Clinical case studies have sparked significant interest in the use of CAR-T for autoimmune disorders, potentially expanding CAR-Ts’ utility beyond oncology. In this podcast episode of Biotech Breakthroughs, equity research analyst Sami Corwin offers an overview of the known biological underpinnings of autoimmunity and rationale for using CAR-T as a therapeutic, breaks down the CAR-T cell therapy competitive landscape and analyzes the potential market opportunity for these therapies.

Podcast Transcript

You are listening to Biotech Breakthroughs, a new podcast series from the William Blair equity research group that explores the news and trends shaping the biotech industry.

Tim Lugo
Welcome back for another episode of Biotech Breakthroughs. I'm Tim Lugo, head of biotech equity research at William Blair. And I'm joined by Sami Corwin, another analyst here on the biotech team and we're here to discuss CAR-T [Chimeric antigen receptor-T] therapy for autoimmune disease. Sami recently put out a piece on the topic, and I'm happy she is here to join us as I want to dig into it more in podcast form. So, Sami, thank you for joining us.

00:48 - 00:49
Sami Corwin
Thanks for having me, Tim.

00:49 - 01:14
Tim L
No problem at all. Maybe we should just start out with can you give us a bit of background as to what has led to CAR-T excitement for use in autoimmune disorders? After reading your report, I realize there's been some really impressive data recently, so I'd love for you to just frame how we've gotten to this point in time.

01:14 - 01:45
Sami C
Yeah, absolutely. I think it would also be helpful to provide some context more broadly as to how rapidly the CAR-T space as a whole has developed. The first IND [investigational new drug] for a CAR-T for Oncology was filed in 2014, I believe, with the first being approved in 2017. If you think about how rapidly the space has evolved, these therapies have only really been in the clinic for about 10 years with some only being approved for five.

So, following those approvals in 2017, there were some preclinical studies showing that CAR-T could be used in mouse models to eradicate lupus. Shortly thereafter, in 2021, there was a case study published out of an academic center in Germany by a group led by Dr. Georg Schett in which he showed that the administration of CAR-T, the one that was commercially available for hematological malignancies, when administered to a patient with lupus nephritis, resulted in durable drug-free remission in that patient with improved clinical activity and a reduction in autoantibodies that drive that disease.

So that was really the catalyst, this case study publication in 2021 that led to so much excitement in the field. And that professor subsequently published a paper in 2022 that showed a replication of that effect in four additional lupus patients. It showed that this was not a one-off occurrence, that it was replicable, and that they were able to drive durable drug-free remission in multiple lupus patients.

So that got the field really excited and led to multiple companies then repurposing or developing cell therapies for the treatment of autoimmune diseases.

03:26 - 03:43
Tim L
So, it was the Schett data that really kicked off the excitement of CAR-T in the space and that he used CAR-T specifically for hematologic malignancies first. He was repurposing a cancer therapy first?

03:43 - 04:12
Sami C
Correct. He was repurposing a variation of an approved CAR-T for hematologic malignancies. So there had been clinical data kind of establishing it, showing its effect in the oncology setting, and he repurposed it for autoimmune diseases based on that thesis that if it could kill B-cells in the context of hematologic malignancies, why couldn't it kill B-cells in the context of an autoimmune disease?

04:12 - 04:32
Tim L
And we've obviously been targeting B-cells for a long time in oncology. I'd love to know, are these CAR-T still from the oncology space being taken into the autoimmune sector? Is there anything specific to autoimmune diseases: why you would use a different CAR-T?

04:32 - 04:56
Sami C
There are many companies who have repurposed their cell therapy, whether that be a CAR-T or a CAR-NK cell and repurposed it for use in the autoimmune setting. And it is advantageous when you think about it because they have some clinical data to support the underlying therapeutic activity and safety profile of those therapies before repurposing them for autoimmune diseases.

I think it remains to be seen just how exactly those safety profiles and therapeutic efficacy windows will really translate to the autoimmune setting but we have seen many companies take that approach.

