Thanks, everyone, for attending Jefferies London Healthcare Conference. My name is Kelly Shi, one of the biotech senior analysts here. In this fireside chat session, we are very pleased to have Dr. Steven Nichtberger, Chief Executive Officer from Cabaletta. Welcome, Steven.
Thanks.
And maybe to echo the theme of ACR, and I know your team were there, including yourself, what has been the key learnings from both cell therapy and BiTE, given that multiple clinical data dropped there and any implications to Cabaletta's program?
Yeah, so Cabaletta presented our first eight patients' worth of data at ACR this weekend. And the findings that were presented included that the drug, or the construct, when used in lupus, myositis, and scleroderma patients, provided a really nice safety profile for autoimmune patients. Five out of the eight, a majority of the patients, had no serious adverse events whatsoever, including no CRS and no ICANS. Among the other three, we had three patients who had a grade 1 CRS that was fever, or in one case, a grade 2 CRS in a scleroderma patient, which was a transient lowering of the blood pressure treated with a bag of IV fluid. None of the patients needed tocilizumab, and none of the patients had serious consequences to their transient fever treated with Tylenol, lower blood pressure treated with IV fluid. So a really nice safety profile to start with.
Second, all of the patients were able to stop all of their immunosuppressants throughout the follow-up period as long as six months, and third, within the eight patients, we were able to see complete elimination of the B cells from all of the patients, indicating that we don't think there will be room for others to go to either a higher for us to go to a higher dose or for others to achieve more complete B cell elimination with any other standard of care that might be developed. The ultimate outcome for patients, we think, in this field is going to be that patients want to receive a drug-free, symptom-free outcome where organ damage is reduced or eliminated in order to achieve the primary objectives for the patients and the physicians.
If you do drug-free, symptom-free relief, patients can wake up and feel free of their disease, and you prevent long-term organ damage, I think you end up with a product that's transformative for patients, for physicians, and for all of the autoimmune community. So that's what we're shooting for. We have 40 clinical sites we announced at ACR, 40 clinical sites currently enrolling patients across the country, in the U.S. only. We just announced that we've opened up our European organization, headed up by the most recent head of BeiGene's European organization, which he built from scratch as well. Along with him came one of his key clinical development folks, along with the head of regulatory from Kite in Germany and the past international CFO from Seagen. So a rock star team in Europe is already starting to open new clinical sites in Europe.
As we get towards 2025, we're looking for those sites to start opening. We have clearance to go ahead with the lupus program already in place. And so we're looking forward to, in 2025, doing two things. Based on the data we've presented, we are looking forward to engaging with FDA as soon as we can in order to expand our current clinical trial paradigm to a registrational program. And we'll engage with FDA as soon as we have a sufficient bolus of data that we believe is going to trigger the agency to want to support a registrational program. And we will get there with the industry's leading number of clinical sites, including all of the big pharma and biotech companies, with 40 currently open and enrolling, with many dozens more on the docket to open and enroll as we enter into 2025.
At the end of the day, our chief medical officer has the experience developing lupus drugs, both Benlysta and Saphnelo. He led both programs. Each of those took over 100 clinical sites to develop a lupus pharmaceutical product. So it is no small task. It took us two years to get here. And all of the fanciful additional things that are coming down the pipeline, first, they have to show that they can be more than acutely effective. Everybody's going to show acute elimination of B cells. Wait, rituximab does that. So you need durability to be demonstrated with whatever you're doing. And if it's allo or it's NK, or it doesn't matter, you need durability.
The value proposition is not, "I can make you feel better at six months." The value proposition is, "I can get rid of your medicines and give you symptom-free life for the rest of your life," and the autologous CAR-T programs have the opportunity and, frankly, the blessing of the academic experience leading the way. Whether others will be able to deliver on durability is as much related to their ability to reliably and reproducibly eliminate all of the B cell clones that were there before the treatment, so it's not about a lymph node, it's not about a lymph node biopsy. It's not about a peripheral check on something. It's about B cell receptor sequencing over the period of six months and a year to be able to say that every one of those B cell clones that was there before I treated is gone after.
