Yeah, thank Vamil, thanks for helping us. Yeah, we continue to be very excited about the outcomes of our phase II BESTOW study that we talked about at ASN last year. You know, the study was a phase II design, open label, primary endpoint was kidney function, but we actually hit the non-inferiority margin for a composite endpoint, which we can talk about. That's the approvable endpoint for phase III. The kidney function data, even though we didn't hit the endpoint, beat standard of care in every single aspect when we looked carefully at the data.
Some of the subgroup analyses had a 10-point delta, which would have hit our endpoint analysis, except for one group of really great quality kidneys that were imbalanced in their randomization between the standard of care and tego, which is a KDPI measurement. It measures the quality of the kidney from the donor. That subgroup analysis was very unbalanced, with a 10-year age difference between the control group and tego that really affected the tac's kidney performance in that patient population. If you excluded those, we actually would've hit our endpoint. So that data also was quite encouraging. And then, really, where we hit a home run was in safety.
I mean, all of the things that we felt that tego could do to replace standard of care in the long term, really showed up in our study as far as, a ninefold difference in tremors, which is a big problem with, calcineurin inhibitors, a sevenfold difference in, infection rates with bacteremia, so bacteremia. Two- to four-fold differences in, in sepsis and delayed graft function, and a twofold difference in some of the cardiovascular events. So we really, from a safety profile, did much, much better. The infection rates between the standard of care and tego for CMV and BK were the same. So very encouraging data, that we got out of our BESTOW phase II study.
Okay. Yeah, so as, as you've sort of had these conversations with, you know, thought leaders in the space, digested the data, but then also talking to investors, what is it you think that the market is most underappreciating in the data?
So I think they underappreciated the fact that we missed our endpoint for kidney function. They, I think that we didn't dive deep enough into, at the time, of why we saw that difference, because we presented the top line data pretty quickly after the data came out. And I also think that, you know, folks didn't appreciate that the approvable endpoint for kidney transplant has always been a composite endpoint that doesn't have anything to do with kidney function. It's biopsy-proven rejection, patient and graft survival at 12 months. And as I mentioned, we actually hit that endpoint in our study, even though it wasn't powered to do so.
Yeah. And one question we've gotten from investors around the acute rejection rates, which were a little bit higher, but then people, you know, who stayed on therapy were still, you know, did well. So how do you, how do you think about that rejection or acute rejection risk, and how are you thinking about managing that as you, you know, do, do further work here?
Yeah. So it's a great question. There was a numerical difference between the two arms, where the tego arm was 20% and the tac arm was 14%. One of the things that was very interesting, though, was that all of the rejections, 100% of the ones in the tego arm, happened in the first 6 months, and we haven't seen any since. And only 40% of the rejections were picked up in the tac arm in the first 12 months. Most of them were captured in the protocol 12-month biopsy, which really suggested that there was a difference in the way that the study was treated as far as looking for biopsies based on changes in kidney function. So that's something that, you know, we have to manage expeditiously as we move into phase III.
We need to work very closely with our sites and our investigators to make sure that, the protocol is balanced between the two, and that we don't catch most of the standard of care rejections at the 12-month biopsy.
Okay. And then building on what you showed ASN, just in January, you showed some longer-term phase Ib data, 24-month data for a smaller group of patients. No acute rejections, 100% survival. How do you- how do those results, you know, in, how do they inform you on how to design your phase III program?
Yeah. So also really, really exciting results. That data came from our open-label phase I study-
Yeah
... that's been enrolling for quite a few years. As you point out, there was no additional rejections on that longer term follow-up. The eGFR kidney function continues to be really, really good, which is quite outstanding, because as, as we know, one of the biggest drawbacks of tacrolimus, the current standard of care, in addition to the toxicities that I just mentioned, over time, it's actually toxic to the organ itself, so you tend to see loss of kidney function over time. And kidney function is actually the best long-term predictor of graft function and graft survival. So with really great, stable, and even increasing eGFRs over time, that would suggest that tego is gonna do much better than standard of care in that regard. So that data is really important for a couple of different reasons.
