Cecilia Vitali, Marina Cuchel, in The HDL Handbook (Third Edition), 2017

2.5 RVX-208

RVX-208 is a novel compound in the family of bromodomains inhibitors, that specifically target the BET (bromodomain and extra-terminal) proteins [129]. Inhibition of BET bromodomains modulates the transcription of selected genetic programs. In particular RVX208 seems to interact with the second bromodomain of BRD proteins, with higher selectivity for BRD2, BRD3 and BRD4 [130]. RVX-2008 induces an increased expression of apoA-I and total HDLc. In preclinical studies RVX-208 was reported to raise apoA-I plasma levels and increase preβ-HDL concentration in primates [130,131]. In apoE(−/−) mice, it successfully decreases LDL-C levels and raises HDLc levels, without a parallel increase in apoA-I concentration [132]. In both models it has exhibited a good anthiatherogenic and antinflammatory profile [132].

Despite the promising results in animal studies, clinical studies have provided mixed results. The first Phase IIa trial, ASSERT, was aimed to test efficacy and safety of RVX-208 administration for 12 weeks in statin-treated patients with CAD [133]. The trial didn’t achieve the primary endpoint, defined as significant raise in apoA-I, but RVX-208 was associated with dose-dependent increases in levels of apoA-I, HDLc and large HDL particles [133] A Phase IIb study, the SUSTAIN study, was conducted in patients with CVD and low HDL. In this trial, 24 week treatment with RVX-208 significantly increased HDLc, apo-AI and promoted the formation of large HDL particles, suggesting a potential improvement in RCT [134]. A second Phase IIb trial, the ASSURE study, was design to evaluate plaque progression in 323 patients with coronary disease and low HDLc levels. After 26 weeks of treatment, only a modest increased in HDLc and apoA-I was observed, and no significant plaque regression was measured [135].

A combined post-hoc analysis of the two Phase 2b studies recently reported a 55% relative risk reduction in major adverse cardiac events in patients that received RVX-208 as compared to controls, and a more pronounced 77% relative risk reduction in patients with a history of diabetes mellitus [136]. Interestingly, in pre-diabetic subjects, RVX-208 treatment generated shift of HDL size distribution toward medium-size particles that was accompanied by a change in the HDL lipidome [136,137]. RVX-208 has entered a Phase III trial (BETonMACE) in patients at high CV risk, diabetic and with low HDLc levels (NCT02586155). The primary endpoint is the relative risk reduction of major adverse cardiac events (MACE). This study will hopefully clarify the potential clinical benefits of RVX-208 treatment.