Hi everyone and welcome to episode 108 of Cell and Gene, the podcast. I'm Cell and Gene's chief editor and host of the pod, Erin Harris. In just a minute here, we'll dive into a great story of scientific persistence, clinical innovation, and high-precision cell therapy. I'm joined by Nathaniel Fernhoff, co-founder of Orca Bio, a company that spun out of foundational work in Dr. Irv Weissman's lab over a decade ago. Orca has come a long way from an early vision rooted in refining stem cell transplantation to today's late-stage clinical breakthroughs. The company's flagship therapy, Orca-T, recently delivered strong data from a pivotal phase 3 study, showing dramatic reductions in transplant-related complications like graft-versus-host disease. Nate and I talk about how Orca leveraged engineering and manufacturing innovation to overcome decades of logistical and biological hurdles. We talk about their commercial strategy as they move toward BLA submission, and oh, a whole lot more. Nate effortlessly shares really important information, and I think you'll find him to be just as knowledgeable as I do. And so, without further ado, here's my conversation with Orca Bio's Nate Fernhoff. Enjoy.
Hi Nate, welcome to Cell and Gene, the podcast. Thanks for being here.
Good. So, all right, you co-founded Orca Bio on work that started over a decade ago, probably more, in Dr. Irv Weissman's lab. So talk to us a little bit about what did that journey look like from where you were then to where you are now in terms of commercialization following your positive phase three results.
Sure. So, if I could take a step back and maybe tell you a little bit about Orca to start with. So at Orca, we are aiming to build better, safer cures for patients with blood cancer. If you are a patient today with acute leukemia like AML or ALL or MDS, an allogeneic stem cell transplant is really your best chance for a cure. But there are severe complications that can result from a stem cell transplant, and it's one of these sort of where the cure is worse than the disease for some of these patients. And the patients will have complications like graft-versus-host disease, serious infections, organ failure. And so Orca Bio is a late-stage clinical company, and we're building high-precision cell therapies to target only the therapeutic cells in the graft so that we can really isolate that effect. Ultimately, we're aiming to cure that underlying hematological malignancy, but do it with fewer toxicities and fewer complications. As far as where the company's at in general, we're a late-stage clinical company. Our lead candidate, Orca-T, has now met its primary endpoint in a pivotal phase three study, and we are working very closely with the FDA to make Orca available to patients and their doctors as quickly as possible.
Okay. You asked about the origin story, correct? For Orca, so let me dive in a little bit to that. Sure. Pretty interesting story. I'm going to take you way back to the late 1980s, when Irv Weissman, who was already at the time a famous immunologist, was working on bone marrow transplantation and a really important problem. People had known that bone marrow can regenerate in a recipient. So you can regenerate the hematopoietic system, the immune system, using bulk bone marrow. Irv did something really interesting, and he purified a very rare but potent cell from the bone marrow. This was, you know, less than a fraction of a percent of the bone marrow. And he showed that this, the ability, the capability to regenerate the entire blood and immune system in the mouse was found in this exceedingly rare cell type, and only this exceedingly rare cell type. And what was different about this experiment was that Irv was one of the first adopters for flow cytometry. And this is the ability to purify the cell to effectively homogeneity, right? So you have a pure cell population, and now you can really understand what it does in the lab in the context of an experiment.
Fast forward 15 years, and now Rob Negron, who is a bone marrow transplant physician, similarly finds that he can purify regulatory T cells to control graft-versus-host disease and prevent it, really prevent it from occurring in mice. These findings are reproduced in labs worldwide, and people can really robustly prevent GVHD in mice by using purified regulatory T cells.
A number of pioneering graft engineers try to adapt this finding to the clinic, and it's very difficult for a number of reasons. Mice have about 100 million cells in their bone marrow. Humans will have about 100 billion cells that you're working with. So it's really, there's a huge, massive difference in the scale that you need to purify. Further complicating matters, the regulatory T cells were shown to perform best when they are not cryopreserved. And so now you've got to get the cells from the donor to your manufacturing facility. You got to do all of your manufacturing and get it back to the recipient site all within 72 hours. And so a few folks were able to, with heroic efforts in single-site, small-scale academic clinical trials, they were able to test some of these ideas. But the big idea for Orca was to come in as a manufacturing platform and to try to do this in a more scalable fashion. I think what was really interesting about this for us at the time was that the problem with this approach could be solved with engineering solutions. It wasn't really a biology problem anymore where you're worried about, you know, is this drug going to work. It's a novel mechanism of action. It's the first-in-human study. You know, so many people had reproduced various studies with regulatory T cells to show that they could prevent GVHD. This was really a question of could we build all of the other systems that we needed to do this type of production and logistics so that we could maintain product quality and get it out to every patient who needed it in a short amount of time.
In a short, in a very short amount of time.
