Talking with some drug discovery folks the other day, I said “You know, if you don’t hold your breath when your compound goes into tox testing, you haven’t been doing this stuff long enough”. Well, it’s pretty hard to hold your breath across a full tox study, but you know what I mean. There are so many possible problems, and we know so little about them (and so little about what our drugs might do) that you really have to be braced for the unexpected. And that goes for the first two-week rat tox study and all the later follow-ups in other species and for longer times (13 weeks, two years). Even after all that, you still have to be on guard when your compound goes into humans. The animal studies will catch a great number of things that you don’t want to expose the human population to, but they won’t quite catch them all.
That was illustrated yesterday by the news that Amgen’s antibody therapy Evenity (romosozumab) shows an unexpected cardiovascular liability – that is, it seems to increase the risk of heart attacks in its target population of post-menopausal women by up to 30%. The drug was supposed to come up for an FDA decision by mid-July, but that’s not happening any time soon, and it may not ever happen at all.
Romosozumab is a joint project of Amgen and UCB Pharma, and it targets a protein called sclerostin. That’s involved in the Wnt signaling pathway, which I’m willing to stipulate can cause almost anything to happen. There are some very rare bone disorders, characterized by abnormally high bone density, that can be traced back to mutations in the sclerostin gene, leading to a less functional protein. These genetic clues are just what drug discovery people are constantly looking for, and set off the idea of interfering with sclerostin as a possible way to increase bone density in patients that actually need it – those suffering from osteoporosis.
This idea actually worked (not all of them do, of course), and both animal studies and human trials showed increased bone density, as hoped for, and a lower rate of the common fractures in the osteoporosis population (vetebrae and hip). So things really were moving along as hoped for, and a completely new method of treatment was coming along, when the toxicity signal came up. That Matthew Herper piece linked to in the second paragraph talks about how this illustrates the limits of genetics in drug discovery, and also mentions the PCSK9 story in this wise. I see the two as somewhat different, though. What we learned from genetics was that interfering with sclerostin could increase bone density, and this is exactly what happened.
The few dozen people with such mutations, though, are not enough to tell you very much about possible toxic effects (as Herper notes as well). It might be that even a big population would not give you the signal, either, because of compensatory processes that could be acting in people who were born with such mutations, and which don’t have a chance to kick in when you hit someone with the same thing at age 70 – that sort of thing is well known in both human patients and animal models. PCSK9 is similar, up to a point – the genetic data suggested that it would have a big effect on lipoproteins, and so it does. But the PCSK9 mutant humans do also show a much-reduced risk of heart disease, which made that pathway even more exciting. The currently good-but-maybe-not-great human outcomes data for PCSK9 antibodies, then really might illustrate the limitations of genetic signals in developing new drugs, because you really would have expected more (although it’s still possible that longer-term studies will look better).
But sclerostin and romosozumab, at least to me, seem to be the more normal way that drug discovery has always worked. The genetic information did not (and could not) say that much about safety, and it wasn’t a beneficial mutation in the first place. Turning this around and using it for osteoporosis was a good idea, but was always going to be more risky than trying to recapitulate the good phenotype of PCSK9 mutant humans. And here’s the risk, reminding us that it’s still here, reminding us that it never goes away.