Graphic: What did your study examine and what were some of the significant findings?
Joshua Richter, MD: Sure. For the most part, what we know in myeloma is that when you go beyond some of the main available drug classes, immunomodulatory drugs, proteasome inhibitors and monoclonal antibodies, outcomes tend to be rather poor. And what’s really on the horizon in changing the landscape is what we call BCMA-directed therapies. And there’s three main modalities, the antibody-drug conjugates like belantamab mafodotin, CAR T therapies like ide-cel and cilta-cel. But what is my big interest and what I think is going to have the biggest impact on the landscape is bispecific antibodies. And the reason I think these are going to have the biggest impact is that CAR T therapy is really something that’s only going to remain in big universities because of the infrastructure needed, but bispecific antibodies, in the right versions, can be given in the community and in the U.S., the majority of myeloma’s in the community.
The study that we are presenting at IMW is on Regeneron 5458, which is a BCMAxCD3 bispecific antibody, and really just a T-cell engager activating T cells to fight the myeloma. This has been an extraordinarily efficacious drug. If you look at the history of drugs approved in myeloma at the end, single-agent pomalidomide/carfilzomib, daratumumab, when you give it at the end has response rates of 20% to 30%. But here we saw now in the higher doses of the drug, and we now have a recommended phase 2 dose of 200 milligrams, but for patients who got between 200 and 800 milligrams of the drug, a 75% overall response rate, which is humongous. We’re seeing very big responses, but what’s even more important at some level is the CRS rate.
Just like CAR Ts, bispecifics can induce cytokine release syndrome. And for many of the assets that are currently under investigation, the CRS rates have been in the 60%, even 70% rate. Whereas with Regeneron 5458, were around the 35% to 38% CRS rate with the overwhelming majority of this being grade 1 grade 2. Because of the step-up dosing and the nature of the dosing strategies, we have a drug that is extremely efficacious and very promising, but also tolerable in terms of those big CRS side effects. We’re really excited to move into the phase 2 with this drug, both as monotherapy and in combination with a lot of our other myeloma drugs.
Graphic: And what was the methodology for the study?
Dr. Richter: The methodology was basically looking at patients who were relapsed and refractory, who have progressed beyond the standard lines. And if they had good organ function, they were administered Regeneron 5458 as an intravenous infusion. Essentially the drug is given weekly for the first 16 weeks. Following that, patients then go on to a Q2 week dosing strategy. They remain on the therapy until progression or intolerability. However, it’s not included in this abstract, it was a recent amendment. Based on some PK/PD data, we know that we can actually switch over to a Q4 dosing strategy. For patients who remain in a VGPR or better, and have been on the therapy at least 24 weeks, we can now transition them to a once-a-month dosing strategy, which is a lot more convenient for patients.
Graphic: What was the safety profile for REGN5458?
Dr. Richter: Yeah. In general, as a phase 1 study our primary endpoints have to be safety. And the two big ones that we worry about are infections and CRS. And as I mentioned a little bit about the CRS rates, they were there, about 35% to 38%, and the majority of those grade 1, grade 2. Very manageable with things like Tylenol, steroids, and tocilizumab. Infections were certainly there, and we’re seeing infections across this drug and all other drugs in the category for several reasons. One, there are other cells in the body that express BCMA. Again, it’s mostly malignant plasma cells, but you get some B cells, you get some normal plasma cells.
You get a little bit of an immune suppression of sorts from that standpoint. But as a T-cell redirection therapy, we’re taking all these T cells over here that are preventing you from getting viral reactivations and say, come over here and fight the cancer. You may put yourself at risk for other infectious complications. This is really something we’re trying to better understand for the class as a whole, knowing that infection rates are higher, knowing that BCMA-based therapies impact COVID vaccination response. We’re trying to develop a prophylactic plan for patients like this, which includes things like IVIG and prophylactic antivirals when indicated.
Graphic: Did dosing have any impact on cytokine release syndrome?
Dr. Richter: It’s a really great question, and the answer is no. We’ve kind of evolved a long way from our classical chemo drugs, where there was kind of this linear response between efficacy and toxicity, and you just found the point on the curve just below a dose limiting toxicity. But with immune therapies, nothing is linear, nothing follows the rule book, and we actually saw no difference in cytokine release or cytopenias, or really almost any of the toxicities that there was no difference whether or not you got five milligrams of the drug or two or four, 800 milligrams of the drug. That’s really something that we’re still trying to better understand. The rates of CRS are probably more related to your underlying disease burden and disease biology, meaning do you have a lot of it? And is it progressing quickly? Those are probably the biggest predictors of whether or not you’re going to have CRS and how high a grade CRS you’re going to have.
Graphic: Was there anything, including dosing impacts on CRS, that surprised you?
Dr. Richter: That all surprised me. I would’ve thought... I … trained in the day and age where if you had the toxicity with the drug, you just dropped the dose down, but that actually doesn’t seem to affect anything here. I think really what it brings about is our approach to managing adverse events is going to be far different. Controlling disease burden going into a bispecific is going to be important, prophylaxing against these things, as opposed to saying, all right you had it at 200, let’s bring it down to 100. A whole new way of having to approach efficacy, toxicity and side effect management.
Graphic: What are your next steps in this area of research?
Dr. Richter: Sure. Bispecific antibodies are extremely encouraging, and Regeneron 5458 has both shown efficacy and tolerability. Few next steps, one is getting the drug approved. Registration trials are in the process of opening in the not-too-distant future, which will hopefully push the drug towards approval. Combination strategies, combining the drug with other myeloma therapies like immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies, those trials are underway. And then equally if not more important is moving the drug further up in the paradigm. Trials underway looking at both early relapse as opposed to late relapse. One to three prior lines, not four or more. And there’s a study that – the protocol is written, it's not quite open just yet – upfront therapy with this asset. The sky’s the limit when you’re able to harness the immune system, and we couldn’t be more excited about the future.
