Summary

On the latest episode of The Bioverge Podcast, we are pleased to welcome serial entrepreneur David Johnson, Founder & CEO of GigaMune and Entrepreneur-in-Residence at Illumina Ventures.

Dr. Johnson was previously part of the founding team and COO of Natera (Nasdaq: DNA, $4B market cap), and most recently sold his last company (GigaGen) to Grifols.

Dr. Johnson sits down with Neil Littman to discuss his newest company's efforts to develop lentivirus pseudotypes for the in vivo delivery of cell and gene therapies.

If you're interested in the regenerative medicine space, you won't want to miss this one!

Listen on SoundCloud: https://lnkd.in/g5ZtFCyB

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Transcript

00:29
Danny Levine (producer)
Yeah, we've got david johnston on the show today. Tell us about david.

00:33
Neil Littman (host)
I am incredibly excited to welcome dave to the show today. Dave is an inventor, entrepreneur, and expert in genomics with a track record of bringing new medical technologies to the clinic and to the commercial marketplace. He is currently an entrepreneur in residence at aluminum ventures and is the founder and CEO of a new company called gigamune. Gigamune is developing a suite of novel technologies for in vivo targeted gene delivery. Dave and I will get into that. Previously, dave was the founder and CEO of giga gen, which was acquired by griffin for $143,000,000 just last year. Prior to that, dave was the founder and was on the founding team excuse me and was the COO of nutera, which went public in 2015 and is currently trading at a $4 billion market cap valuation. Dave has a ton of experience as a serial entrepreneur, company builder, deep expertise in genomics by informatics, and I'm excited to talk to him about his entrepreneurial journey and his new company, gigamune.

01:42
Danny Levine (producer)
What's the problem gigamun is trying to solve?

01:46
Neil Littman (host)
Yeah, so gigawe is really trying to solve this problem of efficient delivery of cells and genes to the human body. One of the bottlenecks is the specificity to which gene therapies can be targeted to specific cell and tissue types. There's a variety of different approaches that are using lentiviral vectors or AAV, which are ad noassociated viral vectors. There's also nonviral based approaches like lipid nanoparticles or LNTS. Those are the approaches that the recent slate of mRNA COVID vaccines used to deliver mRNA to target cells, for example. What dave is doing is actually trying to deliver his therapy in vivo. Instead of taking cells out of the human body and somehow engineering or manipulating them and putting forth the viral vector and the payload exe vivo or outside the human body, dave's technology and what gigamun is trying to do is do all this in vivo through a much higher degree of specificity.

02:51
Neil Littman (host)
There's a lot of sort, technical nuances, but I think it's really exciting, and it has the potential to really supplant what is being done in many ways today.

03:03
Danny Levine (producer)
Dave is a serial entrepreneur.

03:05
Speaker 1
How do you think that might shape.

03:06
Danny Levine (producer)
His approach at gigamune?

03:08
Neil Littman (host)
I think it probably dramatically shapes his approach. Actually, danny, that's a question I'm going to pose to him, but he's been there and done that before, and there's no guarantee the new endeavor is going to be successful. I think he probably has a lot of lessons that he's learned through his take a note through his time at gigajin from initial ideation and building the company through scaling through exit. I think there's probably a lot of learnings that he can bring to giga mute days. I'm excited to dive into those and I think it's both from the company building, social aspect, culture, team, all those types of things. I think also from just a pure technology standpoint, I'm sure he's seen a lot of pitfalls, what works, what doesn't work, and which will allow him to really hone in on what to focus on as he builds Gigamune.

03:59
Neil Littman (host)
Well, if you're all set, I'm all set. Let's do it. Danny, David, thanks so much for joining us. I am incredibly excited to have you on the show today.

04:13
Dave Johnson (guest)
Happy to be here.

04:15
Neil Littman (host)
We are going to talk about your new company, Gig Immune, and your vision for in vivo gene delivery to treat cancer and autoimmune conditions. Before we get into that though, I do want touch on the two prior companies you founded and successfully exited. I might add, you were the founding COO of Nutera, which IPOed in 2015 and currently has a market cap of $4 billion. After Nutera, you founded and were the CEO of Gigajin, which was acquired by Griffiths for $142,000,000 last year. Can you start by talking about the technology underlying those two companies, how you came up with those ideas and if there was a common thread or underlying theme between those two businesses?

05:01
Dave Johnson (guest)
Yeah, so I helped start Nutera during my postdoc at Stanford, and what I did at Stanford was a lot of high throughput genomics. Around that time, the first high throughput sequencing methods were coming out. Aluminum was just getting started with their sequencing. It was really exciting time trying to think about the different applications that sequencing and genomics could be used for. One early low hanged fruit was for what we call noninvasive diagnostics. This is basically you take a blood draw from some kind of patient and then you deep sequence and really deconvolute different kinds of signals in the blood. Nutera was involved in this for noninvasive prenatal diagnostics. We also did it for IVF. Later on, actually, after I left, Nutera got into cancer diagnostics as well from blood. During that time in Nutera, I started getting really interested in single cell work. Actually it was a really kind of obscure thing that I was doing with single cell and the terra for our prenatal biagnostics and reproductive diagnostics, were doing a lot of single sperm analysis and one of my jobs was to pick single sperm from subjects and a little micro needle and put them into tubes.

