's got these properties, these general anti-inflammatory, you know, neuroprotective properties, etc.
00:46:02.960 --> 00:46:14.159
And um so we we didn't know this with TLR4 and neck, but it turned out that it's attenuating that pathway that needs to be attenuated, right?
00:46:14.559 --> 00:46:21.440
In order to um be able to uh better treat necrotizing okalitis.
00:46:21.599 --> 00:46:29.519
When we did our intranasal studies, also we didn't know at the time until we we looked at these, or Dr.
00:46:29.679 --> 00:46:34.880
Schindler's group did, that there's um certain certain surface cell markers.
00:46:35.440 --> 00:46:40.320
One is up regular upregulated, which is involved in mitochondrial biogenesis.
00:46:40.559 --> 00:46:45.039
Um, there's the PAKT pathway, which is involved in cell survival.
00:46:45.280 --> 00:47:01.440
What we've seen universally in every single study that we've that we've looked at is that, you know, again, there are often disease models, etc., is what kills cells ultimately is a reactive oxygen species.
00:47:01.599 --> 00:47:03.039
You can see that every time.
00:47:03.360 --> 00:47:12.480
In every study that we've looked at and tested ST266, reactive oxygen species are decreased significantly.
00:47:13.519 --> 00:47:24.960
That's like a key mechanistic um uh commonality between every study that we've that we've looked at that endpoint.
00:47:25.360 --> 00:47:38.960
So that opens up, you know, I think the opportunities to look at uh a variety of of of uh diseases where you just want to prevent cell death.
00:47:39.360 --> 00:47:52.000
I sort of uh the mitochondrial um involvement is kind of interesting because I sort of make it's like analogous to how is this work st266 working?
00:47:52.239 --> 00:47:55.679
If your battery's running out of your on your on your cell phone, right?
00:47:55.840 --> 00:47:57.519
Or your what do you do?
00:47:57.679 --> 00:47:58.880
You plug it in.
00:47:59.920 --> 00:48:04.079
I think st266 is recharging the cells.
00:48:04.800 --> 00:48:11.119
That's sort of that's sort of like my analogy for how it it's working.
00:48:11.280 --> 00:48:19.840
It's recharging them and keeping them dying cells alive, or hopefully reversing it if you catch it early enough in the disease process.
00:48:20.159 --> 00:48:20.800
Yeah.
00:48:21.360 --> 00:48:22.400
It's incredible stuff.
00:48:22.480 --> 00:48:30.079
I mean, it's it's exciting to hear about, and I can't wait to hear more about the the clinical readouts as they happen and and all the indications you guys get to move into.
00:48:30.159 --> 00:48:32.000
I'm I'm much looking forward to that.
00:48:32.159 --> 00:48:44.239
Um I I'm not sure if when you if we had already had the press release on the first cohort of uh uh NEC neonates that had been successfully safely treated.
00:48:44.800 --> 00:48:45.119
That's right.
00:48:45.199 --> 00:48:45.360
Yeah.
00:48:45.760 --> 00:48:48.400
Can you maybe tell us a bit about that cohort for the for the audience?
00:48:48.480 --> 00:48:49.280
Uh how many times?
00:48:49.519 --> 00:48:57.199
Um in our clinical trial in in NEC, um we have a protocol with four cohorts.
00:48:57.519 --> 00:49:10.320
So essentially it's babies that are over a kilogram to 3,000 grams, and babies below from 500 grams to 999 grams.
00:49:10.559 --> 00:49:16.320
So we have big babies and small babies, then we have a dose escalation, we have two doses.
00:49:16.639 --> 00:49:21.679
Um, and so they first the big babies got the low dose, we showed it safe.
00:49:22.480 --> 00:49:30.480
Um uh there was no issues with the FDA or any institutional review board because of that.
00:49:30.639 --> 00:49:36.000
The FDA eased up our um made it easier for us to recruit.
00:49:36.239 --> 00:49:42.719
We're actually recruiting the the second and third cohorts of babies currently simultaneously.
00:49:42.800 --> 00:49:49.599
So now we're doing small babies at the low dose and larger babies at the higher dose.
00:49:50.079 --> 00:49:56.400
And uh hopefully this will help us accelerate you know the completion of the clinical trial.
00:49:57.119 --> 00:50:02.079
Yeah, that's a good and that that was some that's a good example of how the FDA has helped us.
00:50:02.400 --> 00:50:03.679
Yeah, that's great to hear.
00:50:03.760 --> 00:50:07.199
I mean, especially for inorphan indications such as this.
00:50:07.360 --> 00:50:11.920
Um I'm I'm happy to hear that they're enabling more than obstructing.
00:50:12.239 --> 00:50:16.639
Um not that they're notorious obstructors, but just still not before.
00:50:16.719 --> 00:50:17.199
No, no, no, no.
00:50:17.360 --> 00:50:25.760
They don't necessarily I mean the less the the goal of the FDA is to make sure that everything that's administered, any drug is safe and effective.
00:50:25.920 --> 00:50:30.159
But and so they're very concerned about the safety.
00:50:30.559 --> 00:50:40.880
And um ST266 has now been in 282 humans, including these six neonates.
00:50:41.599 --> 00:50:51.599
Um and we've never had a drug-related adverse event in any trial, no concerns from the FDA or in any IRB.
00:50:52.320 --> 00:50:56.000
So safety is number one, and that's what their main concern is.
00:50:56.400 --> 00:50:58.960
Absolutely, as it should be, as it should be.
00:50:59.280 --> 00:51:00.079
Thank you, Dr.
00:51:00.159 --> 00:51:00.639
Brown.
00:51:00.800 --> 00:51:04.079
Well, I just have two last questions here I wanted to touch on.
00:51:04.239 --> 00:51:06.880
Um and you know, the hallmark question of the show.
00:51:06.960 --> 00:51:12.320
But before I get to that, what a lot of people might not know listening is that you were the legendary Dr.
00:51:12.400 --> 00:51:15.039
Robert Langer's first doctoral student.
00:51:15.360 --> 00:51:24.320
And I want I was curious to hear from you what the most important thing Bob Langer has taught you, uh that you if you can recall your time with him.
00:51:24.400 --> 00:51:31.679
And kind of on the other side of that, I'm curious what do you think is one thing he'd say that he learned from you as his first doctoral student?
00:51:32.000 --> 00:51:33.039
Interesting questions.
00:51:33.360 --> 00:51:39.199
So, one thing that I clearly learned was think outside the box.
00:51:39.599 --> 00:51:39.920
Okay.
00:51:40.159 --> 00:51:44.400
I think that's actually something true that's taught throughout MIT.
00:51:44.719 --> 00:51:51.199
Just because we are used to a particular way of doing something or technology, there may be even a better way.
00:51:51.519 --> 00:51:53.920
Yeah, like take the cell out of a cell therapy, right?
00:51:54.079 --> 00:51:54.480
Right, right.
00:51:54.559 --> 00:51:56.159
Take the cell out of the cell therapy.
00:51:56.239 --> 00:51:57.519
That's that's a great example.
00:51:57.760 --> 00:51:58.239
Quite outside.
00:51:58.559 --> 00:52:04.559
Um, so you know, this may be always another better way to solve a problem.
00:52:05.280 --> 00:52:07.519
And so that that was key.
00:52:07.920 --> 00:52:14.400
Um, what he taught me, I think what what's interesting, I've been I've been very lucky.
00:52:14.480 --> 00:52:18.159
I've had a lot of superior teachers my whole life.
00:52:18.480 --> 00:52:30.800
Um, one thing that I think helped me all along was um I had some really good English teachers who taught me how to write well.
00:52:31.840 --> 00:52:35.440
So I always get at Novio, mom always get, Larry, can you review this draft?
00:52:35.599 --> 00:52:40.159
Right, and that the grammar is correct, etc., etc.
00:52:40.719 --> 00:52:46.400
Um when as you mentioned, I was his first doctoral student.
00:52:46.480 --> 00:52:52.400
So when Bob submitted his first R01 grant, NIH R01 grant, he sent me a draft.
00:52:52.480 --> 00:52:53.920
Larry, could you just review this thing?
00:52:54.000 --> 00:52:57.119
And um, yeah, I think it was over the weekend.
00:52:57.360 --> 00:52:59.760
I think I completely rewrote it.
00:53:00.480 --> 00:53:04.960
And he called me up, like I don't know, Sunday night, whatever, what whatever, whatever it was.
00:53:05.119 --> 00:53:07.440
He said, Larry, this is great.
00:53:07.760 --> 00:53:08.239
Right?
