Alnuctamab

Today we're going to talk about Alnuktamab, which is one of the newer bi-specific antibodies that's in development. It's a drug that's made by BMS, and it's currently in relatively mature phase of development. So what's been kind of slowing up the process is that it was originally developed as an intravenous infusion, and now because of sort of the high rates that we saw of some toxicity, including cytokine release syndrome, they decided to kind of switch the formulation over to a subcutaneous injection, and that's really drastically improved how the drug is delivered and the toxicity rates. And the main thing that makes this drug different, at least in my opinion, that makes this drug different to some of the other drugs on the market right now is that rather than just binding to one single BCMA molecule, which is the target here, it binds to two. So it's got two forks. It binds to two different BCMA molecules in order to become activated, and because of that there's a theory, again this isn't proven yet, but the theory is that this might be able to circumvent some of the issues with high circulating levels of BCMA, instead favoring to try to bind to the surface of the cell where that concentration is higher, and you might be able to cross like those two different BCMA molecules. So what makes BCMA a target that we want to go after in multiple myeloma? There actually are a lot of different targets for multiple myeloma, and the idea is that we want to try to find something that's going to be on the surface of the multiple myeloma cell that's not really on any of the other cells in the body, and this is going to be to increase the specificity of the drugs that we're using, while also trying to minimize the toxicity, right? A target that's on the surface of every cell is going to lead to a huge toxic effect of the drug, whereas a cell surface marker that's only present on the multiple myeloma is going to be one that we can really target effectively and directly. And so BCMA is one such protein that's on the surface of myeloma cells. It's a great target because basically all of multiple myeloma expresses it, and only a couple of other cells in the body also have that kind of expression. So most of the approved therapies that are aimed at redirecting our host immune T cells towards multiple myeloma are targeted against this target BCMA. Now of course there are others in development, but so far BCMA is the furthest along. As we talked about in terms of how this drug is administered, originally it was developed as an IV infusion. It kind of got scrapped when we saw those very high rates of cytokine release syndrome. Now it's being given subcutaneously. And there is somewhat of a step-up dosing schedule. It lasts about eight days more or less. But the key of this is that once the target dose is reached, there is a stable dose for every single patient. So I believe the dose right now in development is 30 milligrams. It's a flat dose, and there's very little variation there. The nice thing about it is that in terms of dosing, initially it's almost like Dara, you might remember, is that it starts out weekly, it becomes every other week, and then eventually it's built into the protocol that you'll be getting the drug once a month. And that makes it very, very easy to do. You get a subcutaneous injection once a month. It's very attractive as compared to some of the other approvals that have been made in the space. In the protocols themselves, I'm sure there are certain pre-medications that are given to try to reduce the inflammatory reactions. These are kind of pre-medications that I think will become institutionalized in the future, and there will be some modifications made. But the idea is going to be like, we need to give things that are going to reduce the risk of injection reactions at the site and also systemic reactions, including inflammation and CRS. In terms of side effects for treatment with this drug, Alnuktamab and others, the issue with targeting BCMA specifically by redirecting our T cells to attack this target is the same that we're seeing across the board. So we're seeing cytokine release syndrome, which is a massive inflammatory response that occurs when basically you tell the body's entire immune system to redirect itself and attack one single target. We're also seeing over the long term infection. And this is probably due to multiple different mechanisms, but we see it sort of as a class effect with targeting BCMA, specifically with the bispecific antibodies. Now the data is very preliminary, but it does appear that perhaps because Alnuktamab has a reduced dosing schedule over the long term and because it's subcutaneous, the infection rates may be lower with this drug as compared to others. Now again, it's very early, and we don't know that for sure, but there is somewhat of a signal for that. So in terms of management of some of these side effects, again, these are common side effects that happen with all T cell redirecting therapies. So over the years, obviously, as these drugs have become more popular, as they're more widely used, they're ubiquitous, we have developed better ways to try to manage these side effects. So in terms of cytokine release syndrome, multiple different institutions have different management strategies. The basic idea is that you either wait for the event to happen and then you treat it with steroids or anti-inflammatory drugs, or some institutions, for example, at Princess Margaret and also at the University of Miami, are giving some of these anti-inflammatory agents up front. So one such example is Tosolizumab, which is an anti-IL-6 monoclonal antibody. Usually it's given when people first develop CRS. We've been trying to give it prophylactically. In other words, right before you get that first dose, you get a dose of this anti-inflammatory, and that has dramatically reduced the rates of cytokine release syndrome. Then on top of that, for the long-term infections, there's emerging data that says that, first of all, on top of all of the prophylactic antibiotics and the antivirals that you need to take when you're on these drugs, there's some data that says that if we give you an immune boost with something called intravenous immune globulin, this is pooled antibodies, basically pooled immune system of healthy donors, if we boost you up with that on a monthly or a recurring schedule, we can drastically reduce the risk of infection. In terms of what specific antivirals, antibiotics, prophylactics we call them that we should use with these drugs, again, this varies a little bit by institution, and there are guidelines that exist for this. But generally speaking and across the board, there's going to be an antiviral, things like acyclovir or valacyclovir. There's going to be a certain antibiotic to try to prevent a certain pneumonia called PJP. This is going to be Bactrim, you might be familiar with that. There's also going to be, at least in the early stages, treatment with Levoquin, which is more of a broad bacterial prophylaxis because the risk of big bacterial infections often happens in the first couple of months. And then as we spoke about earlier, there's going to be the treatment potentially with an immune booster as a global sort of protection against infections. In the Alnuktamab trial, in terms of the target population, I believe patients on the trial had had at least three prior lines of therapy. And so these are patients that have generally pretty relapsed refractory disease, not quite as refractory as some of the patients that we've seen in other bispecific trials, which were four prior lines. But nonetheless, a patient population that's generally speaking been exposed to a lot of other therapies that are in need of something new and novel. In terms of when we might see this drug come to market, so the data is relatively mature for this phase one trial. It's been presented twice, both in 2022 and at 2023 at the ASH conference. In terms of the next step, looking at phase two data, I know the trials are currently in progress, but we don't yet have a date that we can expect this drug to come to market. Hopefully it will be also on the accelerator approval pathway.