06:37
Dave Johnson (guest)
Nobody else wanted to do it. Eventually I trained somebody else when I was sitting there. It's just one of those things. I was like, I just got to be a better way to do this kind of thing, which is where inventions often happen. I knew other people had been working on droplet microflytics and I think everybody was casting around for really good applications. At the time, some people were doing digital droplet PCR, but I thought it would be interesting if we could combine the single cell challenges with Droplet microflytics. I got excited about that. We had launched several products and it was a good time to leave Nutera because it was a lot about just sales at that point and that wasn't my job, was to and so I left and started Giga gen. Really the whole idea there was let's use Droplet microflytics plus genomics to do single cell analysis and this actually predated Ten X genomics.

07:42
Dave Johnson (guest)
I'm sure some people listening are like, that sounds like Ten X genomics. And yes, it totally does. Were doing this stuff before Ten X but we kind of went a different route. Ten X went the route of, I guess, research tools and have been really successful, kind of way more successful than I ever thought they would have been. I just was always interested in translational work. The best medical applications I could find is always what really gets me excited. That's where I steered Gigajen and what we found was there was this neat application where we could use the microflitics to capture entire immune systems which are very diverse. Everybody knows all about this stuff now because of codes, it but immune systems are very diverse. There's tens or hundreds of millions of different kinds of antibodies and immune systems and so what we could do is use microflitics to capture the antibody sequences and we actually made that into a drug.

08:44
Dave Johnson (guest)
Basically around the time that COVID started we had really matured our technology to the point where were looking for our killer application. COVID kind of gave it to us because as soon as the Pandemic came out people were talking about convalescent serum and as soon as people started talking about convulsive serum I said, well, I can make that using my technology in a recombinant way. Basically capture all the antibody sequences and then make it in a bioreactor just like monoclonals are made. It was just a great in the right place at the right time. We got into the clinic and we ended up getting bought by a longtime partner, Griffith, for a nice exit and none of that would happen at Pandemic. There's one thing I've learned throughout the years it's that to be a good entrepreneur you have to be very willing to grasp opportunities when they're in front of you.

09:55
Dave Johnson (guest)
Just kind of go for it when something's in front of you. I think for the Pandemic that was a lot of good entrepreneurs said, well, what can we do? How do we make a difference? Right? It's a combination of how do you make a difference and then how do you really grasp something that's a great business opportunity. I guess kind of moving fast forward to Giga Mune, I worked for Griffles, the buyer of Gigabyn. My second company for a while, about a year. Before we got Giga Gen bought, we spun out a bunch of technologies and intellectual property that the buyer wasn't interested in. That was where Giga Immune came from. That's why it's got a similar name and a little confusing. All those technologies that we spun out had to do with cell therapies. This was stuff that gripple doesn't work on at all.

10:51
Dave Johnson (guest)
I started thinking about what could we do with those technologies? I talked to a lot of experts and what the experts said was, well, really a lot of investors, they said it's really hard to get cell therapies funded these days because it's so darn expensive, particularly making manufacturing systems, just scaling that it's really expensive before you even get to your clinical studies. I started thinking about how we could solve that problem. Really? Again, I'm always trying to keep my ear to the ground and solve problems that others are telling me are out there and think about ways that are divergent from more conventional solutions that other people are thinking about. This is kind of a long waited intro. I guess I'll stop there and I'll let you get another question.

11:49
Neil Littman (host)
Yeah, no, Dave, that's super helpful. I do want to circle back to a point that you made about being an entrepreneur and being Opportunistic. I'm always fascinated by the entrepreneurial journey. I just wanted to go back and ask you a question along those lines. Could you talk about your experience with the Terran and Giga Gin going from idea to building the company through to a successful exit? I mean, that's such an amazing journey to do once, let alone twice, and now you're attempting to do it for a third time. Could you just talk about some of the pitfalls or lessons learned or things that you're bringing to your new endeavor?

12:26
Dave Johnson (guest)
Yeah, well, I'm at a point in my career where people start reaching out to me for advice because like I said, I've done twice, I've been successful, now I'm doing a third. Younger entrepreneurs or people trying to move over into entrepreneurship have reached out for advice. One of the first things I always say, which kind of I think gets people maybe a little flustered, is I say, can you do anything else? Because being an entrepreneur is really hard and it's also involved long periods of time where you're not making any money and there's a lot of doubt. Right. My first comment is just like, well, because if you can do something else, you should consider that because it's a tough prospect. I'll ask, do you have one or two years of money to just fund your food and your rent or mortgage or whatever you have?

13:30
Dave Johnson (guest)
How are you going to do that? Right. I can't think of too many true entrepreneurship journeys where people just started and then day one, they've got a great salary and funding. You have to go out and do a lot of search and whatnot. So that's one thing. The other thing I would say is do you have any kind of secret weapons? Like what is your real superpower skill that's going to differentiate you? Because if you have that hustle, once we pass that mark, you have the hustle and you're willing to work for nothing, work for equity for a while, for that dream. There's a lot of those people too, right? What is it about you that makes you amazing? Some people are really good deal makers. Some people are really good at going out and raising money. Some people are really good at something technical.

14:33
Dave Johnson (guest)
Maybe they're an artificial intelligence person or something like that. You have to think carefully about what is that thing that you're really good at and that's not important to focus on that. When you talk to investors and when you're thinking about building a product, what are you going to better at than anyone else? That's really key. Also when you're building a team, you have to think about who are you bringing into a team? I thought about this, for example, at Gigajen, I know I'm a technical founder. I often have my head down and I want to work on the technology stuff. In that case I found a co founder who is gregarious and really outgoing and is out there lots of meetings, shaking hands and whatnot. He was a really good cofounder because we rounded each other out really well. He didn't have any technical skill, right?

