Replies to post #149459 on Biotech Values

[mcbio]

Yet again my pet peeve - once a drug gets reasonable efficacy with tolerable sized pills or subq injection or ... then further potency is generally of little importance. Comparative specificity, pk, ... are much more meaningful since they indicate potential improvement of efficacy vs toxicity - but much more difficult to accurately characterize pre-clinically and so there are a ton of PRs touting a statistic that sounds cool but means little. FWIW In practice I count such touting as a strike against a company because it either indicates sloppy understanding or a hyping attitude.

Withdraw said strike as EC0531 has a completely different 'warhead' as it's using Tubulysin-B whereas vintafolide uses DAVLBH as its 'warhead' (http://www.endocyte.com/?page_id=21 ).

[BTH]

FWIW In practice I count such touting as a strike against a company because it either indicates sloppy understanding or a hyping attitude.

You must have a lot of "strikes" then, because just about ever company with a competing oncology drug says something to this effect when looking at preclinical data.

[DewDiligence]

As an extreme example, Abgenix (later AMGN) touted that Vectibix was 100 times more potent than Erbitux. Which one turned out to be the better drug?

[exwannabe]

Yet again my pet peeve - once a drug gets reasonable efficacy with tolerable sized pills or subq injection or ... then further potency is generally of little importance.

Understand and generally agree. But is there a bit of an exception in targeted agents such as ADCs (and ECYTs small molecule equivalent)?

At a certain dose the receptors would more or less saturate. At that level, the agent may or may not be at a near optimal efficacy. The difference between this and a simple small molecule is that in the latter you can ratchet the dose to achieve the goal, in the former you can only do that to some extent.

I do agree that even in the targeted case, once the desired efficacy is reached the "we are 25x stronger" claim is nonsense.

[biomaven0]

once a drug gets reasonable efficacy with tolerable sized pills or subq injection or ... then further potency is generally of little importance

I agree that potency per se is not that important, but my impression is that ultra potent small molecules (single digit nM IC50's) tend to do better in practice. Not something I've ever looked at systematically, but very high potency is likely a proxy for selectivity - if the molecule fits the target "just right" then it tends to not fit other targets with similar structure as well as might a molecule with just an "OK" fit. A similar argument can be made on the tox side - all other things being equal, a smaller effective dose will be less likely to produce some unexpected liver toxicity or the like.

In this particular case with a "warhead," I have no clue whether higher potency will be better or not - could just as easily be worse, with more collateral damage limiting the tolerable dose.

Peter