RE:RE:RE:DO BLOOD LEVELS OF APOA-1 REALLY MATTER SO MUCH????JK,
Thanks for soliciting feedback from Bjarke. I had to look back at some of my previous posts from last year after I actually saw the slides. From what I can tell, I agree with Bjarke's synopsis that RVX-208 combined with rosuvastatin has not been been shown to increase apoAI above the levels achieved by rosuvastatin alone. My bad. Does this worry me? Not one bit.
The best study to assess the ability of RVX-208 to raise apoAI has never been done. That is, treat the low-HDL target population with RVX-208 alone, without rosuvastatin. ASSERT, SUSTAIN and ASSURE all treated patients with RVX-208 as an add on to a pre-existing statin therapy. Cell culture studies in human HepG2 cells and studies in primates clearly showed that RVX-208 treatment (without the confounding addition of statins) significantly raised apoAI. So in response to Bjarke's statement that RVX-208 has not convincingly been shown to increase apoAI in the target population, I agree with his statement. But I must qualify by pointing out that RVX-208 has never been tested in the correct way in human (by itself, no statins) and in the correct target human population (low HDL) to ascertatin the effectiveness of RVX-208 itself on apoAI. Since the target populations for ASSERT, SUSTAIN and ASSURE all had documented history of coronary artery disease, and the standard treatement for these conditions is statins, it is quite unethical to refrain from statin use when exploring RVX-208.
Bjarke also contended that RVX-208 may still work, at least to a certain extent, through apoAI, but that this effect is just not reflected in the levels of apoAI found in plasma. In one of my old posts, I wrote that RVX-208 combined with rosuvastatin increased HDL particle size and HDL-cholesterol a bit more than rosuvastatin alone. This was written after I saw that Table that Bjarke refers to. I don't know about the statistics though. Nonetheless, it does appear that RVX-208 and rosuvastatin are synergizing to increase HDL-C and particle size beyond rosuvastatin alone. One must keep in mind that rosuvastatin itself (in addition to its primary role to lower LDL) is in part enhancing some of the same pathways leading to increased apoAI/HDL and reduce plaque volume. Again, this highlights my point in the previous paragraph that the best experiment (RVX-208 by itself in low-HDL patients) has never been done.
Long story short, 1) I think there's enough data out there to fairly state that both RVX-208 and rosuvastatin can independently modulate apoAI/HDL; 2) RVX-208 has additional mechanims of action than just apoAI modulation (anti-inflammatory, anti-diabetes?); 3) RVX-208 will likely be marketed together with rosuvastatin; 4) decreased inflammation, plaque volume and MACE are the more important endpoints.