MDS 2023 | The efficacy of low-dose ASTX727 in low-risk MDS

ASTX727 is actually approved in the United States, it’s the oral decitabine and cedazuridine. So, we performed a number of studies, Phase I/II, to an eventual Phase III trial called the ASCERTAIN trial that led to the approval of this compound. So, what we did was to, and I think it’s kind of really interesting clinical trial design, we did the study where we compared the pharmacokinetic and pharmodynamic characteristics of ASTX727, the oral form of the drug with the IV one. We were kind of lucky because the results showed that they were basically identical. So, when you take this oral medication that is the oral decitabine, you get levels in blood that are identical to what you get if you inject the drug intravenously. So, this is very nice for the patients because now they don’t have to go five days every month to get these injections. If you are giving them the decitabine, you can take a tablet a day. The drug actually is two drugs, it has the decitabine and a second compound known as the cedazuridine, this is what we call a cytidine deaminase inhibitor. It is a drug that inhibits a key enzyme that basically destroys this cytidine in the intestinal tract and the liver. So, by inhibiting the inhibitor, you now basically can absorb full levels of the drug. So that was very exciting, and we basically were able to emulate the results of the decitabine on a five-day schedule. The standard dose IV is 20mg/m², so this medication at a ratio of 335 to 100 is identical. But now we want to do more. So, we have developed at MD Anderson, a lot of studies looking at the use of these hypomethylating agents in lower-risk myelodysplastic syndrome. So, it was logical for us to start looking into low-risk approaches. This is actually not approved in Europe, but it’s commonly used in the United States. So originally, we had published like three days of IV decitabine were optimal. So, we looked at that with the three-day oral, decitabine/cedazuridine and we saw kind of nice positive results. But then the sponsor of the trial realized that perhaps we could go even lower with these doses. So, what we presented at ASH last Christmas-last December, and at the meeting now, is this this kind of further research in known ratios of the decitabine with the cedazuridine. So, for instance you could look at not three days but five days, ten days, but perhaps lowering the dose of the decitabine into, let’s say ten milligrams with a fixed dose. So that’s already 100. So basically, resulting in lower doses. So, we don’t know yet what is going to be the final dose. By the way, this could have a pediatric angle. We’re starting to use this drug in kids that are, of course, smaller than adults and these are fixed doses. So, we probably need a lower dose even in children where we’re going to be using these drugs. So, we’ll probably soon have an idea of what is the proper dose, of this kind of even lower doses of oral decitabine/cedazuridine for low risk MDS and pediatrics and we are starting to see significant activity in that group of patients. So, I think this is a really important area of investigation. Indeed., going back to the second question that is going to be maybe discussed at the meeting on Friday, my task was to discuss like non-targeted approaches to MDS, but the program actually covers a lot of the things that are non-targeted, like for instance, combinations with BCL2 inhibitors, antibodies, etcetera. So at my talk, I’m going to focus on development of the oral hypomethylating agents and I’m going to show some data already presented at ASH, but I’m going to review it in a little bit more detail. For instance, where we have now doublets with total oral therapy that could be oral decitabine/cedazuridine with venetoclax, with really high response rates and actually intriguing data that we presented also attached showing that patients with P53 mutations actually seem to respond very nicely to these [ASTX]727. So, this drug may not be just the decitabine, it may be that there is some component of this combination maybe through this cedazuridine that makes this very active. So, I hope that this is of interest to the people here at the MDS meeting in Marseille. Thank you very much.