What is Teclistomab? Teclistomab is a new drug in development for multiple myelomids in a class of drug known as a bispecific T-cell antibody. So basically, these are essentially two armed antibodies where one arm of the antibody binds to a tumor associated antigen. In the case of Teclistomab, BCMA or B-cell maturation antigen. And the other arm of the antibody binds to CD3 on a T-cell and essentially brings the myeloma cell and the T-cell in close proximity. It's like the kiss of death where the immune cell will hopefully kill the myeloma cell and hopefully lead to a nice response in terms of the treatment for the myeloma patient. Do all myeloma cells have BCMA on them? And are there any other cells that have BCMA on them? BCMA emerged as an important target for multiple myeloma several years ago through some profiling of myeloma cells and plasma cells which are essentially the benign form of myeloma cells. Essentially, BCMA is expressed at a high level on plasma cells. There's data that shows that BCMA is expressed even in higher amounts in buligna plasma cells or myeloma cells. And what makes BCMA an attractive target for multiple myeloma is that it's nearly exclusively expressed on plasma cells and very little expression on naive or immature B cells and non-hematopoietic or non-blood cells as well. So at least for right now, there just seems to be very little sort of off-target effects of BCMA targeted therapies in multiple myeloma. Do these kill normal plasma cells and if they do, what would be a potential side effect? Yes, absolutely. There is expression of BCMA on normal plasma cells as well. And so I think one of the downstream effects we do see in terms of sort of potential side effects to BCMA targeted therapies in general is that we do see depletion of immunoglobulin secretion in general in patients getting BCMA targeted therapies. So immunoglobulins are essentially antibodies that help fight off infections that myeloma patients may encounter. So they may develop something called hypogammaglobulinemia which is a decrease in the IgG levels. And sometimes myeloma patients have bad IgG which represents the myeloma component of the IgG, but we all need some good IgG to help fight off infections. And so that potentially can make patients more prone to infections. And one way to support patients in which this may develop is that we may give something called intravenous immunoglobulin or IVIG to help boost up the immune system. And that's something that we do give to some of our patients on BCMA targeted therapies is to give intermittent IVIG to help support the immune system better. Most of the data that's been sort of published today has been with the anti-CD38 based monoclonal antibodies like daratumumab or esotuximum just because they're in widespread use in multiple myeloma currently. I think there's probably less data on the COVID vaccine response with BCMA targeted therapies just because there are newer treatments. Most of them aren't on clinical trials. But theoretically and practically speaking, it'd probably be the same effect. Both anti-CD38 monoclonal antibodies and BCMA targeted therapies can deplete normal plasma cells and would potentially attenuate the vaccine response. Is toclosumab an off-the-shelf treatment or a manufactured treatment? And if it is off-the-shelf, what does that mean? It is an off-the-shelf therapy. So we refer to off-the-shelf therapies as basically more like traditional drugs that are essentially manufactured by the drug company. They're shipped to the site, you know, for instance, at MD Anderson, for instance, and basically can be delivered immediately to the patient through either the vein or sometimes drugs are given as a shot or an injection or as a pill. And so this differs from some of the CAR T therapies or Tologos CAR T therapies such as silted cell or IDA cell, which are essentially on the shelf, meaning that, you know, patients need to get their T cells harvested, manufactured, and then essentially, you know, shipped back to the treating site and then infused into the patient. There is a little bit more of a manufacturing time obviously with the Tologos CAR T's, whereas bispecial antibodies like toclosumab are off the shelf, can be delivered immediately to patients. And I think one advantage of off-the-shelf therapies is that, you know, if a patient doesn't have time, for instance, for the collection and manufacture of T cells, like in the case of autologous CAR T cells, then bispecials represent an attractive option of a highly efficacious therapy that can be delivered immediately to a patient who is potentially progressing on their current therapy without any delay. How is toclosumab administered? So bispecial antibodies in general, some of them are being developed intravenously, some of them are being developed subcutaneously. In the specific case of toclosumab, initially when they first did their first in-human study, it was being administered intravenously, but then subsequently they did develop a subcutaneous form, which just for patient convenience and ease of administration is the way that the drug is being administered currently. And so it's given basically as a subcutaneous shot once a week. Is toclosumab administered continuously or do you break it up in a schedule? At least how the trial was designed, patients would receive weekly toclosumab subcutaneously for up to four cycles, and then if they achieved a partial response or better, then potentially the frequency of dosing can be decreased to every other week. And so at least that was how it was administered in the clinical trial. Eventually, if it does get FDA approved, it would be, I guess we'll wait to see what the label says. How do you decide dosage? Toclosumab and as with many bispecifics incorporates something called step-up dosing. And so early on when bispecifics were administered, we did note that there is a risk of something called cytokine release syndrome. So this is probably the main potential side effect of bispecific antibodies. It's basically, since this is an immune type therapy, basically with some types of immunotherapies like bispecifics and CAR-Ts, it could potentially lead to some type of inflammatory response known as cytokine release syndrome, typically manifesting itself as a fever potentially, but there can be other potentially more severe side effects like low blood pressure, decreased oxygen levels. If you give the full dose of bispecifics right away, it could actually increase the risk of severe CRS, and that's what we want to avoid. Later on, and nearly all bispecifics incorporate something called step-up dosing where we give a lower dose for either the first dose or the first couple doses before reaching the target dose. And so in