ABBV-383

What is ABV383 and what is a bispecific antibody, its target and mechanism of action? ABV383 is a very promising drug that's currently being studied in a phase one trial. The way that it works, it's a bispecific antibody. And so what that means is that it can bind to two different things. One of those things is the plasma cell marker called BCMA or B cell maturation antigen, the present on myeloma cells. The other target for the antibody is CD3. CD3 is a marker of T cells that's part of our immune system that can fight some forms of infection. In this case, we're using this antibody to essentially bring the immune system to the plasma cells or the myeloma, the cancer, and have the immune system destroy the cancer, have our own immune systems destroy the myeloma. So that's how it works. It's a little bit different than some of the other bispecific antibodies on the market in that this one was designed with the intention of having less strength towards or affinity towards the CD3 or T cell marker. And the reason for that is to help offset some of the more common side effects such as cytokine release syndrome or CRS, which is a very big side effect with all of these kind of immunotherapies on the market with myeloma. ABB383 is one of the bispecific antibody and bispecific antibody because it binds to two different proteins, one on the surface of myeloma cell called BCMA and the other on the surface of T lymphocytes, which is part of our immune system or immune cell. This bispecific antibody brings this T cell in close proximity to the myeloma cell so that these T cells can kill the myeloma cell. So that's the bispecific antibody. So far, all the data and evidence points out that it is quite specific to plasma cells with multiple myeloma and almost all myeloma cells express this target, this protein. So we don't have to actually screen for this because it is quite ubiquitous, quite universal. So it is expressed on all myeloma cells and that's why it's considered a good target because it's quite specific to cancer cells and not expressed everywhere. And it is present on normal myeloma plasma cells as well, which make our antibodies and are part of our immune system. So one side effect because of that, that it not only kills the malignant plasma cells but also normal plasma cells and because of that, the immunoglobulin level goes down or hypogammaglobulinemia. There was a recent paper based on side effects of CAR T cells, especially some Parkinson's like symptoms of neurotoxicity, that perhaps there may be some BCMA expression in the cells of the brain in the region called basal ganglia where Parkinson's is associated. That needs to be verified or confirmed. So that's the first indication that this may be expressed outside. But so far, from what we know, it's quite unique to plasma cells. What is hypogammaglobulinemia and how is it managed? We can monitor that and if patients are having recurrent infections or if their immunoglobulin level is profoundly low, we have it available as IV immunoglobulin or IVIG and patients can get those replacements at a certain frequency every three weeks to once a month. It's an IV infusion to basically replenish that immunoglobulin deficiency. What is the schedule, dosing and administration for ABV383? It's administered intravenously so patients will need to get a needle in the vein and then administer it that way at an infusion center. Currently, the way it's being studied is every three weeks, one dose every three weeks and I believe it runs over one or two hours. Generally, with these types of therapies, because we don't know how a patient's going to react to the first infusion, it can take a little longer for them to get that first infusion on the order of maybe four hours or so. But once they demonstrate tolerability, the rest of the infusion times will be shorter. Yes, it's currently being studied in a phase one trial. So the purpose of a phase one study is to determine the safest dose that we can give a patient of a specific drug. The antibody so far has been used intravenously. So it's IV, it's IV infusion given over one to two hours. The first dose is given inpatient in anticipation of some side effects. But if everything goes well, subsequent IV infusions can be given in the clinic. For most of these, where there are antibodies that are given, whether they are bispecific or otherwise because they're proteins, so pre-medications are given in those situations to minimize the risk of side effects. Could be antihistamines, low dose steroids sometimes can be given to minimize the risk of toxicities. And the frequency for this one is every three weeks based on what we know. The dose is currently being worked out. So they started out with very low dose. It's given in milligram doses based on the information that has been presented and published. And what they found to be a relatively effective dose is anything above 40 milligram and the recommended dose is 60 milligrams. So the expansion phase where more patients are treated at a certain dose that is considered to be safe and effective is a 60 milligram dose. And that's what is being used currently in the clinical trial. Is ABV 383 an off-the-shelf therapy? Most of the therapies other than CAR T cells, especially CAR T cells that