All about Venetoclax

What is venettolax? Venettolax is a small molecule inhibitor of protein called BCL2. Uh the protein is really important for the survival of tumor cells. It's also expressed in normal cells but the tumor cells depend on that for a number of reasons and the levels of BCO2 are high in many hematological malignancies including acute myoid leukemia. So what vanetlux does it specifically binds to uh b2 protein through specific protein protein interaction and it prevents essentially collaboration between b2 and pro death proteins. So what happens is that uh BC2 is sort of being neutralized and therefore the pro death proteins that are naturally occurring in the cell they're free to go ahead and kill the tumor cells and because the leukemas are highly dependent on BO2 uh this approach is really effective in leukemia and does not kill as much normal cells as some of the other for example chemotherapy does because it's not as specific to the uh tumor cells as to the normal cells. That's how it works. It also uh called universal sensitizer because by lowering the threshold of self death, it essentially increases the sensitivity or responsiveness to many many different types of therapy being a regular chemotherapy, targeted therapy, immune therapies. So right now vet is used in multiple multiple combinations. So if you look at the uh clinical trial.gov off website there probably more than 50 clinical trials that are ongoing with different combinations of another clocks in different hematological diseases. So I think that's added value. So by itself you may not be as effective uh because the tumor cells are very smart and they get around single agent but if you combine it with some other therapies then it becomes really uh a killer and get gets rid of leukemia. What are the BCL2 proteins and how do they play a role in AML? So, venetux is inhibitor of BCO2. Uh B2 is a protein, but there's a whole family of BO2 proteins and B2 is obviously one of the key ones we think, but there are multiple other cousins of BCO2. For example, they're called MCL1, BL XL, BCO2 A1, and BLW. So there are four other proteins that can take upon the function of BCO2. So the function of BCO2 and some of the other cousin proteins is to protect cells from dying. So it's pro survival proteins that are usually residing on the mitochondria membrane. So mitochondria as a organal within the cell. And so this proteins are essentially um defending this mitochondria from cell death because inside of the mitochondria are some other molecules that can kill the cells if they're being released. So there's a BO2 family proteins that protect from cell death like BCO2, but then there are other family members that are in fact killing the cells. So there's a very tight equilibrium between the pro-s survival and pro death proteins. And uh what vet does is impairs this equilibrium so that now VCO2 is being neutralized but the proess proteins are being freed to go ahead and kill the cell. So that's the idea and uh now we have uh emergence of the some other small molecule inhibitors that inhibit other family members of BCO2 for example MCL1 inhibitors they're in clinical trials PCL XL inhibitors and clinical trials and so some of them have a slightly different function and of course the expression levels on different types of leukemia could be different and also within the given leukemia for example acute myoid leukemia there probably some cells that depend on VO2 and some cells that depend on ML1. So ideally you would like to target all of them but it comes down to the sort of therapeutic ratio and if a patient or organism can withstand the toxic toxicity of this agents. Who are the most appropriate patients to use vanquax? So vanllex was approved in 2019 for acute myoid leukemia usage. It was approved in combination therapy. So initial trial that we actually have done back in 2016 was a single agent inhibitor with others in patients who had relapse refractory disease. And despite the fact that studies in the lab have predicted that as a single agent they will be highly efficacious. The tumor cells were smart and they got around it. So we saw responses but they were shortlived and that the response rate was too low for it to move forward as a single agent for the approval. So the next clinical trial was in combination with the two different types of agents. One's uh called uh lowd dose chemotherapy caitabin and the second is what we call hypomethylating agents. So these are the agents that affect uh epigenetic uh makeup of the cells. they approved for therapy of acute maloid leukemia such as isocitim or isocit in or desiccidabin. So this clinical trials they were running in parallel initially as a phase one two trials and they have shown unexpectedly very high response rates. For example, if you take a single agent is a cited the response rates are somewhere I would say 20% or less in acute malo leukemia. uh but when you combine with vet it goes up to nearly 70%. So that was like a more than doubling of response rates. Again coming back to the idea that uh inhibition of BCO2 is really kind of sensitizes it to chemotherapia and that's why that kind of translated into phase three trials for both of these approaches. Eventually there was a phase three trial called V A for aocided in combination and then there was V C for citarab combinations and both of them confirmed the data in phase one two studies and they also showed that uh