00:53:09.360 --> 00:53:13.440
It turned out that we got one of the highest scores that year.
00:53:13.760 --> 00:53:14.239
Wow.
00:53:14.480 --> 00:53:24.960
And so, you know, um I've always, you know, I think I think he's always respected uh, you know, my ability to to write.
00:53:25.199 --> 00:53:42.719
And um maybe, you know, that taught him he's been has his many grand um funded as anyone, that perhaps from that first one, uh he learned something from me of how to how to write things clearly, right?
00:53:43.039 --> 00:53:43.840
I wouldn't doubt it.
00:53:43.920 --> 00:53:44.559
I wouldn't doubt it.
00:53:44.960 --> 00:53:49.840
Um it was it it was interesting because uh one of the first papers from my thesis was published.
00:53:50.000 --> 00:53:54.880
There were two papers, they were part A and part B, to the journal Diabetes.
00:53:55.920 --> 00:54:01.440
And when it came back from the reviewer, they were re I wrote them, right?
00:54:01.840 --> 00:54:04.800
Um they were in my thesis basically.
00:54:04.960 --> 00:54:11.119
Uh they came back from the review said um no edits, no suggestions.
00:54:11.280 --> 00:54:12.960
This is were accepted as is.
00:54:13.119 --> 00:54:15.440
I've I've never heard of anybody else doing that.
00:54:15.920 --> 00:54:17.119
I haven't either.
00:54:17.440 --> 00:54:21.360
Not that I'm in in those circles as much as you, but that's still nuts.
00:54:21.519 --> 00:54:21.920
Yeah.
00:54:22.159 --> 00:54:22.480
Wow.
00:54:22.719 --> 00:54:27.679
And I, you know, again, I attribute to my English teachers, right?
00:54:29.039 --> 00:54:31.360
That's great if you ever want to write for bioprocess online.
00:54:31.599 --> 00:54:34.880
You know, we're always we're always accepting expert guest columns.
00:54:35.599 --> 00:54:36.559
Um well, Dr.
00:54:36.719 --> 00:54:44.480
Brown, thank you so much for for walking me through the story of ST266 and and sharing all that with us, um, me and our audience.
00:54:44.639 --> 00:54:50.880
I just have one last question here for you before we before we wrap up, and that is the hallmark question of the show that I asked every guest.
00:54:50.960 --> 00:54:52.000
And that is, Dr.
00:54:52.079 --> 00:54:54.880
Brown, how do you think we can better biopharma?
00:54:57.039 --> 00:54:59.360
Uh, how can we better biopharma?
00:54:59.920 --> 00:55:03.599
So everything in biopharma is new.
00:55:04.079 --> 00:55:04.400
Okay.
00:55:05.199 --> 00:55:29.679
Um, I remember, you know, when antisense oligonucleotides and sirna came on, everybody thought that it would they were going to be drugs were going to be on the market in a couple of years after their first, the first Nobel Prize by Doug uh by uh who was at the University of Massachusetts, uh, who got the Nobel Prize for uh discovery of SIRNA.
00:55:30.159 --> 00:55:35.039
Um everything takes you know longer.
00:55:35.280 --> 00:55:40.480
I think we need to learn to be you know patient with the process.
00:55:40.800 --> 00:55:47.519
Uh I think that uh, you know, at the same time, how do we streamline the process?
00:55:47.679 --> 00:55:56.159
Uh, you know, as I mentioned, documentation is key for the FDA and regulatory approval.
00:55:56.559 --> 00:56:04.079
Is are there ways that um artificial intelligence can help us streamline that process?
00:56:04.320 --> 00:56:25.440
I think that that's uh a goal where AI could help because documentation is collections of large amounts of data and putting them into an organized fashion so that uh you know they can be reviewed with as fewest questions as possible.
00:56:25.599 --> 00:56:41.119
And and uh I I think that's where we can be better biopharma, streamlining you know, all the processes uh to move drugs into um not just into the clinic, but into approval.
00:56:41.840 --> 00:56:42.400
That's great.
00:56:42.639 --> 00:56:43.599
Couldn't agree more, Dr.
00:56:43.679 --> 00:56:44.000
Brown.
00:56:44.079 --> 00:56:49.679
Thank you so much for joining me on this episode of Better Biopharma, the official podcast of Bioprocess Online.
00:56:49.760 --> 00:56:51.599
And thank you in the audience for tuning in.
00:56:51.760 --> 00:56:52.800
We'll see you next time.
00:00:16.879 --> 00:00:21.039
Hello and welcome back to Better Biopharma, the official podcast of Bioprocess Online.
00:00:21.199 --> 00:00:24.559
I'm your host, Tyler Manichello, and on today's episode, I'm joined by Dr.
00:00:24.640 --> 00:00:34.159
Larry Brown, Chief Scientific Officer at Noviome Biotherapeutics, a Pittsburgh-based biotech company developing ST266 to treat necrotizing and pterocolitis.
00:00:34.399 --> 00:00:40.240
ST266 is a secretome, which I've heard described as a cell therapy without the cells.
00:00:40.399 --> 00:00:42.159
Without further ado, Dr.
00:00:42.240 --> 00:00:45.280
Brown, thank you so much for joining me here on Better Biopharma.
00:00:45.759 --> 00:00:46.960
Thank you very much, Tyler.
00:00:47.200 --> 00:00:52.960
I'm really happy to uh meet with you and talk about our product ST266.
00:00:53.359 --> 00:00:53.920
Likewise.
00:00:54.079 --> 00:01:02.320
And so I want to uh just start off with having you tell our audience about ST266, um, as which is a secretome.
00:01:02.399 --> 00:01:06.959
And for people that aren't familiar, why don't you just give everybody a brief rundown of what that means?
00:01:07.280 --> 00:01:11.599
Well um secretome is actually it's a new class of biologic.
00:01:11.760 --> 00:01:16.000
There are no secretome products yet in the marketplace.
00:01:16.239 --> 00:01:28.560
Uh, we're probably at the leading edge in this field, but if you recall, I don't know, 10, 12 years ago, everyone hoped that stem cells were going to cure every disease.
00:01:29.200 --> 00:01:40.640
And it turns out that stem cells are quite complicated because you have issues such as the potential when injecting cells of obviously rejection.
00:01:40.879 --> 00:01:49.359
Sometimes they just simply can occlude when they're uh the blood vessels when they're injected, we get to narrow capillaries, etc.
00:01:50.000 --> 00:02:01.680
And um there's also the potential that because stem cells we produce sometimes uncontrollably, they could be responsible for the development of tumors.
00:02:02.000 --> 00:02:16.000
So there's been a tremendous amount of uh probably pullback on stem cells, and we haven't seen what uh the potential that was promised, you know, or a lot of people were looking forward to.
00:02:16.319 --> 00:02:35.120
Um the flip side of the story is that more and more research is showing that it's not the cell-to-cell contact necessarily of the stem cells that result in their regenerative or their anti-inflammatory or their um cell survival processes.
00:02:35.360 --> 00:02:39.039
But what it is is what's called paracrine signal signaling.
00:02:39.199 --> 00:02:57.840
That is, these cells actually send out many, many messages, which is called the secretome, what they secrete into the extracellular fluid or into the bloodstream, and they send out messages that tell other cells what to do.
00:02:59.120 --> 00:03:22.800
And so what we do at Noviome, and we've been researching this now for probably 15 years, I've been with a company going on my 14th year now, uh, that we collect a unique set of cells, which are not stem cells, they're stem cell-like, from the placenta amnion cell layer.
00:03:22.960 --> 00:03:51.599
And it's interesting because um the motivation from using these for using these amnion epithelial cells, as they're called from the placenta, is the following is that in the late 1970s, it was first observed that when surgery is done on a fetus in utero for diseases such as spina bifida, where the uh basically the spine is external to the body, or sometimes for heart disease conditions.
00:03:52.000 --> 00:04:01.919
So babies are operated on X um and the uh fetus is then replaced back into the placenta.
00:04:02.080 --> 00:04:08.479
And when those babies are born, sometime later, month or so afterwards, there's no evidence of scarring.
00:04:08.560 --> 00:04:25.600
It's called fetal non-scarring, and it's attributed to all the growth factors and cytokines that are floating around in the amniotic fluid, um, which are important for proper fetal development.
00:04:26.639 --> 00:04:59.839
So Novium took upon this idea, and we decided let us collect those cells, those amnion epithelial cells from the placenta, and we collect them from screen donors who um have passed a variety of other tests and so forth, and they're donated anonymously, so we don't know where the origin of these cells um or placentas are um are coming from.