And we're starting to see at ACR presentations in which companies are claiming immune reset, but in fact, what they did is not even B cell aplasia. They achieved B cell cytopenia. So if I reduce your B cells, I'm just like rituximab. If I get rid of all of your B cell clones, now I've got a shot, and now I have to see what the long-term data look like. So I think there's great promise for all autoimmune patients. I think the definitive, reliable, durable, curable approach is going to be autologous CAR-T. And I think everything else is going to figure out where they fit in the paradigm, whether it's T cell engagers or whether it's whatever their modality. You need to be in the category of reliable, durable, curable outcomes, safely delivered. So we'll see what the data are. We need a lot more data.
Great. And for the cell therapy programs to explore B cell-based autoimmune opportunity, curious from your clinical trial experience, what kind of biomarker studies you think could be very indicative for predicting durability of response?
Yeah, so as I mentioned, but I'll go in detail here. We first presented flow data indicating that we had immature or transitional B cells, which come from the bone marrow, as the predominant cell type that was recovering when we saw B cell recovery. We also then subsequently, at a later time, saw more of the naive B cells that come after that in the paradigm of B cell development. Flow cytometry is a useful indicator of whether you have new cells from the bone marrow or naive cells that are slightly developed from there. But it's not useful if the patient has had recent rituximab therapy, where, again, a patient at ACR was presented by another modality. rituximab was administered within six months. Most of the B cells in this patient on the poster were naive B cells.
So saying that most are naive after you've treated it six months doesn't mean anything. But it's easy to fool some of the people some of the time. So I think there's a real need for investors and for all of us to be very sobered about how hard this could be and how diligent you have to be about what you're looking at in order to understand the promise of what you're seeing. The flow cytometry is one aspect of analysis that's useful. Another would be to look at the B cell receptors and the sequencing of them sequentially, longitudinally over time.
We think this is the sine qua non of true immune reset, which is prior to immune treatment with a T cell engager or any kind of cell therapy, prior to the attempt at resetting. You document the 10,000 clones of B cell receptors that exist, and you see if any of those clones are there after the fact, after you've treated, when you see the B cells start to restore. And when they start to restore, if you see 20%, 30%, 15%, 10%, you're going to have some recurrences. You're going to have treatment failures. If you see less than 1% of all the B cell clones that were there prior to treatment, you know that there's less than a 1 in 200 chance that there's going to be a breakthrough. Everybody has to put out a lot more data, us included.
But I think there's no shortcut to long-term data. You need to see the long-term data.
Great. And maybe also the pioneering IIT trial, which actually showed a very impressive complete remission rate and also durable. But when we look at registered trials from Cabaletta and from your peers, first, do you think the patient inclusion exclusion criteria are similar to the IIT trial? And also, what kind of clinical benefit do you think should be the right reference point based on physician feedback, maybe give it two years after the treatment for cell therapy in autoimmune?
I don't know the answer to the first question because investigator-initiated trials are, by definition, investigator-initiated. And they don't publish, as industry does, its formal protocol. These trials are every site is to its own. And you really don't know. You don't have QA and QC checks. You don't have the rigor that industry brings to its own clinical trials. So I think there is a meaningful difference between IITs and investigator-initiated trials and industry-sponsored trials, with industry-sponsored trials having the purpose of rigorously trying to replicate what the investigator-initiated type of trial would show you. So I don't know what those trials or how they're designed. So I would imagine that if you're a zealot and you're an academic investigator, by the way, we need these people. We need these trials, these investigators. They're really important. They tell us what might work.
But they have one purpose: to demonstrate that the thesis is the hypothesis they have is correct or not. And it's one person with their team trying to figure out if they have a positive study or not versus a machine that has to operate within FDA guidance. Your second question was around.
Basically.
How do you define success?
Yeah, exactly.
I think success is, of course, hitting the primary endpoints that are validated and that are known to be regulatory clearance-oriented endpoints. In lupus, whether it's SLEDAI or TIS scores in myositis, those sorts of objective criteria that are widely validated and accepted. But I think for patients, your question was, what do physicians want to see? What do patients want? And there we do have a fair amount of research. And with 40 clinical sites open now, a pretty comprehensive insight into what these doctors and their patients are looking for. And the answer is they want to wake up, not take medicine, not worry about their symptoms, and be free of their disease. And so it's drug-free, symptom-free outcomes that are durable, safely delivered, and that they can rely on over time because you've got the objective evidence that organ failure is not going to occur.
