The complex development and manufacturing processes needed to bring biologic drugs to market almost always translates into exorbitant prices, even after the drugs go off patent. Consequently, many areas of the world simply do not have access to the accepted standard of care.
Chief Content Director Karen Langhauser sat down with the founders of Phylloceuticals to discuss how they plan to change this.
Learn more about Phylloceuticals at http://phylloceuticals.com.
Transcript
Karen Langhauser: A decade ago, a baby born with spinal muscular atrophy type 1 was not likely to survive past two years old. Treatment for the rare genetic condition consisted of simply managing the symptoms — symptoms which robbed babies of the ability to eat, hold their head, sit up and even breathe. Imagine if the only course of treatment for your infant was to put them on a ventilator and feed them through a tube. But new treatments for SMA offer hope.
Most recently in 2019, the FDA approved an intravenous infusion made by Novartis to treat newborns and toddlers. The gene therapy known as Zolgensma is designed to target the genetic root cause of SMA by restoring some of the SMA protein that is missing due to the condition. While time will tell if this treatment can enable children to live normal lives. Trial data has so far demonstrated that the one-time infusion not only increases the chance of survival and motor function, but also brings remarkable achievements in baby's ability to swallow, eat and maintain healthy weight. But there is something else that makes Zolgensma stand out — price.
I'm Karen Langhauser, Chief Content Director for Pharma Manufacturing magazine, and you're listening to Off Script, our podcast that runs beyond the pages of our magazine to discuss the issues that matter most in the pharma world.
So, back to Zolgensma. I'm using this treatment as an example because it has now claimed the title of the world's most expensive drug. Along with its many benefits, the gene therapy comes at a whopping $2.1 million price tag. In a country like the U.S., this will severely limit access. In a place like Sub-Saharan Africa, it makes it impossible.
Accessibility issues are not limited to the extravagantly expensive biologics. In fact, that's not really what we're here to talk about at all. It has been estimated that on average, a daily dose of a biologic cost 22 times more than that of a small-molecule drug. The more complex development, scale-up, manufacturing and distribution processes needed to bring drugs harvested from living cells to market almost always translates into exorbitant prices even after those drugs go off patent. So really, the problem isn't limited to brand new advanced therapeutics.
In many cases, we were talking about access to the accepted standard of care, the cost constraints of biologic drugs compound what is already a serious issue. According to the World Health Organization, nearly 2 billion people have no access to basic medicines. Drug accessibility is an ongoing challenge around the world. It's a problem that for years has been vexing governments, global health authorities, and humanitarian aid organizations. After all, access to medicines is a fundamental element of the right to health. Joining me today are Barry Holtz and Bill Brydges, two people with the plan to help get affordable medicines to underserved areas of the world.
Barry and Bill, together with a small team of experts have recently started a company called Phylloceuticals. Filo, not just the delicious pastry dough, but also the Greek term for leaf. This is apropos as their new company will employ a unique concept that uses plant-made technology to rapidly develop biopharma products at lower capital expense and operating costs.
I, fortunately, have had the pleasure of having met both Barry and Bill before in person. Barry, I think the first time we met, it was when I was writing a plant-based pharmaceutical story out in Texas. It was a temperate 110 degrees in August for that story. And of course, now, you're a vital part of our Pharma Manufacturing Editorial Advisory Board as well. And Bill, I know our paths have crossed at several trade shows in the past. But I think for the benefit of our listeners, maybe you can both briefly walk through your respective bios.
Barry Holtz: I have been around the biotechnology business for entirely too long, all my career. I started out in Silicon Valley back in 1978, which was before you could buy a bioreactor. We had to make one. So, that dates me. But I've spent most of my career in the plant-made pharmaceutical field where we pioneered most of the facilities to date that have been built, taking some time out to do autologous cancer vaccines, and some time out to invent a thing called the POD, which became the G-CON POD, and started that business. I was one of the founders of that business. And that business led to being recognized by the Defense Department. And DARPA then solicited us to use the POD technology and the plant-made background to get into the rapid response manufacturing business for biologics. And that's kinda what ends us up at this conversation.
Bill Brydges: And I've been in this industry for about 40 years now, I hate to say. And I started out, and I guess my education was chemical engineering, and then I got some advanced education in project engineering management. Started out as a chemical engineer doing process engineering work, and also doing automation work focused in life science industry. I moved up and mostly on the instruction side, and it's through the project management end of it. I found myself at some time being the owner and president of what we call Biokinetics. Biokinetics was a prestigious engineering and design-build firm. And we were primarily involved with all life sciences industry work with a strong focus on biologics. And did a lot of work around bioreactors and some of the stainless-steel bioreactors in some of the largest facilities out there.
