Since we were just talking about antibody therapies in immuno-oncology, here’s a timely column by Bruce Booth at LifeSciVC on antibody therapies in general. It’s well worth a read if, like many small-molecule drug discovery folks, you haven’t had to keep up with that area. I’ve written a few times over the years about how antibodies have been gradually taking up spots on the lists of best-selling drugs, and Bruce’s piece continues in that same way. Did you know, for example, that five antibodies have already been approved by the FDA this year? Or that mAb projects have just about double the chances, when entering the clinic, of making it through to an eventual approval versus small-molecule ones? (In case you’re wondering, those percentages actually go up outside of oncology).
There’s also a good discussion of humanized versus fully human antibodies, and how the latter are gradually taking over the market (at present trends). Here’s something that you may not have realized:
In particular, it’s worth highlighting the transgenic UltiMab technology developed at Medarex. With ten product approvals*, Medarex’ UltiMab platform has produced more approved drugs than any other human antibody platform in the industry. As an aside, BMS’s acquisition of Medarex for $2.6B in 2009, viewed with some skepticism at the time, is probably one of the best biotech acquisitions of all time. Nivolumab (Opdivo), discovered out of the Medarex platform, had sales of $2.6B in the US alone last year, and is forecast to have sales north of $12B within five years. Funny to reflect on this wonderful lead sentence about Medarex in an article in the spring of 2009: “If there’s a pharma company that rewards executives for delivering absolutely nothing, thy name is Medarex.” Delivering nothing? How about one of the most productive antibody platforms ever created.
In all fairness, a lot of people had complaints about Medarex’s management, but the science was indeed solid, and you can make the case that BMS did the acquisition to keep the latter and ditch the former. At any rate, Bruce is right that the platform itself has been very impressive.
Read the rest of his post as well for an interesting discussion of the attempts to use biophysical properties and in vitro assays to sort out which antibodies have a better chance of success in the clinic. Medicinal chemists will immediately recognize the impulse to start “Rule-of-Fiving” things in order to (ostensibly) improve the quality of lead drug candidates, but (just as in small molecules) the evidence, while there is some, is still not as compelling as the ideas behind it. The various attempts to score antibodies before they get to the clinic, while they do flag some interesting differences between the various modes of producing them, so far don’t seem to correlate well with eventual clinical success. And that’s the whole point of the exercise – otherwise, a difference that makes no difference is no difference. This doesn’t mean that no one will ever be able to do this sort of thing, but it does mean that it’s not necessarily far enough along to be a real actionable step in the process.
And Bruce’s final point stands, and just as strongly for antibodies as it does for small molecules. In the end, success depends on our knowledge of disease biology. That is still the big rate-limiting step. You can march into Phase II trials with a potent, selective small molecule or with a beautifully targeted non-immunogenic human antibody, and if you’re wrong on the disease mechanism or the importance of the target you’ve selected, then you’re going to go down in flames either way.