First of all, everybody in the phase I trial had the option to roll over to a long-term extension, but everybody in the BESTOW study also had that option. We're doing long-term follow-up from both the tac and tego arms, so we can collect that data. It's gonna be really important to share that with the agency, so that they can see that we're improving on current standard of care for long-term outcomes.
Okay. And, obviously, a lot of interest from the investor side around your discussions with the FDA, and you've highlighted that as a key event for this year in terms of the meeting and kind of figuring out the phase III plan. Just the latest updates there, in terms of when you may be meeting and kind of how you think it'll play out in terms of putting together a phase III plan and getting that started.
Sure. Yeah. So we've been working through getting the briefing book materials together for that, and have guided that we're gonna get that done here in the first quarter, and request an end-of-phase II meeting, hopefully in either late Q1 or early Q2. We've been working towards that, and we think we're still on that timeline to have a discussion with the FDA on what a phase III registrational study could look like.
Okay. If you do have that time, you know, some would say end of 1Q, early 2Q, is it still realistic, then, you'd get the Phase Three trial maybe started later this year?
Yeah, we're still guiding that we would launch the study by the end of the year.
Okay.
You know, and the briefing book has to cover the typical things that you would cover at a phase III design: number of patients, statistical power, endpoints, quality and safety monitoring. So those are, those are all the things that we'll be discussing with the agency at that time.
... And obviously, after the discussion, things may change. But, I guess, at this point, what would be your sort of base case assumptions on how should we think about what you likely would look for in the Phase III in terms of, you know, the, especially in terms of the endpoints and-
So the agency's been pretty crystal clear for over 20 years that the primary endpoint for our kidney transplant studies is that composite endpoint that I alluded to-
Yeah
which is PPAR, patient graft survival. So we'll be powering the study towards that endpoint.
It'd be non-inferiority?
Non-inferiority.
Yeah.
Correct.
Okay. And one question, we've talked about this a little bit before, too, but I think what I sort of sense is, you know, everyone's focused on your, the eGFR levels as the data came out, and the safety side, maybe as people are not prescribing Tacro and seeing patients dealing with the side effects of Tacro, wasn't maybe appreciated as much, these numerical benefits that you showed over those patients. Is there anything you can do to kinda, I don't know, in the phase III design, whether it's, you know, quality of life measures or other measures or, so that it really sort of resonates more in terms of how much of an impact this safety benefit is really having on the patients in the trial?
Yes, you bring up a really great point. We will capture all of those key toxicities associated with standard of care, such as new onset diabetes and tremors, as part of our secondary, key secondary endpoints. But one of the things that we did not formally capture in the BESTOW study was patient-reported outcomes, and we'll be doing that in the phase III study. We'll have a formal quality of life, patient-reported outcome endpoints in the phase III.
Okay. And what do you think in terms of, like, the induction dosing, the ATG induction dosing? I know there's some questions as the, you know, BESTOW data came out there and also KDPI stratifying for that. How do you think about that at this point, at least in terms of-
One of the biggest take-homes that I think we saw from the BESTOW study is we need to do a much better job managing how physicians treat the two arms. There was imbalances in the not only ATG dosing, but also in the bolus methylpred dosing that's given around the time of transplant. There was a difference in the time of prednisone weaning over the 30-day period to wean down to 5 mg, that ironically favored TAC over tego, where they weaned tego much too quickly compared to TAC. We also have to manage how investigators play with methylpred dosing, which is part of the maintenance dosing. It's really the lever, if you will, that physicians play with when they see BK viremia, CMV, neutropenia, leukopenia. They tend to reduce that MMF dose.
We need to guide on how they do that so that they don't overreact and go from 2,000 mg dose a day down to zero, 'cause that really leaves people open for potential rejection rates and so in Phase III, we need to manage all of the immunosuppression in totality between the two arms and really monitor that quite carefully.
Okay. Then before we get to the other indications, just sticking on the, you know, transplant side, just your views on sort of the commercial opportunity, assuming, you know, successful data in phase III. We certainly get questions. It's been a long time since we've had a launch in this space. That launch from Bristol didn't go quite as well as people thought. Tac has despite limitations. Doctors seem okay with it, like they've kind of figured out a way to sort of make it work. So how do you think about sort of the uptake that you'd have, assuming positive phase III?