are made of patients' own cells or autologous T cells, which have to be obtained from the patients themselves. But if you do not have to get those things from the patient, then it's considered off-the-shelf. That yes, you can order it and it would be delivered and supplied. So fortunately, these bispecific antibodies are pharmaceutical products, so they can be considered off-the-shelf. That you write the prescription and it will be delivered by the pharmacy to the clinic to be administered to the patient. What are common side effects from ABV 383? So with these classes of medications, sometimes they're referred to as bite therapies, BITE, or immunotherapies or bispecifics. Terms are all used interchangeably for these classes of medications. And so because they involve engagement of the patient's own immune system, what they can do is at times they can kind of hyper activate the immune system of the patient and lead to inflammatory symptoms such as fevers, chills, a rash. In more kind of rare but serious cases, the immune system can at times even attack the patient's own body. So certain organs like the liver, the intestines, where patients can have diarrhea, abdominal pain, sometimes if the immune system attacks the lungs, they'll have trouble breathing. And so because these are newer agents on the market, we're monitoring patients very carefully at this time where we tend to observe patients while they're receiving this drug, especially the first dose tends to be given in the hospital where a patient has to be monitored all the time. And then maybe in the future once patients demonstrate tolerability, they can start to receive it as an outpatient. And that's because if a patient develops very severe symptoms of cytokine release syndrome, we have someone monitoring them and we can step in right away and treat those symptoms with anti-inflammatory agents. Essentially the goal of these is they find, they're engineered to basically identify a marker that's specific to plasma cells, as specific to plasma cells as we can make them. And specific for T cells so that you can connect these two cells together. That's all this molecule is doing. It's connecting these two cells together to get the immune system to attack and kill the cancer. Treatments that are targeting the BCMA or that are utilizing the immune system, one unique side effect is cytokine release syndrome, also called CRS, that when these T cells are stimulated they release certain proteins or chemicals, just like someone gets it with severe infection. It could be fever, sometimes skin rash, low blood pressure. Sometimes patient can get a little short of breath. So cytokine release syndrome is a common side effect in the clinical trial. More than half the patients experience that. Fortunately, very mild and can resolve spontaneously. But there are treatments that can be given to reverse that. Again, most of these drugs can also suppress blood counts. So the second most common side effect was neutropenia or low white blood cell count, reversible short term. And then the third most common side effect that was reported was fatigue. And then there were a host of other things, but luckily those were rare. So cytokine release syndrome, low white blood cell count and fatigue were the more common side effects. Almost always with different bispecific antibodies. The first dose is where most of the CRS is seen. And with subsequent doses, the incidence goes down significantly and it becomes rare. Is step-up dosing being used to reduce the effects of CRS? So far, no. It's a single dose, at least based on what I saw in the presentations and in the trial. And I'm not aware of the step-up dose. But again, it depends on the safety and the efficacy. And sometimes to achieve that, people have done that. But I have not seen those data with this antibody. What is step-up dosing? Step-up dose in this context from what has been reported is that certain drugs can be given that where you administer the same dose, but you either split or fractionate it instead of giving the whole dose at one time or one day, you can split it over two days. So you deliver the same dose to get the same benefit, but by splitting it, you can reduce or minimize or mitigate the side effects and toxicity. So that may be very useful for cytokine release. And it's been done with some of the other antibodies. But I'm not aware of being done with this particular antibody. Is there a risk of developing ICANs while taking a bispecific antibody? Good question about ICANs or the neurotoxicity that can be seen. So very well known and reported with CAR T cells. We have to because we have to monitor for ICANs with the bispecific antibodies also because they are also working through the stimulation of T cells and its function. But with this antibody, at least on the clinical trials so far, that was not a significant side effect and it was not reported. So hopefully it won't be a big problem, but still we have to stay vigilant because of the mechanism of action. We have to watch for neurotoxicity or ICANs. Who is the target population for the ABV383 trial? The target population are patients with relapsed or refractory disease, especially patients who are triple, what we call triple refractory. And in this era with all these new