00:05:00.399 --> 00:05:15.199
And uh we remove the amnion cell layer, the amnion membrane, and then there's a way of harvesting these amnion epithelial cells, and then we take these cells, and I'm skipping literally 2,000 steps.
00:05:16.079 --> 00:05:33.279
We um take these cells, these amnion epithelial cells, and we culture them in a single-use bioreactor, and they produce a variety, over a thousand different uh molecules that are growth factors and cytokines.
00:05:34.079 --> 00:05:56.959
We've taken these growth factors and cytokines, and we've seen that they're anti-inflammatory, they're anti-apoptotic, that is, they strongly promote cell survival, they're neuroprotective, and we've shown that they have regenerative properties in addition.
00:05:58.000 --> 00:06:10.000
And um my involvement in the company came about as a result of um very about 12 or 13 years ago, maybe a little bit longer.
00:06:10.240 --> 00:06:17.120
I was invited to uh a seminar that was given when one of uh Noviome's collaborators.
00:06:17.279 --> 00:06:20.000
In those earlier days, the company was called STEMnion.
00:06:20.240 --> 00:06:22.639
They changed the we changed the name to Noviome.
00:06:23.199 --> 00:06:34.000
Uh and in this collaboration with the Walter Reed Army Institute of Research, they used a penetrating ballistic brain injury model.
00:06:34.160 --> 00:06:44.639
That is, it was supposed to look like if, God forbid, a soldier had sustained a bullet wound to the head, but was surviving.
00:06:45.040 --> 00:06:52.959
Um in this particular animal model, they used uh rat model uh where they put a little probe in.
00:06:53.680 --> 00:07:03.839
Uh, it doesn't matter how they do it, but it it doesn't kill the animals, but it produces basically uh a wound which looks like a bullet wound.
00:07:04.079 --> 00:07:10.319
These animals, as a result of the placement of the particulous part of the brain, lose their motor function.
00:07:10.800 --> 00:07:22.160
So I'm listening to this presentation, and um the way that the ST266 was delivered, it was also called Axe in the old days.
00:07:22.399 --> 00:07:32.399
Amnion derived cellular cytokine solution, ACCS, and uh they infused it into the open wound.
00:07:32.639 --> 00:07:36.319
And within two weeks, these animals regained their motor function.
00:07:36.720 --> 00:07:51.199
And when you look at the histology and a lot of other biomarkers, everything was going toward reversal of this really traumatic brain injury, penetrating brain injury into these animals.
00:07:51.519 --> 00:07:59.439
Um, the group from Walter Reed then said, Well, we tried to give the drug rather than directly into the wound intravenously, but it had no effect.
00:07:59.519 --> 00:08:06.720
And I'm sitting in the audience, and I raised my hand and I asked the question Had you ever considered the intranasal route?
00:08:08.000 --> 00:08:23.439
So it turns out that I had had previous experience with the ability to take um large molecular whey proteins, deliver them through the intranasal route, and you target essentially the olfactory nerves, these nerves that allow us to smell.
00:08:23.600 --> 00:08:32.480
They're the only cells that basically penetrate from the brain into uh outside of the blood-brain barrier.
00:08:33.120 --> 00:08:41.039
And um others had shown that if you can deliver drugs to that area, you can get large moleculate proteins in the brain.
00:08:41.279 --> 00:08:49.519
So um the group from Walter Reed said to us that we've heard of it, but we've never done it.
00:08:49.679 --> 00:08:53.600
Prove to us that you can get ST266 into the brain.
00:08:54.240 --> 00:08:58.879
So um I had ST266 radio labeled.
00:08:59.120 --> 00:09:04.080
We did a study at um uh the Health Partners Institute in St.
00:09:04.240 --> 00:09:07.200
Paul, Minnesota, in the University of Minnesota.
00:09:07.360 --> 00:09:13.679
Uh, there's a leading group there who first investigated intranasal delivery of proteins to the brain.
00:09:13.919 --> 00:09:29.120
Um and they found that when administering ST266 intranasally to rats, indeed we could get the drug throughout the brain, but it turned out that the highest concentration was on the optic nerve.
00:09:29.360 --> 00:09:32.559
So I knew that the drug was anti-inflammatory.
00:09:33.519 --> 00:09:42.320
And uh I looked in the literature for diseases that are show the inflammation of the optic nerve.
00:09:42.480 --> 00:09:51.759
And what pops up when you do a literature search is optic neuritis, which is a presenting symptom of multiple sclerosis in 40 to 60 percent of the cases.
00:09:52.000 --> 00:09:59.679
When a patient shows up to an ophthalmologist with optic neuritis, they are immediately watched to see if they develop MS.
00:10:00.320 --> 00:10:08.720
Um, so I looked through the literature again and I wanted to see if anyone had an animal model of uh optic neuritis.
00:10:08.799 --> 00:10:35.519
And it turned out that Professor Ken Schindler, who's a neuroophthalmologist and has a research lab in addition to being a clinician at the University of Pennsylvania um medical school, he had one, and I called him up and I told him that we had this mixture of hundreds of proteins, have growth factors, and we uh one I wanted to test it in his animal model of optic arritis.
00:10:35.679 --> 00:10:39.440
Um and I said, Oh, yeah, by the way, I want to give it intranasally.
00:10:39.840 --> 00:10:41.120
And he laughed at me.
00:10:41.360 --> 00:10:43.039
And then I said, Well, we'll pay you.
00:10:43.200 --> 00:10:44.399
He says, Okay, I'll do it.
00:10:44.559 --> 00:10:50.639
So he does the studies, and in life, the studies take about 40, over 40 days.
00:10:51.519 --> 00:11:02.639
So after three or four months after we started the project, he calls me and he says, Larry, I've studied the optic nerve my entire career.
00:11:02.799 --> 00:11:14.480
I've tried drugs that I thought might be effective in optic doritis and other drugs that um other pharmaceutical companies thought might be uh effective in optic doritis.
00:11:14.720 --> 00:11:18.960
Nothing comes close to what ST266 reversed.
00:11:19.120 --> 00:11:23.279
Basically, it was able, he he induces the disease.
00:11:23.360 --> 00:11:30.879
It's called the experimental autoimmune encephalamitis model of multiple sclerosis.
00:11:30.960 --> 00:11:32.799
It's a widely accepted model.
00:11:33.279 --> 00:11:37.600
And these animals develop optic neuritis and they actually lose vision.
00:11:37.679 --> 00:11:40.960
So controlled animals were blind in 40 days.
00:11:41.200 --> 00:11:51.120
The ST266 treated animals were able to reverse loss of vision um with just a daily six microliter drop.
00:11:51.600 --> 00:12:06.240
Uh and by the and at day 40, they the visual acuity was uh equivalent to those of the non-diseased animals.
00:12:06.399 --> 00:12:21.120
So that was one of the in addition to the wound healing stuff, the work that was done with Walter Reed, um, we had two really clear indications that ST266 was neuroprotective.
00:12:21.600 --> 00:12:25.279
The anti-inflammatory component was very, very clear.
00:12:25.519 --> 00:12:43.120
And by doing this intranasal study, we showed that you could get the drug into a larger volume as opposed to just locally, and um we were able to show that the neuroprotective nature also was borne out.
00:12:43.200 --> 00:12:56.320
And so I was always curious what would happen if you gave ST266 systemically, and um ultimately the opportunity came to study in a collaboration with Dr.
00:12:56.399 --> 00:13:02.879
David Hackham at Johns Hopkins Medical School, who's the chief of pediatric surgery.
00:13:03.679 --> 00:13:12.799
Uh, and he has been focusing his research lab's efforts on necrotizing endocolitis animal models.
00:13:12.879 --> 00:13:16.879
So he had an animal model, both a mouse and a piglet model.
00:13:17.279 --> 00:13:18.320
Very interesting.
00:13:18.639 --> 00:13:44.639
And we did multiple studies where when we administered ST266 to premature burn uh cesarean section delivered piglets that weigh about the same weight as babies who were diagnosed with necrotizing anerocolitis, and their GI tracts are very similar to the humans in the in the pig.
00:13:45.120 --> 00:13:53.840
Um it was we were able to prevent um and in the mouse model reverse necrotizing an alkalitis.
00:13:54.399 --> 00:14:19.519
Uh, is his model is very interesting because he's a pediatric surgeon, he's doing surgery on these babies with necrotizing anorcolitis or neck, and he's removing the necrost or the disease parts of the GI tract in this really devastating orphan disease, which has a significant uh mortality still associated with it.
