Revolutionizing Healthcare: How Bioengineering & Stem Cells Are Transforming The Future Of Medicine
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Hello, this is Richard Jacobs with the Finding Genius Podcast. My guest today is Kevin Caldwell. He's the co-founder and CEO of Ostium Health. We're going to talk about organ donor bone marrow banking, stem cell therapies, and some related blood type products.

products that they offer. So again, as a CEO, co-founder and president of Osteum Health, Kevin Caldwell has built it from a small startup now into a clinical stage bioengineering company. The mission is to improve human health through bioengineering and platform-based model for cellular therapeutics. So welcome, Kevin. Thanks for coming.

Thanks for having me. Well, if you would, just tell me a bit about your background. What made you have a desire to work in this area of human health? And then we'll talk about Osseum. Yeah, you know, I did lots of different things before starting at Osseum. I, you know, studied astrophysics and economics in college. I went to law school, economics.

I managed, I was at an investment management firm for a number of years doing sort of currency and bond trading, lots of different things. And then over time, you know, I realized that I was making really meaningful sort of changes in my career, my studies every couple of years, mostly because I was chasing whatever I thought the most sort of interesting problem I could work on was. And invariably, I would work on something for a couple of years and then just get bored with that problem and do something else. And so I sort of shifted my frame away from what is the most

sort of exciting or sort of intellectually stimulating thing I can work on to what's the most meaningful work I can do. And that was really game-changing. And it's that shift of frame that ultimately led to Ossium. So, you know, I spent a lot of time with my grandparents growing up. I saw them going in and out of the healthcare system, and

and I observed that it was very reactive. First, they would get sick. Then we would take them to a doctor who would typically retroactively prescribe them an intervention that usually did improve their health or reduce their suffering, but didn't really restore their health to the level of the doctor being at just a few months before. And I would ask questions like, you know, why can't we anticipate what's going to make people sick beforehand? And why don't we have, you know, more drugs that are really designed to restore their vitality rather than just treating their pain? And the

The answer that I got was, well, that's just not how healthcare works. And I never really accepted that. And so, you know, part of what is incredibly exciting about this particular moment in history is that I do think we're in the middle of paradigm transition where it's becoming more and more inescapably obvious that the traditional tools of medicine, which have been phenomenally successful, by the way, in massively extending the human lifespan, dramatically reducing our risk of death from infectious disease, reducing

dramatically reducing our risk of death from accidents, et cetera, that they're not as well equipped to these sort of growing problems of chronic disease and aging. And so, you know, I think the path to those solutions, one of the elements of that is going to be truly sort of regenerative, restorative therapeutics that make lasting sort of changes to sort of the organism in question, and in this case, the human beings. And so,

The good news is that we don't have to, there's a lot of work that's already been done in this space for decades. Some of that work involves treatments of a type of, a category of diseases that is still sort of a major cause of death, and that's blood cancers. And so bone marrow transplants are a type of cell therapy that has 70 years of history behind them. We use them, they're used every day, many thousands of times around the world every year to treat patients with blood cancers. And

And when we do these transplants, we permanently replace the blood and immune system of the recipient for that of the donor. It's an incredibly powerful procedure that in principle could be used to treat a broad range of blood and immune diseases in permanently curative ways. Are you doing bone marrow transplants in conjunction with an organ transplant? Or this is just separate for someone that, you know,

maybe has a problem, they can't produce enough red blood cells or white blood cells, and they just need bone marrow. Okay, so I'm glad you asked that. So the answer to that question is yes. And what I mean by that is that what you're really pointing out is that there are these two really, at least two very different applications for bone marrow transplants.

There's the traditional application where you are reconstituting the blood and immune system of a person who typically has some blood disease that causes their native blood and immune system to no longer be functioning well, whether that's malignancy like leukemia or

perhaps an anemia like sickle cell. So that's the sort of established application. There's another application, which is someone's getting an organ transplant anyway, like let's say a kidney transplant, and rather than going on immunosuppression for the rest of their life and living with a weakened immune system and elevated infection risk, they're given an infusion of bone marrow stem cells from their organ donor to

to induce what we call hematopoietic chimerism, where the recipient lives with blood and immune cells from both their native bone marrow and their donors at the same time and can live without immunosuppression, or at least with a reduced immunosuppression regimen. And so your question of which of these are we doing? Well, part of the power behind Asim's model is that we are enabling the ability to do both, and we have done both. Now, we do that by tapping into a new source organically