15:28
Dave Johnson (guest)
So he needed somebody like me. I think those are kind of big things, thinking about teams, thinking about what are you willing to put into it and then being willing to be opportunistic, like you said. I think that's really important. You got to look for the opportunities and you have to figure out how to make the most of them in a really unique way.

15:53
Neil Littman (host)
Yeah, I think that's all great advice. I think of it almost as like activation energy, right? There's so many different ways you can go, but you got to get out there, you got to do different things. You got to position yourself to find the right opportunities and then of course, you have to recognize those opportunities. Okay, Dave, I want to switch gears and I want to dive into what you're doing now at Gigamune. Let's start with where cell and gene therapies are today. We've seen some great advances in the treatment of hematological cancers, rare genetic disorders, for example. I do just want to take a minute and set the stage for our listeners to make sure we're all on the same page. Bear with me for 1 minute here.

16:33
Dave Johnson (guest)
Yeah.

16:34
Neil Littman (host)
As Dave, right, the first wave of treatments approved by the FDA were cartes. Those were for hematological malignities, such as acute lymphoblastic leukemia, nonhodgkin lymphoma. Those treatments have profoundly altered the treatment landscape because they've demonstrated both high overall response rates in the order of magnitude over 85% and durable remissions in patients who have otherwise failed standard therapies. Those were really game changing technologies when they came out. Those are roughly what I tend to categorize as generation one. Let's not forget, the biotech companies that developed these first generation products were both acquired. Juno was bought by Celgene for $11.1 billion. Kite was bought by Gilead for $11.9 billion. You fast forward a couple of years. The FDA approved the very first gene therapy for an inherited genetic disease. This one was called Lux turna for a very specific mutation associated with a form of retinal Dystrophy.

17:37
Neil Littman (host)
This was also there was the first approved AAV gene therapy in the US. I believe that the cartoons all use lentiviral vectors and we'll get into more of the differentiators there that technology. That therapy was developed by Spark, which of course was acquired by Novartis for four $8 billion. Right, so you're seeing a common theme here. Right, so fast forward again. There's another small biotech of existing developed a gene therapy for spinal muscular atrophy. They were acquired by Novartis for 8.7 billion. Most recently in April this year, the FDA gave the green light to bluebird BIOS gene therapy for beta thalassemia. So that was really exciting. I think that's a big inflection point as well. As, all of these new therapies as they've come to market have also broken pricing records, right. Starting in a couple of hundred thousand dollars for the cartes that were displayed, now up to $2.8 million for bluebirds treatment.

18:31
Neil Littman (host)
So, Dave, with all of that background, how are these types of products currently produced today?

18:38
Dave Johnson (guest)
Yeah, I think that's a great intro, and I think it's especially great to include cell therapy as a subset of gene therapy, which I don't think everybody necessarily does, but obviously that's what it's all about. You're taking cells out of a patient and putting a gene in and then putting it back. It's a gene therapy. So, yeah, I appreciate all that. I also appreciate that it's an interesting inflection point in the market. Biotech has been about antibodies for a long time, a couple of decades, really. I think we're at a turning point where different kinds of gene therapy are really going to be the future. In fact, I wouldn't be surprised if 15 years from now, antibodies aren't even made in bioacters anymore. They're actually made as a gene therapy which is delivered in vivo. I just think there's going to be a real sea change there.

19:37
Dave Johnson (guest)
This is basically all about how do you get the right genes, the right cell in the right place. Another thing to think about when I think about where the market has gone more recently, these are firms that are kind of in the next generation. The emphasis has really been on how you get the right gene to the right cell, like I mentioned and those first ones that you mentioned. The cell therapies, for example, from Height and Juno that's made using a lentivirus ex vivo in a lab. You just put the lenti on. It doesn't really matter how specific the delivery vector is. The same for the AAV therapies that have been coming out. The next generation is all about how do you get very specific, efficient delivery of the genes, the right place at the right time. It's important for efficacy because you have to make sure you're getting the right gene to the right cell and the right amount.

20:47
Dave Johnson (guest)
And then also safety. I mean, you don't want to give the wrong gene to the wrong cell because certainly FDA is going to wonder what are the safety downsides of that? Very important to think carefully about that. I think the next wave of those billion dollar outcomes are going to be in that area. Most of the work up till now has been an AAV. There's a company called Dino, for example. There's another one called I can't remember there are several companies working on that in AABs, and I think there's definitely space for other kinds of platforms to come in and really kind of duke it out in the market. There's definitely an opportunity, I think, for even multiple kinds of platforms to win here.

21:41
Neil Littman (host)
So let's talk about that. Dave. Let's turn to gigabyte. You're working on in vivo targeted delivery methods that could theoretically replace existing cell and gene therapy methods at a high level. Could you talk about how your technology works?

21:59
Dave Johnson (guest)
Yeah, well, actually sorry, I didn't really fully address your cost issue, so let me address the cost issue and then get back to that. Sorry, I kind of missed that point. The prices of selling gene therapies are somewhat dictated by the market. They're somewhat dictated by the cost of clinical studies, but they're also dictated by the cost of manufacturing. So, for example, let's say you can get a price of $1 million for cell therapy, and it's fairly extremely efficacious and safe still to manufacture that. This doesn't even include all the clinical trial costs. This is just like what it costs to manufacture that. It's typically in the $300 to $400,000 range, at least based on information that we have now. Of course, you're making several hundred thousand dollars every time you make a sale. That's good for pharma, but it's not a great profit margin.

