Sana Biotechnology, Inc. (SANA) Earnings Call Transcript & Summary

All right. Welcome back to the 46th Annual TD Cowen Healthcare Conference. I'm Marc Frahm from the biotech team here. Next up, we're really pleased to have with us from Sana Biotech, their CEO and President, Steve Harr.

Maybe to start off with, Steve, do you want to kind of give a kind of overview and level set people on Sana, what you've been working on? And what do you view as kind of the key value-creating milestones for investors over the next 12, 24 months or so?

Well, first, thank you for having us. And thank you to everybody who's joined us here in the room as well as online. It's a great pleasure to have a chance to tell you about our progress. So as you probably know, we make a few forward-looking statements, and so do refer to our filings. We spend a lot of time on the risk factors. So the company was founded with really a goal of going after 2 super challenging problems in taking this exciting field of cell and gene therapy and turning into something that was going to be more actionable and something that would have a broader impact. And the 2 things that we chose to go after, one, figuring out if whether or not and how we could hide cells from immune recognition when transplanted. And since the advent of transplant medicine, one of the real challenges has been that you put someone else's cells into your body or an organ, you will reject it. You'll see this for is rejected. And the way people have overcome that historically has been profound immunosuppression, which has a lot of toxicity and really limits the applicability of the technologies or to use autologous cells. And again, those are very difficult to scale and manufacture. So first thing was can we hide cells from the immune system. The second is I think you know you can more or less do anything you want to the genome in a petri dish. And the real challenge is delivering the reagents to the cells in the body. And so we really wanted to go after this idea of being able to really be able to deliver any payload to any cell in a repeatable and specific way. I'm pleased to say both in terms of overcoming immune rejection and in vivo delivery, we've made a lot of progress. And I think we'll know, again, within that time frame, you're talking about very clearly whether or not what we're doing has a broad impact or we still have more work to do. I think the crown jewel of the company and the drug that I think gets people most excited is a potential onetime curative treatment for people with type 1 diabetes. And so type 1 diabetes is a disease where a patient's immune system gets confused and it knocks out all the beta cells in the pancreas. And the beta cell is the only cell in the body that makes insulin. Up until 100 years ago, it was a death sentence. Over the last 100 years, it's been something that people can live with, with insulin and glucose monitoring. But just to give you a sense of the scale and the challenge. Number one, if you're 22 years old and you're diagnosed with -- you would think this would be -- if you have HIV, breast cancer or type 1 diabetes, type 1 diabetes has the shortest expected lifespan today. It's pretty incredible, right? And the number of people that have type 1 diabetes in the U.S. alone is more than the number of people who have HIV and multiple sclerosis. So it just also gives you a sense of the scale of what this is. And progress has been made, and I think we're going to -- we've got this. So about 25 years ago, a group in Canada began transplanting pancreatic islets. So I'm going to use 2 different terms. Beta cells make the insulin and think of islets as beta cells plus their support structure, right? So people started transplanting pancreatic islets, and they found it from cadavers that people could remain off insulin for a decade plus. The challenge is it's not a scalable or replicable supply source and people have to be on lifelong immunosuppression. And that's very toxic, and there just aren't that many people for whom lifelong immunosuppression is better than lifelong insulin. So the impact -- there are thousands of people who have gotten it, but the impact has been pretty limited. Over the course of the last several years, several different parties have shown that you can take stem cells, pluripotent stem cells and make them into pancreatic islets and transplant those. That's a much more replicable supply source. It's almost certainly more scalable, but they've still had the challenge of immunosuppression. And what we've shown over the course of last year, published in the New England Journal of Medicine is that we can get rid of the immunosuppression. So now all of the component parts are there for a curative therapy. And it's a gene-modified stem cell-derived pancreatic islet. And we'll transplant that intramuscularly. We will get through the -- hopefully, the regulatory process in the U.S. and other countries this year and start the study. I think it's going to be relatively straightforward to understand if this is working or not. We kind of think of 3 separate value inflection points or time points that you can understand. One, do these cells in graft function and overcome immune recognition? I think you know that within a matter of a handful of weeks. The second question is, do you get normal blood glucose? Meaning just like what I have with no insulin, no immunosuppression in patients who will not need insulin or monitoring or immunosuppression for years and years. I think we'll know that within several months after the -- let's call it, 2 to 6 months after we start doing this. And then the third question will be, is this really replicable across many, many patients? And I think again, if it's like others, it seems to work in basically every patient, you'll probably know that within a handful of patients. Let's kind of think of like the next, call it, under 24 months for the company for that program. The second is we have an in vivo CAR T cell. I'll be very brief on that. I can get into that technology and the competitive landscape. But we expect to start a study this year and begin generating data. And again, within 12 months, have a pretty good idea of if is this really working. This is a CD -- this is a single shot where you inject a virus-like particle that goes directly to T cells and makes an in vivo CAR T cell. So I think you'll -- what we're taking that forward in first is blood cancers. So things like non-Hodgkin lymphoma. Hopefully, we would know, again, pretty quickly if that's working, if you're getting people safely into a complete response. And if you know the CAR T cell field at all, it's -- I've been involved with it for a long time. It's had a tremendous impact. Its impact has been limited somewhat by scalability and complexity of manufacturing, as well as some of the toxicities that come with the CAR T cells and the complexities of lymphodepletion. And hopefully, we're able to navigate all of those with a single treatment and make the CAR T cell in the body and people do well. So a lot of information coming in the not-too-distant future and optimistic based on the work we've done that we have really exciting therapies for both of them.