in addition to high response rate actually patients lived longer and this was the most important uh end point because sometimes we have drugs that can induce what we call remission response but then uh patient would relapse and after they relapse it's really hard to get them back into remission but these responses were durable especially in some patients with acute malo leukemia and so they led as I mentioned to extended survival compared with the uh standard of care at that time so essentially right now it is approved for use in older patients who are what we call unfit for standard chemotherapy there specific criteria for that so either age above 75 years old or specific comorbidities if they are above 60 years old and these are approved therapies for this patient population. So they essentially became a standard of care and being used now in US and many other countries as a frontline therapy for all the patients and you have to remember that AML is for the most part disease of older patients. So the medium age is 65 years old and so majority of the patients we treat are in fact above 60 years old. So vinylax is right now being used for the majority of acute mal leukemia patients. With that said, we think that it's going to be highly effective also in younger patients when added to chemotherapy. And in fact, the clinical trials just published uh last year from our institution showed that addition to the highdose chemotherapy in younger patients leads to the high response rates and the majority of these patients were able to transition towards stem cell transplantation. But the studies are still ongoing and at this point vial is not approved for younger patients. But I think it's just a matter of time and we will have it available for essentially all AML patients in some sort of combinations. Can venettollex cure AML? Unfortunately, venettolex by itself cannot cure AML. We know that. We don't know that 100% because um the initial clinical trial with vet was in the relapse population which is always harder to treat. So we don't have vet single agent data in newly diagnosed AML but vettox in combination can cure AML uh but not all. So it highly dependent on the subset of acute malo leukemia. It's very heterogenous disease. So it has multiple different genetic subsets. So what we know now is that patients who have two particular types of mutation one is called MPN1 the other one is called Idh12 again MP1 is very common it's about 25% IDH12 is about 10% so you can take it you know about 35% of to patients if you treat them in combination uh of uh hypomethane agents and vinyl clocks the cure rate I would estimate is about uh 60% %. So these are the subsets that are particularly sensitive to venettolax therapy. What are the common side effects of venettolax? So there are two well-known side effects of venettolax. So one is something called tumalyzis syndrome. So that was first seen in a different disease called CLL or chronic lympositic leukemia. So while I'm not talking about that, the vet has been approved for CLL a while ago before AML and CLL cells are truly like depend on BCO2. So they you hit them with a little bit of anx going to die. So what happened in the CL patients because they have a large tumor mass usually with the lymph nodes and high white count. That's kind of typical presentation. When they took veno clocks in the initial studies there was so much tumoralizes. So there was so much tumor killing at the same time very short time so the drug works very quick so within hours essentially that there was this complication called tumoralizer syndrome. So what happens is essentially when the cells bursts open they release a lot of substances one of them is being potassium and when the potassium levels are high that can impair cardiac uh function and cause arhythmias and this could be lethal. So this was uh this became what we call black box warning for venetto clocks and the initial studies in fact in cila were held for some time till we figured out how to give it safely. So then again it's different in acute malo leukemia but uh it can still happen in acute malo leukemia. So to mitigate that we limit the starting white blood cell count to less than 25 and we have drugs to reduce that. And then when we start vetto clocks uh we usually monitor the lapse very carefully like twice a day for the first few days just to make sure that uh we don't have that complication. It's easily treatable when you can recognize it. But the main thing is just to kind of see that is happening in AML. It happens very rarely. It's only about 4% risk of TLS which is mainly like laboratory and not a clinically significant risk. But still uh this guidelines of monitoring and starting with a low white count they exist. The second more common side effect that I already mentioned that's something that we're trying to educate uh all the physicians across the US is what we call malo suppression. So the patients develop low counts for a long time especially when you use it uninterrupted. So it's again the label tells you to use it 28 days a month and uh so what happens is that many physicians would just keep going with this treatment. It's oral medication. So you know you just give the chemotherapy like we give some other medications on continuous basis and uh then the counts have very long time to recover and patients usually develop infection. So that's on target side effect because again normal myoid cells depend