Studio, we're going to start this fantastic session. My name is Kelly Xu, one of the biotech analysts here at Jefferies. For this session, we're going to talk about cell therapy, T- cell engagers, and other emerging novel modalities, including VivoCar, AlloCar, and their future tackling autoimmune diseases. We are so thrilled to have three great panelists: Stephen from Cabaletta, CEO; Christian from Autolus, CEO; and Jeff from Cullinan, Chief Medical Officer. Thank you so much for joining us. Maybe to start, why don't you give us an introduction of your unique platform and how does it tackle initially oncology diseases and now actually some of you shifting to autoimmune diseases as well? Maybe we start with Jeff first.
Sure. At Cullinan, we're interested in exploring the potential of T- cell engagers as a pharmacologic way of redirecting T cells to deplete aberrant immune system cells responsible for autoimmune diseases, both B cells being the primary target. I think speaking about the analogy from oncology, in oncology, as my colleagues will certainly know, T- cell engagers are a competing modality with CAR-T and in many clinical instances provide very similar clinical outcomes. Follicular lymphoma, CAR-T and T- cell engagers really do achieve similar rates of overall and complete response, durability of response. We believe that there is the potential for bringing that same potent T- cell redirecting therapy to patients outside of specialty centers, ideally to community-based centers, likely outpatient treatment as a way of bringing this potent therapy to patients where they live and really broadening the potential for patients with autoimmune disease.
Question?
Yeah, so Christian Itin with Cullinan Therapeutics. Our lead asset is a CD19 CAR-T, an autologous product that we have launched at the beginning of the year. We got approval at the end of last year for patients with acute lymphoblastic leukemia. What we're seeing with the product is a very unusual combination of a very good safety, very well manageable safety profile together with an exceptional level of activity and an ability to induce long-term outcomes even in patients with very advanced disease. We're going to have an update at that actually at EHA with a long-term follow-up. It is quite remarkable to see the ability that you actually can get patients that up to now we could not get into long-term remissions, actually achieve long-term remissions.
That is an indication where in my past I have developed T- cell engagers, the first category of them in the same indication. What we could see is we could see very high levels of activity. We could never quite make it sustained in the advanced patients. We could see actually very good outcomes in early stage of the disease where there are quite remarkable outcomes that can be achieved. We are very excited about this program because it basically combines an extreme level of activity with a very good safety profile. Obviously, it is an approved product. We have a commercial manufacturing base we are launching. To actually now take this into the autoimmune space where we believe those features do actually carry and I think are important.
Lastly, Stephen.
Kelly, thanks for having us. It was a really important discussion. I'm actually hoping that all three of us are wildly successful because for too long, too many patients with autoimmune disease have silently suffered with the full complement of available therapies. They live with their disease. They define themselves as patients who have to take these medicines chronically. Between us, I think we're going to have something to offer for every patient out there with an autoimmune disease where interruption of the B cell compartment can actually deliver meaningful clinical advances. Cabaletta was never an oncology company and only formed in order to develop cellular therapy for autoimmune patients on the belief that we could discover and develop the first cellular therapies that could be curative for patients with autoimmune diseases. Been doing that since 2017.
In 2022, we in-licensed the binder on our lead product, Rese-cel, which is entering phase three trials now for myositis. We recently announced agreement with FDA on the first of 12 or 13 cohorts in six different INDs. We're running trials in approximately 65 clinical sites around the world. In each of the six trials with cohorts within those trials, we use the same drug, the same dose, and therefore we have the same safety data able to be applied to each of the efficacy profiles that we are developing in our phase three program. Those indications initially will be myositis followed by either lupus, lupus nephritis, or scleroderma, myasthenia gravis, multiple sclerosis, and pemphigus vulgaris. What we're seeing with our data is in a weight-adjusted dosing regimen, the only company in the industry that is following the SHED protocol to do that.