23:02
Dave Johnson (guest)
Of course, the market needs to bear these high prices, which means that not as many people are getting them these therapies as a s***, right? Okay, that's basically the problem statement. We are working on a type of gene delivery vector called lentivirus. I think we talked about this earlier. Lentivirus is the vector that's used to deliver genes ex vivo to T cells which then becomes the cell therapies for B cell malignancies. That's kind of the paradigm at this point is to take cells out of a patient, engineer them with the gene and then shift them back to the patient and then deliver the cells to the patient. Those vectors are designed in a way there's a protein which is called a pseudotype which sorry, I'm getting technical jargon here, but what the pseudotype does in the lentivirus vector is it basically is the machinery that binds to the target cell and it's also the machinery that fuses to the target cell and delivers the gene internally.

24:24
Dave Johnson (guest)
The pseudotype that's being used for the lengthy virus right now is one where it has a generic specificity. Basically what the protein does is it docks to a protein which is expressed on every cell. That's convenient in a lot of ways because you can develop a lengthy virus that works for any cell. But there's a problem too. It's okay if you just purified T cells and you want to deliver them to every T cell. What if you had a mixture of T cells in say, B cells and macrophages and you only wanted to deliver to T cells? Then it's not going to work. Okay? We are looking at that problem and the way that we're looking at it is using a genomics and bioinformatics approach. These proteins that are used as pseudotypes are viral proteins. The one that's been used historically is just something that was picked out early on in the history of biotech and there's a lot more out there.

25:37
Dave Johnson (guest)
We did a sequence search, large scale on the cloud and sequence looked for many trillions of bases of material to find new pseudotypes and we found a couple hundred or so and started testing them in the lab. The features that we're looking for in the lab are we wanted to be able to pair the pseudotypes with antibody. This allows, again, bare view, the other technical here. We're trying to use an engineering approach where the antibody is what shuttles the lengthy virus to the right cell, a specific cell type. If you have a T cell, there's markers on the T cell where you can design antibodies against them and they're very specific to that T cell. The pseudotype doesn't bind to the T cell or anything else maybe because it's a very divergent viral protein. It's nothing to do with any human protein but it does allow a delivery of the gene internally inside the cell.

26:46
Dave Johnson (guest)
It's like a logic gate where you have to have both the antibody binding and the delivery of the gene and they're enabled by different proteins. If you just added the antibody to the normal pseudotype, then it might help with specificity, but not a lot. What you really need to do is find something that needs the antibody in order to deliver to the cell at all. I hope that's fairly clear. I know it's fairly technical and it's always something that's better if you see a diagram or a figure or something.

27:32
Neil Littman (host)
That's right. I mean, we're not afraid of getting technical on the show. Okay, so one clarifying question. It sounds like the lentiviral pseudotypes that you're using are all naturally occurring versus you engineering them to confer some specificity, but I just want to make sure I got that right.

27:51
Dave Johnson (guest)
Yeah, that's right. That's pretty different from, for example, the AAV techniques that are being used. Most of the companies that are working on Avs, as far as I know and understand, are making mutated libraries of AUVs. They're artificial sequences which are designed into the capsules of the viruses. This approach is trying to leverage natural sequences. There is some chance that we'll end up trying to engineer them. I usually get the sense that natural sequences, if you can get them to work, it's always better because nature has a way of making things that work well. And of course there's always downsides too. There's something called immunogenicity and you always have to worry that, well, everybody knows immunogenicity these days because of COVID, right. If you're using these vectors in vivo, you want to be sure that they're not super immunogenic because that can obviously cause safety problems.

29:04
Dave Johnson (guest)
So there's a unit gang there. Yeah, I usually do like to use naturally occurring proteins. Yeah.

29:13
Neil Littman (host)
I want to get back to the state of the overall in vivo gene therapy market. Before I do, your approach seems like it would open up new applications that are not currently possible or practical with how things are done today, if that is a fair assessment. How so?

29:35
Dave Johnson (guest)
Yeah, I guess it depends on what you're really for the most part, you would make that statement and you would be in comparison to AAV because that's where almost all the clinical trials are for vivo gene therapy. I think there's probably a lot of clinical applications where AAV is best right, or maybe the same as using a lengthy virus. There are certain things that we think we'll be able to do, which I think would be hard with AZ. First of all, AAV has a pretty hard set limitation in gene payload size. 4.5 kilobases is typically considered the max gene size that you can deliver. It works for a lot of genes. Other genes, I think dystrophin for muscular dystrophy is the classic example. Way too big for a V so investigators in that area are doing RNAi methods, for example, or they're doing something called a microdystrict, which is like a truncated district.

30:51
Dave Johnson (guest)
And those have worked great. I think there have been some approvals, but generally the efficacy isn't that high. Certainly having a bigger payload will help. Another area which I think is pretty interesting is, of course, the cell type specificity of antibody. It's kind of hard to compare apples to apples against AAV, but what I've heard through the grapevine is that for certain cell types, engineering AZ has been really challenging. If the method there is just to make a big random library and then screen for specificity against a cell, well, it may work. If you have an engineering approach, you can design antibody against the specific cell target on that cell, and then you really understand where it's going and why. You can also understand the off target specificity really well, too, because you can just look at where that target protein is expressed, what other cells that target protein is expressed in.

32:02
Dave Johnson (guest)
That's a big advantage, I think, for certain kinds of indications where you want that specificity, that's a big deal. This is kind of a new thing that we have recently been investigating in the lab, but again, kind of in those technical weeds here. Lentivirus is what we call a vesiculavirus. A vesicle is something that buzzed off of a cell and basically like pinches the cell membrane off from the cell. Lentivirus is manufactured, there's a host cell and you introduce a bunch of genes into the host cell and then they kind of blib off from the host cell. Every protein that's expressed on the cell membrane of the host cell has a chance of being on the lengthy fires. Your antibodies that you express precondinently are there and your pseudotype, and that's how you get into the cell. You can also put other stuff in there.