00:14:19.600 --> 00:14:21.200
There's no treatment for the disease.
00:14:21.360 --> 00:14:31.120
All they do is they take the babies off of oral feeding and um they give them antibiotics intravenously and total parental nutrition.
00:14:31.360 --> 00:14:42.320
And we found that our ST266 had some quite remarkable anti-inflammatory GI tract preservation um activities.
00:14:42.559 --> 00:15:04.639
Uh and we went from there basically to take the publication that was printed in the um American Journal of Physiology, and uh we used that data to obtain orphan disease and rare pediatric disease designations for SD266 in the treatment of NEC.
00:15:05.279 --> 00:15:11.519
And then we submitted an IND to bring this drug into the clinic.
00:15:12.240 --> 00:15:23.200
And so I'll pause for a second, see if you have any questions, because I know I just threw a tremendous amount of uh information uh about ST266 at you.
00:15:23.679 --> 00:15:24.240
No, thank you.
00:15:24.399 --> 00:15:25.039
I asked for it.
00:15:25.200 --> 00:15:27.679
I appreciate the rundown for our for our audience.
00:15:27.840 --> 00:15:31.120
And for those at home, um, just to to recap and clarify, Dr.
00:15:31.200 --> 00:15:37.360
Brown, uh necrotizing heterocolitis is or neck is is in premature babies.
00:15:37.440 --> 00:15:48.559
It's as as I remember from the demonstration or like the uh the presentation at at Life Sciences SW, Pittsburgh Life Science Alliance, which is where I first heard about this company.
00:15:48.799 --> 00:16:03.039
Um neck is is in in premature babies, it's pretty much their GI tracks are not fully developed because they are born, they don't have that last couple weeks of gestation when when babies learn to swallow and they swallow the amniotic fluid.
00:16:03.200 --> 00:16:16.399
And in essence, that all the growth growth factors and nutrients in the amnion, amniotic fluid, when they bathe the internal GI tract, it kind of finishes baking the orbit, so to speak.
00:16:17.200 --> 00:16:39.120
Um another way to to to put it is because these premature babies were born roughly though those who develop neck at 22, 23, 24, 25 weeks gestation, um, normal full-term infants swallow 200 mls of amniotic fluid um in the last two months of gestation.
00:16:39.840 --> 00:16:46.320
And we didn't know this either at the beginning when we first started this broad um project.
00:16:46.639 --> 00:17:01.600
But there's a uh surface cell marker molecule called TOL receptor 4 on many cells in the body, but in particular in the GI tract, and it's responsible for innate immunity.
00:17:01.759 --> 00:17:17.119
So when these babies first start getting uh oral feedings, uh and there may be bacteria in the oral feedings, the GI tract's immune system doesn't know how to handle it.
00:17:18.079 --> 00:17:28.960
And um it this disease, when it develops and infects the GI tract, this total receptor 4 remains um unabated.
00:17:30.000 --> 00:17:48.960
And uh normally the amniotic fluid swallowing attenuates that, it lowers the level, and um that allows the normal GI tract to respond to this you know infection.
00:17:49.599 --> 00:17:54.240
So um what we showed, and again, before we did these studies with Dr.
00:17:54.319 --> 00:18:01.759
Hackman, we had no idea that ST266 indeed attenuates toll receptor 4 or TLR4.
00:18:02.319 --> 00:18:29.920
And that's probably one of the key mechanisms for this particular disease on the anti-inflammatory and in the immunology point of view that this multi-targeted secretome is able to address a disease both at the innate immunity level and at the anti-inflammatory level uh and in the restorative level.
00:18:30.160 --> 00:18:46.720
When we did these studies, we also showed in mice that were induced with necrotizing and endocalitis that the what's called the RNA transcriptome, the genes that are upregulated for the maturation of the GI tract were all upregulated.
00:18:47.440 --> 00:18:56.000
So it was further proof now of the regenerative um capability of the ST266 secretome.
00:18:56.240 --> 00:19:00.319
And it speaks to basically how cells talk to each other.
00:19:00.559 --> 00:19:21.039
We're just providing what results in both the cell homeostasis, the cell survival, and the ability to uh basically survive and treat hopefully a devastating disease that uh that again has no treatment.
00:19:21.680 --> 00:19:23.599
Yeah, thank you for the explanation.
00:19:23.759 --> 00:19:25.039
I just think it's so cool.
00:19:25.119 --> 00:19:28.240
I it was a couple of weeks ago when I heard about Novium for the first time.
00:19:28.319 --> 00:19:32.799
I was at uh Pittsburgh Life Science Alliance show, uh Life Sciences Future Southwest.
00:19:33.599 --> 00:19:38.160
And uh I watched the presentation, it blew my mind away because I'd never really heard of it.
00:19:38.240 --> 00:19:47.599
I mean, correct me if I'm wrong, I kind of think about it as like a um um extracellular vesicle full of signaling molecules and proteins and nutrients.
00:19:47.759 --> 00:19:51.200
Is it would you can would you call it and classify it as a vesicle?
00:19:51.359 --> 00:19:52.640
Is it a lipid in nature?
00:19:52.720 --> 00:19:54.640
Like how would you describe the sacrotome itself?
00:19:54.799 --> 00:19:55.440
I won't get into that.
00:19:55.920 --> 00:20:05.519
Yeah, so this is interesting because now we're getting into the manufacturing by so extracellular vesicles contain many of the same um growth vectors and cytokines.
00:20:06.240 --> 00:20:19.440
Um our product is a solution, so it doesn't have any extracellular uh vesicles, so we've actually we actually filter that, ultra-filter them out as part of the manufacturing process.
00:20:19.920 --> 00:20:26.960
Okay, so it's not necessarily a bunch of you know little pockets of there's not necessarily no contents in a solution.
00:20:27.279 --> 00:20:47.359
No, it's it's not, it's it's actually a solution, you know, a large array of molecules from you know small molecules all the way up to peptides um and large molecular weight glycoproteins with um molecular weights, you know, close to or over a million.
00:20:47.839 --> 00:20:54.880
Um and but they're in solution, they're not vesicles floating around um in the product.
00:20:55.519 --> 00:20:55.920
Got it.
00:20:56.000 --> 00:20:56.240
Okay.
00:20:56.319 --> 00:20:57.599
Well, that was a misconception on my part.
00:20:57.680 --> 00:20:58.240
Thank you for talking about it.
00:20:58.559 --> 00:21:00.480
But they're very they both have similar activities.
00:21:00.640 --> 00:21:06.720
Um to be sure, you know, we may be cheating ourselves of some activity.
00:21:06.880 --> 00:21:31.440
I mean, I I don't I shouldn't say it that way, but um the but we we're doing it in order from from a safety manufacturing perspective to have better control on the drug product by knowing uh that uh we have no undefined particulates in the in the product, although they're quite small, you know, extracellular vesicles.
00:21:31.599 --> 00:21:35.519
So yeah, I think sometimes called exosomes, also, you know.
00:21:35.839 --> 00:21:36.880
Exosomes, gotcha.
00:21:37.359 --> 00:21:44.880
Yeah, I wanted to dig into the the whole manufacturing regulatory aspect of this first of its kind secretome therapy.
00:21:45.039 --> 00:21:52.079
So um what what would you say are the unique challenges in manufacturing this ST266?
00:21:52.240 --> 00:22:03.279
And then also kind of piggybacking off that, what would you say are the most critical elements of the CMC package that you had to put together for something that I think it's safe to say regulators have not seen before necessarily.
00:22:03.359 --> 00:22:04.240
Is that correct?
00:22:04.720 --> 00:22:09.599
So, um, first of all, as you mentioned early on, this is cell therapy without the cell.
00:22:09.759 --> 00:22:12.400
So this is a first of its kind biologic.
00:22:13.039 --> 00:22:14.880
It's it's it's new.
00:22:15.519 --> 00:22:27.680
There are m there are others clinical trials that have been done primarily throughout the world by academic institutions as opposed to companies.
00:22:27.839 --> 00:22:38.400
I'm pretty certain we're as far down the quote-unquote regulatory pathway as anybody in the industry, you know, to move such technology forward.
00:22:38.640 --> 00:22:53.839
Um and uh some of the key challenges, obviously, are defining the specifications so that we are able to produce a very reproducible product.
00:22:54.160 --> 00:23:11.440
Batch-to-batch comparability, reproducibility on everything from the contents to biopotency assays or bioassays to show that we're actually delivering an active product are critical.
00:23:12.079 --> 00:23:17.359
And obviously, maintaining the safety uh and quality of the product are.