We think that is crucially important. As you will see in our data at EULAR, we have three oral presentations, one in lupus, one in myositis, one in scleroderma. We believe safety is going to be the key differentiator because all therapies seem to provide some amount of efficacy in this very high unmet need of autoimmune disease. The choice of product and the choice of modality is as much as anything going to be driven by safety. We look forward to presenting that data.
Thank you all for setting the stage of each program. I think one key question here is first, I think everyone probably agreed that we are still in very early stage for this very exciting space. Curious if you think 12 months ago, based on the cumulative data from cell therapy programs and also T- cell engagers, how's your view changed as of today compared to last year based on the clinical discoveries? Also, if we think about oncology, multiple modalities like CAR-T, T- cell engagers, and antibodies have coexisted in the market. How do you envision the autoimmune space going to evolve with multiple modalities? Either coexist or going to have a fierce competition? Maybe again, start from Jeff.
Sure. I think at this time last year, there hadn't really been data yet for T- cell engagers. The first in autoimmune disease, the first paper, a small series of RA patients treated off-label with blinatumomab showed that the patients achieved not only peripheral blood B cell depletion, but also dramatic improvement in their symptoms. Now, since that time, there have been subsequent reports of patients treated for other diseases, systemic sclerosis, inflammatory myositis, and other targets, BCMA, tocilizumab. A series of patients were published later in the year in the New England Journal of Medicine. What they showed was that there is dramatic potential for disease-modifying therapeutic benefit in patients who are treated with T- cell engagers that deplete B cells quite deeply.
I think the things that we still have to learn are how best to employ these drugs, what's the optimal dose, what's the optimal schedule, what's the optimal durability, pardon me, the duration of therapy that will achieve durable responses. These are things that are fundamental questions for any modality in its infancy. We really have seen only these academic case reports so far. We haven't yet seen data from thoughtfully developed sponsored research where these very important questions of dose and schedule are explored with the intention of bringing this therapy ultimately to patients.
Christian, I love your view given that you also have a same product launched in oncology.
Yeah, I think what was interesting during the course of last year is that when you looked at the totality of the data across all programs, it's actually the consistency and the reproducibility of the outcomes. That I think was the most important outcome that I think we had last year. Individually, the programs had a limited amount of data, but if you take it together, the features that we're seeing are actually quite similar. There's some early differentiation that we're starting to see on safety, which I think was probably a bit earlier than I had expected. I had expected some of those to come out of larger trials. It looks like there are differences between the programs, and that's going to be interesting going forward.
What is fundamental, I think, is the opportunity here to really have a set of approaches that give you an ability to fundamentally change the outcome for these patients. I mean, this is a set of diseases that actually haven't seen progress in a long, long period of time. To see this change has been really dramatic. When you have a lot of those examples, we have some of those examples when you have patients who've basically been dealing with these types of diseases for 20-25 years, and they've gone through the whole gamut of therapeutic options that they could have, and they're not getting better. It just gradually gets worse. You see that, and you see those patients go on one of our therapies and basically within a matter of weeks are free of symptoms that they can experience.
They may still have tissue damage. They may still have issues with kidneys, et cetera, but it's not sensible. What they can sense from that experience, it looks like the disease is gone. That is a remarkable transition. It is a fantastic opportunity. This is also when we look at these diseases, there are quite a range in terms of the level of intensity that you see. You have patients who have relatively moderate levels of events that they actually go through. You have basically going to extended levels, more significant forms to very severe forms of the respective disease. It is quite a continuum that you see go through. You do see different modalities that actually work at these various places.
I think what we'll see with a lot of the modalities that you mentioned in the incoming remarks is that I think they're going to have the right sweet spot along that continuity of severity where I think you're going to find those particular approaches to be very well suited and sort of an appropriate level of intervention. There is also, if you look across the range of autoimmune diseases, you start with the classical rheumatoid arthritis on sort of the lower end of the range to progressive MS on the other end of the range. There is quite a change also and a difference in terms of the intensity that you see and the medical need that goes along with that. That also is an element where I think we see differentiation in the various approaches where these exact sweet spots will be.
