Venetoclax (ABT-199) is an unusual drug. But now there’s some unusually bad (and unexpected) news about it. That’s the structure at right, and medicinal chemists will understand immediately why it’s a bit of an outlier. With a molecular weight of 868, that structure just keeps on going, with a somefeatures that you don’t usually see, like that dimethylcyclohexene linkage and the ortho-nitro aniline part. No one makes a molecule like that without a reason, and in this case the structure is necessary for it to bind to the Bcl-2 protein, which is involved in apoptosis signaling in lymphoma cells.There’s no traditional small-molecule-ligand site on that one, and protein-protein interactions like that have always been considered a tough place to get anything to work in drug discovery. Bcl-2 keeps apoptosis from proceeding, actually, so blocking that pathway sends the cells to a speedy end – so speedy that earlier in the drug’s development some patients had kidney problems from how fast the lymphoma cells were being cleared.
But AbbVie perservered, even after their original molecule in the field (ABT-737) ran into trouble in the clinic with effects on platelets. That was another whopper compound, but it wasn’t selective enough for Bcl-2 over other related proteins. The more selective ABT-199 did the trick, though, and showed very good efficacy in clinical trials against chronic lymphocytic leukemia (CLL). It’s approved for that indication, and has been under investigation for multiple myeloma as well. In that case, there are particular subtypes of the disease that show high Bcl-2 expression relative to the other Bcl subtypes, and those are just the patients that seemed to be responding to the therapy.
Unfortunately, that joint Roche/Abbvie clinical effort has come to a sudden halt. Just yesterday, it was revealed that the treatment group (venetoclax, bortezomib, and dexamethasone) was showing a substantially higher mortality rate (+20%) than the control standard-of-care group (dexamethasone alone, in refractory patients), and the FDA immediately put a partial clinical hold on the work (no new patient recruitment, for the moment). As well they should. But this bad news was completely unexpected, as far as I can see. Earlier clinical trials in myeloma patients don’t seem to have shown any signs of this problem. This doesn’t affect the drug’s existing approvals for CLL or AML, but it does perhaps show how different multiple myeloma can be from either of those.
There are more trials going on with various venetoclax combinations than I have time to count, and this news has sprayed uncertainty over pretty much all of them. Now to find out what the problem is – if that’s findable – and to see what the clinical path forward might be.