Yeah, so BMS is a drug, Nulojix. I don't know that it's a great comparator for commercial launch for a few different reasons. I mean, when Nulojix or belatacept was run about 15 years ago, the standard of care arm they ran against was cyclosporine, which at the time wasn't even standard of care because tacrolimus had just been approved. So when they actually got their clinical trial results, they actually didn't have data against standard of care. The other thing that I think really hurt them, as far as commercial launch goes, was they didn't win in the safety profile. Even though their eGFRs were pretty similar to what we see, ours are a little bit better, but their eGFRs were better than standard of care at the time, they didn't win in safety.
They had new onset diabetes in the study that was fairly comparable to the control arm, which was surprising. But more importantly, they saw some really troublesome infections like PTLD that ended up in a black box label on the drug that also hampered uptake. And then finally, you know, 15 years ago, it was a four-week, every four-week IV infusion, which is done in the hospital. And that was problematic, I think, for key stakeholders, including nephrologists, transplant surgeons, et cetera. Whereas today, that's really not much of an issue. We have infusion centers, we have better infrastructure, we even have boutique ability to do infusions at home. So, you know, for us, when we think about commercial launch, we're really committed to this.
We think that tego is going to be the next standard of care in transplant. We think it's going to work with cells, organs, and it doesn't matter what the source is. It could be allotransplant, human to human. We will switch over to xenotransplant on here shortly. We think tego is going to be the standard of care, regardless of cell, organ, species, allotransplant or xenotransplant, so... And we have data that's backing that up. We're in multiple different studies at this point, as you know, both clinically as well as pre-clinically.
Yep. Okay. All right, so why don't we shift over then to the islet cell program? We see a lot of interesting updates on social media as some of these patients are going through the program, but the latest that you've shared in terms of the number of patients and the data, and sort of the pretty impressive sort of results we've seen so far.
Sure. I mean, the TikTok stuff is pretty fascinating. Now you can follow your clinical trial enrollment on TikTok-
Yeah
... it's pretty amazing. Dr. Rutkowski recently reported the most recent social media update was that he enrolled 9 patients at this point. Seven of them got off exogenous insulin. An eighth one is pretty close. I think he's being a little conservative. If you watch his TikTok video, he's enjoying eating too much right now, so he's been doing a little bit of insulin when he's eating 2 cheeseburgers and french fries. But I think he could get off insulin as well if he wanted to. Just really exciting data, obviously. The way that the islet cell transplant function is working under our drug has really never been seen before. We obviously, to date, have only really protected islet cells with calcineurin inhibitors, which has all of that baggage that I just described.
We're seeing no safety issues in the study, which is really incredible. It's truly, it's a functional cure for people with Type 1 diabetes, which is a really unmet need. So a really exciting opportunity to move that study over to a sponsored study here in 2026.
Okay. Yeah, and so that was gonna be my question now. So how do you bring this within the company now as a sponsored study? What, well, how would you design it? What, what's your sort of timeline looking like?
The agency's given pretty specific guidance on what islet cell transplant studies look like with a, a new, immunosuppressive regimen. It's a phase I,II,III bridging-type design, where we already have guidance on what a phase I looks like as far as number of patients. We just need to open up an IND and basically get through that phase I and go back to them and show safety and efficacy data, and then we can bridge that into a phase II, 3 study design.
Okay, so there'll be a separate FDA meeting at some point later this year to discuss that?
Correct. Yeah.
Okay. When do you think you'd be able to potentially start?
We're working on guidance, and we're probably gonna get an IND filed by the end of the year.
Okay. Okay, and then as interesting as islet cell transplants, I still get sort of shocked by the xenotransplant success we're seeing now. Almost like science fiction, what we're seeing out there, but-
Yeah.
Maybe you talk about the latest, you know, numbers in xenotransplant. I know you're working with other companies that are involved there, so kind of the progress you're making in xeno.
Sure, yeah, no, xeno's pretty amazing. If you'd asked me five or six years ago that we would have organs from genetically modified pigs lasting even more than a few days in humans, I'd be shocked, actually.
Yeah.