33:09
Dave Johnson (guest)
The interesting discovery we had here is there's a target on Tcells called CD Three. CD Three, for people who have been a biotech for awhile, is a target that people have been interested in modulating as a way to activate Tcells for a long time. When we used CD Three antibodies for targeting the T cells, they also activated, which was really interesting, right? You had delivery of the gene, the transgene to the right cell specifically, but then you also activate as a Tcell. What we've been exploring, and we're interested to do a lot more, are ways that you can activate Tcells, keep them from becoming what we call exhausted by delivering certain signals on the lengthy virus itself to activate the T cells. Kind of an interesting area, which would again be really hard to do using other kinds of platforms like Avs. Other people interested in vivo are doing lipid nanoparticles.

34:24
Dave Johnson (guest)
Like the Mederna vaccines. I think, again, there's a toolbox here that I think is evolving and one area where there has been really little innovation to date is lentils because we've kind of been using the same designs that have been used for a long time.

34:51
Neil Littman (host)
Yeah, Dave, that's great. I want to go back in a minute and talk about some of the other in vivo clinical data that has been generated over the recent years. You did mention a really important point that I want to pick up on first and that is there are a number of therapies in development or even that have been approved at this point that offer self free delivery of genetic material and they rely on viral vectors. Right. You mentioned one lipid nanoparticles or LNPs for our audience. This is the technology, for example, that the mRNA vaccines used to get the mRNA into cells, right? Without the LNP as a delivery vehicle, which by the way, that technology had been in development for decades, all the COVID vaccines, at least the mrnabased ones, wouldn't work, right, because you can't get the mRNA into the cells. Can you talk then about how your approach maybe differs from LNP or these lipid nanoparticles or other types of cellphone delivery methods?

35:45
Dave Johnson (guest)
I wouldn't be surprised, I don't know the history because it predates my activity in the field, but I wouldn't be surprised if somebody at some point looks at lenti virus and other kinds of vehicular viruses and said, hey, maybe I can do that whole thing artificially. Because basically an LNP, it's a lipid membrane. It works a cell membrane. It's just something that's fully artificially manufactured. Whereas lente buyers uses cell machinery and even though it's made predominantly, there's some relationship with nature, whereas LMPs are not. These are vesicles that hold RNAs to get them to the right cells. The downside, of course, is that again, going back to the original statement that you can be closer than nature, it's usually better these particles, whereas I think the vesicular viruses have evolved to figure out how to persist in vivo and get to the right places in vivo and do the right things.

37:06
Dave Johnson (guest)
LNPs are pretty much immediately recognized as foreign and that's why they're taken up by the liver and macrophages preferentially. That's great for a vaccine because you get quick and brief expression of the antigen, for example, a COVID antigen. If you're trying to make an in vivo cell therapy, that's not necessarily what you want because it's not going to the right sells. And then it's also pretty transient. Of course, people who really know about the field, there are some companies out there who have recently got funded, there's one called Capstan to do exactly what we're discussing here to do in vivo cell therapies using LNP's affixing antibodies to the surface of the LNP and then delivering, as far as I know, RNAs. So, like I said, there's going to be a lot of different ways that are trying to do this thing. I think, obviously, we love our approach and there's a lot of advantages.

38:15
Dave Johnson (guest)
I think companies like Captain sure have a ton of money, so they're going to give it a go. Of course, they're benefiting from the incredible manufacturing infrastructure that came with the coveted Pandemic. I mean, it's nice that they can leapfrog off of that. That would have been a hard company to start, I think, four years ago.

38:43
Neil Littman (host)
Absolutely.

38:43
Dave Johnson (guest)
People like, what are these things? I know mine is doing that, but they're not even have a product yet. It would have felt pretty out there. Yeah. By the way, I think the timing is good for Lenti on that note, too, because there's a lot of manufacturing infrastructure for cell therapy, lenty specifically. It's not like anybody doing next gen lenses, starting from scratch and trying to commit some manufacturing site to do something I've never heard of before.

39:21
Neil Littman (host)
Yeah, no, it makes sense. David, I want to pick up on that thread about there are other companies that are pursuing in vivo gene therapy, right? This is still relatively new, but not entirely novel. There has been some clinical data over the recent years. So, just briefly, the first company to deliver clinical results, as you're probably aware, was Sangamo Therapeutics in 2019. They had data from phase one two trial. Their technology was based on what they call zinc finger Nucleus or ZFNs. It was basically a different version of CRISPR. I think they were in the clinic for Hunter syndrome. I think that trial ultimately wasn't successful and didn't move forward because, as the CEO at the time said, they couldn't get enough of the gene editing components into every cell. Very much a delivery and sounds like specificity problem. More recently, as I'm sure you're aware, intelliapeutics is, to my knowledge, the second company to test in vivo gene therapies in a clinical setting.

40:23
Neil Littman (host)
This time, though, the trial was held as a major success. I think shares of intelligence on the news. In my mind, that was really the first ever clinical data suggesting that you can precisely edit and target cells within the body in an in vivo fashion to treat genetic disease. That was based on a single intravenous infusion of CRISPR and tells. You pretty much said those words at the time of the press release. Circling back to your technology, what's out there? LNP these other approaches, how do you see your technology fitting into the competitive landscape? Are there certain applications or indications that may be more suited to one versus the other, for example?

