Good morning. Welcome once again to TD Cowen's 45th Annual Healthcare Conference. I'm Phil Nadeau, one of the biotech analysts here at Cowen, and it's my pleasure to moderate a fireside chat with Cabaletta Bio. We have with us today Steven Nichtberger, the President, CEO, and Co-Founder. Steven, I thought we'd start with the updated results from rese-cel's RESET trial that were presented at two conferences in February. In our opinion, the data are impressive, with patients having durable responses, including DORIS remissions in lupus, complete renal response in lupus nephritis, and major TIS improvement in dermatomyositis. Safety was consistent with what we saw before. Can you help us put the recently presented efficacy data in perspective, specifically on those lupus patients who achieve DORIS remission? This seems like an impressive level of efficacy to us. How does that differ from what the standard of care today can produce?
Yeah, thanks. First, thanks for having us. Second, today's standard of care in the treatment of lupus can provide a DORIS remission in about 10%-15% of patients treated with ongoing therapy. In today's standard of care, there is no promise to have this sort of DORIS remission with no therapy at all. With therapy, with today's best therapies, about 15% of the time you get to the outcome that we've seen in three of the first four so far. As we said recently on February 18th in our press release, we're seeing deepening of our clinical responses over time. I would not be surprised if we continue to see more and more DORIS remissions from patients who are treated, both those who have been treated and those who we will treat in the future.
Off of all therapy, as our patients are, off of all immunosuppressants, you would not expect any DORIS remissions. With best standard of care, you might expect 15% at best.
In the myositis group, all patients had an improvement in TIS, though the degree of improvement did vary by the subset, consistent with the heterogeneity of the disease. The DM patient achieved a major TIS improvement, while the other two IMN M patients had varying degrees of improvement. Again, how does this compare to what standard of care could achieve? What's been the feedback from KOLs and sites on the myositis data in particular?
Let me start with your first part of your question, then we'll go to the second, what is the doctor's impressions. Each subtype of myositis has a different clinical situation and a different treatment option available. In dermatomyositis, it's 70% of the market opportunity, and there are about 70,000 myositis patients in the U.S., 70% of the about 49,000 patients who have dermatomyositis. Their best option is to use monthly high-dose IVIG for treatment of their disease. In those patients, you can expect to see a minimal response. That's actually the basis on which a minimal TIS response, which is the integrated validated primary endpoint that was used with 16 weeks of follow-up and monthly IVIG infusions, a minimal improvement in this muscle measurement and integrated physician and patient assessment scale. That's in dermatomyositis.
In ASyS form of myositis, where you oftentimes have lung dysfunction, the standard of care is nothing is available. There are no FDA-approved treatments for ASyS form of myositis, and that's about 15% of the market. Another 15% is the IMNM subtype. This is really interesting because Immune-Mediated Necrotizing Myositis, the necrotizing is different and unique in myositis patients because once that muscle is gone, it's gone, which explains in part why we're not seeing the sort of dramatic responses that you see in DM and in ASyS . DM and ASyS subtypes have these really dramatic major responses at 29 days that persist in the academic data for many years, our data so far for many months. The IMNM subtype has a much more modest response in the academic and in our own data sets. That said, all is not what it always appears to be.
As a CEO, as a cardiologist, as an investor in Cabaletta, and for you as investors, it would seem obvious that the DM and the AS subtypes are the ones where doctors would be most impressed and most wanting to put their next patient into the trial. While we continue to see enrollment in all of the arms of all of our trials, the enrollment in the IMNM subtype has been really off the charts. I attribute that to what we're seeing is in each of the myositis sites that has enrolled their first patient, has seen data on their first patient, the vast majority, if not all of them, have enrolled a second patient already. In many cases, they are now looking for their third patient in the trial.
To give you a sense of usually what you see in myositis and lupus trials, you tend to get about an average of one patient per clinical site per year. You get about one-tenth of one patient per month. Having three patients from a number of sites, having two patients from all the sites is a real testament to what the physicians and the patients see in the therapy that we're offering. I think that's the best guide for the answer to your question, what's their impression. It's not what they tell me or what they tell you in whatever surveys you might read or do. It's what are they doing in the trial. They're putting their patients into the trial more and more frequently once they treat the first patient.