the case of toclosumab, actually the first dose is a really, really small dose, 60 micrograms per kilogram dose by weight. And the patient tolerates that well. The second dose is administered on week number two is 300 micrograms per kilogram. And the third dose, which is the target dose, is given week number three, which is 1500 micrograms per kilogram. And that's the dose that the patient would continue on. Where is step-up dosing administered? So it's still administered in the hospital for typically the first three doses, so the first two lower doses, the step-up doses, and the third sort of target dose. And the reason is because patients are being monitored for this CRS, cytokine release syndrome, making sure they're not having untoward side effects to the treatment. And so if you get the CRS, how is it managed? So typically, for instance, if a patient has a fever, which is arguably part of the most common manifestation of CRS, we call that grade one CRS. We typically administer supportive care, Tylenol, for instance, to help with the patient's fever. Sometimes the CRS can progress to more severe manifestations, low blood pressure, for instance, where we get fluids, for instance, oxygen, if needed as well. Oftentimes, when it progresses to that level as well, we'd administer something called which is a drug to help mitigate, it's an antibody that helps mitigate the CRS symptoms. In very, very severe cases, which is rare, we'd also consider administering corticosteroids like dexamethasone. Do you use pre-meds for bispecific antibodies? So we do use pre-medication for bispecific antibodies. In the case of teclistomab, corticosteroids are used at least for the first three doses, so with the first two step-up doses and the first full dose. Once the patient seems to tolerate the treatment well without any untoward side effects, then the corticosteroids are tapered off. And I think that's one nice thing, at least with monotherapy, bispecifics, is that oftentimes the worst part of myeloma treatment regimens, as patients may attest to, is the steroids, that they don't like the steroids. And a lot of these regimens eventually go to more of a steroid-free regimen. Besides CRS, are there any other side effects you are seeing with these bispecific antibodies? You can see the typical low blood cell counts, low platelet counts, neutropenia, which is a low white blood cell count that can occur, nothing too severe, nothing too out of the ordinary compared to other myeloma therapies. I did mention the hypogammaglobulinemia that can occur that needs to be watched. Sometimes patients get very low IgG levels, which are good antibodies, high FIFF infections. In that case, one would need to consider something called IVIG to supplement the immune system. The other thing is that there is also the risk of potential injection site-related rash where the drug is being injected, and so that's something that can also be seen with Taclissoma administration. Is neurotoxicity in CAR-T being seen with bispecific antibodies? It can occur. I would say generally the rate of any neurotoxic is low, in a less than 10% risk of neurotoxicity and severe neurotoxicity, what we call grade 3 or grade 4 neurotoxicity, is exceedingly rare. Who is eligible for the trial, and what responses have you seen so far? The Majestic 1 trial was the pivotal trial with Taclissoma. It's a phase 1, phase 2 study that evaluates Taclissoma in relapsed refractory multiple myeloma patients. So the trial enrolled patients with at least three prior lines of therapy who were also triple class exposed, which means patients were exposed to a prosim inhibitor, an imid, or amino matricide drug, and an anti CD38 monoclonal antibody. And at least in the phase 2 portion, over 160 patients were treated with Taclissoma. And at the most recent update of the Majestic 1 trial at the ASH 2021 meeting, among those patients dosed at the recommended phase 2 dose, the overall response rate was 62%. The very good partial response rate was 58%. So actually, among the patients who did respond, they did respond quite deeply, which was very encouraging. In terms of sort of the duration of response or progression free survival, that data is still maturing as we speak. What the study did report at the ASH meeting was that there was about a 59% nine month progression free survival among the patients dosed with Taclissoma. So if I had to sort of guesstimate about what the PFS might end up being, it probably end up being around 12 months or so is what I'd probably predict. What is the availability of Taclissoma in clinical trials? So right now, it's available through clinical trials. There's other clinical trials looking at Taclissoma in combination with other new agents in myeloma and other FDA approved agents in myeloma. There's trials looking at Taclissoma in other indications as well. There's a maintenance trial with Taclissoma being planned as well. So there's a lot of excitement about Taclissoma and bicipisic antibodies in general given the data generated so far. Janssen, which is the pharmaceutical company that is developing Taclissoma, did file with the FDA for hopefully to get FDA approval. At some point, the initial filing was in late 2021. So it's hard to know the exact timelines and dates, but we'd hope to see potential approval to Taclissoma sometime in later 2022. What is pre-approval access? There can be certain situations where the FDA, for instance, and a drug company would allow for use of investigational agents in a certain clinical context prior to FDA approval. So this is generally when data has already been generated showing the benefits of a particular drug in a certain patient population like relapsed refractory multiple myeloma. So typically it's in the form of a compassionate use program or an expanded access program where basically a treating physician can reach out to the pharmaceutical company and essentially apply to get a patient to have access to the drug. Again, prior to FDA approval, these are typically patients that have exhausted all treatment options for their multiple myeloma. Patients otherwise wouldn't be eligible for clinical trials. So possibly once it's approved by the pharmaceutical company, then the treating physician would then submit to their local IRB or institutional review board to get permission to treat the patients with sort of a compassion use or expanded access program with Taclissoma. Where is Taclissoma available? There is a notification on clinicaltrials.gov that the Taclissoma pre-approval program or compassion use program is active. And so if one was interested in getting to Taclissoma, I would encourage them to speak to their physician and if that process would be available at their particular treating site.