Okay. Thanks for that overview. Maybe starting still at a bit of a high level with 451, the islet program. Just there's a few other -- you started to touch on it a little bit in your comments, but there's a few other islet programs out there that are either in the clinic or getting close to the clinic as well. Just maybe compare and contrast how Sana's approach is different, particularly about some of the ones that are also kind of hoping to have gotten rid of immune suppression as well.

Yes. So I'll just start by saying that there are approximately 10 million people in the world with type 1 diabetes. If I get super optimistic about our manufacturing, I can see us treating 100,000 people or something like that. I mean that's like super, super optimistic. And if you do that, all you do is take the global growth rate from 5% a year to 4%. So there's plenty of room for competition. That's going to be my first thing I'd say. And I presume that others will find out different approaches to make this something that really does work. So you mentioned a few of them. So Vertex is a company that is ahead of us, and they have a -- they have a regular stem cell-derived islet where they're going after a very sick group of people who have both high blood sugars persistently as well as multiple severe hypoglycemic or low blood sugar events per year. And that's a very sick population and in need of something much better and they're doing this with immunosuppression. So it's a smaller market, but it's one that has a very big unmet need and hopefully, they're successful. There are other companies that are doing kind of hypoimmune attacks. And there are 2 parts of the immune system to think about. There's the adaptive immune system of B and T cells, and that reacts to specific signals. And there, everybody is kind of doing the same thing, which is knock out Class I and Class II, right? And then when you do that, our immune -- the innate immune system says, hold on a minute I don't want these cells here, and it tries to kill them. And in particular, natural killer cells will knock them out. And different people have tried different approaches. We overexpressed a protein called CD47. We've shown it works in all kinds of animal models. We've now shown in humans. It's actually when you take a step back, the most -- the only cell that's transplanted successfully is our red blood cells. And what's unique about red blood cells, they have no MHC Class I, no MHC Class II and they markedly overexpress CD47. That's not what we do, why we do it, but it does tell you that there's no part of the immune system is set up specifically to take out those cells. So others are looking at different proteins instead of CD47 to try to take out natural killer cells. I think some people have shown interesting things in, in vitro assays. And in some cases, those haven't translated into humans. Others have just shown what they're doing in vitro, and they may translate into humans, and we'll just have to see what happens. Century is one of the people ask us instead of CD47, they use CD300A. They also have an IgG degraded enzyme on their cell surface. A great group of scientists, the Chief Scientific Officer used to work at Sana. So I have no reason to think that they won't figure something out over time, and we'll be rooting for them.

Okay. Maybe more specifically on your program, just kind of what is the status of Sana's work to kind of establish that master cell bank and show that comparability and reproducibility of lots to get the FDA comfortable.