The SSc patient also had gradual improvements in skin manifestations or in a modest improvement in lung function. Can you put what you see in SSc in the context of the disease course as well as what standard of care today would do?
Yeah. Look, standard of care in scleroderma is nothing. The risk of death 10 years after a typical 30-year-old woman is diagnosed is about 50%. The risk of death in a recently diagnosed approximately 30-year-old average patient, typically a woman, is 50% at 10 years. There is no treatment. It wouldn't be surprising, based on what I already told you about myositis, that in this disease, we're seeing pretty dramatic acceleration of enrollment to a greater degree than we're seeing in some of the other cohorts. The reason is really straightforward. The disease progression is what we expect to halt by eliminating the B cells in these patients. We're not going to reverse the fibrosis. At least we haven't seen it yet. It's possible over the years that it'll diminish or reverse to some extent.
It is the ability to literally get your life back and to hope that lack of progression equates to survival ultimately. I think the doctors see the promise of the therapy that way. I think the patients are seeing it that way. They are showing up with and without organ damage. We are seeing enrollment. More broadly, it was February 18th we announced that the enthusiasm for rese-cel had hit really a new level. After two years of trying to enroll one patient a month, one patient from here to there, we now have the machine working. We always said that having the sites, the clinical sites, was really the key to advancing everything. Two weeks ago, we told you we had 50 sites open. Today, we have 53 sites open. Two weeks ago, we told you we had 26 patients enrolled.
Two weeks later, now we have 31 patients enrolled. The machine is working. It's not so much just the excellence of the team, able to get a rheumatologist, neurologist, dermatologist to coordinate with the hematologist, oncologist, and to get the apheresis beds, to get all of the machinery working. It is the data, the clinical data. Since we presented at ACR, while it's not obvious from the investor perspective, I think, from the physician and patient perspective, it couldn't be more obvious. They are showing up with their actions, enrolling in the trial, and repeatedly so from each of the sites that are treating patients. These two things are going to resolve themselves. As we go forward, we expect continued acceleration in enrollment. Really, we believe we are pacesetters across the US now for enrollment in any CD19 therapy. That's not at all a surprise.
It's actually how we planned it. The next step is have a lot of data and bring that data forward to FDA.
We will talk about the FDA discussions. Before getting there, maybe to look at the safety profile, what has been the instance of severity of CRS, ICANS, and infections in the trial thus far? How would you qualify the risk-benefit in light of the severity of these diseases?
Yeah, thanks. Our safety profile, we believe, is as good or better than any other form of therapy that's going to be used in this disease, including all of the autologous competitors. Specifically, to address our data, we had one patient, for those who remember, who had a grade 4 ICANS event. This was a lupus nephritis patient who had a grade 4 ICANS event, the only ICANS we've seen in our program in any announced data. That grade 4 ICANS event was seizure activity with diminished consciousness around day nine in the patient. We subsequently did extensive translational work, which was received with real clarity in a scientific meeting when it was presented, but also in the regulatory discussions. This is an outlier to all of our other patients on every measure. We believe it was due to an occult infection in this patient.
When the T cells that were fighting the infection expanded, they took along for the ride the CAR that was in one of them. So that half of the cells that expanded had our CAR in it. The other half didn't. Our CAR was not driving the expansion. What drove the expansion was an occult infection. Having disposed of that, the most severe side effect, we've had no ICANS but that in any other patient. On the CRS side, we have one case of grade 2 CRS, a number of cases of grade 1 fever CRS, and many patients have absolutely no side effects. I think the reason for our exceptionally great safety profile to date, we need a lot more data, but so far looks really good. The reason for it, I think, is weight-based dosing.
Everybody was focused on what modality are you going to use. Is it autologous? Is it allogeneic? Is it bispecific? Is anything else going to work besides autologous? Who knows. It was focused on which co-stim domain are you using, 4-1BB or CD28. I think all of that is interesting. I think the show is really going to be determined by whether you are dosing appropriately. When the data came out from the academic community in Europe, we said, let's take all of the risk out. This is a hard business. It's hard enough without making changes. Let's design our product to be the fully human equivalent of the one that Schett used. Let's make sure that we can dose identically because the activity is documented to be identical between his targeting domain and our fully human version of his targeting domain.