with bone marrow, that's organ donors. So the same solid organ donors that for decades we've relied on for hearts, kidneys, lungs, livers, Osteum has developed a process for obtaining clinical grade bone marrow from those donors in high yields with large numbers of cells, then cryopreserving or banking that bone marrow for later use in transplant. And so we have an active clinical study now where we're treating patients with blood cancers who need a bone marrow transplant. We've done this successfully

successfully a number of times now. And we'll be publishing on that later, likely later this year. And that's a life-saving application of this product. Does the bone marrow transplant cut down on the rejection rate or the rejection intensity? Because now you're getting more cellular signals from the donor. It's more and more of the material donated to the donatee now has the same cell membrane characteristics. I forget what it's called, but it's just less alien. And

And so therefore, I guess I'm just predicting that the rejection would be less, perhaps. Okay, right. So the cell membrane characteristics that you're talking about is the human leukocyte antigen or HLA type of the donor recipient and just how well they're matched, basically. And the answer is that so far, we are seeing lower rates of rejection. And this type of rejection is called graft-versus-host disease. We see sort of historically from a mismatched transplant,

like those that we're doing. And there's a couple of reasons for that. One is we are using, we're using a protocol that uses post-transplant cyclophosphamide, which just reduces the amount of activity in the patient's immune system shortly after the transplant in a way that seems to durably reduce the rejection risk. Another thing though, that's important, that's more unique to this organ donor derived source, because the PTCY can be used with living donors too,

is in really the composition of the cells. And so because we're using real bone marrow taken from the bone of the donor, we have far fewer of the lymphocytes, like the naive T cells, for example, that are in peripheral blood, and about 70% fewer of those cells. And so that means that there's just less reactivity between the donor and the recipient and lower risk of rejection. And again, it

it's early yet, but so far we are seeing very, very consistent engraftment and very low rates of rejection in our patients. And that's really encouraging. So why do you think that is? Is that again, because now the bone marrow, there's just more signals again, like, you know, the calm HLA response. And so that, I mean, does this manifest in...

the person needing less immune suppression or for less time or less of a degree of immune suppression? What are some of the clinical markers that show you, oh, great, this is having good efficacy? Right. So for efficacy, the primary important is neutrophil engraftment. And

The other points that are important are platelet recovery. And so we look for neutrophil engraftment by day 28 in this study, and we've seen it before day 20 consistently. That reduces the amount of time that the patients live without a working immune system, the period when they're immunocompromised, and therefore reduces their risk of infection. And then from a safety perspective, one of the major problems

endpoints, the major data points that we're collecting related to CEVD is GVHD and the grade of GVHD the patient gets and how long they have that GVHD for and when they get it. So we, and graft-versus-host disease is really one of the sort of principal complications that patients with these bone marrow transplants incur. It's the mirror image of organ rejection. It's

The patient has a new immune system and it rejects the rest of their body, essentially. And I think most of your listeners are probably familiar with the organ rejection context where the patient gets a new organ and their native immune system rejects the rest of their body. It's the reverse of that idea. So here, you know, we, that reaction, that graft-versus-host disease reaction is caused in part by naive reactions.

T cells that are in the graft, that are in the bone marrow that the recipient gets. That's become clear from sort of recent research into some of the mechanisms of GVHD. And there are a number of approaches to dealing with this. One approach might be to just remove those cells from the product before infusing it. And certainly we could, we can do that. But part of the beauty of our work is that the bone marrow just naturally has 70% fewer. The organ donor-derived bone marrow has 70% fewer of those cells.

than you would get from a typical living donor graft. And so the product is sort of naturally, effectively naive T cell depleted. And we're seeing GVHD results that are consistent with that.

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For the recipient, where is this bone marrow going? Are you simultaneously aspirating some out and then putting new bone marrow in? Or how do they get this additional or new bone marrow? So before a bone marrow transplant, recipients are conditioned. And the conditioning regimen, basically, it's an ablation of the native bone marrow. So

In order to make room for the new cells that are infused to effectively engraft, their native bone marrow has to be ablated. So that's a standard part of bone marrow transplant. Most every transplant center has their own sort of protocol for doing this. But that's done prior to the infusion of cells from us. And then once the cells are infused, they can migrate their way into the niches in the bone where they reside and engraft. Okay. So are there selected bones that you...