So making these drugs is very complicated. I'll start there. And the first step and really -- so you're taking one cell. And forever, that single cell will be all of your product is derived from, right? And so that starts with -- you take -- in our case, it was a young female, O negative blood type female, and we reprogrammed her cells back into an induced pluripotent stem cell. You then need to do all kinds of testing to ensure that the genome is really in a good place still, right? We then gene modified that. We knocked 2 genes out and we knocked 2 genes in, right? We knocked out MHC Class I, MHC Class II, and we knock in overexpression of CD47, and we put in a safety switch just in case something goes wrong, we can kill the cells. And then as we did that for years and the field -- we and others in the field have struggled with gene mutations popping up, right? And in particular, there are a couple of DNA repair enzyme defects that seem to be selected for as you're rapidly growing cells. And so for us, the key was to see that we could do this. So we had a GMP genomically stable master cell bank that retained pluripotency and effectively made pancreatic islet cells. And that took us a long time, and we now have done that. And we -- with an O negative donor, and we have clear alignment with multiple regulators around the world that again, around the testing and what we have there. So that's done. It's released. It sits in a several different -- we don't keep a single -- we keep them separate, freezers in different geographies just in case something happens. And from that, so what you do is you thought a single vial of master cell bank and then you'll make hundreds of vials of working cell bank. And again, you'll freeze those, right? Then you'll take one vial of working cell bank and then we'll grow that into a number of different stem cells, iPS cells and then you make islets. So think of it as like for every cell you get in, you get one cell out. It's not quite like that, but it's close enough, right? So if it doses circa 1 billion cells, you need 1 billion iPS cells more or less at the start and then to get for one patient, right? And that will -- you'll make them into pancreatic islets. And then all that is, is like think of like an embryo, right? You go from stem cell to like remember anybody took biology, mesoderm, ectoderm, endoderm, -- it was about there why I tended to fall sleep. And -- but once you have definitive endoderm, you can start making for gut and then you go to pancreas and then endocrine pancreas. You have to go through that system -- and that's what we do for manufacturing. So how do you get reproducibility? Number one, you have to have -- again, we start with the same cell product every time, which helps. But you have to have really a very robust manufacturing process with -- it's a lot of testing that goes into this. And as bad as I said, type 1 diabetes is, and it is a very difficult disease to live with, if you have family or friends or anybody that lives with it. That being said, but for us, these patients would likely live for decades. So we have a very high safety bar we have to have to ensure that we're not doing something like causing a tumor in the patient.

Okay. And what needs to happen still to ultimately file and have an accepted IND in the next -- within '26. Is it filling out the IND and you have all the data? Is there still data that needs to be generated? Just ...

I'd like to think we can fill out the IND. This is where I am. Although it always takes longer than you think to kind of put together study reports and things like that. But the -- there are 2 things that have to be completed. One is to complete the nonclinical testing package. And the most -- the longest pole in the tent on that is just finishing GLP toxicology studies. We've done many animal studies for a long, long time. One would like to think that all we're doing is replicating things we've done in the past under GLP conditions. And hopefully, that will turn out to be something that's done. The second thing is that we have to transfer the manufacturing from we do it first in our labs, and then you have to make it with GMP material, right, and have a real process. And you have to move it into a GMP manufacturing facility with operators who are manufacturers, not operators who are research scientists. And so we have to finish the tech transfer. So it's finish the GLP tox study, finish tech transfer, make drug, release it and get go.

And what is the -- as you get closer to the IND, what is kind of the disclosure plan? Do you plan on telling investors once those steps have been done to your satisfaction internally, not talking until an IND is cleared or somewhere in between?

I don't know. I don't know. That's a good question. I think some of it is our obligations to tell people what is deemed to be material. And I'm pretty sure that given the challenges that this field has had, the challenge that we've had, that clearing an IND would be very important and people want to know that. Steps along the way, I think I don't know if we'll need to disclose every -- we won't disclose everything we do. But maybe we'll do filing. I have no idea, we would definitely let you know. We'll let you know we probably -- we have data, too, pretty clear. I think you know pretty quickly, again, within -- if the cells engraft, if you have overcome with this product, immune recognition and immune rejection. They function. They need to function really well. If you guys have read -- for those of you who don't know, we did a human study last year where we gene modified islets that we've taken out of a person who has recently deceased. So they're cadaveric primary islets. And we dosed a low dose into the muscle of a person with type 1 diabetes. And what we've shown is that those cells both evade immune detection and they continue to function. The last time we showed data, we're out at 12 months plus. It was a low dose. And so it was -- so you're seeing in endogenous insulin production. The way you measure that is when a beta cell makes insulin, it actually makes something called proinsulin, and it's secreted as C-peptide plus insulin in a one-to-one molar basis. And so you know if you're seeing C-peptide and someone who's never -- hasn't had it in years and years and years that the patient is making insulin for -- on their own for the first time. And so we've just seen -- what we need to see in the stem cell-derived product is we're not going to give a very low dose. We're going to give a much higher dose. And we'd like to see that they're really making lots of insulin. And the goal is to get them off of all insulin shots.

