Good. All right. Let's go ahead and get started. Thanks for joining in for this session, guys. Up now we have SAB Bio. So we have Sam Reich, who is the CEO and co-founder, and Lucy To, who is the CFO. Sam, let me kick it over to you just for an overview of the company, where things stand today, and then we'll get into some Q&A.
Great. SAB is a clinical-stage biotech company. Our lead asset is a human anti-thymocyte immunoglobulin for the treatment of newly diagnosed type 1 diabetes patients. We are going into a phase II-B clinical trial right now that is a pivotal study, and we have every expectation based on data from comparable products and competitive products that it'll be a best-in-class product.
Awesome. Sure and sweet. That's great. All right, so let's just dive into the product profile and some more details. That's a good place to start. Maybe you could just kind of recap benefits, differences versus ATG.
OK. So there's a rabbit anti-thymocyte globulin that's manufactured by Sanofi, and it is approved for organ transplant. In fact, it's the global standard of care for organ transplant. Several diabetes researchers have studied it in patients with type 1 diabetes, and in two different clinical trials, demonstrated excellent efficacy, which is the ability to preserve C-peptide, which is preserving beta cell function, as well as the ability to reduce HbA1c, showing improved glycemic control, so data from two different studies, clinical studies, have shown excellent efficacy, but the drug does not have a safety profile that is acceptable for the use in these patients because it is a rabbit anti-thymocyte globulin. It causes serum sickness, which is not an acceptable AE for these patients, and it can't be redosed due to the immunogenicity of the protein in the drug.
Perfect. How many measures have you looked at to know that you're getting the same CD4 exhaustion as rabbit ATG?
We have all the published available data from the rabbit ATG first clinical study, TN19. We have done sort of a comprehensive analysis of T cells from patients using flow cytometry, looking for cells with different markers of exhaustion. What we have shown is on both multiple signatures of exhaustion, like PD-L1 and TIGIT, that the exhausted cells are increased after getting the drug, but also cells that carry multiple markers for exhaustion, that the cells are exhausted. A real comprehensive analysis has been done to show definitively that we are inducing T cell exhaustion, as well as it is durable and it is lasting.
Do you have any evidence that your exhaustion is going to continue to deepen over time with redosing or extended treatment?
To date, we see exhaustion out to 120 days. We believe it is a waning effect. Our drug is not immunogenic. There should be no impact from an immunogenicity standpoint when the drug is redosed. Human IgGs, as a class of drugs, are redosed chronically and have been for years in hundreds of thousands, if not millions, of patients. The ability to redose the drug is known from the perspective. The fact that the drug induces exhaustion is known. While we don't have data, we have all the data available to us indicates that we can redose the drug.
Perfect. All right. Let's just quickly run through the MELD data. I know you've probably spoken about it a lot over the last couple of months. Maybe just kind of quickly recap how it shows you can decouple efficacy from the lymphodepletion.
Yeah. So the MELD study was a study conducted in Europe in newly diagnosed type 1, stage 3 type 1 diabetes patients. And the MELD data was presented in September and published in Lancet in September. And the first thing that it showed was that it replicated the data from an earlier study, which was known as TN19, an American study. And that key result is that rabbit anti-thymocyte immunoglobulin showed preservation of C-peptide and reduction in HbA1c at one year after a single dose. The new information we learned was that a lower dose, specifically 0.5 mg per kg, was also efficacious. And at that low dose, there was negligible lymphodepletion, which has now completely decoupled lymphodepletion from efficacy.
We knew and we postulated, and other researchers like Laura Jacobsen and Alice Long, who had studied the mechanism of action of anti-thymocyte globulin, had demonstrated that there was no correlation between lymphodepletion and exhaustion. The reason why this is relevant is because rabbit ATG lymphodepletes, and our human ATG does not lymphodeplete. If the question is, well, how do you know lymphodepletion is not driving exhaustion? You could say, well, all the evidence shows that there's no correlation. That still leaves a question. When MELD came out, showed the lower dose worked, and that lower dose didn't have lymphodepletion. Now there's basically incontrovertible proof that lymphodepletion is not the mechanism driving efficacy with rabbit ATG. We don't have lymphodepletion, but we do have exhaustion and Treg preservation, which is shared between the rabbit ATG and our human ATG.
And so we're confident that we have that same mechanism of action, which leads to C-peptide preservation and HbA1c reduction.
Awesome. All right. One question on the regulatory side. Maybe you could just put together the different pieces of evidence that we know the FDA is comfortable with C-peptide use.
Yeah. That's a great question. So if we track the trajectory of Tzield, which is a drug that is in front of us in development, Tzield was being developed by Provention . They got an approval for stage 2 type 1 diabetes, in which the endpoint is time to progression to stage 3. Then they got acquired by Sanofi for $3 billion. They generated data in stage 3 patients. Now we're in stage 3 patients, and the endpoint is C-peptide. C-peptide is the measure of beta cell mass and function. That's where the patients produce insulin. But they missed on any secondary endpoints. So they didn't show what a clinical reviewer at FDA or a skeptic might say is a clinical benefit. Well, you've shown that you're preserving the beta cells, which is the goal of the drug. But you haven't shown that this in any way benefits the patient.