00:23:17.519 --> 00:23:26.559
So, from the safety, one of the biggest concerns since most biologics, you cannot terminally sterilize the product as you can do with many others.
00:23:26.720 --> 00:23:28.960
So everything has to be done aseptically.
00:23:29.039 --> 00:23:34.480
That is, the through the use of um ultrafiltration to remove any viruses.
00:23:34.799 --> 00:23:45.200
So one of the things that we clearly do is there's a whole array of viruses that um are screened in the final product to make certain they're not there.
00:23:45.759 --> 00:23:58.480
But what we do is using these ultra filtration techniques and making certain that there's no endotoxins available in in the product is ensure the ultimate quality.
00:23:58.640 --> 00:24:03.759
Um, we use single-use bioreactors that are commercially available.
00:24:03.839 --> 00:24:11.359
Um, we've had a tweak to be sure how we feed the cells.
00:24:11.519 --> 00:24:16.160
So we have our own proprietary media which is serum-free.
00:24:16.319 --> 00:24:20.319
Most people who grow cells use fetal calf serum, for example.
00:24:20.400 --> 00:24:27.519
And then that has to be removed because there's obviously photo uh foreign proteins um there.
00:24:28.079 --> 00:24:42.960
We have our own proprietary media that we would develop specifically for these amnion epithelial cells to make them grow um over the time period of culturing in the single-use bioreactors.
00:24:43.279 --> 00:24:54.960
Um the secretome is collected continuously during the production, and uh then the cells at the end are ultra-filtered out.
00:24:55.119 --> 00:24:58.400
So we have just a solution of all these growth factors.
00:24:58.640 --> 00:25:10.319
What's really interesting is that if you look at the individual concentrations of any one of these growth factors in cytokines, they're in the picogram per ml concentration or lower.
00:25:10.720 --> 00:25:21.039
So if you took very often we get the asked the question which growth factor in cytokine is responsible for the activity that you observe?
00:25:21.440 --> 00:25:23.119
And it's not just one.
00:25:23.920 --> 00:25:35.519
In fact, we and what we've done is we've actually taken recombinant proteins, uh, like for five or six of them, and put them in some of our bioassays, and they don't work.
00:25:36.000 --> 00:25:39.839
Partially because their concentrations individually are so low.
00:25:40.880 --> 00:25:56.559
Um, and the other is that you need more than just those five or six you know, growth factors and cytokines that are implicated in, for example, in wound healing or anti-inflammatory activities that are from the literature.
00:25:56.799 --> 00:26:02.400
Um, when we were working, or when we work with uh Dr.
00:26:02.720 --> 00:26:12.640
Ken Schindler at the University of Pennsylvania Medical School in the optic neuritis work, we fractionated the SD266.
00:26:12.720 --> 00:26:22.960
As I mentioned, it there's a wide ver array of molecular weights that are composed that the the uh SD266 product.
00:26:23.119 --> 00:26:31.279
So we fractionated them by molecular weight and say, is there any activity that's associated with one particular fraction?
00:26:31.440 --> 00:26:50.160
And it turned out that indeed there's certain activities that are uh seem to be primarily associated with a certain fraction, and others where there isn't any of that same bioassay activity, but nothing works as well as the entire uh secretone.
00:26:50.880 --> 00:27:12.319
So um we have the challenge now from a regulatory and CMC point of view of again showing the batch-to-batch reproducibility for so many of these drug uh components, and um in addition, making certain that we can make this reproducibly.
00:27:12.480 --> 00:27:17.519
So we have a variety of assays, everything from immunoassays.
00:27:18.000 --> 00:27:28.480
We have one of the most powerful uh LC mass specs to basically characterize the proteome of the product.
00:27:28.960 --> 00:27:41.200
And um we're uh a wide array of of bioassays, which we're adding to all the time that address the specific activities um of the product.
00:27:41.599 --> 00:27:46.160
So we've done a lot and it's not over till it's over, right?
00:27:46.400 --> 00:27:46.960
Yeah, right.
00:27:47.200 --> 00:28:08.559
And and to be sure, the biggest challenge I think um you know will be um we've recently moved into uh a new facility and built out uh uh a uh clean room that is um at the highest standard for the production of biologics.
00:28:08.880 --> 00:28:23.039
Um ultimately the FDA will have to come in up um and and and inspect us to show that uh so that we can show that we comply to all required regulatory um requirements.
00:28:24.640 --> 00:28:30.559
Yeah, and I I was gonna ask you kind of, and I think you kind of just answered the question about what what is the biggest challenge.
00:28:30.640 --> 00:28:40.319
Would it be that aseptic piece, or would it be kind of cobbling together this um almost Frankensteinian uh manufacturing process for you know something like that?
00:28:40.559 --> 00:28:44.319
Well, it's not it may sound Frankensteinian, that's a good word.
00:28:44.720 --> 00:28:55.920
Um but it in fact the aseptic part is is is is is we have a great deal of control in in we've never had a contaminated batch ever, even through development.
00:28:56.160 --> 00:29:02.319
Oh wow um showing the effectiveness of the you know the aseptic filtrate ultra filtration process.
00:29:02.559 --> 00:29:20.480
We've we've never so the aseptic part, I think, is well established in the you know in the biologics industry because they're all I mean uh that done uh using um these you know uh particular filters.
00:29:20.799 --> 00:29:26.160
Um the biggest challenge is all the time is documentation.
00:29:26.319 --> 00:29:29.599
Show that you have complete control over the process.
00:29:29.680 --> 00:29:31.920
It's it's it's a complex process.
00:29:32.240 --> 00:29:36.000
You know, and it's you know it's it's a complicated process.
00:29:36.240 --> 00:30:03.279
So making certain that the cells, you know, remain uh viable throughout the culturing period and they're producing the uh expected secretome at the end because we have specifications for the concentrations of um a subset of these uh molecules that we check for every very every batch, and we're able to um keep them within a very, very tight range.
00:30:03.440 --> 00:30:12.400
Our goal is to keep every cytokine that we measure within two standard deviations of the mean, and we've been able to do that uh very nicely.
00:30:12.799 --> 00:30:13.039
Yeah.
00:30:13.359 --> 00:30:14.240
That that's the key.
00:30:14.400 --> 00:30:19.200
And the FDA comes in and they look at your documentation and say, yes, they've been able to do that.
00:30:19.599 --> 00:30:31.279
It's part of the uh the FDA approval process from a CMC point of view, is that one has to produce three batches of the product and show comparability between each one.
00:30:31.680 --> 00:30:32.000
Yeah.
00:30:32.480 --> 00:30:34.240
For all these assays.
00:30:35.599 --> 00:30:48.400
And when you when you kind of emphasize the importance of control and the way you're describing the quality and um that just that the tight control across batches, what would your advice to folks in our audience be?
00:30:48.559 --> 00:30:58.559
And maybe to frame that a different way, like what have you learned in in this development process, like growing alongside ST266, putting that process together?
00:30:58.720 --> 00:31:07.839
Um, what have been the biggest learnings for you uh in your career as far as it, you know, as it relates to this this CMC aspect of control and quality?
00:31:09.200 --> 00:31:11.119
It's a great question because there's there's two sides of it.
00:31:11.200 --> 00:31:14.720
Is showing the efficacy in the clinic is number one, right?
00:31:15.359 --> 00:31:15.839
It works.
00:31:15.920 --> 00:31:21.759
And then number two, making certain that you can dot the I's and cross the T's when it comes to manufacturing.
00:31:22.000 --> 00:31:29.440
So I think what we've learned is that um attention to detail is critical.
00:31:29.680 --> 00:31:35.839
And as I mentioned a moment ago, the documentation of everything that is done is is critical.
00:31:36.480 --> 00:32:03.200
Um, more and more uh people are relying on uh hopefully we're able to do so with such a complicated product uh with AI to help uh keep control of the of the process and um make certain that during manufacture um we produce what we expect.
00:32:03.680 --> 00:32:06.640
Uh that I think is the is is the key.
00:32:06.880 --> 00:32:08.960
Um it's a long road.
00:32:09.039 --> 00:32:17.519
It's it's I can't overemphasize with a new product such as this, because we're inventing the wheel from a CMC point of view.
00:32:18.000 --> 00:32:18.559
Yeah.
00:32:18.960 --> 00:32:36.000
And literally a couple of things that you know that are important to us is that we make it such that uh we have complete control and that uh the process can pass any inspection by the FDA.
00:32:36.880 --> 00:32:46.960
You know, it's product safety, uh, efficacy uh and uh quality are are the key.
