REGN 5459

What is RegN 5459 and what is its mechanism of action? I was privileged to be presenting the data on behalf of my co-investigators on our data from phase 1-2 study of this molecule RegN 5459. The uniqueness of this molecule is it is a bispecific antibody. It grabs on to BCMA on the surface of the myeloma cell and the other arm grabs on to CD3 on the T cell. The uniqueness has to do with how it binds to the CD3. It has low affinity to CD3. What that means is it doesn't actually grab on very tightly to the CD3. While that seemed like it would be an odd thing to think about, the reason has to do with the concern of cytokine release syndrome, which is an ongoing problem with the bispecific antibody. When the T cells engage with the tumor cells and kill them off, there's a lot of inflammation. By having lower affinity to CD3, there's been some preclinical models that suggest that this lower affinity to CD3 may actually reduce cytokine release syndrome. We presented the data of this particular molecule in patients with relapse and refractory multiple myeloma. There are two parts to the study. Part one explored different doses and part two explored efficacy of the expanded dosing. What we learned was with the dose escalation, it was relatively safe to do. Patients end up fully escalate to the full dose and the dose that was chosen was 480 milligram, which is given intravenously weekly. In the expanded cohort, the response rate at the dose of that 480 and also at the top dose of 900 together, response rate was 90.5%. That includes 100% response rate that we saw in the 480 milligram dose. It goes to say that by reducing the affinity to the CD3, you actually don't lose the efficacy. The molecule still continues to kill the cancer cell. The response happened pretty early. Happened in less than a month after the start of the treatment. The overall response rate was high, particularly at these top doses, as I mentioned, but also the response was durable. It's projected that patients will continue to be in remission passing the 12-month mark of over 78, 79%. We were pretty impressed with that kind of efficacy data. Patients continue to have the cytokine release syndrome. However, they seem to all be low grade, classically just fever, and that occurred in about 80% of patients at that top dose. There was only one patient out of that 80% that actually had a declining blood pressure. The treatment was otherwise just your anti-epirotic, and about 15-16% of patients received this infusion of medicine called tocilizumab to manage the cytokine release syndrome. Less than 10% of patients received steroids. So it seemed that the agent is relatively well tolerated. How is REGN5-459 administered? It's determined as lay-vegly, so IV-vegly. Patients get it at that frequency for the first 16 weeks, and then it goes down to every other week. Now, there is a new amendment coming out for patients who have been responding really well, very good partial remission or better. They will go down to once a month after 24 weeks. That's trying to really balance the convenience with the efficacy, but also trying to overcome this long-term issue with this kind of treatment, which is infection. As it turned out, when the T cells engage and kill off the cancer cells, it also kills off the normal plasma cells, making these patients having low level of normal antibodies. In addition to that, by chronically stimulating the T cells, you do run into a problem that we call T cell exhaustion. They're actually losing their fitness, and they're no longer able to either recognize the cancer or fight off infection. So we do see infection being a problem with this class of drug, and we're hoping that by using low affinity to CD3, use it less frequently in patients who have really good remission already. Perhaps we would mitigate some of these longer-term side effects. How long is the infusion? The infusion lasts 30 minutes, but requiring some pre-meds. For the first few doses during the step out, we would do dexamethasone, benadryl, antihistamine, and Tylenol are allowed, not required by the protocol. When patients are done with their incremental dose and achieve full dose without that cytokine release syndrome, in the future, their treatment's shorter because they don't really require that pre-med dexamethasone anymore. So when they get in, get connected with the IV, there won't be a need to wait around for the pre-medication. Well, a patient need a port to receive the infusion. The arm's fine. It is antibody, so it usually doesn't have any irritation to the veins. The sponsor is also exploring the subcutaneous administration of their other acids in the bispecific, but I hear you, the injection would even be more convenient. Who is the target population for the trial? Similar to any other first in human phase one to clinical trial tends to be folks who have otherwise relatively limited choices. So in this clinical trial, it is patients who've already failed at least three prior lines of therapy and exhausted all meaningful available choices. So there are classically patients who've already had the immunomielatory agents, perisome inhibitor, and CD38 antibody. It turned out of those patients we had in the study, 73% actually had already had exposure to five strongest agents we have, and that would be linalytomide, formalytomide, vertizomib, or Velcade, carfilzomib, and a CD38 antibody. So even though we require three different classes of drugs being used, it turned out that not only this group of patients had three classes of drugs, they also used more than one drug from each family, and the majority of them have truly been heavily pretreated. It was, and this hits to the core in that we're still trying to figure out how to best target the BCMA, but also whether sequential therapy would be of benefit. It wasn't addressed in this clinical trial because we did not allow prior BCMA therapy, but as you know, there are multiple strategies now that we're