Great. And also, Cabaletta's trial is designed to enroll multiple indications. And so what is your expectation for the clinical benefit from CD19 CAR? Do you expect variations from lupus to myositis, for example?
Yeah. What we're seeing is that the work we've done so far in the clinic, and so we have most recent announced is as of November 12, we had 16 patients enrolled. We presented eight of them. We have since dosed another two, we've said publicly, which leaves six that are currently being manufactured simultaneously for infusion in the very near future. The enrollment in these trials is going to, from here, we think, accelerate with additional sites that have opened that haven't even started to bring patients in yet. And thank you. And what we've learned, what we've seen from the data we've generated already is that the current dose of CABA-201 is the dose of CABA-201. We can say that because we know the percentage of the B cell clones that are gone after we've treated.
If we needed to increase the total dose of CABA-201, we would know that we have not yet cleared all of the B cells that we need to clear. With a heavy investment we've made in translational research, we're able to in-house do an awful lot of studies. From those studies, we are confident we have the right dose for all of the indications. It's not a different dose for each indication. We do think there might be meaningful differences in terms of the treatment response, the pace of treatment response, as well as the side effects in each type of patient. We'll have to get more data to really figure that out. Those are some of the reasons why we have different cohorts for each patient.
When you do a basket study in cancer, you can extend that to a phase III program in which you count how many people live and how many die or how big a tumor burden there is. But because the endpoints are so different, the side effects are so different, we can't have a basket study suddenly explode into five phase III trials with completely different endpoints, entry criteria, and it would be a first ever.
But with the design that we have, which was hard as heck for the first two years to create, which is five INDs with nine different cohorts, every cohort has homogeneous data from which we believe, and we have reason to believe, we're going to be able to extend from those cohorts directly into registrational programs, saving us five or six months in terms of the time it would take to open a new phase three trial. That's in contrast to the other companies in the field of autologous CAR-T, with all of us racing to the launch, because this is working and it seems to be safe enough. So the question is, how do you launch first?
I think we've set ourselves up by design to be able to move very rapidly as soon as we have the sufficient data set we need to go talk to FDA about the design of phase III programs, or I should say registrational programs.
Okay. And do you think so across indications, the percentage you expect almost all the patients could achieve drug-free remission and define that as a success, or you actually have a different number on that?
Yeah, so it's interesting. Look, I have eight patients that we've reported. Eight patients are drug-free for up to six months so far. No reason to believe that that's going to change, but we're going to continue to report that data out as time passes, and we'll all see together how CABA-201 is performing, but I believe it will deliver durable drug-free remissions.
Do you expect response to deepen over time?
I'm not sure what it is to deepen. What we expect is that we will get rid of all of the B cell clones. We will see that they are all gone, and they will remain absent. And if it's not all of them, it's so few that are missed that there is no way to do better. Because the last thing that we want to do is develop CABA-201 and have the opportunity available for somebody to do something better with perhaps a combination type of approach or a sequential approach with a variety of different drugs. If we're getting all of the B cells or essentially all of the B cells, there's just nowhere else to go in the B cell-oriented universe. There are those who have tried CD19 and BCMA combination therapy.
And just to address that for a minute, the combination of CD19 and BCMA has been on the table as a possibility for a very long time. We have never thought that is a way to go. And I think others are now agreeing with that because BCMA is going to eliminate all of the immunity I've developed for my whole lifetime. So my measles, mumps, rubella, and every other aspect of my immunity is gone if I'm using a BCMA CAR. Using it only in those who have a recurrence of disease makes a lot of sense. So there are two patients. There's this hearsay that goes around where CD19 CAR-T is not itself a durable, reliable treatment. There are at least two cases I've heard of where a failure of CD19 CAR-T therapy has been spoken about. And I disagree based on just the facts.
The first would be Cabaletta's first ever patient treated, which was a 50 million cell fixed dose, which was a starting dose as FDA guided them to do a dose-finding study, as we all now understand. The first patient was an obese individual who was given too low of a dose of cells, and if you look at the UPCR, you look at the SLEDAI scores, this patient never had a remission, so to say they had a recurrence is false. They got underdosed, and that's the whole story. There is no failure of CD19 here. There is an absence of ability to eliminate all of the B cells because they didn't dose high enough. The other case that I just spoke about over breakfast with Professor Schett two days ago is a patient who had myositis.