00:32:48.000 --> 00:32:48.160
Yeah.
00:32:48.319 --> 00:32:53.359
And how have how has your interaction with regulators, how has that gone for you?
00:32:53.440 --> 00:32:57.279
How how are you engaging with them throughout the progress?
00:32:58.240 --> 00:33:12.880
So it's interesting because necrotizing endocolitis is this orphan disease with no treatment, significant mortality, um, no advances in 40 years, right, in in treatment.
00:33:13.200 --> 00:33:28.240
The the orphan disease division of the Center for Biologics um has been very helpful because they're as interested in helping uh these babies as as as anyone.
00:33:28.559 --> 00:33:57.599
Um so it's not just from a compassion point of view, but they recognize that A very few companies because of the risks, this obviously this is high risk, um involved get into developing to try to commercialize their first drug for pediatrics, never the you know, and and and in our case for neonates that are just usually a few days old or a couple of weeks old.
00:33:57.839 --> 00:34:08.400
This disease presents primarily from what like one, you know, a couple of weeks after birth to maybe up to you know a month or two after birth.
00:34:08.639 --> 00:34:21.440
Um and uh so so you know there's a lot of there's a lot of boxes to check off to move forward, but the FDA has been helping us, to be sure.
00:34:21.679 --> 00:34:32.000
You know, at the same time, I think when it comes to the drug product, they're going to put us at the same standard as any other biologic.
00:34:32.320 --> 00:34:36.079
And I we know that, and that's what we're preparing for.
00:34:37.440 --> 00:34:38.320
Yeah, that's great.
00:34:38.400 --> 00:34:41.199
I'm glad that they're uh they're helping you guys.
00:34:41.760 --> 00:35:02.880
And what would your advice be to, again, those those listening in our audience who are in a similar position of developing a novel therapeutic uh that probably folks have never even heard of or seen before, modality-wise, or some some ambitious new type of biologic, like in your experience, what would you would be one piece of advice you should offer to them?
00:35:03.119 --> 00:35:10.159
You know, to be sure, um interacting with the FDA, you know, when you have a question, ask them.
00:35:10.480 --> 00:35:25.119
Um what's generally done, there are a lot of uh people with significant FDA experience, and they have these consulting companies, they're a wealth of information.
00:35:25.280 --> 00:35:46.400
So that a lot of this, when as I mentioned before, documentation, you have to write it everything in FDA language, and so having those uh uh advisors is is critical because they can help you say this is what the FDA reviewers are looking for.
00:35:46.639 --> 00:35:54.960
And sometimes you think something else is important to emphasize, and they said no, they'll accept that you can make the drug aseptically, right?
00:35:55.360 --> 00:35:55.760
Yeah.
00:35:56.400 --> 00:35:57.840
We're doing something new here.
00:35:57.920 --> 00:36:04.719
We want to know about other aspects of the chemistry manufacturing controls that they haven't seen before.
00:36:05.039 --> 00:36:10.000
So um they're very, very helpful in in advising this.
00:36:10.159 --> 00:36:26.800
And and I that was going to tell someone to go out, if they were developing a similar cutting edge biologic, um, you know, the utilization of experienced FDA, uh, you know, ex-fDA consultants is is is very valuable.
00:36:27.920 --> 00:36:28.400
That's great.
00:36:28.559 --> 00:36:29.119
Great advice.
00:36:29.199 --> 00:36:29.840
Thank you.
00:36:30.079 --> 00:36:31.679
Um I had one more question.
00:36:31.760 --> 00:36:35.840
I had one more question on the manufacturing front, another question on the product itself.
00:36:36.000 --> 00:36:37.840
Um first on the manufacturing.
00:36:37.920 --> 00:36:45.760
I know you said that you had to kind of develop your own feed media for your for your um amniotic cell lines.
00:36:46.079 --> 00:37:00.960
And I was curious if the rest of the process, the manufacturing process, was that built on existing GMP technology and infrastructure, or was there other necessary invention along the way that you just you needed a solution that just didn't exist yet?
00:37:01.119 --> 00:37:02.800
And um in this in the sake of the case.
00:37:02.960 --> 00:37:10.159
Yeah, so I mean, you know, again, as I mentioned before, um no one's taken this type of product forward.
00:37:10.639 --> 00:37:17.840
Uh so we had a we're using commercially available bioreactor single-use bioreactor.
00:37:18.239 --> 00:37:32.239
See um and there are others that uh one one key is that these are you have controllers that feed the cells and stir the cells, etc., and pump the media around and so forth.
00:37:32.480 --> 00:37:48.400
Um, and uh these controllers and the software associated with them, you know, is areas where you have to optimize for your particular, you know, product after you we've determined what the ideal growth conditions are for the cells.
00:37:48.639 --> 00:37:53.119
Um so you can get these, but it takes a lot of optimization.
00:37:53.920 --> 00:38:12.000
There's a lot of optimization um when you feed the cells, uh, how often you test them during culture to make sure certain that the cells are viable, as I mentioned earlier, and that they're producing the product as expected.
00:38:13.360 --> 00:38:14.719
Yeah, that makes sense.
00:38:14.880 --> 00:38:15.360
Thank you.
00:38:15.519 --> 00:38:17.599
Uh, and on the product side, I'm curious.
00:38:17.760 --> 00:38:21.440
This is more so just out of my own biological curiosity here.
00:38:21.760 --> 00:38:33.679
You you were talking before about control and and making sure that any given um any given cytokine ratio is is is within what you said two standard deviations.
00:38:33.760 --> 00:38:40.239
So you try to keep tight control on the ratio of all these these growth factors and cytokines and molecules in the solution.
00:38:40.400 --> 00:38:59.199
I'm curious if, and you know, I don't want you to give away the secret recipe or anything, but is that is that ratio of cytokines and and nutrients, we'll call it just the good stuff, is that is that was that the default output of the cell lines, or did that take some trial and error to come up with the golden ratio, so to speak, for the product?
00:38:59.519 --> 00:39:00.239
It definitely, yeah.
00:39:00.559 --> 00:39:11.440
Early on it took trial and error because we have other forms um based on adjustments in the media that yield a different secret tone.
00:39:11.840 --> 00:39:12.559
Oh wow.
00:39:12.719 --> 00:39:24.480
Yeah, so is it is it a matter of the ingredients in the feed, or is it a matter of like upregulating certain or downregulating certain um genes in in the cell lines or it it's feeding the cells and so forth.
00:39:24.639 --> 00:39:28.800
Um, it's a large number of factors that that are involved.
00:39:28.960 --> 00:39:31.280
But you can change what the secret home looks like.
00:39:31.440 --> 00:39:32.960
I'll give you one example.
00:39:33.199 --> 00:39:49.760
There's a if you look in the literature and the secret tomes, if you look at clinicaltrials.gov, you'll find other clinical trials, again, as I mentioned, primarily in academic institutions, using mesenchymal stem cells as this uh to secrete the product.
00:39:50.000 --> 00:40:02.559
It turns out that the secretome that comes from our proprietary cells is significantly different from mesenchymal stem cells, secretone.
00:40:02.880 --> 00:40:06.000
Even they're both, you know, we're stem cell-like.
00:40:06.480 --> 00:40:11.440
Mesenchymal stem cells are in some ways are more mature, right?
00:40:11.920 --> 00:40:42.480
Um and uh there's some published evidence that suggests that the uh activity and perhaps the um the regenerative capability of uh secretomes that come from quote unquote younger cells, of which these anion epithelial cells are you know coming from the placenter, they're as as young as they get, right?
00:40:42.880 --> 00:40:50.559
Right um may be more advantageous, but but we know that the secretome is different.
00:40:51.199 --> 00:40:52.559
We know it's different.
00:40:53.199 --> 00:40:54.079
Interesting.
00:40:54.400 --> 00:40:56.719
Thank you for indulging my curiosity there.
00:40:57.519 --> 00:40:58.559
Um well, Dr.
00:40:58.719 --> 00:41:00.719
Brown, just a couple last questions here.
00:41:00.880 --> 00:41:06.960
Uh first and foremost, I want to know what's next for Novio and what are you looking forward to this year and next year?
00:41:07.039 --> 00:41:14.320
Uh, what are the biggest benchmarks or hurdles in front of you as the as both chief scientific officer and just as for the company overall?
00:41:15.119 --> 00:41:22.800
I think that's a great question because you know we've looked at a number of other potential indications.
00:41:23.840 --> 00:41:34.880
Um one of the unique opportunities of NEC is because it's an orphan disease and there's no treatment, and there's a need, uh, an unmet need.