So quite a lot of progress we've made with the genetic edits that's humanizing pigs, if you will. So we have preclinical collaborations globally in xenotransplants with multiple different organs, including kidney and heart and heart valves. The data preclinically is looking quite encouraging across the board. As we've seen, United Therapeutics and eGenesis have INDs now that are ready to go to transition from a compassionate use into formally sponsored studies. So up to date, we've done a little bit of both. We've supported cardiac transplant with United Therapeutics animals, and we've also been doing and supporting the eGenesis collaborations with kidney transplant.
Up to this point, they've been compassionate use, as you know, and eGenesis' plan is to start to roll that over towards sponsored study here in 2026, and we'll continue to sponsor them. It's really, really exciting.
Then, what is... I guess I've always been confused a little bit on what the regulatory path would be for eGenesis. So, so if eGenesis is leading this, and you're obviously using your product, what more would you need to show to get this, you know, approved for use in xenotransplant? Or is it just kinda, it goes along with the work that they're doing?
Well, it goes along with the work that they're doing 'cause it's their IND. So we have not talked to the agency about what that path looks like for us, but based on how we're thinking about it, is we're going to be supplying tego as part of the immunosuppressive regimen for xenotransplant to prevention of xenotransplant rejection. So we would take all of the safety efficacy data as part of their IND filing and utilize that as a case to get an approval for the use of tego, and the prevention is xenotransplant rejection.
Okay, and maybe you saw, obviously, it's very early days still, but how do you see sort of the commercial opportunity? I think it's integrated science so far, you know,
Yeah
... moving into the more structured trials. But, like, what do you see as sort of the commercial opportunity at the end of the day?
I mean, we haven't done formal work there, but as you can imagine, the biggest problem with organ transplant is the limit of organs, right? There's 100,000 people on the kidney transplant waiting list, and most of them will never get an organ. So, you know, if we can protect organs for even bridging studies, 6 months to a year, while they're waiting for an organ-
Yeah
... or even extend that even longer, you know, it could really change the way that people think about being on the transplant list. So it's a fascinating technology and making really impressive grounds, as we just discussed. Would never imagine that you'd have people out nine or 10 months on a xenotransplant organ-
Yeah
... doing quite well.
Okay. Okay, so maybe rounding it out then-
One last cool thing-
Yeah
... about that, actually, that a lot of people didn't notice is that Mr. Andrews, which was the person that was transplanted MGH, he got out about nine months post-transplant. Even though he lost the organ at that point, he was lucky enough, and he'd been on the transplant list for a really long time. That bridged him to an allo transplant with a really great matching kidney, and he was out of the hospital in about a day and a half, and he's doing fantastic. And I don't think people really appreciated that. They focused on the fact that the organ got out in nine months.
Right.
But that got him to an organ, an allo transplant, that's gonna change his life forever.
Yeah. That is really impressive-
Yeah
... what's happening. So, so maybe then, just from a corporate perspective, bringing it all together, if you can just talk about sort of the current capital, the cash position, what's your cash runway? And then, the last question I have would be just kind of the, as we think about the key events here across the various programs over the next 12, 18 months, how did-
Sure. So we have cash through the second quarter of 2027. The cash is going to get us through some really key milestones this year. We've already talked about some of them. Obviously, we want to open IND after discussing our phase III plan in kidney transplant with the FDA. We'd like to open up a sponsored study in islet cell transplant. Right now, that's an investigator-initiated study that's being done at University of Chicago. We would like to take that on as a sponsored study to really bridge from a phase I, phase II BLA approval for cadaveric islet cell transplant. We wanna continue to support University of Chicago and Dr. Wakoski in his second islet cell study, which would be an investigator-initiated study with a slightly different Type 1 diabetes patient population that also have some kidney dysfunction.
That's being funded by the BT-1D, as part of Dr. Wakoski's efforts in islet cell transplants. We wanna fund that. We'd like to sponsor and utilize tego in an investigator-initiated study for liver transplant, as well, and obviously continue to support all of the xeno work that's being done in the field.
Okay. No, yeah, very interesting progress you've made and obviously exciting year ahead, so looking forward to seeing the progress continue.
Perfect.
Thanks so much for joining us.
Sure.
Yeah, thanks. Thank you.