ASH 2023 | COVALENT-101: investigating menin inhibition with BMF-219 for treating patients with R/R AML or ALL

BMF-219 is a covalent menin inhibitor, which basically means that it interrupts the binding of menin with its client proteins on a covalent basis, which we think produces a longer lasting and more potent effect than other non-covalent inhibitors that are currently being developed or on the market. And we launched a study of BMF-219, in patients with relapsed and refractory acute leukemias, amongst other menin related or menin driven diseases, such as CLL, myeloma, non-Hodgkin’s lymphoma. But our abstract at this year’s ASH meeting reports early data in the acute leukemia cohort.

The BMF-219 drug is administered orally on either a once-daily or twice-daily basis. There are two different arms to the study. One arm is for patients that are not currently receiving a CYP3A4 inhibitor. The second arm, arm B, is for patients who actually are receiving a CYP3A4 inhibitor, given the fact that, BMF-219, like many other drugs, is a CYP3A4 client protein and there is potential for interaction. So we we tested both settings with and without a CYP3A4 inhibitor, especially given a large proportion of acute leukemia patients are receiving concomitant antibiotic prophylactic therapy with a CYP3A4 inhibitor such as voriconazole or posaconazole or fluconazole, or those types of drugs. And the study is currently ongoing in a dose escalation phase, and we’re reporting out on the initial 29 patients who have been enrolled to date and the early indicators of toxicity and efficacy and pharmacodynamics. 

So what we’ve seen to date, in terms of the pharmacokinetic effect is that there seems to be what looks like a dose proportional effect, especially in arm B, in patients receiving a CYP3A4 inhibitor. And interestingly, we really haven’t reached a consistent dosing that allows us to reach the target AUC levels that we think are associated with the best likelihood of clinical response based on preclinical modeling. So we still have a ways to go to reach that consistently, but today we’re starting to see that level of activity being reached. 

In terms of safety, we have not seen any dose-limiting toxicities to date. We have seen four cases of differentiation syndrome, which is obviously a common type of toxicity with this class of agents. Fortunately, none of the patients that develop differentiation syndrome had to be stopped from the study. For that reason, they were managed conservatively and the differentiation syndrome improved. In addition, we did not see, as I mentioned, any other dose-limiting toxicities, and no patient had to come off of the study itself for any toxicity-related concerns. 

In terms of efficacy, we are seeing some early signs of efficacy. We had, I think, nine efficacy evaluable patients to date, meaning patients that had completed the DLT window of treatment and also had what was considered a menin inhibitor-sensitive type of molecular phenotype, namely NPM1 mutation, MLL rearranged leukemia, or some other molecular anomaly felt to be associated with a higher likelihood of response to a menin inhibitor. So amongst those nine efficacy evaluable patients, we did see two responses. One was a complete response, the other was a complete response with incomplete recovery.

And like I mentioned, the study is ongoing at this point with dose escalation, with the intent to reach the biologically most effective dose that results in a consistent ability to reach target AUC levels and at the same time hopefully minimal toxicity. So we think that, again, this is a promising agent in the sense that it has some unique biochemical features that make it a little bit different than the other menin inhibitors, in terms of its covalent bonding to menin. And that, we hope, could potentially lead to good outcomes for patients and also potentially be a way to treat patients who have previously been exposed to menin inhibitor, by virtue of the fact that this drug works a little bit differently. So that’s where we stand with this particular trial right now, and I hope to have more updates in the coming months as to the safety and efficacy profiles.