00:41:35.199 --> 00:41:52.239
Um, from a regulatory point of view, it made the most sense for our company to uh get hopefully approval on the uh biological license applications for this for this particular disease.
00:41:52.480 --> 00:41:57.280
For other conditions, we we've looked at a variety of wound healing applications.
00:41:57.519 --> 00:42:04.239
Um we did studies with a condition called uh persistent epithelial defects.
00:42:04.320 --> 00:42:08.880
They're actually infected holes in the cornea that don't heal.
00:42:09.119 --> 00:42:13.599
And we had some very interesting results there that have been published also.
00:42:14.079 --> 00:42:18.400
But those have to go through the regular long regulatory pathway.
00:42:18.559 --> 00:42:28.400
So the advantage of this orphan indication is that there's an accelerated path of approval.
00:42:29.199 --> 00:42:36.559
Um, there's no doubt that when you're doing work with an orphan disease, patient recruitment is a bigger challenge, also.
00:42:36.960 --> 00:42:40.079
Um, but we think this is the right pathway.
00:42:40.239 --> 00:42:49.519
Um, I described earlier uh our observations of the work from the nose-to-brain delivery and through the intranasal route.
00:42:49.760 --> 00:43:05.599
Um, we'd like to investigate that particular opportunity is real because of the neuroprotective capabilities that we've seen in a variety of animal models.
00:43:05.920 --> 00:43:17.440
Um, and we actually did a phase one safety trial um with the intranasal delivery and showed that ST266 by the intranasal route was safe.
00:43:17.840 --> 00:43:22.719
And we had an anecdotal safety uh observation.
00:43:23.280 --> 00:43:34.480
Um, it turned out that the last subject in the trial, we were testing ST266 intranasally in glaucoma suspects.
00:43:34.559 --> 00:43:52.239
That is, those are people or patients that have um high intraocular pressure, which is one of the etiologies of uh glaucoma, uh, or they had a strong family history.
00:43:52.480 --> 00:44:10.159
So it turned out that the last subject in our intranasal phase one safety trial uh At her first follow-up visit, disclosed that 13 months before she was in the trial, she had COVID.
00:44:10.480 --> 00:44:13.360
I mean, she didn't have it at the time that she was in the clinical trial.
00:44:13.679 --> 00:44:17.679
And she had completely lost from that over those 13 months.
00:44:17.840 --> 00:44:22.000
She hadn't been able to her sense of smell was gone, anosmia.
00:44:22.320 --> 00:44:23.760
And she had discousia.
00:44:24.719 --> 00:44:27.519
Her sense of taste was all messed up.
00:44:28.559 --> 00:44:35.360
Um so she reported to the investigator that uh her sense of smell came back 100%.
00:44:35.920 --> 00:44:45.519
And she was actually a little bit upset because over the past 13 months, she was able to eat spicy food that she had never been able to eat before, and her sense of taste came back normally.
00:44:45.920 --> 00:44:58.239
So, you know, I I think that perhaps people with long COVID um may benefit from the intranasal delivery of SD266.
00:44:58.639 --> 00:45:10.559
Um I think that other diseases that are uh could be treated would be things such as Alzheimer's and uh or Parkinson's disease, etc.
00:45:11.119 --> 00:45:12.880
Maybe ALS.
00:45:13.199 --> 00:45:20.639
Um, and we'd like to, you know, when we have the resources, investigate those additional indications also.
00:45:22.159 --> 00:45:23.199
Yeah, that's great.
00:45:23.280 --> 00:45:25.519
I mean, a lot to look forward to, a lot of the horizon.
00:45:25.599 --> 00:45:33.280
And it sounds like if I remember from that presentation, it was um, and maybe we talked about this in the pre-call too, where it's just like you can't get it to fail, right?
00:45:33.440 --> 00:45:35.840
Like everything that you've well, you mean or less tried it.
00:45:38.719 --> 00:45:50.559
But it it's interesting too when we every time we've done a new animal model, um, and we turns out that there's a certain biochemical pathway that's known to be involved.
00:45:50.719 --> 00:45:54.159
And again, we didn't go into, oh, we know that we upregulate this pathway or that point.
00:45:54.320 --> 00:46:02.480
You know, we just know that it's got these properties, these general anti-inflammatory, you know, neuroprotective properties, etc.
00:46:02.960 --> 00:46:14.159
And um so we we didn't know this with TLR4 and neck, but it turned out that it's attenuating that pathway that needs to be attenuated, right?
00:46:14.559 --> 00:46:21.440
In order to um be able to uh better treat necrotizing okalitis.
00:46:21.599 --> 00:46:29.519
When we did our intranasal studies, also we didn't know at the time until we we looked at these, or Dr.
00:46:29.679 --> 00:46:34.880
Schindler's group did, that there's um certain certain surface cell markers.
00:46:35.440 --> 00:46:40.320
One is up regular upregulated, which is involved in mitochondrial biogenesis.
00:46:40.559 --> 00:46:45.039
Um, there's the PAKT pathway, which is involved in cell survival.
00:46:45.280 --> 00:47:01.440
What we've seen universally in every single study that we've that we've looked at is that, you know, again, there are often disease models, etc., is what kills cells ultimately is a reactive oxygen species.
00:47:01.599 --> 00:47:03.039
You can see that every time.
00:47:03.360 --> 00:47:12.480
In every study that we've looked at and tested ST266, reactive oxygen species are decreased significantly.
00:47:13.519 --> 00:47:24.960
That's like a key mechanistic um uh commonality between every study that we've that we've looked at that endpoint.
00:47:25.360 --> 00:47:38.960
So that opens up, you know, I think the opportunities to look at uh a variety of of of uh diseases where you just want to prevent cell death.
00:47:39.360 --> 00:47:52.000
I sort of uh the mitochondrial um involvement is kind of interesting because I sort of make it's like analogous to how is this work st266 working?
00:47:52.239 --> 00:47:55.679
If your battery's running out of your on your on your cell phone, right?
00:47:55.840 --> 00:47:57.519
Or your what do you do?
00:47:57.679 --> 00:47:58.880
You plug it in.
00:47:59.920 --> 00:48:04.079
I think st266 is recharging the cells.
00:48:04.800 --> 00:48:11.119
That's sort of that's sort of like my analogy for how it it's working.
00:48:11.280 --> 00:48:19.840
It's recharging them and keeping them dying cells alive, or hopefully reversing it if you catch it early enough in the disease process.
00:48:20.159 --> 00:48:20.800
Yeah.
00:48:21.360 --> 00:48:22.400
It's incredible stuff.
00:48:22.480 --> 00:48:30.079
I mean, it's it's exciting to hear about, and I can't wait to hear more about the the clinical readouts as they happen and and all the indications you guys get to move into.
00:48:30.159 --> 00:48:32.000
I'm I'm much looking forward to that.
00:48:32.159 --> 00:48:44.239
Um I I'm not sure if when you if we had already had the press release on the first cohort of uh uh NEC neonates that had been successfully safely treated.
00:48:44.800 --> 00:48:45.119
That's right.
00:48:45.199 --> 00:48:45.360
Yeah.
00:48:45.760 --> 00:48:48.400
Can you maybe tell us a bit about that cohort for the for the audience?
00:48:48.480 --> 00:48:49.280
Uh how many times?
00:48:49.519 --> 00:48:57.199
Um in our clinical trial in in NEC, um we have a protocol with four cohorts.
00:48:57.519 --> 00:49:10.320
So essentially it's babies that are over a kilogram to 3,000 grams, and babies below from 500 grams to 999 grams.
00:49:10.559 --> 00:49:16.320
So we have big babies and small babies, then we have a dose escalation, we have two doses.
00:49:16.639 --> 00:49:21.679
Um, and so they first the big babies got the low dose, we showed it safe.
00:49:22.480 --> 00:49:30.480
Um uh there was no issues with the FDA or any institutional review board because of that.
00:49:30.639 --> 00:49:36.000
The FDA eased up our um made it easier for us to recruit.
00:49:36.239 --> 00:49:42.719
We're actually recruiting the the second and third cohorts of babies currently simultaneously.
00:49:42.800 --> 00:49:49.599
So now we're doing small babies at the low dose and larger babies at the higher dose.
00:49:50.079 --> 00:49:56.400
And uh hopefully this will help us accelerate you know the completion of the clinical trial.
00:49:57.119 --> 00:50:02.079
Yeah, that's a good and that that was some that's a good example of how the FDA has helped us.
00:50:02.400 --> 00:50:03.679
Yeah, that's great to hear.
