Although we still haven't solved the puzzle for why the median baseline eGFR in the total BETonMACE population is so surprisingly high (see this post from PomponiusCapital), the baseline alkaline phosphatase (ALP) values paint a different picture. 

In the BETonMACE baseline data poster that includes all BETonMACE patients, the baseline alkaline phosphatase value is listed as a median of 78 U/L. In the BETonMACE CKD sub-study poster, patients with eGFR at baseline of 60 mL/min/1.73m2 or less have a baseline alkaline phosphatase values of a median of 81 U/L. 78 vs. 81....pretty much the same. And these alkaline phosphatase values are in line with the median 76 U/L reported in the ASSURE/SUSTAIN post-hoc analysis of CKD patients with eGFR at baseline of 60 mL/min/1.73m2 or less and published in "Apabetalone Mediated Epigenetic Modulation is Associated with Favorable Kidney Function and Alkaline Phosphatase Profile in Patients with Chronic Kidney Disease."

Now, let's tie this back in to cardiovascular/MACE risk and coronary artery calcium score. First, this paper indicates that high ALP, which they categorize as higher than 66 U/L, is associatied with increased coronary artery calcification. Second, the discussion of the recent Atherosclerosis paper on vascular calcification stated "Elevated serum ALP is associated with vascular stiffening and cardiac events [31,32]. Apabetalone was recently shown to reduce serum ALP in CKD patients with a history of CVD [13]." Lastly, Dr. Kalantar-Zadeh's presentation from last year's ERA-EDTA provides several lines of evidence (see slides 16-29) for increased ALP being associated with increased MACE and coronary artery calcification, on top of the established association between coronary artery calcium score and cardiovascular risk. In particular, I like slide 25 that shows that in the Phase 2 post-hoc of ASSURE/SUSTAIN, that patients with median ALP of 78 U/L (quartile 3) and median 97 U/L (quartile 4) had the highest MACE incidence (note: 5-point MACE). 

BETonMACE patients with a median ALP of 78 U/L suggests that ALP and coronary artery calcification are significant risk factors in these patients. The ability of apabetalone to lower ALP in the post-hoc of ASSURE/SUSTAIN (look at that p-value on slide 29) suggests that ALP (and coronary artery calcification) should be significantly reduced in BETonMACE patients treated with apabetalone. 

BearDownAZ