European Association for the Study of Diabetes (EASD): Sept 16-20, 2019; Barcelona, Spain. There is a poster presentation on September 17th, 2019 entitled "Apabetalone modulates Th1 responses in diabetes and CVD through intrinsic and extrinsic mechanisms: in vitro and in human studies." See abstract here also copied below.

"For the first time, we demonstrate the immunomodulatory action of apabetalone on T cells from patients with T2DM and CVD through intrinsic (preventing the upregulation of the transcription factor T-bet) and extrinsic (inhibiting the production of Th1 cytokines) mechanisms. Downregulation of Th1 responses by apabetalone may contribute to the reduction in CVD events observed in phase 2 studies."

Abstract

Background and aims: T cells play a dominant role in promoting chronic inflammation and insulin resistance during type 2 diabetic mellitus (T2DM) progression and the development of associated complications such as cardiovascular disease (CVD). Upon stimulation, circulating T cells enter into tissues/organs where they change their phenotype to either the Th1 tissue damage state or the Th2 tissue regeneration state. This phenotypic switching process, known as Th1/Th2 polarization, is regulated through intrinsic pathways (intracellular factors) and extrinsic mechanisms (extracellular microenvironments). In the process of T2DM and onset of CVD, naïve T cells polarize to Th1 phenotype and produce pro-inflammatory Th1 cytokines leading to tissue damage. Apabetalone (RVX-208) is an oral compound that regulates gene transcription by blocking the activity of the epigenetic readers, bromodomain and extra-terminal (BET) proteins. In phase 2 trials, apabetalone treatment reduced the incidence of major adverse cardiovascular events (MACE) by 44% in CVD patients and by 57% in diabetic CVD patients. Here we examined whether apabetalone contributes to lowering CVD risk by affecting genes involved in Th1 responses.

Materials and methods: PBMCs derived from T2DM/CVD patients or normal donors were stimulated with CD3 and CD28 antibodies and co-treated with apabetalone. Th1 marker changes driven by apabetalone were determined by mRNA assays. To further evaluate apabetalone induced changes, we assessed levels of circulating inflammatory mediators in plasma from patients in phase 2 trials via a SOMAscan® proteomic analysis (a measure of ~1300 analytes).

Results: PBMCs express lower basal levels of pro-inflammatory cytokines (e.g. IL2 and IL17) in diabetic patients receiving glycemic treatments and/or cholesterol lowering therapies relative to normal controls. However, upon CD3 and CD28 antibody stimulation, their resting T cells become hyper-activated and increase the expression of IL2, IL17 and TNFα by approximately 7-, 3- and 4- fold compared to controls. Apabetalone attenuates this over production by up to 65%. Anti-CD3 and anti-CD28 stimulation induces similar levels of IFN-γ in T2DM vs control. However, apabetalone still suppresses the induced IFN-γ by 40%. T-bet is the key transcription factor that drives Th1 polarization and thus exacerbates chronic inflammation. With in vitro anti-CD3 and anti-CD28 stimulation, T-bet is induced up to ~5 fold in PBMCs from T2DM patients, and apabetalone diminishes this upregulation by 50%. Consistent with the in vitro results, in diabetic CVD patients treated with 200mg apabetalone for 24 weeks, IL2 and IFN-γ abundance in plasma were reduced by 11% and 21% versus baseline, respectively. In contrast, plasma IL2 was increased by 22% and IFN-γ was reduced by 2% in patients treated with placebo.

Conclusion: For the first time, we demonstrate the immunomodulatory action of apabetalone on T cells from patients with T2DM and CVD through intrinsic (preventing the upregulation of the transcription factor T-bet) and extrinsic (inhibiting the production of Th1 cytokines) mechanisms. Downregulation of Th1 responses by apabetalone may contribute to the reduction in CVD events observed in phase 2 studies. The ability of apabetalone to prevent MACE in post-acute coronary syndrome patients with T2DM and low HDL-C is being assessed in the phase 3 trial (BETonMACE).