And that's a good segue into the Phase I design. Is that initial -- your expected initial dose? Obviously, as you just said, it's going to be much higher than what you did in that IC with the cadaver cells. But is it high enough that you would expect it to actually achieve those goals of getting people off insulin -- or it's still -- you're still going to need to likely do some dose escalation to get to that bigger goal?

I don't know. I know the doses. We know the doses. We have alignment with regulators on what that will be. We will probably disclose that at a different time just because it's a relatively competitive space. The -- if you I like to think that we are at a dose that will be therapeutically efficacious. If anybody knows Vertex's program, they had -- the first patient was a front page New York Times article. That first patient had half of their regular dose and was off insulin and fine. I'd like to think we'll be well within the range of what we will get people off of insulin, that first dose. But you learn as you go. Biology has this super stubborn way of humbling us. And so hopefully, we will be in the right range, but we'll learn that as the study goes on.

And so the first thing you'll be tracking, right, is that C-peptide production. What level of C-peptide production do you think you need to get to, to get physicians and the patient comfortable enough that they maybe start backing off, if not completely removing?

They won't be looking at C-peptide. They'll be watching the patients' glucose in real time. You're going to see patients are going to come off of insulin. You have to watch -- so first thing is going to happen is patients get there -- you're going to want the patient to be relatively well controlled because you don't want glucose toxicity on your beta cells. And they're going to put these cells in. And if the fields -- some of them will die and they release insulin. So you have to manage them through that so they don't get too low blood glucose. And then you'll just see these cells gradually engraft and get better and better, right, over the course of several months. Patients will almost certainly through that entire time, be tapering off of insulin. So they will know. You'll know. People are -- every person in here will have a continuous glucose monitor. And they will be -- all of them will be on automatic insulin pumps and that feedback loop will be just titrating them off of insulin over a couple of months. But to truly have a patient off of insulin, you probably want -- just to give you a sense, a C-peptide level of around 200 per meal is what we would have, something like that. So those types of things will predict that people will do very well off insulin.

Okay.

By what I mean is exogenous insulin. So insulin shots because they will have -- they'll be making their own insulins. They won't need insulin shots anymore.

You mentioned before the cadaver transplant trial that you supported last year was doing injections intramuscular versus some of the historic cadaver work had often been through portal vein. Are you going to stay with the subcu in the muscle or? So...

Again, if you take a step back just for people here, the insulin, I love like the -- every field has very predictable challenges. And one of the challenges of any cell therapy is can you get the cells to engraft, right? And so one of the great things is when you can go into a field where somebody else is taking the time to figure that out, right? And there have now been thousands of cadaveric islet transplants and there have been many stem cell dried islet transplants. And the vast majority of those have been with the large bore needle into the portal vein with -- under some kind of radiologic guidance and then they're injecting the portal vein up into the liver. So we're not doing that for several reasons. One is we're putting in gene-modified stem cell-derived cells that are kind of invisible to the immune system. And that makes some people a little bit uncomfortable if they're kind of all over the place, you can't find them, you can't monitor them. And so we put them in the muscle, which has been used a lot. I'll come back to that. So you can see them. And you could always if something went right, just hopefully, just cut them out, right? The second is when you do this intraportal, it's very difficult to scale that. It's done under interventional radiology. And about 5% of people end up in the hospital, either from clotting or because they're so likely to clot, they get anticoagulated and they bleed. And we want to get rid of that problem because you're not going to democratize it. You're not going to get -- if you have 10 million people with this disease and 500,000 of them end up in the hospital, that's really bad, right? And then the third is that when you put -- you're not supposed to have somatic cells in your bloodstream, right? That's -- usually it's because cancer has like sort of metastasize. So our immune system will immediately recognize and kill regular cells in your bloodstream. That's called immediate blood-mediated immune response, IBMIR. And so we wanted to get rid of that because you lose a lot of cells. So we chose to go into the muscle. It turns out, by the way, that the most common surgical endocrine transplant is every time someone gets their thyroid removed, the surgeon has to dissect out the parathyroid. If they don't, you can die from not being able to metabolize calcium. And they put -- they grind up the parathyroid and they put it into the fore muscle of the person. And it happens about 14,000 times a year in the United States, and it works every time. So this is really well studied, very well validated. You can transplant endocrine tissue. And we've done it now. All of our animal studies are done as we've done in humans, right? And we will put it into muscle. We think it's safer. We think it's more it's going to be more scalable, and it's certainly going to be easier to monitor from that.