41:09
Dave Johnson (guest)
Yeah, first, I just want to address that we hadn't really talked about CRISPR and gene editing much in this conversation yet. I think we might have alluded to it but I think it's really interesting. I mean, there's been so much effort going into editing genomes and really good at doing it in test tubes. We're really good at doing it like mouse embryos or whatnot. For human, most of the editing has been limited to most of the studies have been limited to, for example, Retinal disease, where you inject the editing components into the eye. You're obviously locally getting it so you're getting the right stuff in the right area. Other methods are taking cells out and engineering them, editing them somehow and then putting them back into the patients. I went through a conference earlier this year where there are few companies out there discovering novel cast proteins, and they've got these amazing IP footprints where they've discovered all kinds of novel cast proteins.

42:22
Dave Johnson (guest)
What the CEO of the company said was, well, we're so good at editing stuff, but we still have this delivery problem. We don't know necessarily how to get the right machinery to the right cells. He kind of just left it at that. He didn't even propose any nothing. I was kind of in the audience like, okay, I feel like I'm going the right direction here.

42:47
Neil Littman (host)
Yeah. Did you raise your hand?

42:49
Dave Johnson (guest)
Yeah, I did not. Yes, it was attempting to do that. Hey, I'm working on something. Where do we fit into the competitive landscape in terms of applications? This is kind of hard. For my last company and also for Nutera, I think it was really clear what the product line and order was going to be. Part of it was because were replacing existing dogma, in a way, were replacing products that for non invasive prenatal, were replacing Amnios. Andesis right. So it was easy. Not easy, but anyways, there was a path where we could study Amnio and figure out how were going to really make a difference in that field and what was the benefit to patients, what was the benefit of doctors, that thing. I look at this project similarly, although there are some complexities, I do think that CD 19 as a target. So these are B cell.

44:15
Dave Johnson (guest)
Malignancies is a great target. It's a great test case. I think we will pursue it. Anybody listening is not going to be surprised to hear that. I've heard that it can be difficult to accrue clinical studies in that area just because it's so active and so competitive. We are looking at other indications which are there's activity and they're fairly competitive, but not quite that bad. AML is one area that I think is pretty interesting. There are several cell therapies in the works, but there's a lot of complexity there. Long story short, for most AML, you get small molecules. They work pretty well for two years, especially for older. Most patients where they're eligible will get stem cell transplant. Usually that fails within a few years. Most of the cell therapies that are coming up after the failure of the stem cell transplant. The reason for that is because you can't do the cell therapy and the stem cell transplant at the same time.

45:37
Dave Johnson (guest)
It's just too complicated. You can imagine doing an in vivo gene therapy at the same time as a stem cell transplant. Those are the kind of opportunities, I think, where we're really studying and interested because they allow you to kind of get your foot in the door in a way before cell therapy competitors could even do. You're really opening something up which is qualitatively different and enabling and not just like cheaper to make. Right. If that makes sense. I think that's pretty important too. We had Sequoia as one of our investors in Sinutera, and they're great investors and they always have these like, things that they say that really stick with you. Right? One thing, two things that this guy, Roll of Bosa, who is one of the guys that Sequoia said to me was, okay, well, first thing you can't fix is a small market.

46:45
Dave Johnson (guest)
Don't believe people who say they're going to grow a market because it pretty much never happens. Right. If you have a small market. And that's that. He also said never compete on cost. That's an interesting thing that's really stuck with me. Why you don't compete on cost is because then you become commoditized, right? I think about this statement that I'm reducing the cost of cell therapy, it's not just to induce the pricing pressure of that. It's actually to go after indications which just aren't even possible right now because of cost constraints. Right. And so there's an existing AML market. It's there people get sick and they're dying. So, if you can improve that, it's going to be paid for. Stem cell transplants are ready really expensive. To snap in a $2 million cell therapy is just forget it. Right. In this case, the cost enables a market in a way that you wouldn't have had otherwise, if that makes sense.

48:02
Neil Littman (host)
No, it makes total sense. I think that's one of the reasons why I personally am so excited about the promise of what you're building and that the technology platform in your approach. Maybe actually this is probably a good segue into taking a step back, looking at the company from a 30,000 foot view in light of the platform nature of the technology, different directions that you can go in. I mean, how are you thinking about your overall strategy for the company? Are you thinking about this more as building a platform company, partnering, licensing out different areas, whether they're different indications or therapeutic errors or whatever? Or are you thinking about developing this more in the lines of a traditional therapeutics company where you're running hard to get your first candidate into the clinic and really running hard with one or two assets to get to clinical results?

48:58
Dave Johnson (guest)
Yeah, I think for this current company, I think a mixed approach is really the best way to do it. Also in the current environment, I think gone are the days of 2021 and maybe in 2020 where you could fog a mirror I'm just joking, obviously you could fog a mirror and raise a billion dollars as a joke. It's not entirely true, but sure, that environment was different. If you can raise a billion dollars and you feel like you could just build the infrastructure and get the cash that you need to go forward, maybe you should do that. I think in the current environment it makes a lot of sense to try to go out and partner as soon as we can. You always have a risk of giving up your crown jewels if you do that, and that's always a challenge. You always hear horror stories of companies that gave up their first product and that was the only good one they ever had.