Fantastic. Maybe I can insert one more question built on top of that. Do you envision biomarkers to be picked up and to identify the most suitable patients for different modalities?
I think it's important to obviously follow these patients and follow biomarkers. There's a lot to be learned. I think where we are in the field is that collectively we have a good range of data that I think is quite convincing that we have a significant contribution to make. Individually, the data sets are still small. I think there's a lot to learn. I think that's one of the key drivers for looking at quite a range of biomarkers to frankly learn about the disease and see to what extent we can actually enrich patients that are particularly in need and also where we might have the biggest impact.
Fantastic. Maybe for Stephen, I will give you a question. Actually, we hear a lot of debates. There are debates around the efficacy for cell therapy versus CAR-T versus T- cell engagers that the gap between these two modalities in autoimmune may be smaller compared to oncology indications. It is actually a better winning case to build for T- cell engagers. Do you agree or disagree?
Our view, my view of T- cell engagers and cellular therapy, particularly autologous CAR-T, where you can't escape the efficacy almost no matter where it's administered or at what dose globally, not just our data. Our view has always been that rituximab is interesting, but T- cell engagers are going to fundamentally change the landscape of where you want to start patients who have serious disease and who don't want to stay on steroids that are higher than physiologic doses. I think it makes perfect sense that every pharmaceutical company is running after the bispecific opportunity. I think they're going to have an annual cyclic therapy in most patients. Rituximab, surprisingly, literature reflects 10% of the patients with pemphigus who are treated with rituximab plus the usual complement of 3 grams of steroid over the first year, 10% of them never need another therapy.
In a pharmaceutical sense, they're cured because they don't need therapy again. I think bispecifics are going to do better than that. Maybe 20, maybe 25, maybe 30. It doesn't matter. These patients have no choices today. Remember that CAR-T in cancer, if all we do is look at that price point, every 2,000 patients is a $1 billion of revenue. Pricing in autoimmunity may well be different from cancer because in the case of, for example, myositis, 20,000 patients in the United States of the 80,000 who have myositis, and for context, that compares to the 110,000 who have lupus, where you've got 35 cell therapies competing. In myositis, you have 80,000 patients. 20,000 of them are on IVIG every month. That costs the system $450,000-$500,000 per year.
The opportunity to go from IVIG to a defining curative therapy, one that can reliably and durably eliminate the need for medications and eliminate the symptoms for the patient, as you were discussing earlier, that's just a fundamental transformative experience. I don't know of any other drug in our industry that can do this across the portfolio of diseases that we're talking about. It becomes truly transformative to the patients. We've treated patients, and I'll limit my comments to those we've presented publicly, who have begged us to be able to write their attestation to get out there and start talking about their world experience, their life experience with the drug. I think bispecifics, and we've always thought bispecifics are going to have a very important role in the future treatment of autoimmune disease. It's been a little tough so far to find the efficacy.
I do not have any doubt that others will find it in the future. In the past, just to review, low-dose blinatumomab used in the RA trial published in the New England Journal was criticized for being too low dose. Professor Schett, and with his permission, I share with you the following information. At EULAR, he will present data showing that full-dose blinatumomab does not clear lymph nodes in autoimmune patients as well as autologous CAR-T does. He will publish a paper to that extent subsequently, which I believe has already been submitted. I think that we need to find the needle in the haystack when it comes to the Goldilocks, because IgM was clearly too big of a molecule. Blinatumomab is too small. There has got to be something out there that can deliver on the promise that CAR-T autologous is already delivering on.