Karen: So, both of you coming from different sides of the industry, what brought you two together to start Phylloceuticals?
Barry: Well, what brought us together initially was a really great project. And that was a project that involved Pfizer, G-CON, and GEA, G-E-A, in Europe, to build the PCMM project, which was the...actually won the FOYA Award and several INTERPHEX Awards for unique technology. But it was a completely portable, modular tableting system that was able to be erected anywhere in the world in three days. And Bill and I got to work on the engineering part of that together and to actually see the project through. So, you know, projects like that either build great friendships or you never speak to the guy again. So, it actually worked really, really well. And we had a lot of fun doing it. Go ahead, Bill. You've also worked with us on other projects too.
Bill: Yeah. And I started working with Barry, I guess, it's a long time. I actually knew of Barry and knew of his reputation before that. But I started working with Barry. And we kind of became fast friends. And enjoyed working together both personally and as colleagues. And we seemed to make a good pair in working on these projects in these facilities. I really knew nothing about plant-made pharmaceuticals at the time. And pretty much everything I know I've learned from Barry during that time.
Karen: I bet Barry was happy to tell you lots of things about plant-based pharmaceuticals.
Barry: Yeah, it's a lowly evangelical position to be in, right?
Karen: Let's talk about Phylloceutical's mission.
Barry: Well, I think Bill, and I, and others got to work together on several of these projects. And we realized that biologics manufacturing in the world is still lacking. It's still not well-served. It's not served in all areas. And certainly, isn't served for populations that have special needs or unique needs. And some of those are in wealthy countries. And some of those are in developing countries. It's a very broad spectrum. But the thing that has attracted all of us to this is the idea of bringing biologics to a much broader group of people without capital constraints and without operating constraints that put these drugs into a category of cost that makes them totally unavailable to populations. And Bill, you can certainly add to that.
Bill: There's a tremendous poluation that does not get medicine as they need today. Region by region, really very small area by smaller area. There's different needs, and creating one product, and trying to distribute it around the world doesn't fill those specialized needs out there. So, there's a large market for it. And there's a lot of good that can be done by serving that market.
Karen: Let's get back to the basics here for a minute. Barry, indulge me, what are plant-based pharmaceuticals, you know? And what advantages do they offer, and development, and scale-up?
Barry: Well, its simplicity is what really is the driver. The bioreactor is one sort of plant. It's just a form of bioreactor that is a group of cells. These happen to be leaf cells in plants. Nice part about plants is they have all the machinery to make human pharmaceuticals and then a little extra. They actually have chloroplasts so they can make their own energy. But they're very similar between mammalian and plant cells. So, the nice part about what we do is we exploit only one kind of plant as a bioreactor. So, we grow the bioreactor and it's generic. We grow biomass. We don't have to grow a genetically-engineered biomass. We grow a plant that's...it's just a little relative of tobacco, and it's about this big, it weighs 8 grams at maturity, and we grow them hydroponically or aeroponically. So that's our bioreactor.
And once that bioreactor is at a state of maturity, we use a bacterial vector that contains a human gene and some other goodies, the other genetic information that goes into the cell. And we literally dip the plants in the solution of this vector, pull a vacuum, and then all of the cells of the leaf become infected. And this vector literally takes over the protein-making machinery of the plant and converts it into a bio factory for our new human protein. And then six or seven days later, we harvest that plant. And as I always say, we euthanize the plants properly in a kind and gentle manner. And then extract the protein and purify it the way you would do from a CHO cell preparation or a bacterial cell preparation.
The real advantage is we always have the same bioreactor and it's only 8 grams, it is generic. We don't have to scale up. We don't have to build new bioreactors for each drug or have conditions for each drug. We always use the same thing. So, the upstream side, the capital expenditure is much, much lower as is the operating expense. Downstream, we're similar to other protein manufacturers, not the same. We do have some advantage there too. But the real advantage is in the OpEx on the upstream side and the CapEx total, because we build facilities with an equivalent output at about 35% to 40% of the total capital of those, like a mammalian cell facility or a large bioreactor facility. So the CapEx is a lot lower. That puts it into the range of...so people can afford it.
So, we've got all those advantages. And we can react very rapidly to a new drug. It only takes us a week or so to make a new vector. It doesn't take 10 months of testing in the lab to go from a shake flask to a 10-liter, to a 100-liter, to a 1,000-liter, to a 10,000-liter. So, we have those advantages with plants. And now, we have a big repertoire of drugs on the way and accepted facilities that have become more mainstream instead of an oddity.