employing the immune system to target that unique molecule on the surface of the cancer cells. This one is an example of the bispecific T cell engaging antibody. There are also chimeric antigen receptor T cells, or CAR-T, that's targeting BCMA, and different class of drug, which is what we call antibody.conjugate, an antibody that carries a little toxin that's attached with the linker to carry this toxin to deliver it specifically at the surface once it binds onto the cancer cells. So that's another strategy too. So there are many things, and the ultimate question we like to be able to answer is what's best, how do you sequence it, or I guess who gets what first. Does it have a better response rate than other bispecifics? So what's difficult is to compare across the study. We're encouraged, of course, in this relatively small cohort of patients to see very high response rate at that top recommended phase two dose, but every patient is unique and expanding it across a broader horizon. A broader group of patients will probably give us a much better sense on its true efficacy, and hopefully being able to also figure out just how different each patient coming into the study contributes to the overall response interpretation. Particularly, a bigger study might also be able to help us understand whether the so-called high-risk genetic abnormalities would respond equally well or any differently to this kind of newer immunotherapy. Is there any information on the duration of response for R-EGN5459? Yeah, so the study is still ongoing, and the median follow-up time was only about nine months, so a good number of patients are still a little bit early in their journey on this particular medicine, so data's coming. But based on just the follow-up so far, there is an estimated probability of patients enjoying remission passing the 12-month mark, being about 79%. So it goes to say that their data suggests that if they respond, they continue to enjoy the response for a significant time. There were several patients that have already passed the 26-month mark and continue to enjoy remission. Were those patients on weekly therapy? They've just consented to scale down their frequency of treatment. I mean, majority of their journey with this drug would then be with the weekly 16 weeks at the beginning and then every other week until they go down further. Now, newer set of patients who are actually not as long in their journey coming up on their 24 weeks will be able to not needing to wait so long before they go down to the once-a-month treatment. Is there a need for IVIG with this therapy? This is an interesting question, and I think really at the core of how do we keep patients safe when we're treating them with this newer technology. So the study did not mandate IVIG. It left it to treating physician to figure who needs what. And we learn as we go in the bi-specific T cell engaging kind of world. It used to be at the onset of this study. IVIG is usually started when patients are already facing recurrent infection, as is generally recommended for patients with acquired hypogammaglobulinemia and recurrent infection. Well, it turned out though that maybe that was a little late in coming in with starting it and with infection. The morbidity sort of infection itself in this clinical trial, we actually had two deaths, one from pneumonia, another one from COVID infection. So once you have infection to try to prevent it afterwards, it's not sufficient probably. So there is more of a move to go ahead and use IVIG in patients with very, very low level of IgG. There was about 18% or so of patients on this study who actually received IVIG, but I anticipate that everyone who is on the study with low enough of the IgG level will end up using it. So we're probably going to see that number go up. What prophylactic medications were used in this study? So that's another thing. Speaking that it was the first in human phase one, a lot of it was really left up to treating physicians who all come together to discuss the care and decide what to use. I would say though that majority of patients on this study were taking a cyclone via prophylaxis, as it's been so well known that this is a group that could have herpes reactivation. On the back trim for PCP prophylaxis, that's a bit more debatable. But I think most of us now are starting to implement this back trim prophylaxis in patients with very, very low number of CD4 counts. And we do have capacity to be able to track the CD4 over time. So this would be the, I think we're going to see more of this back trim prophylaxis being used. I think ultimately we realize that treatment efficacy was really high. Infection is still a bad problem in myeloma. We should prevent when we can because treatment is less successful and long-term complication of infection itself is a big problem. But also how might we be able to select a group of patients where we can say, well, you have had enough treatment and we need to scale back to allow for the T cells to recover, to allow for the immune system to return. That would be, I think, a question that not only should be further explored in this group of patients, but also I'm hoping for the whole T cell engaging technology. The sponsor is still considering the future development of this agent, but the message I think I want to share with our patients is I think the treatment of myeloma is getting better and better. We're learning as we go, really participating in clinical trial if they can will help us go, move forward even faster. For this particular clinical trial, because it was the first in human study, our deep strategy really goes to the patients and their family because they had participated in a study that didn't have as much of the background data and it's their data that now we're sharing to help us moving forward. And this is all happening during the challenging time of the COVID pandemic, which hopefully we're out of. We appreciate everything that they do.