What is venetoclax?

What is Venetoclax? Venetoclax is a small molecule inhibitor of protein called BCO2. 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 hematologic malignancies, including acute myeloid leukemia. So what Venetoclax does, it specifically binds to BCO2 proteins through specific protein-protein interaction and it prevents essentially collaboration between BCO2 and pro-death proteins. So what happens is that BCO2 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 leukemias are highly dependent on BCO2, 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 tumor cells as to the normal cells. That's how it works. It's also called a universal sensitizer because by lowering the threshold of cell death, it essentially increases the sensitivity or responsiveness to many, many different types of therapy, being like regular chemotherapy, targeted therapy, immunotherapies. So right now Venetoclax is used in multiple, multiple combinations. So if you look at the clinicaltrial.gov website, probably more than 50 clinical trials are ongoing with different combinations of Venetoclax in different hematological diseases. So I think that's added value. So by itself, it may not be as effective because the tumor cells are very smart and they get around a single agent. But if you combine it with some other therapies, then it becomes really a killer and gets rid of leukemia. What are the BCO2 proteins and how do they play a role in AML? So Venetoclax is an inhibitor of BCO2. BCO2 is a protein, but there's a whole family of BCO2 proteins. And BCO2 is obviously one of the key ones, we think, but there are multiple other cousins of BCO2. For example, they're called the MCL1, BclXL, BCO2A1, and the BCOW. So there are four other proteins that can take up on the function of BCO2. So the function of BCO2 and some of these 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 is an organelle within the cell. And so these proteins are essentially defending this mitochondria from cell dust because inside of the mitochondria are some other molecules that can kill the cells if they're being released. So there's a BCO2 family of proteins that protect from cell dust like BCO2, but then there are other family members that are in fact killing the cells. So there is a very tight equilibrium between the pro-survival and pro-death proteins. And what Venetoclax does is impairs this equilibrium so that now BCO2 is being neutralized, but the pro-death proteins are being freed to go ahead and kill the cells. So that's the idea. And now we have emergence of some other small molecule inhibitors that inhibit other family members of BCO2. For example, MCL1 inhibitors, they're in clinical trials. BCO2 inhibitors are in 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 myeloid leukemia, there are probably some cells that depend on BCO2 and some cells that depend on MCL1. So ideally, you would like to target all of them, but it comes down to the therapeutic ratio and if a patient or organism can withstand the toxicity of these agents. So Venetoclax was approved in 2019 for acute myeloid leukemia usage. It was approved in combination therapy. So initial trial that we actually have done back in 2016 was a single agent inhibitor, Venetoclax, in the patients who had relapse refractory disease. And despite the fact that studies in the lab have predicted that as a single agent, it will be highly efficacious, the tumor cells were smart and they got around it. So we saw responses, but they were short-lived and that the response rate was too low for you to move forward as a single agent for the approval. So the next clinical trial was in combination with two different types of agents. One's called low-dose chemotherapy, Cytarabin, and the second is what we call hypomethylating agents. So these are the agents that affect epigenetic makeup of the cells. They're approved for therapy of acute myeloid leukemia such as Isocytidine or Dicytabin. So these clinical trials 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, Isocytidine, the response rates are somewhere, I would say 20% or less in acute myeloid leukemia. But when you combine with venetoclax, it goes up to nearly 70%. So that was like a more than doubling of response rates. Again, coming back to the idea that inhibition of B-C-O2 really kind of sensitizes it to chemotherapy. 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 Viali-A for Isocytidine combination, and then there was Viali-C for Cytidibine combinations. And both of them confirmed the data in phase one, two studies. And they also showed that in addition to high response rate, actually patients lived longer. And this was the most important endpoint because sometimes we have drugs that can induce what we call remission response, but then the 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 myeloid leukemia. And so they led, as I mentioned, to extended survival compared with the 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's 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 U.S. and many other countries as a frontline therapy for older patients. 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 venereal cleft is right now being used for the majority of acute myeloid 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 last year from our institution showed that addition to the high dose chemotherapy in younger patients leads to the higher response rates. And the majority of these patients were able to transition towards stem cell transplantation. But these studies are still ongoing. And at this point, venetoclax is not approved for younger patients. But I think it's just a matter of time. And we'll have it available for essentially all AML patients in some sort of combinations. Unfortunately, venetoclax by itself cannot cure AML. We know that. We don't know that 100% because the initial clinical trial with venetoclax was in the relapse population, which is always harder to treat. So we don't have venetoclax single agent data and newly diagnosed AML. But venetoclax in combination can cure AML, but not all. So it's highly dependent on the subset of acute myeloid leukemia. It's very heterogeneous 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 MPL1. The other one is called IDH12. Again, MPL1 is very common. It's about 25%. IDH12 is about 10%. So you can take it about 35% of total patients if you treat them in combination of hypermethylating agents and venetoclax. The cure rate, I would estimate, is about 60%. So these are the subsets that are particularly sensitive to venetoclax therapy.