on BCO2 and uh again the ways to mitigate that is to interrupt treatment when the counts you know when you treat for example for two or three weeks you interrupt treatment and allow counts to recover and if the count recovery takes too long despite this interruption in the next cycle you interrupt it for after two weeks of treatment. So essentially we have to adjust the duration once patients are in remission. We have to adjust the duration of treatment based on their account recovery uh based on the ability of the normal bomero to recover from this toxicity and that requires a little bit of practice and a lot of education uh to make sure that we're doing this safe across the country. How are side effects typically managed? So the side effects again there are two side effects. So one is the tumaliza syndrome. So if potassium is high uh we have special medications to bring it down. We have to repeat labs few hours later. It's not just potassium. So sometimes something called uric acid is being elevated and that's something we see when in general there's a lot of leukemia in the blood and we use prophylactically agents that reduce uric acid regardless of even therapy. So there are certain measurements. Then patients usually have to drink a lot of fluids to kind of wash out everything. the debris. So these are management of tumalyzis also phosphorus is another one that is easily managed um for the mouse suppression I already talked about. So it's basically uh interruption of the duration of ntolux management but these are pretty much only the only side effects again we do not see any side effects related to the kidney liver function cardiac side effects so essentially the only side you know clinically significant side effects is uh the risk of infection because of the low counts that develop with prolonged therapy and then we also use growth factors sometimes so when the counts are low and they do not recover in time. We do use generously the growth factors to help the recovery if patients are in remission. So that's another approach to manage the mouth suppression. What are growth factors? There is a growth factor called granulite stimulating growth factor. It's called GCSF. uh has many different names depending on the company but is essentially a injection uh under the skin and you can give one or two or three injections like every day and that facilitates the white count recovery. It's used routinely for example in patients who are undergoing stem cell transplantation uh to facilitate engraftment of the stem cells. So it's approved for the chemotherapy induced uh uh low counts white count. When during the course of treatment is venadax used when is venuax used during the course of treatment? It's a great question. Uh so as I said previously venox is being used in combination with other agents and vitol is what we call targeted therapy. So it's not a chemotherapy. It doesn't have many side effects which is great despite the fact that BCO2 is expressed in all normal cells. The normal cells somehow they do not depend on BCO2. So nothing happens to the kidneys, liver, heart or any of these other vital organs if you use venad clock. So they're safe. They there's no killing of this normal tissues which actually allows doing it in combinations. So the idea of using vital is really to elicit maximal synergy with whatever drug acts that you're using. So we use it for the most part in combination from the day one when we combine it with chemotherapy or hypermethylating agents or as I mentioned some of the new approaches with the target therapy immune therapy. So we're really trying to get lower that threshold for the survival of the cells while there's another agent on board. So that's kind of the idea that uh we are exploiting. So essentially vital always overlays some other treatment uh that we are using. With that said uh one side effect that I'll perhaps discuss later is it there's some toxicity against normal myoid cells. So normal myoid cells that are cells that are called for example neutrfils um and they're important for protection of infection. So one and it's because they're also cells of the bone marrow. So they're very closely related to leukemia and they have BCO2 and they are dependent on BCO2. So that's one of the um more challenging side effects that we encounter which means that patients who are taking venadoxa they will develop low white count for quite longer time than if they were treated with chemotherapy only let's say. So there's a tight balance there and obviously if they have low white count they're susceptible to infections and uh unfortunately infections is the main cause of death in our patients. So because of that we have to titrate the duration of another clock to the shorter period of time and uh again kind of aiming at the synergy with another drug and then allowing bone marrow to recover. Now um you may want to ask me the venadox is approved for continuous use which is true. So like all other small molecule inhibitors the initial trials that led to approval we're using uh on a continuous basis. With that said over the time we learned that we are unable to do so because patients will just not recover their counts. they will get infections and side effects and that's uh really not the goal of it. So right now uh while we use venad clocks for let's say 1 month of treatment in the induction which is the first cycle of treatment that the patients will be getting after