Yeah, maybe just to answer that. When you speak about full-dose blinatumomab, the schedule that they've been using at Erlangen is still abbreviated. It's 96 hours and repeated. It's not a 28-day continuous infusion of blinatumomab. Further, the dose that was efficacious in lymphoma with blinatumomab, and Christian probably knows this better than I do, was twice the approved dose for ALL. It was 60 micrograms. In long-term follow-up of patients treated with blinatumomab, a paper that appeared in Blood Advances in 2019, there are patients who were still alive seven years after treatment with blinatumomab who were treated with diffuse large B cell lymphoma. Really, the only indication for CAR-T in oncology other than ALL where a substantial fraction of patients are cured by CAR-T.
In most other indications in non-Hodgkin's lymphoma, T- cell engagers appropriately dosed at an optimal dose and schedule achieve equivalent outcomes as CAR-T. I think it is a bit premature to say that there's no evidence of durable effect. In the same institution, they'll share data for a larger group of patients, now 24 that they've treated with T- cell engagers. Eight of 10 patients treated with the BCMA-directed T- cell engager teclistamab, given at the dose and schedule approved for multiple myeloma, were in remission and did not require treatment at six months beyond therapy and ongoing. I think it's a little premature to draw the conclusions that you are. Questions of molecular size and blinatumomab being too small, I just do not think there's data to support that contention.
We do not disagree at all. One day, there will be an appropriately dosed bispecific or trispecific that will demonstrate three, five years of durability and will eventually come to be developed. In the meantime, the autologous CAR-T products, in our view, will be marketed either in 2027 or 2028. We have said publicly we are filing our first BLA in 2027. We will start taking patients out of the market in myositis, in scleroderma, in each of the indications that we march through. By the time we have the in vivo and/or the bispecific products that are properly dosed with sufficient safety, with sufficient durability demonstrated, it will be a different marketplace. There are plenty of very large market opportunities for bispecifics. As I said, I think it is a terrific breakthrough. It is just not there yet. There is abundant evidence, not our product, but autologous CAR-T in general works.
We can be as critical as we want about it and talk about how it has all the disadvantages of it takes too long and this and that. Meanwhile, every investigator that we want to sign up is signing up. All the patients are showing up in numbers that are far exceeding our expectations. The reality is patients need therapy now, and more patients are going to need it in the future. The more that we, the three of us, can be successful, the better off the industry and for sure the patients will be.
On that point, we can strenuously agree.
We loved your insightful discussion. Maybe a follow-up question for Jeff is, so autoimmune disease is heterogeneous, involving different pathologies and severity levels. How are you thinking about tailoring treatment strategies for different patient subtypes? Maybe, for example, different targeting strategy. Do we really need dual targeting? Is CD19 better or BCMA better? Also, maybe the tailored question to you is, when we think about T- cell engagers, how do we optimize dosing to actually have a good balance about the treatment duration given this is a chronic disease?
Yeah, so a couple of points there. The first one maybe is really focused on target. I think the CAR-T data for CD19 has really demonstrated that profound depletion of CD19 expressing B cells can affect this immune reset that's so very really remarkable. I think the data to date also suggests that there are patients who relapse after CD19-directed therapy, even though they've had demonstrably the depth of B cell depletion that's thought necessary for immune reset. There are patients who have pathologic autoantibodies that persist, which are likely produced by cells of the plasma cell lineage that are not eradicated by CD19-directed therapy. What does that suggest? It suggests that there may be patients who require BCMA salvage or some plasma cell-directed therapy for salvage.
There may also be diseases where long-lived plasma cells, in particular the ones responsible for maintaining humoral memory responses, may need to be depleted in order to adequately treat that patient and allow them to be free of ongoing therapy. We're still learning. There are some where the pathophysiology fits. Diseases like MG, for instance, we know that anti-acetylcholinesterase antibodies are produced by long-lived plasma cells. That's an important potential proof point. There are BCMA-directed therapies there. I think, as we talked about biomarkers, this is the kind of data that will emerge from reverse translation from the ongoing CD19 and BCMA studies that will allow us to better tease out which patients are most appropriate.
