Arlo-cel (arlocabtagene autoleucel)

There’s a lot of therapies for myeloma coming out and that are in research right now. And one of them is arlo-cel. So this is actually a GPRC5D directed CAR-T. So a different target than what all our other CAR-Ts have been on BCMA. And it's similar to what talquetamab goes after. And so what's really cool about this, though? It's the one and done rather than a bispecific where you keep getting it. And so the side effects that we were worried about because again, GPRC5D is on the skin and nails and tongue, the side effects of the taste loss or the skin and nail issues can happen. But it's a fewer number of patients compared to talquetamab that get it? And when they get it, it happens for the first three, four weeks and then usually tapers off, because you're not getting you're not hitting that target again and again. Right. Is a one and done CAR-T. And you're done. And so it's been pretty cool to see that the side effect profile is actually different long term. The response rates have been in the 90% high 80s, 90%, and it was 79% for patients who already had a prior BCMA therapy. So, you know, we talk about vulnerable patient populations. And back in the day, we said the triple class exposed patients, those who had CD38, PIs or proteasome inhibitors and IMiDs, you know, like Revlimid or Pomalyst, that those are the patients that are the most vulnerable. And that's where BCMA came in initially. And now it's even, you know, right after a second line that you can get BCMA therapy because it became such a big target. And so but now post BCMA, it's quad exposed patients. And so that's even a bigger risk group. And so GPRC5D at least looks like it, it helps 79% of those patients, which is pretty impressive. In terms of we don't have the longer term PFS data. This was just the phase one study that's been presented. But right now, the phase two, the pivotal phase two study is being done. And that will be for hopefully, FDA approval. So we're hoping the initial cohort is going to be enrolled soon. There's gonna be another cohort open up at a lower dose level. And the reason is that, they had already picked a lower dose level to go into the phase two dosing, because of some of the side effects. And so CAR-T side effects, CRS,neurotoxicity, they're very similar to what the BCMA CAR-Ts do. So most people patients will get CRS but just fever. So grade one. Few patients will get grade two. And neurotoxicity is pretty negligible. Most patients, if they get anything it's grade one. But it's really rare to ever see anything higher than that. But there was a signal for about 10% of patients getting a different kind of neurotoxicity called cerebellar toxicity. And this is something where it affects the the cerebellum and it can cause what's called ataxia. So balance issues that people can't walk or they get really, really dizzy. And I mean, to the point where some patients were wheelchair bound because they just couldn't function. So these are side effects that we're not okay with. Just like with Parkinsonism that we had with cilta-cel that we learned when you do less, you know, we have less myeloma and early line, we don't see it as much anymore. You know, the idea was here that in late line, when patients have already had BCMA therapies, you're not going to be able to do bridging as well. Because you can't use the same target. So even though we have talquetamab can't use that because that could affect the actual outcome of the CAR-T if it doesn't go after the GPRC5D. So for patients that have a lot of disease, we worry that they could get the side effects. So the only other thing you could do is decrease the dose of the cells. Right. Because again, how much cells you have depends on how high they go. And in their early studies, the 75 actually looked really good too, like same level of response rate but zero of the neurotoxicity. So now they're opening another cohort that's going to allow more patients to come on. But at that lower dose. And then we'll able to look at both. So it's really exciting. We're hoping that we'll have another CAR-T approved in the next couple of years based on the study. And again, right now we say it's after BCMA, but just because that's how it was found, like that's how we found it. But in the future, it could be that you can get GPRC5D first and then a BCMA, depending on how these studies, come out. And then there's a lot of studies that are actually being done looking at both together. So you know, our idea for combining which is in all myeloma but different cells have different flags. So BCMA can be really big. A lot of BCMA in one myeloma cell and a different clone could have just a little bit of BCMA, or that could be a clone that has no BCMA, and we don't know how to test that in patients as of right now. But GPRC5D is the same. So GPRC5D could be a lot on one cell, not as much in the other. And maybe not at all in one. So we think that it overlaps enough that one will have a lot of BCMA and maybe less GPRC5D and the one that doesn't have GPRC5D to you hopefully will help you. And again, the more targets you hit, the more likely you're hitting more of those clones. So the goal is that if we do this, we're hoping we can increase that cure fraction, from 33% in, you know, the late line cilta-cel to maybe higher, in late line patients in the early line because T cells are better than myeloma resistant. I mean, our goal is to get to 100% eventually. So all these studies help us learn. How do we help, you know, hit that myeloma to where we can kill more of that myeloma so that hopefully patients stay in remission a lot longer.