05:12 - 05:29
Tim L
Remind me how effective the initial Schett data looked. I remember when I was looking over your report a few weeks ago, being a bit blown away by the lupus data, but remind us how severe are these patients and what kind of responses were they seeing?

05:29 - 06:02
Sami C
Yes. So these were extremely severe patients. I don't think this will be a treatment that's for all autoimmune disease patients. These lupus patients were bordering on renal failure. But as of two months ago, at the American College of Rheumatology Conference, Schett and his colleagues presented updated data from 15 patients across three autoimmune diseases, including lupus. All patients are now in a durable, drug-free remission, with the first patient treated, now having two and a half years of follow-up.

So really impressive results, especially considering how highly refractory this patient was. I believe they were refractory to seven different types of medications. So very impressive. Absolutely life changing.

06:20 - 06:52
Tim L
That's amazing. And they were previously kind of Rituxan failures or biologic failures before entering this study?

Sami C

Tim L
That's impressive. So taking the German data, can you update us to where we are in the States? I know after doing some marketing with you, there have been some questions around enrollment kind of correlated U.S. trials. Can you give us an update on what we expect over the next 12 months here in the U.S.?

06:52 - 07:20
Sami C
Yes. There are a number of companies that are now pursuing or advancing their CAR-T or CAR-NK candidates in the clinic for the treatment of several autoimmune diseases. The most popular being lupus nephritis so there's certainly some competition there regarding the enrollment of patients. We expect clinical data from a number of companies over this upcoming year. What will be particularly interesting is based on Schett's data, we expect that what these companies produce at three months will translate to what these patient’s clinical benefit will look like over the course of the next year as well. So that's something that's differentiated from the oncology space. I would expect data from the 20 early data sets three to six months likely from a handful of patients from each company.

I think there will also be nuances in the baseline patient characteristics. So, keeping an eye on that and looking at how that affects long-term clinical benefit will also be something we want to keep an eye on. It'll also be interesting to see if these companies are able to replicate the deep responses shown with Dr. Schett’s data. There are some questions as to given it was a single clinical trial site observation, will it be translatable in a multi-site setting?

08:25 - 08:41
Tim L
Anything specific to the CAR-T structure? You mentioned CAR-T and CAR-NK cells are being used here in the States. Is there anything specific to those structures or those constructs that would make them less effective or more effective?

08:42 - 09:08
Sami C
I think the jury's still out on that. There is some debate as to whether the use of alternative signaling domains within the CAR structure will lead to a better or more tolerable safety profile. I don't think we have enough clinical data there yet to support that argument one way or the other.

There's also an argument as to whether an NK cell may be more effective or maybe more appropriate than a T-cell. That argument stems from the fact that in the oncology setting CAR-NK cells have shown a more tolerable safety and response compared to CAR-T cells, and they are naturally allogeneic or off the shelf so they could be more readily available for patients. Currently, the data we've seen has only been from autologous-generated CAR-T cells.

09:34 - 09:46
Tim L
Okay. So that's interesting. It could be different from the oncology setting where off-the-shelf products could have a little bit more of a role than what we've seen already in oncology, right?

09:46 - 10:10
Sami C
Yes, absolutely. And there are some differences in how these cell therapies are going to act in the autoimmune space versus the oncology space. For example, in the oncology space, physicians really want to see deep and durable elimination of B-cells and persistence of the existing engineered cells or CAR-T cells, whereas that doesn't seem to be the case in the autoimmune setting.

We actually see a deep transient decrease in B-cells and then those B-cells seem to reemerge in the autoimmune setting around Day 100, with the CAR-T cells also being eliminated around that same timeframe. And that seems to be very important as well because we're seeing the reemergence of naive B-cells, which effectively shows that these patients have been cured.

The re-emergence of B-cells also decreases these patient’s risk for long-term infections, which is a risk associated with long-term B-cell aplasia.