Are they always the same ones or the largest ones where they will ablate the existing marrow? Are there preferential ones that work differently than others? Like, what kind of experimentation did you have to do to make sure this procedure works and what works versus didn't, if you can say? Right. So we've done a lot of innovation in the bone marrow, like innovating on the source of the graft and how it's treated. When it comes to conditioning the patient for receiving the bone marrow, we've intentionally used the standard of care protocols there. And so...

In that protocol, a whole body ablation is done. And so rather than just picking one sort of bone, like the spinal column or the sort of eliminating the bone marrow there, it's done throughout the patient's body because the idea is that the patient's native bone marrow is malignant. Like they have cancer. They have a cancer of their immune system. And so you want to completely eradicate those. Cells are coming close to full eradication as you can before giving an infusion of the new healthy bone marrow. What's the window in which you can do that where it's safe and it's not going to, you know,

you know, they got to produce red blood cells, they got to produce white. So how long can that be the case where you've ablated enough where you're now ready to transplant? But how long can the person be in that state? So the transplant or the infusion typically happens within a few days after the initial conditioning regimen is done, after the ablation is done. But you're right that it does take time for the new cells to engraft and to begin producing a new blood and immune system for the patient. And the longer that time

time window lasts, the more risk the patient is subject to. And so it's very important that you see speedy neutrophil and Grafman and platelet recovery. We'll

which is why that's one of the endpoints for this study. So the goal is to get that before day 28. So the patient doesn't have more than a month when they're not without a working immune system. How can they even go very long at all without a working immune system? Do they have to be like in, I mean, being in a hospital, you're exposed to all kinds of pathogens. So where's like the purgatory which people are at? Do they have to live in essentially the boy in a bubble for a while in a hospital setting or?

How do they live with a diminished or no immune system? The patient is in a hospital system, in a hospital setting during this period when they're immunocompromised. And you're right that they have to be treated with extraordinary care and exposure to pathogens has to be monitored and controlled.

precisely because they have an elevated risk of infection. And that's why getting the engraftment quickly is so important. What about microbiome disruption from antibiotics? I would figure that, you know, they're definitely going to give, unfortunately, antibiotics at least right around the procedure, maybe at other times. So now you have microbiome disruption too. Anything to address that or do you feel like there's no need or...

What have you seen? So patients are often on antibiotics after a bone marrow transplant. You are very likely right that that's going to have some disruptive effect on the microbiome. We haven't changed or modified their typical antibiotics.

antibiotics regimen for this study. We're allowing the transplant centers to use their standard regimen for that. And so it may be that the standard course of treatment has an adverse effect on the microbiome, but that's not something we're investigating. Probably because the patient is going to have a compromised immune system for some time, being on some amount of antibiotics is probably inevitable. They're

There is a question of whether their antibiotics regimens they're on have been sort of, whether it's sort of broad antibiotics that would have a massive effect on the sort of synergistic microbes that are in the gut or whether it's possible to achieve a similar level of protection from a more narrowly focused set of antibiotics that dealt with particular pathogens is an interesting question. Given that you're trying to protect a patient from

So a broad infection who has a weakened immune system as opposed to trying to target a specific disease, that might be challenging. But again, it's not something that we are – that is not sort of a target of ours. We're essentially relying on the hospital sees their standard of care for antibiotics. Okay, I see. All right. So what other health conditions? You mentioned blood cancers. What other products does Osteum Health provide? So Osteum.

One other product that's in the market right now is what we call Ossagraft. And, you know, these products are orthopedic products. And so I mentioned that we're making bone marrow, but of course we make the bone marrow from bone, from the vertebral bone that we get from the organ donors. And we, in addition to using the bone marrow for blood cancer patients, we use the bone itself to make orthopedic products. And in particular, Ossagraft is a cellularized bone matrix, essentially a

a putty made from the bone of organ donors that can be used by orthopedic surgeons who are treating patients who need a spinal fusion. For example, the sort of ossigraph product can create sort of a scaffold or a matrix on which the cells from the patient can ultimately aggregate and sort of renew or reconstruct the patient's spine. And