Let's dose it as the only company in the industry currently dosing on a weight-adjusted basis. Not only does that permit our pediatric program to go forward with the speed that it is already moving, but it permits us to actually give each patient the right dose. It is no wonder that we have this excellent safety profile, and we're seeing every bit of the activity that we should see. I need more data to confirm that this is true. Our current working hypothesis is that as a weight-adjusted dosing regimen, we are going to end up really threading the needle. Professor Schett got very lucky. He didn't do dose finding. He didn't do a lot of things that an industry organization would do. He did have great data. We now know from our own data, his data was real.
We are not in any way, and I do not suggest he was, cherry-picking patients. We are taking all comers who fit a broad set of criteria. We think it is probably 85% of the prevalent population who have failed two therapies, did not have B cell reducing therapy on board or there previously. We know it is our cells, not something else. With that as the cohort, we are seeing this excellent data. We are thrilled with the risk-benefit. All of these patients who are having these responses, they are on no medicines. They are no longer patients. Even the grade 4 ICANS that I started this answer with is now cured. I do not want to say cured because I need to die before I tell you that I was cured. Complete response on no medicines, no need to wake up in the morning and be a patient.
That's the difference between what other modalities might do and what autologous CAR-T is. In 150 patients across the globe so far, by our count, looking at the literature, academic, and commercial products, any dose, any drug, about 148 of those, no argument, have had really important clinical responses to the therapy. Autologous CAR-T actually works. Probably that's the key advantage over the other modalities. It actually does work.
You talked about the grade 4 ICANS. There were two unrelated grade 4 incidents. There was neutropenia and pulmonary embolism. Can you give the background on those and why were they deemed unrelated?
You're such a party pooper. The PE, as discussed and presented and submitted, of course, to FDA and scientifically reviewed, is in a gentleman who had Factor V Leiden deficiency. That's a clotting disorder that predisposes you to PE, DVT, and other such things. In addition, before he got our therapy, among his many other therapies, he was on IVIG, which itself is associated with a higher risk of DVT and PE. You put these two together, and his risk of a DVT at that time was maybe 10-15-fold higher. There were other risks as well, a history of medical illness that would have predicted he would have a higher risk. You put all of this together, and there's no reason to believe that our product was related. There are many reasons to believe this was because of his underlying medical conditions.
The reason I say our product was not involved is we measure how much rese-cel is in the patient throughout the trial. Two weeks prior to the appearance of a DVT and this PE, our drug was not detectable. The drug was not even present. You have to accuse the drug that has been gone for more than two weeks that it has somehow caused it. It does not, and it did not. That seems really clear to us. That patient has been with confounded early data. Did not do as well. The B cells were completely eliminated. The T cells expanded well. The B cells were completely eliminated. I think this story is going to play out just like all the others, which is a good response.
The data as of this minute are confounded by the fact that he was with a PE with an associated MI in rehab and then just recently got out of rehab and is now starting to get his life back. We will see how he recovers from the PE and whether his muscle strength recovers and whether he is able to do without immunosuppressants over time. Still a story to be told, and we will see how he turns out. The patient who had the neutropenia that was not associated, because we do have other blood side effects that are associated shortly after infusion, but this was delayed. It is a clear side effect that is associated with CD19 CAR-T in cancer. It is a cytopenia at a delayed point in time, typically attributed to the preconditioning regimen, not to the CAR-T cells.
That's a pretty clear literature. We relied on and referred to that literature when we categorized this and when the investigators categorized this as not associated with the drug.
On February 13th, you had 26 patients enrolled. You just said you have 31. That is like five patients over two to three weeks.
Yeah.
That's a really rapid pace. Is that pace likely to continue? Was there any reason for a bolus over the last few weeks?
About a year and a half ago when I realized that we, like every other company in this industry, overestimated our ability to enroll these trials with what we thought would be compelling product outcomes. I have stopped predicting. Better off to tell you what happened as opposed to what I think will happen. Here is what happened. We had that rate of that pace of enrollment. I have already signaled to you where it is happening. It is happening where doctors are seeing results and where patients want those results. They are showing up. I do not anticipate that would change. I see the screening and the pre-screening pipeline of patients coming into the trial. We are providing the opportunity for patients to stop being patients. No disease, no medicines. Not just like 10%, 20%, 50%, 70% of you.