10:44 - 10:55
Tim L
And maybe malignancy risk. Right? Isn't there malignancy risk associated with or at least questions around malignancy in the oncology space?

10:55 - 11:25
Sami C
There are some risks. There are some theoretical risks for secondary malignancies and part of that is due to the therapies given to the patients before treatment with the CAR-T cells. There's also a hypothetical risk of the way these CAR-T cells are created so the CAR could be inserted into the DNA of the T-cell, which could then cause that T-cell to become malignant.

That has been of increased interest to investors and the broader space recently following the FDA announcing that they are investigating some cases of T-cell lymphomas following the treatment of CAR-T in the oncology space. I don't think we've seen enough data right now to definitively establish that it was the insertion of a CAR driving those malignancy incidences.

It's absolutely a hypothetical risk, but I don't know how tangible it is at this time. But given that autoimmune patients are not going to imminently die in the next year compared to oncology patients, I think that the risk-benefit tolerance is slightly different and that's why we saw a lot of those autoimmune companies’ stocks get hit more severely after that FDA announcement compared to Oncology companies.

12:17 - 12:47
Tim L
Yeah, that makes that makes a ton of sense. There's also less CRS [Cytokine release syndrome] with these autoimmune parties. Can you dig into that a bit? Why is that the case? We've seen in the hematology setting, I'm always hearing patients, essentially going through a lot of suffering before the efficacy is apparent. But that's obviously a little different in the autoimmune world.

12:47 - 13:21
Sami C
Yeah, it's a good observation, Tim. It's hypothesized that in the oncology space, these malignant B-cells have a replication advantage and that is what in part is driving the high level of tumor burden. And so, there's a lot of these target cells. And when you put a CAR-T cell in a patient to fight this massive army of malignant B-cells, it's causing a dramatic increase in cytokines, which leads to a lot of these high-grade toxicities we're seeing.

So as you said, the high-grade CRS, the high-grade ICANS [immune effector cell-associated neurotoxicity syndrome], but compared to the autoimmune setting, these B-cells don't have a replication advantage so there are fewer of these target cells compared to the oncology setting. And so, it's hypothesized that that is in part what is driving this lower occurrence of toxicity, lower grade toxicity, and also, what's driving the decreased CAR-T persistence, because those target cells, there are fewer of them, and they're being eliminated much more rapidly.

I think that's also why it's a bit more challenging to accurately interpret and guess what the safety profile of a CAR-T in the oncology setting is going to look like when you put it in the autoimmune setting.

14:08 - 14:38
Tim L
I think that kind of leads into 2024 and really some clinical questions. As I was going through your report, I was wondering where these programs go clinically. Are they going to use placebo arms eventually, whether it be active arms? Will CD20 antibodies be necessary for a comparator? Can you talk a bit about where you think the kind of clinical development path is for a lot of these products?

14:38 - 15:09
Sami C
Absolutely. So in most early-stage CAR-T trials, I expect these to be single-arm trials. In most trials, patients will likely receive a standard preconditioning treatment of CyFlu [cyclophosphamide (Cy) and fludarabine (Flu)], followed by the administration of CAR-T cells. It is to be seen what a pivotal trial is going to look like. I would expect most of these patients have previously received Rituximab and other biologics.

The main question is how much of the flu part of that preconditioning regimen is contributing to the overall efficacy that we're seeing in the autoimmune setting? Most of these autoimmune patients have been previously exposed to cyclophosphamide or CY, but most of them haven't been exposed to fludarabine. So there is a lingering question that companies may have to run a placebo, put that in quotations, and controlled study against fludarabine and/or CyFlu alone compared to CyFlu plus the CAR-T to better hone in on the solitary benefit of the CAR-T therapy.

15:51 - 16:10
Tim L
Has CyFlu been used in the past for our autoimmune indications before we start using antibodies? And I guess how often is CyFlu used these days for these severe lupus patients or severe autoimmune patients?

