From Cart-1 you can see in Figure five in the online article referred below that restenosis rates were significantly lower with AGI-1067.
My question is..can you infer/guess that other clinical events will also be lower with just that piece of info with sufficient confidence to bet on it..? I would say no..
First, appreciate the pushback. Now some comments:
I agree that the Ph ii IVUS data by itself is not adequate to make a strong call on AGI-1067. But it is stronger than you may realize. 4.5% reduction is plaque volume just doesn't sound like much over 12 months of treatment. BUT it is substantially more than REVERSAL got for the same metric after 18 months and PROVE-IT (using the same protocol) got 16% improvement in MACE (16% measured improvement in ARISE would be stat sig)
Ok, so that is the plus story. The minus story is:
a) The total atheroma volume change vs SoC in CART II was not as high as REVERSAL (I 'spoke' incorrectly earlier - the CART-II total atheroma volume improvement was the same for treated as the treated arm in REVERSAL ... but in CART-II the SoC arm performed better than in REVERSAL so the difference between the two was less in CART-II). Mitigating this is the fact that REVERSAL was 18 months, CART-II only 12 and a variety of trials (e.g. ARBITER II) indicate that plaque volume changes seem to have inertia (they don't 'min out'.)
b) No one really knows how important or consistent each of the pieces of IVUS data is (lumen volume, plaque volume, total vessel volume, ...). For instance perhaps it is the type of plaque that is important and AGI-1067 doesn't effect the right type. Mitigating this is that there have been enough trials now that qualitatively there does appear to be a reasonably consistent correlation.
c) SoC changes. CART-I and CART-II were run before high dose statins became common. Maybe AGI-1067 just can't add anything now if it is commonplace to prescibe statin doses high enough to cause plaque regression. Mitigation - to date there have been no sign of 'min out'. Another possible SoC issue is DES - probably 50% of all events in the trial will be stent related. We know that AGI-1067 works in BMS stents (see CART-I), but DES ...? No real mitigation for this issue.
All in all I agree that the ph ii's by themselves are middle of the road ph iis. Not strong and not weak. But certainly enough to warrant the ph iii and enough to roughly size it. The real case for AGI-1067 is a combo of all of the data - Probucol (AGI-1067 is not completely first in class), pre-clinical (showing atherosclerosis efficacy despite poor LDL/HDL characteristics), ph ii and slow event rate in ph iii post acute phase. None of the pieces by themselves are particularly strong.
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