“There is quite an overlap in the patient population for the CKD and cognition subgroups, and there is a relationship between alk phos, CVD, CKD and cognition as described above. For this reason, I think that the CKD eGFR data is being kept quiet for now in order to deliver a very exciting story at CTAD on Dec 5.”

I agree.  I think RVX likely has a very nice story to tell at CTAD and they have been diligently setting the stage with the recent focus on ALP.  The lack of details on eGFR in the AHA presentation (and especially in the follow-up webcast) which focussed on CVD and CKD is puzzling.  So, there may be a disappointing lack of improvement in eGFR to correspond with the improved MACE outcomes in the CKD group, but I doubt it.  If that was the case, why not present the eGFR data earlier and get it over with.  More likely there are good eGFR results (values stabilized or improving in the CKD group) and, moreover, they correlate with not only reduced MACE but stabilized or improved cognitive function (MOCA scores) in the highly overlapping, older group of patients in the CKD and MOCA-tested groups.

While RVX hasn’t been said boo about eGFR recently, they’ve been shouting from the rooftops about ALP in recent posters and publications.  Here is a ‘setting the stage’ extract from one of their recent publications reviewing the phase II data;

“The novel BET inhibitor apabetalone lowers serum ALP activity in a dose dependent fashion and reduces the incidence of MACE, and the magnitude of benefit appeared to be correlated with the extent of ALP reduction. However, the current analysis is hypothesis generating. Further experimental and clinical data are needed to determine whether ALP is a direct participant in atherothrombotic events and therefore a therapeutic target in its own right.”

And there’s this from a poster (bolding of text by me):

 Apabetalone dose dependently lowers serum ALP in patients, which is associated with reduction in cardiovascular events. Decreased ALPL expression in cultured hepatocytes with apabetalone is consistent with reduced serum ALP inpatients. In addition, apabetalone downregulates ALPL expression in vascular cell types including VSMCs and endothelial cells, while reducing VSMC calcification. Involvement of BET proteins in VSMC calcification is a novel discovery. Our data indicate apabetalone has potential to decrease progression of pathological VC and contribute to positive cardiovascular outcomes in CVD patients.

Here’s some pure speculation to fill the time before CTAD.  Folks fearful of overly-optimistic analyses should stop reading here.

The older patients in this study are afflicted by high levels of CKD and cognitive impairment (MOCA<22).  On placebo, they suffer a disproportionately high number of MACE, their eGFR values remain low or decline, their ALP levels stay high or increase and their MOCA scores decline.  On apabetalone, MACE events are halved (we’ve already seen that for the CKD subset), eGFR values increase, ALP values decline and MOCA scores stabilize or increase.  Both eGFR and ALP values are a good indication of response to apabetalone in this group of patients within which kidney function was already impaired at the start of the study.  However, most of the trial patients are younger; they had normal kidney function at the beginning of the trial and their eGFR levels did not change throughout the trial.  Here is where ALP shines.  In this group, as well as in the older group, ALP levels are reduced in the apabetalone group relative to the placebo group, and the decreased ALP levels correspond to reduced MACE as it did in the Phase II trials.  That’s a pretty good package but let’s put a bow on it.  Why should low ALP values be correlated with reduced MACE, increased eGFR in CKD patients and improved MOCA scores in cognitively impaired folks?  Is it just a biomarker or is it an actual mediator of adverse outcomes?  Well, high ALP is associated with vascular calcification which results in reduced renal function, increased MACE and dementia.  Apabetalone reduces ALP levels and vascular calcification in VSMC (vascular smooth muscle cells) and endothelial cells and human patients in the BoM trial (have no idea if patient samples were taken to test for calcification).  ALP is a mediator as well as a biomarker and a good therapeutic target. 

So, the whole enchilada may be that apabetalone mediates reduced MACE, increased eGFR where needed and improved cognition where needed in diabetic cardiovascular patients through a reduction of serum ALP levels leading to reduced vascular calcification.  Apabetalone could be a first-in-class ALP-lowering drug that is safe enough to be used as a preventative as well as corrective therapy. Of course, ababetalone modulates additional pathways through it's BETi properties for additional benefits as well.