BETA - What is Midostaurin

What is Mitostorin? What are the most common side effects of Mitostorin? So Mitostorin is an oral chemotherapy agent. It specifically comes under the umbrella of targeted therapy because it targets a mutation found in roughly 30% of cases with acute mitral leukemia. The most common side effect of this mutation is the flit 3 mutation, either ITD, which is internal tandem duplication, or TKD, which is tyrosine kinase domain. So around 30% of patients with AML will have this mutation and Mitostorin is an oral agent targeting this mutation specifically. We don't know if it works for other mutations, but it is approved in AML only for patients harboring the flit 3 mutation. What led to the approval was a randomized phase 3 study in which patients younger than 60 years of age who had a flit 3 mutation were randomized to receive intensive chemotherapy, which is standard of care with seven days of siterabine and three days of an anthracyclin. Patients were then given Mitostorin versus placebo. So the comparison was 7 plus 3 plus Mitostorin versus 7 plus 3 plus placebo. Mitostorin was given at a flat dose of 50 milligrams twice a day, starting at day 8 and continuing through day 21 of chemotherapy. And then it was added during consolidation chemotherapy as well. The overall, the primary endpoint of the study was to show overall survival benefit with the addition of Mitostorin to standard chemotherapy. And the study did meet its primary endpoint and there was a survival benefit for patients who had received Mitostorin compared to those who were receiving placebo. Now there are different ways to look at how much that survival benefit was because a lot of patients went to transplant as well. But broadly speaking, after four years of therapy, patients who took Mitostorin had a roughly 6 to 9 percent chance of living longer than those who had not received Mitostorin therapy. Some of the common side effects associated with Mitostorin were GI toxicity, such as nausea, vomiting, diarrhea, the elevation of liver enzymes, and needs to be monitored very when giving with other fungal medicines or other infection preventing medicines as well. How are these side effects managed? So in general, usually you give supportive medicines for the GI side effects like anti-nausea medicines, anti-diarrhea medicines. Sometimes you would hold a medicine for a little while, patients would feel better and then restart the Mitostorin. And as far as interactions with other medicines were concerned, you would ideally want to use other supportive medicines from a different class which would have the minimum interaction with Mitostorin. What is the difference between a first generation and second generation FLIT3 inhibitor? Broadly speaking, so FLIT3 inhibitors are becoming more and more selective as you go generation by generation. Meaning that the earlier FLIT3 inhibitors, so there was Sodafinib, there's Mitostorin now, there's Gilderitinib that's FDA approved, there's Cozartinib which was recently published and was a positive phase three study. So these are all FLIT3 inhibitors. The more novel the agent, the more specific they are, meaning that agents approved before had more targets in addition to just FLIT3. Now those targets may not be mutations found in AML, but they were just other targets that the medicine would cover, meaning that had a chance of leading to off-target toxicity or more side effects. So a very simple way of saying is that the earlier TKIs would have been more of a dirty TKI, meaning broadly covering several targets. And this could mean that whether that led to increased efficacy through some unknown mechanism, yes, but that also could mean that it could lead to more toxicity as well. And so the novel TKIs are more FLIT3 specific. They also have their own side effects, of course, but these mainly target FLIT3 so they may not have too many off-target toxicities and may just have regular myelosuppression which is low blood counts and other toxicities, but they may not be effective for other mutations like let's say some of the earlier FLIT3 inhibitors were. So that's a very good question. So when you treat people with myelostorin, there are different ways to capture response. So you know the basic response is whether they've achieved remission, meaning there's no, there are no more blasts in the bone marrow and the person has recovered their white cells, red cells and platelets and there's no evidence of disease by sensitive tests such as flow cytometry. So you could do an assay to look for FLIT3 which is called leuko-strat, which is a PCR basically. And that's how you initially diagnose the mutation at the time of diagnosis, either through PCR or NGS, PCR being a little more sensitive than NGS. So you can use this assay to see if the FLIT3 mutation has gone or whether it is present at a low level, which we would call measurable residual disease or MRD positivity. So patients, we know that patients or we have, we think we know that patients who are MRD negative tend to do better than those who are MRD positive in terms of relapse and overall survival. So yes, it does go away, but we now have very sensitive tests, for example, 10 to the power minus six, like looking at almost a million cells or more and trying to find leukemia cells from those cells, from those total number of cells. So we see where there's complete absence of leukemia or bad cells and then we see that there's a small presence and a small presence may predict for poor outcomes compared to complete absence of leukemia cells.