And that has been shown in other data and globally in health care data, but it wasn't shown in the Tzield study. And so what we saw happen was that Sanofi, who had now acquired the drug, did not file for approval in Stage 3. And the general consensus was that was that because they didn't show glycemic control, but they had hit on C-peptide. And then over the last year or so, I'd say about the last 12 months, we've got a new FDA commissioner. It was very motivated to get new drugs for type 1 diabetes approved. There is a major push from the KOLs, the entire diabetes KOL community, and the patient advocacy communities to accept new drugs based on C-peptide alone. And the data shows that if you preserve beta cell function, patients are healthier. There's plenty of epidemiological data showing that.
And then in October, Sanofi announced that they were awarded a Commissioner's Priority Review Voucher. And that showed a lot of excitement that the FDA had. And then they announced that they had filed their BLA for this drug in Stage 3. And so most of us connect the dots and say, well, that means they're getting approved. And if they're getting approved, that means C-peptide is sufficient for an approval. And there's kind of two takeaways for us on that, or what an investor might think. One is we have clarity around the path to approval for a drug in this indication, because there's no drug approved yet. Tzield will be the first. And two, we know C-peptide is sufficient. We have a lot of evidence and data supporting that C-peptide is a very attainable endpoint.
Three, it's important to note that thymoglobulin, our reference product, has always shown a reduction in HbA1c. But nevertheless, if a company can get a drug approved on C-peptide alone, just the bar is lower, the path is more clear. And so that was really great news for the whole field when Sanofi got the priority review voucher in October. And we're looking forward to hearing news from Sanofi soon.
We will see. It should be soon. All right. Let's skip commercial. We'll come back to commercial. Let's actually dive into the SAFEGUARD study. First, since you kind of just recently put out the schema, just starting up the study, what exactly is part A of the study?
Yeah. That's a very good question. Happy to explain so we are studying a new compound in adults, adolescents, and children, and the way that we have agreed with the FDA to do that is by stepping down, doing adults first, before we go to adolescents and before we go to children. Now those three age populations have different rates of progression of disease, so it is very important for us to have a balance of the three age groups, to have this trial stratified so that we have the right number of adults, the right number of teenagers, and the right number of children, but in order to step down to children, we need more adults. We don't want those adults in the efficacy sample for efficacy, and so we're enrolling them in what's called part A.
When we have gotten the number of adults that we need for safety, we will begin part B. Just we have gotten enough so that the balance is right in part B. It's a run-in for safety in adults so that we have the right balance of the different age groups in the efficacy component of the trial, which is called part B.
OK. Do you have like a pre-specified stratification for a number of patients in each of these different age groups for the trial?
Yes.
Have you said what it is?
I don't think we've disclosed it, but it's a relatively equal balance without having too many adults.
OK. And is there anything else other than age that you're stratifying for?
C-peptide at baseline, which I think was something we've talked about, making sure that we have consistency across baseline C-peptide. C-peptide is the primary endpoint, and we want that to be controlled.
Got it. And you're studying two different doses. Are you expecting to see a dose response between those?
We consider them both active. They both show the signal we're looking for, which is T cell exhaustion. We have seen throughout the history of MELD development that lower doses work or work better even when you get to a certain dose, they start working better. So we wanted to range lower rather than higher. But they're both in the active range mechanistically. So we're not predicting a dose response, but we're trying to find the optimal dose and want to go lower than 2.5 to make sure we don't miss on the high side.
I guess it's like you're not getting the lymphodepletion, which I think may be some of the issue with the dose response with ATG. I mean, could there be a theory that you have a different dose response than rabbit ATG, where a higher dose actually works better and gets more exhaustion still without the lymphodepletion?
There's more than just lymphodepletion. There's impact on other T cells and the balance of T cells. One important component is Tregs.
Yeah. Yeah. I guess if you're leaving Tregs untouched, even if at higher doses, right? Or do you start to get some Treg impact as you go to very high doses?
We want to be prepared for the fact that Tregs could be more impacted at higher doses than lower doses.
I follow. OK. That makes sense. All right. What about the powering side? I guess how exactly is C-peptide measured? That's probably one place to start. Is this just one single measurement at 12 months versus baseline, or are there replicates to kind of tease out some variability?
So we're measuring C-peptide. It's a two-hour mixed meal tolerance test C-peptide, which is an accurate, reproducible C-peptide. And you might see that in some trials they've used four-hour, but our consensus is that there's no appreciable difference between two-hour and four-hour. We are testing at zero study start baseline, 3, 6, 9, and 12. Multiple points. But the actual endpoint for efficacy and the powering is done at 12 months. So it's the difference at 12 months compared to baseline.
And you've noted 40% effect size, 80% power previously. I guess what variability assumptions, what control arm assumptions did you use when figuring that out?