00:50:03.760 --> 00:50:07.199
I mean, especially for inorphan indications such as this.
00:50:07.360 --> 00:50:11.920
Um I'm I'm happy to hear that they're enabling more than obstructing.
00:50:12.239 --> 00:50:16.639
Um not that they're notorious obstructors, but just still not before.
00:50:16.719 --> 00:50:17.199
No, no, no, no.
00:50:17.360 --> 00:50:25.760
They don't necessarily I mean the less the the goal of the FDA is to make sure that everything that's administered, any drug is safe and effective.
00:50:25.920 --> 00:50:30.159
But and so they're very concerned about the safety.
00:50:30.559 --> 00:50:40.880
And um ST266 has now been in 282 humans, including these six neonates.
00:50:41.599 --> 00:50:51.599
Um and we've never had a drug-related adverse event in any trial, no concerns from the FDA or in any IRB.
00:50:52.320 --> 00:50:56.000
So safety is number one, and that's what their main concern is.
00:50:56.400 --> 00:50:58.960
Absolutely, as it should be, as it should be.
00:50:59.280 --> 00:51:00.079
Thank you, Dr.
00:51:00.159 --> 00:51:00.639
Brown.
00:51:00.800 --> 00:51:04.079
Well, I just have two last questions here I wanted to touch on.
00:51:04.239 --> 00:51:06.880
Um and you know, the hallmark question of the show.
00:51:06.960 --> 00:51:12.320
But before I get to that, what a lot of people might not know listening is that you were the legendary Dr.
00:51:12.400 --> 00:51:15.039
Robert Langer's first doctoral student.
00:51:15.360 --> 00:51:24.320
And I want I was curious to hear from you what the most important thing Bob Langer has taught you, uh that you if you can recall your time with him.
00:51:24.400 --> 00:51:31.679
And kind of on the other side of that, I'm curious what do you think is one thing he'd say that he learned from you as his first doctoral student?
00:51:32.000 --> 00:51:33.039
Interesting questions.
00:51:33.360 --> 00:51:39.199
So, one thing that I clearly learned was think outside the box.
00:51:39.599 --> 00:51:39.920
Okay.
00:51:40.159 --> 00:51:44.400
I think that's actually something true that's taught throughout MIT.
00:51:44.719 --> 00:51:51.199
Just because we are used to a particular way of doing something or technology, there may be even a better way.
00:51:51.519 --> 00:51:53.920
Yeah, like take the cell out of a cell therapy, right?
00:51:54.079 --> 00:51:54.480
Right, right.
00:51:54.559 --> 00:51:56.159
Take the cell out of the cell therapy.
00:51:56.239 --> 00:51:57.519
That's that's a great example.
00:51:57.760 --> 00:51:58.239
Quite outside.
00:51:58.559 --> 00:52:04.559
Um, so you know, this may be always another better way to solve a problem.
00:52:05.280 --> 00:52:07.519
And so that that was key.
00:52:07.920 --> 00:52:14.400
Um, what he taught me, I think what what's interesting, I've been I've been very lucky.
00:52:14.480 --> 00:52:18.159
I've had a lot of superior teachers my whole life.
00:52:18.480 --> 00:52:30.800
Um, one thing that I think helped me all along was um I had some really good English teachers who taught me how to write well.
00:52:31.840 --> 00:52:35.440
So I always get at Novio, mom always get, Larry, can you review this draft?
00:52:35.599 --> 00:52:40.159
Right, and that the grammar is correct, etc., etc.
00:52:40.719 --> 00:52:46.400
Um when as you mentioned, I was his first doctoral student.
00:52:46.480 --> 00:52:52.400
So when Bob submitted his first R01 grant, NIH R01 grant, he sent me a draft.
00:52:52.480 --> 00:52:53.920
Larry, could you just review this thing?
00:52:54.000 --> 00:52:57.119
And um, yeah, I think it was over the weekend.
00:52:57.360 --> 00:52:59.760
I think I completely rewrote it.
00:53:00.480 --> 00:53:04.960
And he called me up, like I don't know, Sunday night, whatever, what whatever, whatever it was.
00:53:05.119 --> 00:53:07.440
He said, Larry, this is great.
00:53:07.760 --> 00:53:08.239
Right?
00:53:09.360 --> 00:53:13.440
It turned out that we got one of the highest scores that year.
00:53:13.760 --> 00:53:14.239
Wow.
00:53:14.480 --> 00:53:24.960
And so, you know, um I've always, you know, I think I think he's always respected uh, you know, my ability to to write.
00:53:25.199 --> 00:53:42.719
And um maybe, you know, that taught him he's been has his many grand um funded as anyone, that perhaps from that first one, uh he learned something from me of how to how to write things clearly, right?
00:53:43.039 --> 00:53:43.840
I wouldn't doubt it.
00:53:43.920 --> 00:53:44.559
I wouldn't doubt it.
00:53:44.960 --> 00:53:49.840
Um it was it it was interesting because uh one of the first papers from my thesis was published.
00:53:50.000 --> 00:53:54.880
There were two papers, they were part A and part B, to the journal Diabetes.
00:53:55.920 --> 00:54:01.440
And when it came back from the reviewer, they were re I wrote them, right?
00:54:01.840 --> 00:54:04.800
Um they were in my thesis basically.
00:54:04.960 --> 00:54:11.119
Uh they came back from the review said um no edits, no suggestions.
00:54:11.280 --> 00:54:12.960
This is were accepted as is.
00:54:13.119 --> 00:54:15.440
I've I've never heard of anybody else doing that.
00:54:15.920 --> 00:54:17.119
I haven't either.
00:54:17.440 --> 00:54:21.360
Not that I'm in in those circles as much as you, but that's still nuts.
00:54:21.519 --> 00:54:21.920
Yeah.
00:54:22.159 --> 00:54:22.480
Wow.
00:54:22.719 --> 00:54:27.679
And I, you know, again, I attribute to my English teachers, right?
00:54:29.039 --> 00:54:31.360
That's great if you ever want to write for bioprocess online.
00:54:31.599 --> 00:54:34.880
You know, we're always we're always accepting expert guest columns.
00:54:35.599 --> 00:54:36.559
Um well, Dr.
00:54:36.719 --> 00:54:44.480
Brown, thank you so much for for walking me through the story of ST266 and and sharing all that with us, um, me and our audience.
00:54:44.639 --> 00:54:50.880
I just have one last question here for you before we before we wrap up, and that is the hallmark question of the show that I asked every guest.
00:54:50.960 --> 00:54:52.000
And that is, Dr.
00:54:52.079 --> 00:54:54.880
Brown, how do you think we can better biopharma?
00:54:57.039 --> 00:54:59.360
Uh, how can we better biopharma?
00:54:59.920 --> 00:55:03.599
So everything in biopharma is new.
00:55:04.079 --> 00:55:04.400
Okay.
00:55:05.199 --> 00:55:29.679
Um, I remember, you know, when antisense oligonucleotides and sirna came on, everybody thought that it would they were going to be drugs were going to be on the market in a couple of years after their first, the first Nobel Prize by Doug uh by uh who was at the University of Massachusetts, uh, who got the Nobel Prize for uh discovery of SIRNA.
00:55:30.159 --> 00:55:35.039
Um everything takes you know longer.
00:55:35.280 --> 00:55:40.480
I think we need to learn to be you know patient with the process.
00:55:40.800 --> 00:55:47.519
Uh I think that uh, you know, at the same time, how do we streamline the process?
00:55:47.679 --> 00:55:56.159
Uh, you know, as I mentioned, documentation is key for the FDA and regulatory approval.
00:55:56.559 --> 00:56:04.079
Is are there ways that um artificial intelligence can help us streamline that process?
00:56:04.320 --> 00:56:25.440
I think that that's uh a goal where AI could help because documentation is collections of large amounts of data and putting them into an organized fashion so that uh you know they can be reviewed with as fewest questions as possible.
00:56:25.599 --> 00:56:41.119
And and uh I I think that's where we can be better biopharma, streamlining you know, all the processes uh to move drugs into um not just into the clinic, but into approval.
00:56:41.840 --> 00:56:42.400
That's great.
00:56:42.639 --> 00:56:43.599
Couldn't agree more, Dr.
00:56:43.679 --> 00:56:44.000
Brown.
00:56:44.079 --> 00:56:49.679
Thank you so much for joining me on this episode of Better Biopharma, the official podcast of Bioprocess Online.
00:56:49.760 --> 00:56:51.599
And thank you in the audience for tuning in.
00:56:51.760 --> 00:56:52.800
We'll see you next time.