And so it's designed to accelerate sort of healing after a spinal surgery. So you'll create like kind of a nucleation site somehow on the bone itself that will attract more rebuilding material preferentially there to rebuild faster? Exactly. Okay. So after, so this is after like spinal surgeries. So what happens though? They'll, I guess, well, it's probably horrible to say, but I guess some spinal surgery is if they're going to, I guess they'll take out a disc, let's say they'll put in an artificial disc, whatever

What else would they do to damage the, you know, the hard parts of the spine that need to be repaired? Or maybe just as the patient has aged, maybe there's been some erosion of one of their discs and you've got two vertebral bodies that are sort of grinding against each other in a way that sort of creates a lot of pain for the patient, for example. Yeah.

So one approach to dealing with this is to fuse those VBs. And so in order to do that, you need some sort of material that can sort of bridge the gaps between them. And so Osteograft essentially is that material. And spinal fusions are the single most common application. Of course, it can also be used for foot and ankle surgeries, essentially anytime you need two sort of pieces of bone to

sort of adhere in sort of a permanent structural way. Can this be used on cartilage or only bone? So Ossigraft is made from bone for sort of bone fusion and reconstruction. There are cartilage sort of products out there, but this isn't, Ossigraft isn't one of them. Yeah, no, it's interesting. I mean, it seems like, you know,

you'll have a knee or you'll have whatever part of you. At first, the cartilage is worn away. Now you have what's called bone on bone. So I could see this could maybe if you've had a bone on bone situation for a while in conjunction with doing a surgery, if you do some restorative work on the bone ends, that's a good thing. It's kind of put you in a bit of a better place. You still have to have the surgery and everything to fix the area. But it would be nice again, if there was a mechanism to regrow the cartilage. I,

I don't even know how cartilage forms. I don't know what signals come from, let's say bone. If it does come from bone to regrow the cartilage, but is that on the table in the future? Maybe try to make a product that can do both? Potentially. We'll see. Interesting. I know it's very complicated. I know it's just armchair wishes, but, you know, I just had to ask. Okay. So what applications specifically would, you know, bone restoration technology, like what are the common areas on people that need it and why?

The most common need is a spinal fusion, which essentially, one thing you can kind of think about is as we sort of age, you see overall reductions in bone mineral density, increased risk of fractures, reductions in lean mass, in particular in muscle mass, that increase the risk of falls, and reductions in bone mineral density to increase the likelihood of

of a bone breaking should one fall, you see sort of deterioration and sort of the volume of sort of cartilage that patients have over time and increased risk of sort of contact points between bone that create pain. And so Osteograft is just one sort of tool

that orthopedic surgeons can use to really improve mobility, improve quality of life, improve vitality, reduce pain for their patients across any application whatsoever that would benefit from having some real human bone tissue that they can use to support a bone sort of regrowth and healing. Okay. Any other major products that Asim puts out? It's very interesting so far. It's fantastic, you know. Oh, well, thanks. Yeah. So, you know,

Since we briefly mentioned it at the beginning, it's worth circling back to. There is another application of organ donor bonerol, which is, of course, enabling organ transplants without immunosuppression. So today, whenever an organ transplant is done, the recipient receives the drugs that reduce the risk of rejection of the organ by weakening the patient's immune system. And there's a handful of problems with this approach. One is that they're only temporarily effective. The organs are usually rejected anyway.

after about a decade, sometimes less depending on the organ. And two, the person's quality of life is diminished during that period because they have a weakened immune system and have a heightened risk of infection and cancer, organ failure, et cetera. And so you could do the organ transplant without immunosuppression. That would transform organ transplants from a treatment for organ failure into a bona fide cure. It would give the person the rest of their natural life.

in fullness. And so that, just as a successful bone marrow transplant can allow a blood cancer patient to live the rest of their natural life fully. And so that is that sort of dramatic improvement to transplantation, to solid work transplantation in particular, is sort of another frontier of Osteum's work. We've done some early work in animal models that shows robustly that this is doable. And there is a well-developed

literature, academic literature on doing this typically in kidney transplants from living donors where bone marrow transplants were also given from those same living kidney donors to induce tolerance. And, you know, a number of these studies have shown the feasibility of this. The challenge is that 80% of all organ transplants are from deceased donors, like the vast majority are, and access to, therefore, deceased organ donor bone marrow at scale to really make tolerance work. So, Osteum has achieved that. We've achieved that at a scale that the

the world hasn't seen before. And we are very, and we're very encouraged by our initial work in blood cancer treatment on the sort of fundamental quality of the cells that we're getting from the organ donors. And so we think there's an enormous opportunity to improve organ transplantation. That'll be a later frontier for our work. Well, I don't know what you could say about it. I know a lot of it's proprietary, but how are you able, or how might you be able to do organ transplant without immunosuppression? Well,