drugs from IOMA, what triple refractory refers to is patients who either never responded or progressed on immunomodulatory agents such as Revlimid or pomalidomide, proteasome inhibitors such as Valcade or carfilzomib, and anti-CD38 such as daratumumab or Darzalex. It's a dose-finding trial. Oftentimes the study PI will report some data to support that it's a promising drug such as overall response rate. So far what we know from this, the phase one data is that the overall response rate is in the upper 70s, percentage-wise, which is very encouraging because these are not patients that we're treating upfront. These are patients that have not responded or progressed on the upfront therapies we give. And so thus far there's a lot of excitement surrounding this drug. Yes, now more than 100 patients have been treated and it was presented at the American Society of Hematology meeting in both 2020 and then with a larger cohort in 2021. And in those who received a dose that is above 40 milligrams, which is considered an effective dose, the response rate was 79 percent. So again, a very high response rate and there are some complete remission and very good partial remission. If you take all comers, response rate was still 64 percent. So it appears to be a very effective product just like some of the other bispecific antibodies and almost approaching the CAR T-cell results. Follow-up is relatively short so we do not have that much data in terms of progression, free survival, but those patients who have achieved the response and even with those short follow-up seem to be doing well and have been in remission. Is ABV383-FDA approved? So far none of the bispecific antibodies have been approved by FDA, but given the data we are expecting that in the coming months or hopefully in a year or so at least one or two will get the approval. So it is not FDA approved. So it is not available. Your doctor cannot prescribe it, but you certainly can look for clinical trials. And one of the best ways of looking for clinical trials in addition to asking your treating physician would be to go to clinicaltrials.gov and then there are all these authentic sites for myeloma patients where you can get information on the availability of certain clinical trials. In terms of eligibility, most of these trials are done for patients who have received multiple lines of treatment that have failed to work. So for this particular trial, patients have to have at least three prior lines of treatment that should have included a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody like DeraTumorMap. Since the recording of this segment Teclastamab, another bispecific antibody directed at BCMA, has been FDA approved for individuals who previously received four or more prior lines of therapy including a proteasome inhibitor, immunomodulatory drug, and anti-CD38 monoclonal antibody. How close to approval is ABV383? This is early phase. I am not aware of how far, but it is a little behind some of the other bispecific antibodies. Given the results, I won't be surprised if within the next two years we get the approval, but I do not know the exact dates for that. One other thing what they have tried to do is in terms of molecular structure, they have tweaked it in a way biochemically that it binds to a certain type of T cells which would reduce the toxicity and increase its effectiveness. So it would bind more to effector T cells and not to regulatory T cells, which is expected to make it more effective against myeloma. And they have also got some biochemical changes in the structure which is expected to reduce the cytokine release and other toxicities. Based on how it is presented, yes, it is more unique to this particular bispecific because there are so many of those out there. So people are trying to differentiate their molecule from the other by doing these simple adjustments, molecular adjustments, to make them more unique in terms of safety and efficacy. What are the targets for monoclonal antibodies? There are those monoclonal antibodies that are FDA approved like daratumumab and esatuxumab and their target was CD38, which is expressed on the surface of myeloma cells. Elatuzumab, the target is SLAMF7. And then for these bispecific antibodies, the most common target is BCMA or B cell maturation antigen which is also the target for the two FDA approved CAR T cells. Then there are some other targets that are being looked at and there are antibodies in clinical trials against those targets also. One of them is GPRC5D and there is a monoclonal antibody that is shown, PROMIS against that, called dalquetumab. And then there is another FCRH5 which is another protein expressed on the myeloma cell surface. And there is a monoclonal bispecific antibody that is targeting that protein also. And I'm sure that there are more targets that are being evaluated because these cells express a lot of proteins. So as long as those are unique to plasma cells, we may see more targets and more antibodies in the future. Are there any other targets being explored? There are a number of targets being explored, but the best known of that is BALANTAMAB mafidotin which is now FDA approved and that is also targeting BCMA. So that's the most advanced and it is FDA approved for the treatment of myeloma.