To supplement what you're saying, out of the 150 patients reported in the literature treated with autologous CAR-T at any venue in the world, as of approximately, I think December is when we did this analysis, there were exactly two patients who did not have a fulsome response. In fact, one of them never responded. It was a patient who was underdosed with another company's product in a dose-finding study where they were purposely underdosed as they were rising in dose. The patient never responded and did not have a breakthrough per se. They just never responded due to dose. The second case was a patient of Professor Shed who had myositis. That patient was fine for 18 months. He had complicated myositis symptoms, had some interstitial lung disease as well as muscle weakness.
Eighteen months in, developed a little bit of muscle weakness and always had, to your point, persistent anti-Jo-1 antibodies. They never cleared. Professor Shed tried to give a second dose of CD19 CAR-T. Because it's a murine CAR-T, there was no rise in the T cells. The pharmacokinetics reflected that the T cells never engaged and never did anything. He also gave preconditioning in that patient, as you would routinely do. There were no changes in the symptoms, providing some of the first evidence that preconditioning in and of itself has no impact whatsoever on myositis in the treatment regimen given with autologous CAR-T. More importantly, he went on to treat with daratumumab. The patient's symptoms resolved. Stopped the daratumumab, the patient's symptoms came back. Administered on a compassionate use basis, the BCMA CAR from Bristol Myers Squibb that they kindly provided to him.
The patient has now been six months or more disease-free and antibody-free. There are going to be, and we expect, and I urge you to take a look at our data at EULAR, we expect 10%-15% of patients are going to ultimately require the treatment of long-lived plasma cell-derived antibodies that in some patients are going to cause future disease flares. In those patients, it seems logical that a BCMA CAR is a good approach. Treating with BCMA upfront, in our view, is not a reasonable thing to do.
To wipe out all of the immunity in this room, including your childhood vaccines and your exposures to all the infectious diseases you've been exposed to over a lifetime in order to alleviate your autoimmune disease seems to be a little too drastic for all of you in order to have 10% of you not have a recurrence of your clinical disease at some point. We see it as CD19 first, BCMA in those who break through second. To your point further, I do agree with you that in myasthenia gravis and perhaps some other diseases, the rate of BCMA-derived, or I should say plasma cell-derived antibodies, is probably going to vary and be higher in maybe in myasthenia gravis as well.
Yeah. Great. We would love Christian's perspective as well as Autolus has approved the CD19 CAR and also BCMA CAR in the pipeline relatively under the radar. What are your thoughts on the different targeting strategy?
I think the remarkable thing about the work that was done in Erlangen was the realization that the producer cells for the antibodies were CD19 positive. That was the thing that actually we did not know. When we go back to T- cell engagers to blinatumomab, we wrote actually in our original patent application for use for autoimmune disease. We are talking late 1990s. That was obvious. It was something that made sense. What we did not know is that indeed the producer cells would actually be, to a large extent, CD19 positive. That was the surprising finding. That opened up this opportunity to actually, as we all do, using T cells either with embedded receptors, which is the autologous CARs, or a soluble receptor, which is what the T- cell engagers are. Ultimately, it is the T cells doing the job.
We're redirecting them with those different types of tools. It gives us an ability to actually capture the compartment from the very early stage of B cell development through all memory stages of B cells, including the plasma blasts, which are the cells that actually are now, as we know, for many of these patients, the drivers for the expression of autoreactive antibodies. It allows us to get out that compartment without, to your point, not actually eliminating all immunity at the same time. I think that's probably one of the key things. The way we think about it is very similar to, I think, all of us, I think, look at this in the same way, is that the first thing you want to do is you want to take out the CD19 compartment.
If necessary, you could actually go broader than that. It is a tricky proposition when you think about an autoimmune patient having to re-immunize the autoimmune patient after your therapy. That is not a comfortable thought. I think that is something that we should avoid if we can.
Fantastic. Maybe I can build on a question on that. How do you see now the clinical trial progress? Initially, we heard cell therapy programs have some challenge to enroll patients. How do you feel now after 12 months? Maybe also a question to Jeff for engagers. Do you feel physicians, when they make a decision to put a patient on trial, on engager trials, the patient baseline might be slightly different from CAR-T trials? Maybe start from Christian first.