Okay. And what has that experience with that IST in Sweden taught you about kind of how to enroll or conduct a trial in this space besides the obvious of not having to match a cadaver donor to a patient? What other -- are there other kind of exclusion, inclusion criteria that you plan to approach differently? And maybe more broadly than just that IC because there are like the Vertex trial that you mentioned before.

I think our goal is for every person with type 1 diabetes to get access to this drug. everyone. You don't start that way, but you start pretty close to that, right? So we'll start at 18 and older. We're not going to start on kids, but I think we'll get into that pretty rapidly. And you want to avoid some things that can confuse you, like someone who just had a heart attack, you wouldn't want to put them in the study. They have another one, you might think is drug related, it might not be. So we'll have some things like that, but it will be a pretty broad patient population. I don't think that -- if we can't enroll this study, you should really worry about us because this would be a very broad patient population with many, many patients who are eligible. And the fact even that we have an O negative donor, we don't have to match anything like blood type, it's massive. So it's any transplant, that's an issue, and that's -- we would able to take care of that.

Okay. And so if we roll the clock forward a year, 1.5 years from now, hopefully, you start to have that clinical data rolling out that looks impressive. What do you need to do to then be able to scale to keep moving forward?

Yes. I would say there are really 3 -- there are 4 important questions for the company related to type 1 diabetes. Number one, does it work? Once it works, can you scale it? Once you scaled it, can you figure out the commercial model for a onetime curative treatment, right, all of which is different, right? And then the fourth question underlines all that is just capital to do it all, right? Those are kind of the major questions for the company. Scaling, manufacturing is challenging in something like this. And I wouldn't want you to think that we've already done it. And I kind of look at scale in 3 buckets for us. One will be make enough drug to run a Phase I study. I think we can do that now, right? And so then we lock that process and the scientists start working on the second stage, which is make enough drug to have a really nice, viable early commercial launch, right? And then the third will be broad access. We don't need to solve for the third right out of the gate because there will be other things that slow us down, like I'm not going to launch around the world at once. You have to train sites how to do this intramuscular injection, you have to get reimbursement, all those things, right? So -- but I do think we need -- you need to be at that process before you can begin a registration study, right? So what makes scaling hard? I think it's like the very simplest thing. If you just took it back and say, okay, well, Biologics Manufacturing, it took a while to scale. What did they solve? What they solved was you had a bunch of these cells that were supposed to spit out protein and you want to have a stable metabolic milieu, right? Just so all of the cells are kind of under the -- we're able to just do the same thing. So we have to do that and the way that we're taking a stem cell and making it into an islet. And so you're changing the signaling environment very rapidly. So you can go from stem cell to endoderm to blah, blah, blah, right? And so you have to figure out how do I maintain a stable metabolic milieu while I'm rapidly changing the signaling environment, right? And the faster you do that, the more sheer stress you put on the cells and the more likely it is you get genomic mutations. The slower you do it, the more likely it is you make a little bit of stomach, right? You get off-target cells, make a little bit of GI tract. And those things, particularly if they're not terminally differentiated, may keep dividing in the patient, right? And so you don't want those things. So that's -- at the heart of it, that's the challenge, right? And so we'll figure it out. It will probably be less than everybody hopes for out of the gate. And -- but I think we'll get there to where it's a very commercially important drug, and we'll just keep making progress on it.

Okay. We're starting to get a long time, but maybe move to 293, the in vivo CAR that you touched on a minute ago at the beginning. Maybe how does that fusogen platform differ from some of the other CAR in vivo CAR programs that are out there because we have seen quite a bit of M&A volume around these technologies.

