Al Kim, MD, on New Therapeutic Targets in SLE

Dr Kim reviews the latest breakthroughs and coming advances in therapeutics for systemic lupus erythematosus that were discussed at ACR Convergence 2023.

Alfred Kim, MD, PhD, is an associate professor of medicine in the Division of Rheumatology at the Washington University of School of Medicine and director of the Lupus Center at Barnes Jewish Hospital in St. Louis, Missouri.

Hi, my name's Al Kim. I'm an adult rheumatologist at Barnes Jewish Hospital in St. Louis, Missouri. I'm also faculty at Washington School of Medicine in St. Louis and I also direct the Lupus Center there. And so I'm at ACR Convergence 2023 here in sunny San Diego and I'm going to provide a brief update on some of the new therapeutic targets that are being investigated for systemic lupus erythematosus. When I think about this particular space, 10 years ago there was not much to talk about if anything, but this year there are multiple different type of therapies that could be very effective for patients with lupus. And I think the first one everyone is talking about is CAR T-cell therapy. So CAR T-cells are essentially your own T-cells, but it is genetically engineered so that it only then recognizes a specific antigen first pioneered in an ecology space.

So basically the T cell will bind to the tumor and then kill the tumor. In autoimmunity, instead, it's going to bind to CD 19, which is expressed on B cells. So these CAR T cells basically bind to these B cells and kills it. So you may say, oh, this is very similar to rituximab. What's the difference? The real difference is that CAR T cells appear to have much deeper penetration of depleting B cells in tissues where rituximab does not appear to get into the tissues as well. So as a result with rituximab, you tend to have some residual B cells in inflamed organs and those end up repopulating the immune system. And as a result you flare. With CAR T cells, you get rid of these B cells that are pathogenic in the tissues and then the B cells that are coming back out are basically brand new. 

It's in a way kind of like resetting the immune system. So last year Georg Schett had presented 5 patients and this year now they have 15 patients that they've treated with CAR T-cell, 9 for systemic lupus and actually 3 for inflammatory myopathies and 4 with scleroderma. What's remarkable about this is that all of these patients have complete clinical response off of all medications. I think the first patient that he treated with lupus is might be over 3 years out and she remains flare free off of medications more than 3 years after getting CAR T-cells. Safety has always been an issue with CAR T cells, at least in the oncology space. There are 2 things that you worry about—CRS or cytokine release syndrome, and the other one's called ICANS, which is a neurologic inflammatory disorder. These were seen in the 15 patients, I believe 9 of the 15 had cytokine release syndrome, but they were very mild, only grade 1, grade 2 and only one person had ICANS.

And again, that was all pretty benign. So there are multiple companies pursuing CAR T cells and other types of CARs, CAR NK cells for example. So this is ready getting crowded, but I think this is really good for patients because this type of therapy was really aspirational. The results that we're getting are almost unbelievable. We'll see what pans out in the future, but I think this is going to be something we'll have to keep a very close eye on over the next probably 2 to 3 years and really see what ends up happening with long-term safety, long-term efficacy.

Now a competing in a way, a drug that is being investigated for lupus nephritis is called obinutuzumab, which is made by Genentech. So obinutuzumab is another anti CD 20 monoclonal antibody. So very similar to rituximab with a couple key differences. First, it's humanized, so the infusion type reactions, the anti-drug antibodies are going to be much less of an issue for a molecule like this. The second one is that it's a type 2 antibody. So basically what difference that makes is it lost a fuco near the hinge region of the antibody. This confers very different properties on that antibody, so it depletes B cells in a very different way, and in fact it may deplete B cells as well as a CAR T cell. So there has been quite a bit of work in lupus nephritis and some of the responses that we're seeing in lupus nephritis have been quite remarkable. We're seeing in terms of a complete renal response, which is really hard to get in general in lupus nephritis trials; we're getting close to 40% of people on obinutuzumab with standard care hitting complete renal response. This is only compared to 16% for just standard of care. And I think what's even more fascinating is that a new metric of outcome measure in lupus nephritis trials is what's called EGFR slope.

In other words, it's kind of a way to be able to describe the kind of accrual of damage within the kidney by estimating the glomerular filtration rate. The EGFR slope on people with obinutuzumab is completely flat once they get the drug. In other words, there's no loss of GFR, which is really one of the few things that— I can't think of another drug that's shown that type of stability, renal stability, B cells come back kind of late compared to rituximab. Remember in rituximab we start seeing B cells in the bloodstream about 6 months after getting rituximab. That's the reason why we typically redose every 6 months and obinutuzimab most people get B cells coming back around 15, 16, 17 months after getting obinutuzumab. So that may explain some of the durability of response, but at the same time this may also open up the possibility that you have more virus infections, for example, COVID-19 being the biggest concern here. So we'll see again how this all plays out. And I think in the lupus world, we're all thinking in the back of our minds CAR T cells that are targeting B cells or is it going to be obinutuzumab? Is there going to be a winner or are we going to use both in different types of patients? That's still to be seen.

The last drug I'm going to talk about is going to be deucravacitinib. So basically it is an oral pill that binds to a JAK called TYK2. The reason why this is important in lupus is that TYK2 is used by the interferon receptor, the type 1 interferon receptor. And as we know, the type 1 interferons really help trigger lupus flares in substantial in a majority of lupus patients. So there was some data presented last year showing that deucravacitinib was really effective against skin lupus, and this year they expanded on that original observation showing that multiple different types of lupus rashes all respond beautifully to deucra. And the other thing too is that they were able to confirm that people with high interferon activity at least measured in the bloodstream in the blood cells, responded best to deucra. And that makes a lot of sense. So this is in a way could potentially select out people with bad skin disease. And then you confirm with high interferon signatures, these are the people you may want to use deucra in.

You may also be well aware that we do have a FDA approved medication called anifrolumab or Saphnelo, which blocks the interferon receptor. Of course that's a biologic. So it'll be interesting to see moving forward if deucra does indeed confirm itself in the phase 3 studies. When would you use one or the other? One's a pill, one of them's a biologic. And so I think a lot of the—this is great for patients though, some patients don't want to have to remind themselves taking a pill every day, whereas some patients are thinking, I keep forgetting to take my meds like I do, and I may be wanting to get an infusion just to get it over with, right? So again, time will tell with this there are at least 15 other things I could be talking about. That's again, the most remarkable thing about lupus right now is there's incredible opportunity opportunities for these new therapies to kind of see how they're going to do in a lot of difficult to treat lupus patients. So that's going to be my summary for a ACR convergence 2023 in terms of kind of the new targets in lupus, and I appreciate your attention.