Cevostamab

Sovastomab is another great bispecific antibody that we have against a different antigen than BCMA, and it's FCRH5 that is an antigen that we see on myeloma cells as well as earlier precursors as in smoldering myeloma etc. but it's really just on myeloma and plasma cells, the normal plasma cells, and not really on any other cells anywhere else including B cells, which is pretty awesome so that we don't kill all the good cells along with everything else. And in terms of the drug, it's been again studied as a phase one trial where they've been increasing the dosing and patients who have had multiple refractory disease, so folks who have had pretty much all the other therapies that are available for myeloma were allowed to go on this, were eligible to go on to this trial, and there were actually multiple patients who had BCMA therapy before, almost a third of their patients, which was great to see, and penta refractory patients were in the 65 percent, so there are a lot more refractory patients on this trial. Sevastoma, being a bispecific antibody is off the shelf, so meaning that I can order it and give, as soon as it's FDA approved of course, so right now it's only on clinical trials, but even on trial, when we want it, we already have it in our refrigerators or in our chemo suites. I don't have to make the drug in real time, and so the difference is with CAR T cells. With auto CAR T cells right now, I have to collect someone's cells, send it off to a lab, put in new receptors, grow the cells, and then I get them back, and then we can give. Here, the drug's already made, so even though it's still a biologic, because it's taking that protein, it's going to take the T cells, put it next to the myeloma cell, activate those T cells so they can really kill them. It's a drug that we can just order, take, give. This bispecific antibody is actually given intravenously, so it's IV, and it's once every three weeks, which is actually nice. So we know that less often patients have to come in, quality of life usually is much better, so their study looked at giving a step-up dosing or a priming dosing, where you give a small dose first, and then you get a second dose that's still small, but a little bit bigger than the very first one, and that's given weekly in that first cycle of three weeks, and then the third week you get the full dose. And again, the last dose is what they were looking at to see if they could increase it and see which patients would do the best in terms of response with the least amount of toxicity. So the dosing is basically the first cycle. You get pre-meds, so you get the diphenhydramine and the acetaminophen and steroids, and you get a small dose on the first week. The second week you get a little bit bigger dose, but still small, and then the third week you get the full dose. And after that, it's every three weeks you're getting the full dose. And so the pre-medications really are to make sure that patients don't get infusion reactions, that some of these proteins and antibodies in general can cause. So diphenhydramine and acetaminophen, just to make sure we kind of calm all that down. And in the first cycle, actually first two cycles, the patients were given steroids as well to sort of decrease the risk of CRS, cytokine release syndrome. So just like the priming or the step-up dosing is to help slowly wake these T cells up so they don't just cause all the cytokine release while they're trying to kill the myeloma, the steroids are supposed to help decrease that as well. So they're sort of making the T cells a little bit more sleepy, while this drug is sort of making it activate more. But once you're done with those first two cycles, we stop the steroids, because now we want the T cells to work fully, but they already know how to work properly and to do it without causing too much toxicity at that point. So the savasana infusion is about four hours, so far I don't see it changed, so we'll see once it becomes FDA approved if that will change, but four hours every three weeks. So the nice thing is that once you're done with the first cycle, it can be done outpatient, but for the cycle one dose one, cycle one day one, you are in the hospital for about 72 hours just to monitor for those side effects like CRS and neurotoxicity that really we want to make sure we can treat right away so that we can abrogate anything before it gets to a much worse level. So the great thing with savasana is that the antigen is not on a lot of other targets in our body, so organs that are really vital, we don't see it. So we see some issues with counts just because immune therapy in general can make your counts go down, but these are really easy for us to take care of, nothing that we've seen major. We do see CRS again in the 70 to 80 percent range, so mostly grade one two, meaning that patients might need some acetaminophen, Tylenol type thing to help with fevers. They might need some fluids if their blood pressure drops a little bit, or a little bit of oxygen, and that would be grade two. So if someone needs fluid or oxygen, we consider that grade two CRS where patients would get another drug called tociluzumab, which helps knock all that inflammation back down so that we can maybe stop all the extra toxicity that these T cells just cause as a side effect. The other side effects really are infections, again maybe a third of patients that had infections, and low globulins, so hypogammaglobulinemia. It wasn't a huge risk, but just something that we see in all immunotherapies, so we have to give IVIG to make sure you don't get infections or try to prevent infections. And then a couple of the bi specifics including this one had some low electrolytes, so phosphorus that goes down, so hypophosphatemia or hypomagnozymia, so low magnesium, low phosphorus, and we think this happens because as your T cells are, you know, as they're killing the myeloma, they're also growing to have more T cells come and they're killing, and it can use a lot of energy, and that can help, you know, sometimes you can get a decrease in those electrolytes, so a lot of people might need infusions for those. So, Sevastomab so far in trials has been as monotherapy, and again, once it becomes FDA approved, you know, I think by then we'll have lots of other trials where they are doing combinations. Sort of bi specifics in general seem to be great being off the shelf and being easy to give, I think probably great partners with a lot of the other therapies we have in myeloma. The response rates have been pretty impressive. So again, remember, this was a little bit different where these patients, almost 70 percent, so 65-70 percent of patients were pentarefractory, so that's really important that these patients have had, you know, have been resistant to all these other therapies. And in that group, they looked at the smaller dose level versus they grouped the bigger dose levels together all the way up to 198 milligrams, and out of those two groups, in the smaller dose group, the response rates were closer to 30-35 percent. In the bigger dose groups, that's where we see this higher 50-60 percent response rate. So in that population of patients where you have this many refractory patients, that's really impressive for us. And I think also that a third of these patients had BCMA therapy, again, usually means they've had a lot more therapy, not just the usual therapies we have for myeloma, but now you have BCMA that are newer, and then you're getting this drug. So again, really impressive for the patient population that's on there.