that we are trying to limit the clock use to 3 weeks or two weeks depending of sometimes there's different patients who can tolerate different duration so to allow the recovery of the normal bulo but to to answer the initial question where when you use vinylax it's always come from the beginning. So you always use it in combination with something else and actually a little bit longer after the agent X has completed. How is Venettoax administered? So Vaglox is a oral uh therapy. It's a pill. Uh the different strengths of pills. Uh the approved dose is 400 mgram. So the pills the largest size of the pill is 100 milligram. So the full dose the patient would take 400 milligram or four pills a day. So now with that said, venettolex is a drug that is uh being metabolized uh in a way that is affected by other medications that the patients take and our patients in particular they take a lot of uh antibiotics and antifungal medications that can affect the levels of ventolux. So there are very clear dose reductions of venadlocks if patients are taking some of these medications. So what I'm getting at is for example if the patient is getting antifungal medication usually he or she would take lower dose of anox and get to the same effect which is you know some ways would be good right so first of all it saves you know cost of the medication second is a few pill burden for the patient generally because it doesn't cause a lot of nausea or diarrhea it's well tolerated pill even when it's used like at 400 milligram dose so very few patients have any particular uh gastrointestinal side effects. But you know there are some patients who may have issues with their GI tract with the stomach sensitivities or diarrhea and of course for those patients having oral therapy perhaps is not ideal but these are I would have to say minority right so for those uh having the introvenous medication might be more effective and uh more controlled in some sense but of course all medication allows you to take it as an outpatient so you don't have to be in the hospital for that and in fact uh we do not use that strategy but I know that in other centers of America even the first chemotherapy for leukemia when they're using vinyl clocks can be done as an outpatient again we feel that this is perhaps uh too courageous and we still admit the patients for the first cycle of treatment just because they are old and they have side effects related to their leukemia and infections but on the subsequent cycles all the therapy is outpatient And so for example if they get isocitin or decide they they have to come for that IV portion of it. So every months for 5 to seven days a month they have to come every day to get IV portion but is a pill they take at home. So right now we have a lot of clinical trials where we're using oral chemotherapy agents as well but these are not yet approved in combination with vet but eventually once we show that they work similarly for example this oral decide that we're testing oral isocitin if we show similar efficacy then it will be like totally oral therapy which is amazing thing for the patient with acute leukemia because in the in the past you know all we had is high dose chemotherapy with high side effect profile, a lots of transfusions, a lot of complications that patients had to be in the hospital. So that really changes uh is in a way what they call paradigm shift for older patients because of the quality of life and uh they don't have to be in the hospital that much and that eventually becomes really important for many of those uh people to be able to take uh chemotherapy at home and for example in my clinic I have a lot of patients who are in remission and they continue on this regimen so they don't even come to me so we have now fortunately the tele medicine you know, option. So, I'm calling them once a month. You know, we're checking their accounts. Obviously, they have local oncologists and, you know, depending on how they tolerate, how they do, you know, we tell them, "Oh, you're good to go. So, you start on Monday next cycle." So, I have, for example, one patient, I call her this week, and she didn't have to to do any blood counts for the whole month. So, she does blood work once a month. Uh, it usually it's good. She starts her little chemotherapy for 5 days, right? and then she's done for the rest of the months. So, of course, it's not always like that easy, right? But there are quite a few patients that are able to, you know, just get the therapy for a few days and then kind of be free of that. So, I think it's really important and in that sense, of course, having an oral agent is really beneficial. Now, one population where it's a little bit more challenging are pediatric patients. Now is not yet approved for children. Um but they do have a liquid formulation for the kids. Um and that's something that is being tested because we really want this agent to be available for the children with leukemia as well. Is venettolax used alone or in combination? What combinations with venettolex are often used? So what are the combinations that are being used with venettolex? Some of them I already mentioned. The ones that are FDA approved are combinations with hypometane agents and with lowd doerabin. So these are the only ones that are approved. But there are many other combinations that are ongoing with highdose chemotherapy in younger patients. The studies are actively ongoing and we hope it will get