49:59
Dave Johnson (guest)
Right. They gave it away for terms that were kind of a steal. I think that's the environment that we're in. Looking opportunistically at partnering early would be great, but we are definitely also interested in developing our own clinical products. Kind of a mixed approach. The other thing I really like about these approaches, again, it is the market we're in and I think that is what it is and you have to make do. It is neat to get to Big Pharma potential partners early. And why? Because they're smart, they have experience, they know how to do stuff. Of course, I think it's our job in the startup arena to just really push and innovate and maybe there isn't as much motivation to do that in Big Pharma, but they also know how to do a lot of stuff manufacturing, clinical studies, they know a lot about markets, they have competitive intel that we don't have.

51:08
Dave Johnson (guest)
Working with a Big Pharma, I think is always exciting and there's a lot of benefits to that beyond just yeah, absolutely.

51:18
Neil Littman (host)
David mentioned that market environment and obviously drastically different than a year ago, for sure. I would also argue as an investor or as a company builder, actually, now is a great time to build a company. Now is a great time to build an investor. Some of the household names that we all know were built during economic downturns. Right? I mean, it forces you to really prioritize and take a hard look at how you're spending and what you're spending and those critical decisions which you should always be looking at. Maybe you're not forced to as much during the go period when cash is abundant.

52:04
Dave Johnson (guest)
In the go periods, a lot of crazy things happen. For example, investors push you to go really fast and then you end up hiring bad teams or teams that don't work well together, or they don't get trained, they don't get cohesive. You end up there's a lot of companies that IPOed and clearly shouldn't have and they're trading below cash. This is not good for anyone. They're going to have a hard time. Markets like today, there's just benefits, right? There's going to be more people to hire. You can build a team more slowly, get the right people in place. You can wait around and find the right investors. If I don't feel like I need the IPO in six months, then maybe I can wait another couple of months to find a good investor rather than one who's an investor who's not necessarily the right fit.

53:08
Dave Johnson (guest)
I can spend time talking to doctors, I can spend time talking to farmers.

53:13
Neil Littman (host)
All those things I think are incredible for you. It's just about building your company. You know that's, right. Finding the right set of investors is critically important because it is like a marriage, right? I mean, you're in it for the long term with those partners, with that. I know we could probably spend another three days talking about all these topics. I do want to be cognizant of your time. I want to sort of circle back. I asked you this question before, but given your experience as a cheer entrepreneur, you gave some advice. I maybe stay in your day job, if you can, to new entrepreneurs, but anything else that you might say in terms of advice or folks that are looking to take that entrepreneurial journey or already deep in it.

54:03
Dave Johnson (guest)
Yeah, I think what are some things I mentioned? One is find your sweet spot between being kind of bullheaded and going really hard in the direction that you believe in, but also keeping your ears open and listening and being willing to pivot. I think that's so hard, right? Because if you pivot too much, then you just never move forward, right? Because you're getting all kinds of conflicting advice all the time and so you can't listen to it all. Some people will say, well, you should have listened to me, right? It's like, well, but I also had some other guys telling me the opposite, right? You have to somehow figure out a way to sort through the noise and come to your own wisdom. If you do pivot, you better be really sure about it because you can't keep doing that all the time. You have to pick a handful of pivots and maybe that's all you're going to get.

55:05
Dave Johnson (guest)
The other advice I always have is pick your team and your advisors and your investors really carefully. You always hear just horror stories about companies. They had a terrible board. Like why do they have a terrible board? Well, the VCs wanted some gray hairs in there and they found some gray hairs and it's theranos drunk. Right. That terrible board. Right. It looked good on paper, maybe. Terrible board. Obviously picking your advisors carefully, you could tell by my advice, like keep your day job kind of thing, right? I tend to be really blunt about my advice and that's not always going to be for everyone. I still think every adviser is only as good as if they're not going to tell you the truth or be afraid of that or always just kind of agree what you say, what are they there for? They're not your cheerleader necessarily.

56:08
Dave Johnson (guest)
Although a little bit of that helps. And same with employees. I have a really careful process for picking employees. I think it's really important cofounders too. It's really important to find people who balance you out and who fit kind of a culture that you need. I know some people are snarky about culture and just like it shouldn't matter, find the best technologists that you can find. It's like not true. You have to get along and you have to compliment each other and you kind of have to work in the same way. I guess I have a lot of advice for entrepreneurs. Hopefully that's helpful.

56:55
Neil Littman (host)
No, that's all great. It's all super helpful. I can really echo the point about advisors and you don't want them sugar coating that, anything and it goes through your team too. I mean, the most productive companies and teams I've been associated with really engage in positive conflict productively. Right. Not everyone agrees on everything, but you have the courage and you have the respect among your peers to engage in thoughtful disagreements and that is in my mind, just invaluable.

57:25
Dave Johnson (guest)
It's so important, right. Let's say things are going wrong in the lab and I asked to see your protocol, right? The worst thing you can do as the employee is say you don't trust me. It's just like you got to be kidding me, right? We've had that before and usually those are people who don't have to be a good scientist, right. Because you have to understand that the manager is only trying to help and is like pouring their life into this. Of course as a manager too, you always have to you have to be delicate about that thing too. Right. Don't point fingers or anything. But yeah, you're right. You have to build that trust. There's always going to be things that come up and you have to be willing to all kind of go in together and get to the truth, get to discovery, figure out how to solve it.

58:30
Dave Johnson (guest)
If you can, you're not going to get anywhere. I totally agree with that. There's a certain personality I look for when I go through interview processes and I kind of stress test those things. I definitely do.

58:44
Neil Littman (host)
Obviously you have the track record where you've done it successfully in the past. Dave, I think we better leave it there. So, David Johnson, founder and CEO of Gigamune. Dave, thank you so much for joining the show today.

58:55
Dave Johnson (guest)
Thanks for having me. It's been really fun.