16:10 - 16:30
Sami C
So CY is pretty standard in the treatment of a lot of these autoimmune patients and most of them will have been previously exposed to CY. Most of them have not been exposed to flu or fludarabine. So it's really whether fludarabine is driving some of this efficacy is an outstanding question in the space.

16:30 - 16:53
Tim L
And I also saw as I was going through the report, you mentioned some of these products have dual acting strategies for BCMA and CD20. Are we there yet, knowing kind of which strategy is more efficacious, or do you have a sense of where you think the market will be heading over the next few years?

16:53 - 17:19
Sami C
Yeah. So to date, we've only seen data from therapies targeting single antigen targets. We haven't seen any clinical data from these dual antigen targets in the context of autoimmune diseases, at least. We've seen them in the context of oncology. I think it's too early to say whether a dual-target approach may be beneficial for some autoimmune indications over others.

It will be kind of interesting to see if some of Schett's patients or some of these other companies’ patients eventually do relapse and to figure out what the driving factors are under that. And maybe there are some baseline characteristics or identifying factors that would suggest that those patients may be more amenable to a dual-targeted approach. But at this point in time, I think it's too early to say whether they'll be more efficacious, especially when looking at Schett’s data where we're seeing a bit of a ceiling effect, right? It seemed to work in all 15 of these patients with very robust responses. So how much better can you get than perfect?

18:02 - 18:12
Tim L
So it might not be completely perfect when it translates into more patients. That's kind of something we always see in biotech. Right?

Sami C

Tim L
And you're going back to the regional differences. So obviously the Schett lab in Germany has been leading the way with CAR-Ts in the autoimmune space. Seems like there's going to be a lot of U.S. trials reading out or beginning enrollment. And then we'll see more data over the next one to two years. As I was going through the report, I also saw a ton of Chinese studies.

Is that something where we're going to get some data from that region that is kind of not expected or, you know, someone shows up at a medical meeting with 50 patients of data? What do you think is going on there?

19:03 - 19:36
Sami C
China’s always had a heavy hand in the development of CAR-T. I think they have used it plentifully both in the oncology and autoimmune setting as well. It tends to be a mixed bag there. I think that we've seen some really incredible datasets come out of China that have translated into commercial products. I think we've also seen some data come from single clinical trial sites in China that maybe have not translated as those clinical trials have expanded to U.S. applications as well.

So I think, again, it's too early to say there might be some fantastic product out there, but I think it'll be really critical to have a multi-clinical trial site, clinical trial to really establish the efficacy and safety profile of these products.

19:52 - 20:04
Tim L
And so we're seeing really effective data on lupus. We're seeing really effective data in myositis. Where other areas do you think this is going to impact over the next few years?

20:04 - 20:35
Sami C
Yeah, we've seen some really great data in lupus, myositis, and scleroderma. We've also seen some emerging data in myasthenia gravis and we've heard a number of companies are also pursuing CAR-T in multiple sclerosis. We've noticed that companies have narrowed their focus and are slowly expanding into some larger populations that are maybe a bit more high risk, high reward, and aren't as clean cut, but for a much larger population.

So it really just speaks to the breadth of the opportunity here. Based on my conversations with the thought leaders and companies, that's just the tip of the iceberg it sounds like. Eventually, a lot of companies would like to go into rheumatoid arthritis or fibrosis and some of these nontraditional or larger indications.

20:57 - 21:23
Tim L
I saw Fab CAR mentioned in your report. And yeah, that seemed incredibly interesting. These fibrotic diseases have been very difficult to have effective therapies and so this will be incredibly interesting.

Well, I think that summarizes the report very well. So thanks for joining us. This has been awesome and it was great to dig into what is - how many pages was your report Sami?

Sami C
I think it was 80.

Tim L
A mere 80-page report. So was great to dig in. Some light reading. So if anybody who sees this wants some additional detail, there is plenty in the report. A lot to take in over the holidays. So, thanks for joining us, Sami, and we will be sure to hear from you more in 2024.

Sami C
Thanks, Tim.