approved. But there are a lot of different things that are being still on the stage of clinical trial or early clinical trials. For example, one of them that is being pretty far advanced is a combination with the targeted therapy. There's a subset leukemia of of AML that have particular mutation called FLT3 mutation. It's pretty common. It's about 30% of patients have that especially in younger patients in fact and uh this is what we call poor risk mutation. So this patients are usually respond to chemotherapy and then they have to go for transplant but even then they relapse. So what we found is that if you uh use venadoclux in combination with the inhibitors of this particular mutation there number they're now two approved FDA approved one is called mitoin another one is called guiltinip they're FDA approved for combination with chemotherapy but if you add venadlocks to that that will can lead to the responses in patients who for example relapse after standard of gear therapy even if they had this uh drug before if you add vinyl class you can get them into remission. So this is pretty amazing and now we have many clinical trials looking at this patients who are relapsing with the standard of care but also we moved it into the frontline therapy. So because we found that addition of vinyl clock will increase the depth of response in combinations with again with this flexy inhibitors and also perhaps uh increase the cure rate but again we don't have that data that's kind of what we're aiming at to increase the cure rate. So this is one example of combination that is pretty kind of far advanced but there are other ones that I mentioned with immune therapy for example that are being on that are currently ongoing that look very promising as well. How effective is venetax? Does it tend to work best in a certain subset of patients? Yes. So I already mentioned that vanoclax is working best in certain subset of patients. uh for example patients which have MP1 or IDH mutations and it does not work well in some other subset of patients. So it does not work well for patients who have p-53 mutations and these are usually patients who have what we call therapy related leukemas after they had some other malignancy and this is the most difficult subset of patient that we cannot cure. What research is being done with venox to make this therapy more effective? So there are many many different ways uh that are being looked at. So one of them is using the inhibitors of other BO2 family members. For example, MCL1 is another one that is uh highly expressed in good malo leukemia. So if you take in the lab B2 inhibitor and MCL1 inhibitor, they're highly synergistic in almost all types of AML including P50 mutated EML which is we cannot cure with vinylox. Uh so the clinical trials are ongoing with MCL1 inhibitors. Unfortunately they ran out into some side effect issues. So they have been taking longer time than we expected. So that's one uh highly promising but uh challenging to deliver uh therapy. The second one that uh I like a lot is combination with immune therapy. So for example and immune therapy is not yet approved in acute malo leukemia. So it's somewhat experimental. We have developed for example couple approaches like that. Uh one is uh core targeting of something on the cell surface called CD123. So it's a protein that is highly expressed on the AML cells. It's very specific. Well, it's expressed to some extent on normal cells too. Uh but there's antibbody that can affect that uh that binds to the cell surface gets internalized and kill the cells. So we show that the combination with vintox is highly effective and when you do this combination and the other antibbody also it's against a protein called CD47. So that's very interesting story. So that's was discovery by Stanford uh researchers. So CD47 is called don't eat me signal. So essentially when tumor cells not just leukemia but tumor cells express the CD47 cell surface they prevent macrofasages from eating them up. Um so even if they're being like hit with something the macrofasages are unable to engulf them and that kind of makes the cells survive better. So they developed the antibbody uh called47 antibbody has commercial name which was taken by the company and it did not work as a single agent again um but in combination with aocitin it works very well. So what we showed that if we take veno clocks then cells actually in addition to like blocking this 47 they express more like eat me signal. So they have like some eat me signal and then you block don't eat me signal. So now the macrofasages can come in and eat up this leukemic cells. And this is very cool because in some sense uh you know the macrofasages digest all the debris of leukemia cells. So you expect lower side effects and both of these approaches are very safe. So that's something that is in clinical trials right now and uh we are kind of highly excited about that. And then the last one that I already mentioned is combination with other targeted therapies for example the flex inhibitors that you know we discussed before but also other for example in CML combinations with tyros and kindinis inhibitors but again there is more used for the patients who have accelerated disease more like AML type of disease. So these are the major combinations I can think of that are being currently exploited. But there are many many many more that are highly perhaps promising that I don't have time to do.