And this patient had 18 months of drug-free, symptom-free, glorious living after a single infusion of CD19 CAR-T. Showed up for a follow-up visit, said, "Yeah, I got some muscle pain. I don't have any lung disease, shortness of breath. All that is gone. All the severe muscle pain is gone. All the severe weakness is gone. A little muscle pain, though." CPK was up. He tried to give him a repeat dose of CD19 CAR-T. His CD19 CAR-T is the murine version of what we use. We use the fully human. The murine had antibodies to it. Not surprisingly, the cells never expanded. So he went right to daratumumab, a drug that is targeting plasma cells. He gave daratumumab, and the symptoms improved. So by getting rid of plasma cells in this patient, you got symptom improvement.
The next step was to remove the antibody treatment and see if he's cured. Because after all, we all have hearing from the community without data that bispecifics and other antibodies are going to cure patients. It didn't work. It didn't cure the patient. So what did he do? He used a BCMA CAR-T. He got compassionate use and thrilled that he did. And with compassionate use, six months ago, the patient received a single infusion of BCMA CAR-T. His symptoms resolved, and it's now six months later, and he's completely symptom-free and drug-free once again. So there are going to be patients who break through, maybe more in myasthenia gravis than in any other of the indications, in our opinion.
But there are going to be some right now, it's one out of about 100 CD19 CAR-T patients that we know of in the world who have broken through with relapse of disease. But it's not for CD19 failure because CD19 does not treat, does not eliminate, it does not target plasma cells. And as a result, it's a false statement to say CD19 failed. What happened is the patient has a BCMA source, I'm sorry, a plasma cell-derived source of antibodies that was somehow enhanced by the environment or otherwise. And those antibodies that that plasma cell is now making are causing some minor disease. So you got to get rid of the plasma cell. But this is not a failure of CD19 CAR-T therapy. So I would tell you that our belief is there has never been a described case. Will there be? There might be.
Will we end up with 90% of all patients having a response to CD19 CAR-T? I think at proper doses, with proper patient selection where the target is the right target, yeah, probably it's going to be remarkable. But it doesn't have to be perfect to be awesome.
Follow the same topic. So could you share any insights on this new dual-targeting CAR-T data actually presented at ACR? For example, do you think CD19 BCMA dual CAR could be preferable or a sequential use could be more preferred?
So we strongly prefer, and we don't think we have a BCMA preclinical program we've never talked about. We could bring that forward into the clinic. We're choosing not to because we don't think there are evidence, the clinical data I referred to, there are not enough breakthroughs of disease due to the plasma cell producing these antibodies. So we just don't think that's something we should invest our resources in. Others can do that and will, I'm sure. As to other combination approaches, there are a number of companies that are trying CD19 and CD20 approaches. So the combination, if you look at B cell lineage charts, it makes perfect sense. So CD19 covers a broader range than CD20.
So in cancer, where the CD19 target is modified because you have these cells that are always looking to survive and you have selective advantage if you get away from the CD19 binder, having a CD20 plus CD19 in cancer makes perfect sense. Based on our clinical experience and our B-cell receptor sequencing in our patients, having it in autoimmunity makes no sense at all because there are no B cells that we're missing. So there's no reason to think a more narrow approach with CD20 is going to give us a better clinical response. If we were missing certain B cells, if we were unable to achieve the B-cell clearance that is complete, that's a different discussion. Then CD20 seems to make some sense. Or if there's escape, but you don't expect escape.
Okay. Great. Maybe lastly, what do we expect from Cabaletta in terms of next data update?
Yeah, so we haven't put out a specific data update, but you can expect that we're going to continue to present in relatively real time the boluses of data. We have, as I said, six patients that are waiting to be dosed. Typically, at the beginning of each year, we'll update where we are, and we'll do the same at the beginning of 2025 in terms of what one can expect throughout 2025. I think what we have said about 2025 that maybe is worth closing on is we fully expect that enrollment will continue to accelerate from where we already are, which is a great place. That means the pace of ability to move to FDA-based discussions based on data and discuss and describe and then initiate phase III clinical trials.
That engagement with FDA is expected to occur as early in 2025 as we can possibly move to do it, just based on our clinical data.
Okay. We will wrap up here. Thanks for a great discussion. Thanks, everyone, for attending.
Thank you.