It appears nearly all patients who undergo a single infusion, not three infusions over three weeks, not six months of therapy, one infusion are able to get rid of their disease. That's like becoming free of shackles. It's not a wonder that they're showing up the way we originally thought they might. I would not anticipate that we're going to slow down anytime soon. We have 53 sites. We've opened three sites in the last two weeks. We're starting to open sites in Europe now. There's a world out there that needs these therapies. The more data we show, the more patients are showing up, the more doctors want to be in the trial. There is, as I said earlier, a complete total disconnect between the value proposition for patients and physicians based on their actions, what they believe, and what the investment community believes.
At the end of the day, it'll be progress with patients, continued reflection of data, and most importantly, the ability to clarify our phase three pathway and whether it's a single arm, whether it's 150 patients, 100 patients, 50 patients, or something else, as well as emergence of more data from other modalities, which I think your questions might come to. I'll pause.
Maybe just one or two more on the enrollment. I guess first is, how many patients per week can your manufacturing support? Is there any chance that you'll bump up against some sort of manufacturing capacity? Second, when could we see data from these additional patients? When would you present data? When could we see an update?
I love this question. I love it because it was a year ago today at this conference that we first signaled that the initial clinical data we would be able to provide based on pace of enrollment was only a couple of patients within the next couple of months. The investor reaction was totally clear, and it was what it was. Today you're asking me, am I worried about manufacturing capacity? I love that. Not a lot of companies are getting that question. Let's start there. The answer to your question is no. The reason I'm not is in the last two or three weeks, we've doubled our capacity. We can now handle, as of July, we expect to be able to handle a dozen patients a month. If you want to know what we're really thinking, don't ask what we're thinking.
Ask what we're doing. This is a train that has left the station. While everybody else is trying to prove one or two, this or that, we have a reliable, durable, complete response ability for patients with autoimmune diseases who have been on anywhere from two to eight drugs and who can be free of that the day they get the infusion. That's just a compelling drug. We know we have a drug. The next step is, as I said, take this data. We will not be turning away patients. There is no scenario that I foresee where we're going to turn away patients at sites. Why? On our board is the past Chief Commercial Officer of Kite during its formative years up through acquisition and subsequently. We are not going to allow anybody to take patients at sites where we have a foothold.
Because a site can handle maybe two cell therapies. If they're really big and busy, maybe a third. That's it. Once they have a curable option, it takes a lot to displace that. We saw that with Kymriah and Yescarta. It was the site ownership that led to the commercial success. We see it the same way and have since 2022. One of the investors we met with earlier today said, how come you guys have so many sites? We have 50 sites in the US. At last count, I haven't looked in a week or so, Bristol had about 30. I use them as an example not that they're not great, because they actually probably are the most important competitor in our space right now, and they have far more resources than us. This is hard.
To get the rheumatologist, the neurologist, the dermatologist to get along with and to use the resources of the oncologist or hematologist, everybody's bumping into trouble. My biggest issue is manufacturing capacity. I love the question. I love where we are. I don't expect we're going to turn away patients. Everybody who knows us knows that we have cohorts of six patients in each of the subtypes of each disease that will permit us to then talk with FDA about the cohort. After each cohort of six is filled, we have a very large expansion cohort opportunity that was already built into the protocols but not discussed publicly for each of these cohorts to put as many new patients as we want into each of the indications. Because collecting more safety data is always a good thing. We have that opportunity.
We're using it in some of the indications already. We are looking forward to treating as many patients as we can as soon as we can.
Any sense for when we could get the next update?
I think that the next update is probably going to be the results of our discussion with FDA.
Got it. Maybe diving into that, you've said you're going to meet with the FDA at some point during the first half of the year. What are the key elements of the design of a pivotal program on which you're seeking feedback?