That's right. That's right. So we spun Orca out of Stanford with the idea of this manufacturing platform, and we built a really incredible team of scientists and engineers and just generally people who were passionate problem solvers. And as we stabilized the formulation and the manufacturing process to do this for patients, we started engaging with clinicians, you know, folks from around the country, a lot of these early pioneers that I had mentioned earlier, the folks who were passionate about graft engineering as a way of reducing transplant complications, and they were invaluable in designing the clinical study and helping it get off the ground in the early days of the company. For Orca-T, we treated about 200 patients across all the different studies in early-phase clinical trials where we were learning things about how the drug behaves once you introduce it to a patient. We were learning about the optimal way to deliver it to a patient. Things like the conditioning regimen and pharmacological GVHD prophylaxis. We were figuring out how to target all of these things and dial in the best efficacy with the lowest rates of complications. Once we had done that work, we engaged with the FDA and designed a pivotal phase three study with them, and that study is now complete. It was a randomized trial comparing Orca-T against a standard-of-care stem cell transplant. We randomized about 200 patients, almost 200 patients across 19 different centers in the US. So this is a large randomized multicenter study. This is really sort of a gold standard experiment in clinical development, and we've recently announced that this was a positive study, a very positive study. We saw the primary endpoint in this study was survival free from graft-versus-host disease, which we saw in 78% at one year of our Orca-T patients, and we only saw in 38% of the patients who received the standard-of-care allograft. So a really important difference. We also saw that overall survival at one year in the Orca-T arm was 94%, you know, 83% in the standard-of-care arm, and so we think that there are a lot of benefits. That was not, the overall survival is not statistically significant yet. The study wasn't powered to look at overall survival, but we think these are really promising signals for the potential of Orca-T to essentially replace stem cell transplant for these patients.
Yeah. Promising and impressive for sure. That's, you know, certainly, and for patients and their caregivers, providing a lot of hope, which is amazing. Orca Bio, before we move on, can you talk about where did the name of the company come from?
Orca Bio. Yeah. So, I'm debating whether to use our like fun joke here about curing cancer in Wales, but no, the orca moniker comes from the manufacturing technology that we use, and it's one of the abbreviations for sure. One of the homegrown technologies. It's optical retrieval from cell arrays. Orca just kind of has a nice ring to it as well.
It does. It does. All right. I want to talk to you a little bit about how you're defining high precision. So, your platform is pretty unique when it comes to high-precision cell therapy, and how are you personally, I guess, defining precision, and how does that translate to better outcomes with, like we talked about, patients with AML, ALL, MDS?
Right. So high precision here really boils down to the purity of the cells that are making up the drugs, and really I'm talking about with most interest here about the regulatory T cells that we use. So T-regs are a naturally occurring immune cell that controls inappropriate immune reactions from other T cells and other immune cells. In a conventional transplant, there are T-regs in the allograft. They are exceedingly rare. They're about 1% or less of the total population of cells. They are surrounded in a conventional transplant by, in particular, T-effector cells, which are needed in the context of a transplant, but they present a number of potential complications for the patients as well. In particular, even a single alloreactive T-cell clone can go on to mount and sustain a GVHD reaction in the patient for life. Just like our drug is a living material that is meant to durably cure the patient for life, it's meant to regenerate their blood and immune system, so too the contaminants that go alongside your drug have the same ability to proliferate indefinitely in the patient for life. And so the purity of those regulatory T cells becomes really important. What we do is we, from the allograft, which starts as a very complicated blood product that has dozens of different immune cells, each of them has its own function, we pull out just the stem cells and just the regulatory T cells. And when a patient, in the course of their treatment, they receive cytoreduction to reduce or eliminate their own immune system, then the patient is sort of a blank slate. We first give the patient these stem cells and these regulatory T cells. That's really important. Essentially, we are priming the patient with a tolerogenic environment for the new immune system to reconstitute. So the T-regs, when they're introduced into the patient, they home to the lymph node and to the spleen and they set up shop. They start proliferating. Two days later, we add back a controlled dose of those T cells, but now those T cells are not exposed to a completely naive environment. They're exposed to an environment that's been primed by the regulatory T cells. In this manner, the T cells are controlled in their ability to react against solid organs that would result in GVHD, but they are still able to prevent infection. They're still able to carry out what we call graft-versus-leukemia and control disease relapse. And so the T cells can go on to perform their normal functions without causing these pathogenic functions that essentially destroy the recipient's tissue.
Gotcha. Thank you. So I want to talk a little bit about your PDUFA date that's coming up in 2026. A few of our listeners, I'm sure, are anticipating the same thing with PDUFA dates upcoming, and I'd love to hear from your perspective, what are, so you and your team, what are your priorities as you prepare for the potential launch?
Yeah, great question. Well, look, for clarity, we don't yet have a PDUFA date. So we haven't yet submitted our BLA package to FDA. We're planning to do that imminently, and so we'll be working with the agency to get a PDUFA date, like you said, hopefully in 2026. But there are a number of things that we're focused on to prepare for that date and for product launch and to make this drug available to physicians and patients. So there are really three major initiatives that we're focusing on: manufacturing, making sure that the supply is available, setting up our commercial team again to make sure that the drug is available to patients, and the third is continuing our pipeline development for other indications as well. So, but maybe we can talk first about the manufacturing and what we're doing to get ready to scale our manufacturing, our GMP manufacturing for commercial operations.
