Narmac wrote in another thread "what ever happened to our ability to reduce inflammation,,,,,,,,,,wasn't this one of the key functions around BET inhibitors?"

Great question Narmac. I was mentally exhausted when I finished writing my original post yesterday so I didn't comment as I should have on the anti-inflammatory stuff. Yes, there is a large amount of published data on the anti-inflammatory effects of apabetalone in both pre-clinical models (animal work, human cell lines, etc) as well as from blood samples from patients in apabetalone clinical trials. I will focus on hsCRP below, but I link to a select number of publications and posters at the end of this message documenting the variety of anti-inflammatory effects including, but far from limited to, hsCRP. 

Specifically focusing on hsCRP...changes in hsCRP is a pre-specified outcome in BETonMACE. hsCRP is a common surrogate for inflammation in cardiovascular outcomes trials. Many statins, as well as Esperion's bempedoic acid, have an added benefit of not only inhibiting cholesterol biosynthesis to lower LDL-C, but also lowering hsCRP. Amarin's Vascepa also lowers hsCRP as one of its several potential mechanisms of action. However, the CANTOS trial with canakinumab anti-IL-1B anibody was the first trial to show that inflammation is an independent risk factor for cardiovascular disease. Resverlogix pointed out a couple years ago how the findings of the CANTOS trial supported the rationale of apabetalone having anti-inflammatory properties as one of its cardioprotective mechansims of action. They even recently had a poster at Vascular Discovery "Hepatic Expression of C-Reactive Protein is Epigenetically Regulated by BET Proteins and Inhibited by Apabetalone (RVX-208) in Vitro and in CVD Patients" that specifically focused on these hsCRP effects. 

Specifically in the post-hoc analysis of ASSURE, "First, the data showed statistically significant improvements in coronary IVUS atheroma measurements and Major Adverse Cardiac Events (MACE) in patients with a high (>2.0 mg/dL) serum high sensitivity C-Reactive Protein (hsCRP). Serum levels of this biomarker when >2.0 mg/dL reflect a heightened state of inflammation that is a well-known and major component of CVD risk. Patients with hsCRP>2.0 mg/dL at time of entry into ASSURE totaled n=184 of which n=54 were given placebo while n=130 received RVX-208. In the RVX-208 treated patients, there was a 60% reduction (p<0.0001) in hsCRP vs. baseline and (p=0.054) vs. placebo. Furthermore atheroma regression was observed in patients treated with RVX-208 as measured by percent atheroma volume (PAV), total atheroma volume (TAV) regressed, and the worst 10mm TAV segment by -0.75% (p<0.03), -6.3mm3 (p<0.001) and -2.63mm3 (p<0.001), respectively vs. baseline. Equally intriguing and perhaps more important is that in RVX-208 treated patients with hsCRP>2.0 mg/dL the incidence of MACE was lower by 63% (p=0.023) vs. placebo. The preceding observation is of value in that hsCRP of >2.0 mg/dL is well known to be clinically important in predicting CVD risk."

A pooled analysis of the Phase 2 trials (ASSERT, SUSTAIN, ASSURE) found that apabetalone "decreases in high-sensitivity C-reactive protein (hsCRP) of - 21.1% (P = 0.04)." Post-hoc MACE analysis found that in those patients with elevated baseline hsCRP, elevated hsCRP levels apabetalone elicited ~62% RRR in 5-point MACE (5.4 vs. 14.2%; P = 0.02). 

Canakinumab, while effective, is an expensive monoclonal antibody therapy. Novartis is currently not pursing a cardiovascular label for canakinumab (it's complicated...see here), so there is an opportunity there. Inflammation is not just related to cardiovascular disease, but a component of many many many other diseases. So proving that apabetalone is a safe, tolerable, orally available and effective anti-inflammatory medicine (with lots of other benefits too) could make it an attractive drug. See this article "NLRP3 inhibitors stoke anti-inflammatory ambitions" for an overview of the potential for and excitement to find a safe and effective anti-inflammatory drug.

Apabetalone (RVX-208) reduces vascular inflammation in vitro and in CVD patients by a BET-dependent epigenetic mechanism

Benefit of Apabetalone on Plasma Proteins in Renal Disease

RVX-208, a BET-inhibitor for treating atherosclerotic cardiovascular disease, raises ApoA-I/HDL and represses pathways that contribute to cardiovascular disease

Plus tons of posters over the past few years documenting these potent anti-inflammatory effects.

https://www.resverlogix.com/science-and-programs/publications#rvx-posters

BearDownAZ