Karen: I mean, speaking of that, are there specific biologics Phylloceuticals is going to target?
Barry: Well, we're targeting monoclonal antibodies to begin with in underserved areas. We've been discussing with African nations, the MENA region, Vietnam, Singapore, China, Australia, places that, right now, need expansion of resources to make drugs. The crisis has focused on facility's development and facility's availability, so it's even more focused...We're really focused on bringing these hard-to-make drugs. So monoclonal antibodies are a great place to start because there's universal need for these things in cancer treatment, anti-inflammatories, all of these things that are...we take for granted here in the United States. So, if you have non-Hodgkin's lymphoma, you know you're gonna get rituximab. It's off-the-shelf. Well, that's not the case in South Africa where pregnant women have AIDS, and then they get non-Hodgkin's lymphoma, and they don't have access to rituximab.
Karen: So of course, this also brings up the question of the COVID-19 pandemic as well. Were any plant-based systems explored as part of this response? I mean, did the pandemic unearth any issues in our supply chain or anything that could be dealt with in this way?
Bill: So, yes. I mean, we can respond to things like a pandemic and COVID-19. But we're not building a business here based on a response to the pandemic and COVID-19. However, I will say that one of the things that really was brought to light during the pandemic is the supply chain issues for around the world. I mean, you know, the U.S. has issues, right? The U.S. has the 800-pound gorilla in all of this if we have issues getting certain supplies and medicines during something like that. We know that underdeveloped countries was a major issue. But beyond that, you know, there are countries in well-developed areas of the world that due to their size or just their lack of internal manufacturing that had extreme difficult times getting basic medicines [inaudible 00:16:19].
So, as well as us getting to the underserved areas of the world out there as we talk about, all of a sudden, a lot of countries are talking to us about, you know, can we do something to help them provide local manufacturing so that they have a source in the future? So that's kinda become a big part of what we're talking about. And we're gonna see a lot from the different regions looking to locally manufacture. And you can't do that with a lot of the large products that we've had in the past where we're building a large facility in Ireland to supply the world.
Karen: That's an important part of this discussion here is it's not just getting the medications out there, it's helping them build the facility so that they can continue to produce these medications on their own.
Barry: And I gotta say that, to your question was well-asked... I had joked with Bill earlier, I said, "We might be the only new company in biologics that isn't being based on COVID-19 claims.” But when you look at the supply chain, and Karen, you and I have had this conversation before, right now, it's clear that biologics cannot keep up with demand for pandemic. And so, we're robbing Peter to pay Paul someplace along the line in manufacturing at this point. And the pandemics are going to be part of our lives. That's clear. And it's gonna be more so as there are more humans, viruses like humans, so that it's gonna happen. That's what viruses do.
But if we're going to be prepared, we have to have manufacturing facilities that are hot and ready to go all the time. And the PMP system affords you that luxury at a price that's a lot more compatible with people's budgets all over the world. So, if we were to have a center in Africa or a center in Southeast Asia, one in the MENA, so forth and so on, that could make vaccines or convalescent plasma, cloned monoclonal antibodies for a disease, these facilities could be built and maintained at a much lower cost. And I think that might be a very good fallout of all of this. It's just another technology that adds to our armamentarium of ways to cope with disease. So, I say we're not a COVID company, but it's certainly very relevant.
Karen: If the intention is to nucleate multiple facilities in these underserved areas of the world, what does that do to logistics? You know, who's going to run these facilities? And how are you gonna manage the large amount of data coming out of these facilities?
Bill: So, yes. So, I mean, that is our intention is to nucleate the facilities around the world. I mean, when I first thought about this, I was thinking more in those underserved, underdeveloped areas. But as we've seen again, as we've seen with the COVID pandemic, supply chain issues are out there for every region. And the more locally we can manufacture, the better off we would be. One of the issues, of course, is especially when you get into the regions that have not been producing, have the infrastructure, they don't have the people, there's a lot of need there. What we supply is pharmaceutical as a solution technology. We're there to help, not only from the very beginning from selecting what product to produce, to designing, building these facilities, getting them up and running, we'll help them find people.
Our intent is to do everything to support these facilities throughout the life cycle of the plant. And, you know, in some areas, you know, we'll get in, we'll help them, we'll get them started, we'll get them running, and maybe we get out. And in other areas, they're gonna need more and more of our support. As time goes on, they'll build that infrastructure themselves and be able to become independent. That's our goal. As far as whether we'll operate them or who will operate them, we can do that. But the long-term intent is to have an independent company and to keep going.