I'm going to start just scientifically, we made 2 big bets. I hope they're both right. One is that cell specificity really matters. And I think that's not clear that most people don't believe that. They actually think just getting enough into your target cell is really the goal. We're trying to avoid all the off targets because they can get into why. The second is within the CAR T, you could do this with an mRNA, which some people would view as safer because it doesn't integrate into DNA of the cell you're going to after the T cell in this case. What we want to see is we're going to take -- make 100 million, maybe 10 million, who knows, CAR T cells, and you want to take out 100 billion B cells and tumor cells, right? So you need logarithmic growth of your CAR-T. So we made the bet that one specificity matters; and two, you have to integrate into the target T cell. So that's like the heart of what we've done that's different. So there are 2 different platforms that people are using at the highest level. There's kind of the mRNA LNPs. And you've seen a lot of strategic activity in those, right? And that is a bet that just good enough is good enough and that you don't need to integrate, right? They're easier -- if it turns out that they're good enough, they're a lot easier to make than what we're doing. And I think that pharma is -- that's where you've seen more strategic activity because it feels more like a drug to people, right? We think this virus-like particle or VLP is the way to go. I get -- ours is more specific than others in its delivery, and it has different ways of giving the cell, which I think will end up being safer. They've shown to be -- a couple of companies have shown quite impressive early efficacy data, right, where they're getting basically all patients have undetectable myeloma. I'm hoping we can do something similar on efficacy where it really works well and then it's a bit safer. And we'll start to learn that this year. So I mean, I can get into why they're different. We have a different way of targeting cells than others, which is -- which leads to the -- will hopefully be better safety profile.

Yes. So how would those safety differences manifest? Because is it on the kind of traditional metrics we think about with CAR T cells of CRS and things like that? Or it's something completely different?

Yes. So 3 things to worry about safety-wise in these VLPs. First off, what you've seen is unlike with regular CAR Ts, there's like acutely a very substantial acute reaction. So it's had -- it's had Grade 3, 4 liver toxicity, grade 3, 4 cardiovascular effects within the first day or 2. And it's basically because most of them are utilizing CD3 to enter the cell. And CD3 is what we use to activate T cells. So these T cells are overactivated, right? So that we don't do. Second is you should worry about the regular CRS and ICANS, right? And you could see it even being worse than with an autologous CAR T cell because an autologous CAR T cell, you're giving someone chemotherapy and you're knocking out a lot of the target cells, right? And we're not going to do that. We're just going to give them a single injection. In animals, that doesn't prove out to be true so far. I think it's because it takes a while to make these in vivo CAR T cells grow. I'm hopeful that we will maintain its safety. The third theoretical risk that we have is we are going to integrate the DNA into the target cell, right? And I don't find that to be -- I mean, that's something we have to study and be thoughtful around. But 40 million, 50 million people in the United States -- I'm sorry, in the world have had HIV, and you're using HIV integrase to get in. And none of them have ever gotten a T cell like a tumor or something. So it does seem to predict to be relatively safe. I'm not saying it will never happen. We need to monitor it, but I think this will be very safe. So those are the 3 things. And acute reaction is something where I think you'll see a big difference and hopefully, no liver toxicity and hopefully no cardiovascular collapse. And again, you can see some of those things in the off-target binding and other things in preclinical models. And we look for -- to be very well tolerated in nonhuman primates. And so hopefully, we'll translate to people.

And I think you promised data late this year earlier.

It will generate data.

Generate -- so okay, what is the -- like when is the disclosure? Is it that you see some CAR T cells being made, some B cells being killed? Or is it like an induction of a CR?

I think it's when we think we can tell you something that's meaningful. And I'm pretty sure within the type 1 diabetes space within a very small error bar, I could tell you what the right dose is, right? I think with these, we could be a log off on dose very easily, right? And so exactly if we're going to nail the first dose with the right dose level, maybe pretty quickly, right? Might we be off by a log or something like that? It's possible and -- we'll either be too high and then we'd have to disclose it because a lot of toxicity issues or we'll be too low and we need to keep going up. I'm pretty sure we're going to work hard not to be too high. You never know, but you'd rather not do something detrimental to people.

Okay. Unfortunately, that -- we're going to have to cut it off there. We're over time. But thanks a lot, Steve, and everybody in the room as well as online.

Thank you, Marc. And yes, we'll be around everybody has questions.