We collaborate with TrialNet and JDRF. They ran the TN19 study, which is the study that is the foundation of our program. That's the first study with rabbit ATG. We had all the data, literally raw data from TN19, to look at variability and to power the study. We had an excellent sort of basis to model off of, which was the raw data from TN19.
Got it. And I think the primary endpoints in AUC measure.
Yes.
What about other time points and ranges and other ways to look at C-peptide?
That's why we have an excellent clinical advisory group composed of PIs who are experts in the field, who ran TrialNet, who were on the Tzield studies, so who ran the TN19 study and the MELD study. That's just the consensus viewpoint for the way to look at it, which I think is most close to how they've done ATG. There are different ways to look at it, different ways to present the data. This was the method we chose based on an expert group of advisors.
Got it. What are your expectations for the baseline C-peptide level? And how does that actually inform any of the outcomes based on what we know from prior data?
The inclusion criteria requires that the patient have 200 picomole per liter. Right? I always get confused.
200.
200 at baseline. And that is considered a meaningful amount, and that there's enough to preserve, and that there's enough for the placebo group to decline. So there needs to be a significant amount of beta cell mass to preserve to benefit the patient and to measure scientifically. And that's 200.
Awesome. What about powering for HbA1c?
The study has 80% power to show a difference in HbA1c. I don't know based on the delta, because I think I don't know how clear it is. Any reduction in HbA1c is considered clinically meaningful.
Yeah. Awesome. What about plans for a confirmatory trial then?
Based on our conversations with FDA and what we're seeing in the field, this trial should be sufficient from an efficacy standpoint for an approval, and that there won't be need for a clinical confirmatory trial. With that said, we intend to study the Stage 2 population, which will allow the drug to be given as early as possible to provide the best possible outcomes for patients with the possibility of keeping a patient insulin-free, and that would be another study. We don't think it's required for an approval. It's certainly required to get Stage 2 on the label, and that would be a confirmatory result in a diabetes population, albeit somewhat different.
When do you think you would start the stage 2 study? Why not start it sooner rather than later?
We hope to start it sooner.
What are the big considerations and differences from everything we just talked about from a Stage 2 versus 3 trial?
So first and foremost, Stage 2 patients do not have symptoms. And they can only be identified by getting screened for autoantibodies. So a patient has to get screened for autoantibodies and have some dysglycemia in order to be identified. And then they have to be enrolled in a trial. So it's a very difficult trial to enroll. You need to be very careful about site selection, and you need to be patient. Another key difference is that the endpoint is time to progression to Stage 3. It's almost like a vaccine trial. You need enough patients in the placebo group to develop Stage 3 in order to be able to show efficacy. So you have this time-based component, which makes it something that will be very time-consuming, both from enrollment and from an endpoint.
So we certainly expect to and want to get the drug approved on Stage 3 alone. But from a package perspective, a BLA package perspective, data can come from that trial, not for efficacy on the label, but for supporting the package.
Awesome. Maybe you can just kind of finish up with the commercial side as we're thinking about stage 2 versus stage 3, all of those considerations.
Yeah, well, first of all, Stage 3 Type 1 diabetes patients have nothing today, and if you meet anyone in the community, meet a patient, or meet a treating physician, or meet a parent, there is a desperate need for therapies for their children or adults. 60% of the patients are 18 or older, so I don't want to discount them, but when a patient is diagnosed with Type 1 diabetes, they feel a tremendous urgency to have a medicine. Using insulin and glucose monitors is managing the disease for survival, but it is not treating the disease, and it is not changing long-term outcomes, so patients with Type 1 diabetes are at high risk for going blind, for losing limbs, for getting chronic kidney disease, needing to be on dialysis, and for having a shorter lifespan, which is a big problem, and it's something that causes social anxiety, depression.
In addition to that, managing type 1 diabetes is a minute-to-minute burden all day long—what I can eat, what I can do, what's going to happen when I go to sleep—and it is a massive management burden on the patient. The ability to preserve beta cell mass and a patient to make their own insulin should improve everything over time, and it also provides the patient and the family the ability to do something and intervene on their disease. When a new patient gets diagnosed with type 1 diabetes, they are making their own insulin, and over time, they will lose the ability to make that insulin. We can give them a drug to preserve their ability to make insulin. There are 65,000 new patients every year. Today, there is no drug approved.
And this will be the first opportunity for doctors and patients to say, "Hey, you just got diagnosed. But what we want to do is save your ability to make insulin." So we think major unmet medical need, tremendous demand, and that the commercial opportunity is really huge and will be appreciated by the diabetes community in a major way. It's something you really have to kind of go out and explore, meet these people, look at their videos on YouTube, sort of follow them on Twitter. And you see what you don't hear, or meet the parents or meet someone who got diagnosed to really appreciate the impact this is having on their life and how much they really want to intervene and do something about their disease. And today, there's nothing.
All right. I think that's actually a great place to wrap it up. So Sam, Lucy, thanks so much for joining. Appreciate it.
Thank you. Thanks for having us.