One of the things we believe that we're able to supply here different than other manufacturers, we're not looking to do this product or that product, and send it out to different locations. By doing this, we believe that we'll be able to meet greater needs of medicine, drugs that people in all the different areas around the world than we could, otherwise.
Barry: But one of the neat things that we're doing right now, Karen, too, you touched on it is data collection, data security. I hate to think about this, but it's been 12 years since we designed the facility in Bryan-College Station, Texas. But over that period of time, we learned a lot. And the state-of-the-art has really advanced. So, the new facilities that we've designed, we'll have the latest data management, much higher level of automation. If you can believe that, we're gonna automate this one even more than the one in Texas. And along with that automation, we've built in artificial intelligence, especially in the areas that are producing and optimizing drug production.
So, this gives us a huge advantage as we've spread these facilities around the world in that a lot of the quality assurance and automated data processing can come to one location. And we learned that through the PCMM project. We made it so you could literally run it from your iPhone. But what it allows you to do is have expertise in one area of the planet, monitoring multiple facilities, and very efficiently looking at trending data, quality data, so forth, and so on. Granted, you're gonna have to have QA people on site. No doubt about that, but not as many. And you can centralize the expertise.
The other thing that we've done is designed an AI system so that as we do new drugs, we learn constantly from the plants about conditions, timing, daylight, nutrients, so forth, to optimize each drug. And that data is collected automatically from the new process. So then, all of the facilities that we generate will get the benefit of those data. But again, it's all done in one spot and it isn't diffused and gets lost in the clutter. It's gonna be in one spot. And that's by design. So, it's really going to be a lot of fun. This is really a terrific, go-forward strategy.
And like I told somebody the other day, they said, "Well, I thought you knew everything there was to know about doing plant-made pharmaceuticals." And I said, "I really know what I don't know. And the neat part about it is now, there's techniques so that I can learn what I don't know." And that's gonna be very, very helpful.
Karen: So where do you start with this? I mean, do you have any projects in the works? Do you have any contracts at this point?
Bill: So as far as where do we start, we have discussions going on with multiple regions right now. We've got discussions going on with Australia, the MENA region, a few places in Europe, Ireland. We're around the world. And as far as any contracts go, we chose now to announce because we have been talking for some time. This didn't start yesterday. We've been talking to people for a while. And we will have some things to come. So, I would say stay tuned for the near future because we will have some announcements, but not yet.
Karen: Fair enough.
Barry: Our egos are such, Karen, that we probably wouldn't have announced unless we are gonna deliver something.
Karen: Oh, I know you have a plan. I mean, it's an amazing concept and just an amazing admirable plan. Why isn't anyone else doing this?
Barry: Well, some are. They've been sidetracked to specific programs. But, you know, I always point to our friends in Quebec and Medicago. They've just announced a big joint venture with GSK for a COVID vaccine. And Trudeau has put a lot of money into it so that Canada can become vaccine-independent. And our hats are off to these people. I mean, Medicago started back in the old days along with large-scale biology and other places that we've all known each other for a long time. And there are other companies in the business. Kentucky Bio was instrumental in the Ebola epidemic and making the vaccine for that. But they're more product-oriented companies.
And the idea of PhAAST, P-H-A-A-S-T, is pharmaceuticals as a service technology. So, we borrowed heavily from our bits and bytes, binary friends to come up with that trademark. But it's the right idea at this point is that this is empowerment of other folks to make drugs that they need, not it becoming a drug-specific company. And that's kind of our bag. That's what we like to do. And I know people said, "Well, why are you...do this again?" And I did have to ask myself that very carefully because I could sit here and play guitar badly for the rest of my days.
Karen: I did think you were retiring. And now, I check my email and you're saving the world.
Barry: It might sound a little schmaltzy, but Bill and I, and our partners, have all enjoyed really good careers. And I think we've all been productive and done good things. But my motto is there's always time to do good. And time should be well-spent for that. So, I'm looking forward to this because I think it's a good thing. And besides, it's a good business proposition. And that's not so bad either, you know? Both go along with each other. They both have to be successful. It's hard to do work if you can't make money at it.
Bill: And reality is if things go well, yes, we can make money. We can serve parts of the world with medicine they wouldn't otherwise get. And we enjoy working together. It doesn't really get much better than that.
Karen: Oh, the best of luck to both of you, because I'm really looking forward to seeing how this plays out.
Barry: We are too, Karen.
Bill: Thank you, Karen.
Barry: And we'll keep you in the loop, as our conscious and everything else. So, this could be great.
Karen: This is Karen Langhauser, and you've been listening to Off Script: A Pharma Manufacturing Podcast. Stay healthy and stay informed.
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