Similar to our going-in clinical strategy, we were the only company that took the pain to have a separate IND in every indication. Others sought to gain speed by having basket trials. There were a lot of reasons why we filed individual INDs for every indication. Similar to the early days of the initiation of our clinical program, I'm going to be a little bit nondescript in the details. We set up these INDs separately so that we could plug in, not start new phase three trials, but plug in a phase three program into the existing 10 or 15 sites that are enrolling already for each indication. The idea is save four months, save five months at every possible step to launch and be able to leverage the phase one two data directly into a phase three program.
The design of each phase three program, when you look at what others have done in the field already, it's our understanding from public statements that there's a 120-person lupus trial that is ongoing, largely in Europe, a few sites in the U.S., looking to prove CD19 CAR-T is effective in lupus and safe. I don't think it's outrageous to expect that you need at least 100 patients' worth of safety data in order to get a drug approved in this space. We've always said that part of our clinical trial design was for each IND to have the identical dose, the identical manner of safety data collection, and to use all of the indications, all of the patients to inform the safety of each indication.
If you think that through, if I need a minimum of 100 patients in lupus to have enough safety data, the question that we asked FDA a long time ago is, what if we had 30 or 40, 50 patients' worth of lupus data, but we had on top of that another 100 patients' worth of autoimmune patient data, same dose, same form of collecting data, same preconditioning regimen, very systematically done, would that be sufficient? The data, of course, are going to tell us whether that would be sufficient. It was a viable alternative to enrolling a lot of patients in every one of our 11 subcohorts, I think is the right number that we have ongoing right now. That approach allows you to then calculate what is the size of my trial based on the need to prove efficacy.
When you're proving efficacy of a drug that can get you off of all your medicines and give you a complete response versus any standard of care that's out there in any of the diseases we treat today, the numbers are not very big. That is the construct of thought that we've gone to FDA with. No new phase three trials, rather phase three cohorts in our existing trials, save time, get it up and running quickly. Number two, size the trials in order to prove efficacy and support safety with the complement being all patients treated with rese-cel at that dose across the entire program. At the pace we're going with, as of today, 31 enrolled, we historically recently have said we see enrollment currently since October, November at about one per week.
Even if we're only at that level, by the end of this year, we're approaching 100 patients. We're thinking that our strategy is differentiated. It is rapid. It's going to allow for very clear efficacy and safety signals for physicians to know what they're getting, for patients to know what they're getting when they seek to use rese-cel.
It sounds like you think single-arm trials will be sufficient.
I think FDA is open to the idea of single-arm trials when what we're doing is unheard of. Just take a step back. Forget the logistics and autologous and all the beliefs and misbeliefs and misunderstandings about the different modalities. Imagine that somebody came to you and said, not in one, not in some, but in nearly every patient that's treated, we can take them off of the two to eight medicines they have been on the day that you get treated, and you can go home and never think about your disease again. You have lupus, lupus nephritis. You have scleroderma. You have myositis. You have pemphigus. You have myasthenia gravis. You have MS. Whatever. It's just completely compelling. To us, times have never been better. We don't like the valuation that investors have put on the company currently. That's going to resolve itself.
We don't have any problem that clinical data, regulatory clarity, and competitive data, which we can't wait to see more of, comes out. I see how little time we have left. I do want to say one other thing. You may have other questions as well. What I want to say is there is a publication that's going to be submitted this month, and it'll come out subsequently, I don't know how fast, from an academic leader in the field that looks at the critical tissue-based B cell depletion data with a full dose of BLINCYTO, not the small dose that was used in the New England Journal that received fanfare that bispecifics would do everything for all patients all the time, even though this did nothing other than 12 weeks of ongoing therapy followed by salvage therapy. They took full-dose BLINCYTO, and they did tissue biopsies.
They compared that to a monoclonal CD20 at full dose as currently approved for cancer and did tissue biopsies. They compared that to 15 patients with autologous CAR-T. The bispecifics and the antibodies at full dose do not clear the tissues. The autologous in every patient clears the tissues. I think we can't frankly wait for the external environment to clear because curing patients of their disease, at least complete responses that seem durable, is just life-changing for all those patients and the physicians who treat them.
That's great. My last question was going to be on competition. I think that sums it up nicely. Thank you for a very interesting discussion.
Thank you.