Biotech Values

[iwfal]

The issue is that lowering cholesterol upregulates PCSK9. So adding say Zetia to a statin will indeed lower cholesterol further, but the effects will be largely offset by increased PCSK9 - the massive IMPROVE-IT trial showed no benefit in overall mortality in a very high-risk population.

I would suggest that the knock on IMPROVE-IT (that it didn't improve OS) may be a valid criticism from a clinical treatment perspective - but is not as a readout on LDL benefit perspective.

Yeah, it was a small CV risk reduction - but there still was one. And it now appears across 3 drug classes. Could it be coincidence? Certainly, but as a working hypothesis it seems reasonable. Would I fully approve a drug for typical high cholesterol based upon it (i.e. without a CVOT trial)? Probably not, because I'd still give a 20 or 30 % chance for the next class that lowers LDL that it is significantly wrong.

Separately, I would suggest that reading from LDL Lowering to PCSK-9 raising to no effect is pushing out knowledge of the cholesterol control loops a lot further than our knowledge warrants. The cholesterol control loops are, like many body systems, wildly complex and we understand many of the links very poorly. So we are stuck extrapolating connectedness (of LDL lowering to CVOT benefit) from the RCT observations.