This is turning into Cardiovascular Week around the blog, I have to say, and not in a good way. The latest news is the failure of a drug candidate from Takeda, TAK-475 (lapaquistat). They were in the lead in the field of squalene synthase inhibitors for cholesterol lowering (many other companies have taken a crack at this target, and dropped out along the way)., and their compound once had hopes of being a pretty big deal.

Not any more. In retrospect, the bell sounded late last year, when the company had to stop dosing at their highest level. Elevated transaminase levels were being seen in the treatment groups as the dose went up, which is a sure sign of trouble, as in liver damage trouble. Some investors seem to have held out hope for the compound to show enough efficacy at the lower doses, but Takeda has announced that the safety/efficacy ratio doesn’t justify taking the drug forward.

Liver enzymes are definitely one of those things you worry about when you go into man. There are all sorts of assays that are supposed to give you a read on that problem beforehand, and it’s safe to assume that Takeda ran them. But you’re never sure until you hit humans. Animals can react very differently to some compounds, although that can go either way. But if you set off liver enzyme trouble in rats or dogs your compound is probably dead, no matter how it might act in humans. You won’t get the chance to find out, most of the time.

The alternative is to use human liver tissue, but cultured human liver cells rapidly lose their native abilities and become untrustworthy as a model for the real world. Human liver slices are another alternative, but those are rather hard to come by, as you can well imagine, and the data from them have a reputation for being hard to interpret and hard to reproduce. No, for now, there’s no way to really know what will happen in humans without, well, using humans.

The big question that always gets asked in these failures is whether this is a compound-specific effect, a compound class effect, or a mechanistic effect. Most of the time it’s one of the first two. There are particular compounds, and particular structural series, that are known to be Bad News for liver enzymes. There will be some lingering doubt, though, because there’s plenty of squalene synthase activity in the liver, and it’s not impossible that any compound that hits it could cause the same trouble.

There are a number of other inhibitors out there – interestingly enough, they may have other uses besides lowering cholesterol. For some time, it’s been thought that such compounds might be useful antibiotics, since many bacteria need cholesterol synthesis pathways to survive. And there’s a recent report in Science putting this to the test in a particularly relevant system, particularly virulent strains of Staphylococcus aureus.

The “aureus” part of the name refers to the yellow hue that many strains of the bug exhibit, which seems to be correlated with how nasty they are as an infectious agent. The color comes from staphyloxanthin, a pigment that seems to be used as a defense agent by the bacteria by neutralizing reactive oxygen attacks from a host’s immune system. As the current work shows, the first enzyme in the biosynthetic pathway for staphyloxanthin (known as CrtM) has a lot of structural similarities to human squalene synthase. The authors prepared a number of known squalene synthase inhibitors from the literature, and found that one class of them (the phosphonosulfonates) also inhibit CrtM.

They went further, showing that one of these compounds (a BMS clinical candidate from about ten years ago) actually works quite well as an antibiotic in vitro and in an in vivo mouse model. I'm not sure why this compound didn't go further, but perhaps it (and the others in its class) will have a second life in the antiinfectives world. . .