So we mentioned earlier that when you do bone marrow transplant, the recipient, the patient, produces for the rest of their life their bone marrow donor's blood and immune system, which is to say they produce cells with the genetics of their bone marrow donor. And so in the case of a person who receives an organ transplant, there's nothing wrong with their native immune system other than that it doesn't agree with this new organ that they just got. And so

You don't need to completely blight eradicate their native immune system. You just need to create room for cells from the donor to take hold. And so we do what I call a partial bone marrow transplant or bone marrow stem cell infusion. And in doing so, we...

we've created a state that we call hematopoietic mixed chimerism. And that's just a way of saying, so chimera, sort of the term for mythology, an organism that actually is sort of two organisms combined in its biology. So the patient would be producing blood and immune cells from both their own native bone marrow as well as from their donors at the same time.

And so what we find is that this chimeric immune system is capable of accepting cells from both the patient's native organs as well as the donors. And this allows us to wean them off.

of amino suppression. A number of things have to be done exactly right to make this work, and the pressures have to be monitored very carefully. And the protocol is different for each organ that you might be transplanting, but it is possible. And if done properly, it could really dramatically improve transplant outcomes. Very interesting. I mean, is that like really early stage, or is it starting to become well understood by you guys? Or how far in the future do you think to be able to demonstrate something? Well, we are building on a...

There's a lot of clinical experience of doing this in living donors, especially kidneys, as I mentioned earlier, that we're building on, that mostly academic groups have done for decades, and then in smaller studies. And then we have done some animal work in using deceased donors for heart transplants that's been quite promising. And so the combination of that experience and that literature makes us quite optimistic

optimistic about doing this. But yes, it is early. And the next step for this program will be a phase one clinical trial, which would begin at some point in the future. Okay, very good. So how can listeners keep tabs on all your projects? And, you know, if one of them gets to a point where it's, you know, it's clinically available, you know, through clinical trials, and you know, they want to ask their doctor, hey, you know, I

I want you to check into our team health's XYZ protocol. How do people get tabs on what you guys are doing? Well, if someone needs a... So if they've got blood cancer and they need a bone marrow transplant and they don't have a perfectly matched donor in the family, like a sibling who's an ideal donor, that means they're going to look for an unrelated donor. And if they need to look for an unrelated donor, then they should consider enrolling in the study. They should talk to their doctor about

Osteum Health's Preserve clinical trial. They can even just go to www.osteumhealth.com and look up the Preserve or clinicaltrials.gov and look up the clinical trial called Preserve and just send that info to their doctor and see if they can get

enrolled so that's that's thing one if they're not at a center that's participating in the study we have a program called the hope program which they can just click on on the osseum health website where they can sort of request access to an expanded access program we would send them some questions get in touch with their doctor and see if they are a good candidate for that so not being at one of the participating centers should also not stop someone from who needs a transplant if um

You know, if they're doing an orthopedic surgery and they're going to get some sort of, most patients don't know what source or what graft, like what company makes the bone allograft. It is, they're going to get a spinal fusion. If they're going to get one of those procedures done though, they should sort of ask their doctor if they've heard of Osteograft, they could send them to the website and then their doctor could just, he'd just order it if they want to use it or talk to us about it. And if, if you need an organ transplant, we're not yet doing clinical work there, but I

But I would encourage listeners to sort of remember the content of this call and in the future, if there's someone in their life who needs an organ transplant to look into the status of our clinical work then. Well, very good. Well, Kevin, thank you for, first of all, for what you do. You know, you're really working to help people. I can tell it's amazing some of these products you're working on. And second of all, thanks for coming on the podcast. I appreciate it. Thanks for having me. It was a pleasure. If you like this podcast, please click the link in the description to subscribe and review us on iTunes.

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