59:00
Danny Levine (producer)
Well, Neil, what did you think?

59:02
Neil Littman (host)
I thought that was a great conversation with Dave. I was really excited to dig into his technology in more detail. You heard us talk a lot about and compare and contrast what he's doing at Giga Immune compared to what has been done in the past in the field of selling gene therapy, what the state of the market is today, how he differentiates from what the other in vivo gene therapy approaches are today. You've heard us talk about some of the clinical data. While this is new and this is novel, there is clinical proof of concept for what he's doing. I think the lentiviral pseudotypes that they are using is really cool. You heard him talk a lot about this idea of that, well, nature can engineer things much better than we can, so why not rely on nature? Which seems to make a lot of sense to me on the surface.

59:56
Neil Littman (host)
I'm really excited about what they're doing.

59:58
Danny Levine (producer)
One of the most interesting parts of the conversation for me was when he was speaking, he got this little glimpse of the entrepreneurial mind when he talked about the genesis for this company being in leftover parts that the buyer for his previous company wasn't interested in. What kind of insights did you get into his thinking there?

01:00:21
Neil Littman (host)
Yeah, I think it's really interesting. You heard me ask a question about his entrepreneurial journey and if there are any common themes between The Terra and Giga Gin and now Giga Munin. And it seemed like absolutely right. I mean, from his postdoc work at Stanford, he was really deep into a specific area of technology that served as a basis for a lot of the work he did in the Terra and the Terra. He got very deep and specific in a certain aspect and then that forms some of the basis for how he thought about Giga Gin and then what they're doing at Giga Gin that wasn't useful to the acquired griffles formed the basis for Gig Immune. You can see a common theme and how this thinking has evolved and moving pretty I don't know what to say strictly sequentially, but in a pretty what seems like linear manner from one thing to the next thing in terms of where he's gone in his career and the companies that he's built.

01:01:14
Neil Littman (host)
It's not like he just grabbed something out of thin air. It's all based on his experience, and a problem he's tried to solve during his career has led to something else. The next thing, which I think is really cool and I think to your point, speaks a lot to his mindset. As an entrepreneur, it's not hard to.

01:01:30
Danny Levine (producer)
Appreciate the promise of selling gene therapies. How do you see the obstacles limiting their benefits? Will we just come to accept them? Or do you think it's important to find ways to solve these?

01:01:43
Neil Littman (host)
No, I think it's incredibly important to figure out ways to solve these. I mean, you heard us talk about some of the challenges and whether it's the cost of these products.

01:01:53
Dave Johnson (guest)
Right.

01:01:54
Neil Littman (host)
Because manufacturing is complex and complicated and all those things different patient populations. It's one thing to have a $2.8 million therapy for a very rare condition. You're not going to have a 2.8 million therapy for a much broader patient population right. That'll break the healthcare system. Until we can figure out some solutions that allow these therapies to work on a broader patient population, we're not really ever going to realize the true potential of a lot of these therapies. I think things like what Dave is doing is incredibly important. And, no, I don't think we should ever be satisfied with how things are today. We should always look for how to improve things and open up these therapies to new patient populations and new indications, because there's a lot of unmet medical needs out there, and I think these things have broad applicability. I really do feel like we've just begun to scratch the surface of what's possible with these novel therapies.

01:02:48
Danny Levine (producer)
The other thing he said that I found a little surprising was the advice he had gotten from a venture capitalist about not looking at cost as an advantage and not looking to grow the size of a small market, because you won't be able to do that. It seems to me, though, that if he's successful in doing what he's doing by nature, there will be a cost advantage here that will grow the size of accessible markets.

01:03:20
Neil Littman (host)
Well, Danny, I think that's right. It's not just a venture capitalist who gave him that advice, but Ralph of Sequoia is like one of the best in the business. To your point so if you think about the existing market for cell therapies, it's like a $10 billion market today. It's an enormous market today, and that's expected to grow to, I think, like 40 or 50 billion within the next eight to ten years. I think what Dave is doing is really going to help open up and grow that market right. Four or fivefold over the next decade or so. It's already an enormous market, but you have to talk about some of the different applications that he could pursue that maybe can't be pursued today, given some of the limitations of AAV or lentiviral vectors. I think while that may not be his primary motivation, I think it's going to be an outcome of the technology being successful.

01:04:15
Danny Levine (producer)
When you were talking to him about his partnering strategy, he indicated he would be interested in entering early on to a big pharma partnership. What do you think of that?

01:04:27
Neil Littman (host)
I'm all for that as an investor, right? Not specifically digging me, but just in general. I think you heard him talk a lot about the benefits of partnering with larger organizations. Large pharma, big buyer tech, whomever it may be, they have a whole suite of expertise that the startups don't have at their disposal. A whole suite of resources. It's a give and take, right? How much are you giving up for that benefit of the partner at the earliest stages? It also provides a lot of validation for the technology, right? Companies that are relatively young early on, if they can secure that marquee partnership, right, I mean, that is a lot of validation for the technology, social proof. It can also help companies raise capital, right? So there's a lot to be said. Not to mention having that partner in place can provide invaluable expertise to design idea enabling studies, preclinical clinical development plans, to think about the target product profile, all of those things that are really important as you're designing the path forward for whatever product you happen to be working on.

01:05:32
Danny Levine (producer)
Well, until next time.

01:05:34
Neil Littman (host)
Alright? Thanks Danny.

01:05:38
Speaker 1
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01:06:17
Dave Johnson (guest)
The Jonah Levine Collect.

01:06:19
Speaker 1
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