"I am trying to see if I can spot any investigations that directly correlate with clinical measures......The GFR is a measure that direcly correlates with kidney function so any change is clinically and immediately significant while alkaline phospahatase is more of an indirect clinical tool.  The same thing holds for a number of the tests that are cited, I agree they are all indirect evidence the drug works but that is not the same as direct evidence of a change in a clinical parameter."

Fenix, if I understand you correctly you are looking for examples of apabetalone modulating a hard endpoint (such as kidney function, atherosclerotic plaque volume, or MACE incidence) that was also found to be statistically significant. To my knowledge, there are very few reported findings for apabetalone are going to meet this strict criteria. The post-hoc analyses of SUSTAIN and ASSURE for eGFR, post-hoc analyses of the ASSURE trial plaque measurements, and the post-hoc analyses of ASSERT, ASSURE and SUSTAIN for MACE reduction may be the only items that meet your criteria. Additionally, for plaque reduction and/or MACE reduction there were high responder populations for patients with diabetes, high baseline hsCRP, below median HDL, or co-treated with rosuvastatin (Crestor). But this is all post-hoc and not pre-specified hypothesis testing.

As I have dwelled upon in a prior post, the clinical development of apabetalone has not followed the traditional, smooth path. The original plan was 1) Find optimal dose for apo-AI and HDL-C modulation in ASSERT; 2) Confirm optimal dose effects on apo-AI and HDL-C in SUSTAIN; 3) Prove that optimal dose elicits plaque reduction in ASSURE; 4) Cardiovascular Outcomes Trial. Quite the roadblock happened at step 3 when ASSURE failed. Even if ASSURE succeeded to show significant plaque reduction in the total population, there might not be any other strict clinical measures other to add to your list other than the ones mentioned above.

To me, it sounds like you don't apply much clinical relevance of apabetalone's reported effects to decrease vascular calcification, downregulate the complement cascade, improve glucose metabolism in pre-diabetics, lower glucose in diabetics, decrease several markers of inflammation and acute phase response, and reduce components of the coagulation/thrombosis cascade. The Resverlogix poster library has many other examples of these effects.

I have no problem with one being skeptical of Resverlogix and apabetalone because of its bumpy clinical path. However, remember Amarin's Vascepa was only a triglyceride lowering drug prior to REDUCE-IT cardiovascular outcomes trial (CVOT), and triglycerides are only now starting to be accepted as a valid cardiovascular risk marker. Even the LDL-cholesterol hypothesis has been challenged in recent years; it wasn't until the PCSK9 drugs proved that aggressively lowering LDL-C beyond statin and/or ezetimibe standard of care elicits further MACE reduction, that aggressive LDL-C lowering was validated as a surrogate for cardio risk. Alkaline phosphatase is getting there. There is a lot of interest in vascular calcification as a cardiovascular risk, and evidence is building that alkaline phosphatase activity, which apabetalone lowers, correlates with vascular calcification and MACE (see the ERA-EDTA presentations).  But right now alkaline phosphatase is not an established cardio risk marker. The apo-AI/HDL hypothesis is complicated. Lots of failed trials, dominated by the CETP story. But there really haven't been any drugs tested to increase HDL-biogenesis starting from apo-AI and testing effects on MACE. Even if BETonMACE succeeds, this won't prove the apo-AI/HDL hypothesis. With apabetalone having so many effects beyond apo-AI and HDL, it will be impossible to say that any MACE reducing effect is due to apo-I or HDL modulation. The CANTOS trial lended support to the hypothesis that inflammation increases risk for MACE, and apabetalone has many anti-inflammatory effects. However, some other recent anti-inflammatory trials have failed to show MACE reduction. So the inflammation story is still developing. 

So I totally see where you are coming from. Lots of indirect evidence that the drug should work to reduce MACE. Now we just need BETonMACE to prove it!

BearDownAZ