Yeah. I think one of the important things that we haven't talked about is obviously that the outcome of these autoimmune diseases is tissue damage. It's organ damage. One of the challenges is that obviously there is an inflammatory process that induces the damage. There is a point where there's so much damage actually already existing that just taking down the inflammatory process will not actually revert these organs back to normal. You have to be very thoughtful about kind of what's sort of the bracket in terms of disease progression that you want to include in your trial because you want to maximize the outcome. Clearly, if you have patients that have slide eye scores of 30 plus, et cetera, you will not be able to get them back and have their kidneys or other organs recover in full.
If you actually choose kind of a reasonable stage within the progression of the disease, there is actually an ability to see a lot of these patients revert to a remarkable extent. Many of them actually fully revert. I think that's one of the important elements to do. In terms of the enrollment, one of the important things is that today, for the most part, the CAR-T is delivered by a hematoncologist. What you have to do is you have to actually create pairs between hematoncologists and rheumatologists to actually be able to treat these patients. That's clearly very, very important. We've seen that in our own experience quite extensively.
It allows us to obviously leverage our commercial presence as well across the U.S. and from a clinical trial perspective in other jurisdictions as well to leverage that presence in the centers and the experience with the product to then actually do the matching with the rheumatologist. I think that pairing is very important given that it is a very different modality for a rheumatologist to actually work with.
Just a quick comment. Within Cabaletta, all of our six INDs and all of our trials, any patient with any severity of disease will be enrolled if they have failed two or more therapies. In some trials, it's three or more therapies without hesitation. We do not believe there's a window of opportunity. We're treating everybody and learning as we go to see who responds. Again, I would urge you to see our data to understand what I'm trying to say.
Yeah, I think the situation is not too different for T- cell engagers. I think understanding there are patients who have fixed defects that cannot be reversed by inhibiting inflammation is really important if your interest is to show evidence for efficacy in an early phase trial. I think on the other end of the extreme, enrolling patients who are minimally affected or have very low symptom scores limits your ability to discriminate whether or not you're having therapeutic benefit. There's a lot of placebo effect in many immunology autoimmune disease trials. If you're pursuing monotherapy in dose escalation, it's important that you have some sense on whether or not there's therapeutic benefit along the way. There is a sweet spot, I think, in the patients that are affected. We've had really enthusiastic uptake of our trial program. We've got very engaged investigators.
I think for investigators, we hear that they are interested in something that's better than their monoclonal antibodies, but still something that they think is within their wheelhouse. As a consequence, our investigators are primarily rheumatologists, not hematologists, oncologists. In some senses, they may involve care on an inpatient service managed by a hematologist. In general, these patients are managed primarily by a rheumatologist in a non-heme-onc setting, which I think is sort of indicative of where we see the place in therapy down the line.
Fantastic. Maybe also to Jeff, if we still early days, but if we have to make a guess, what kind of regulatory paths we can think of for engagers for autoimmune?
I think my colleagues for paving the way because I think for CAR-T, the regulatory path has looked different than the one that's typically presented in the divisions of the FDA that regulate drugs. There's been a lot so far, it would seem, greater regulatory latitude. I think the ultimate path, though, will depend on the magnitude of the therapeutic benefit and the risk-benefit for therapy. Single-arm trials make sense when the therapeutic benefit is clear, where the safety is acceptable, and where it would ultimately be somewhat unethical to randomize patients to inferior therapy or placebo. I think that's probably a big part of why you've been successful.
Yeah. We announced, for those who do not know, a couple of weeks ago, we are 15 patients away from a BLA filing in myositis. And we have 100 patients' worth of safety data required along with that filing from anywhere in our clinical program. The reason that we were able to get that alignment was our safety data. If we had safety issues, and I again urge you to look at the EULAR oral presentation data that will be out next month.