Synonyms: RVX208, RVX000222
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
U.S. FDA Status: MCI-VaD (Phase 3)
Company: Resverlogix Corporation
Apabetalone binds and inhibits bromodomain and extra-terminal domain (BET) proteins, preventing them from binding acetylated lysines in histones to activate gene transcription. In published papers, apabetalone is reported to increase expression of ApoA-1 and suppress genes associated with kidney disease and vascular calcification (McLure et al., 2013; Wasiak et al., 2018; Gilham et al., 2019).
Apabetalone also reportedly suppresses expression of complement proteins (Wasiak et al., 2017). In wild-type mice challenged with lipopolysaccharide, apabetalone suppressed pro-inflammatory cytokines, complement proteins, and endothelial cell adhesion markers (May 2019 conference news).
The Phase 3 BETonMACE trial evaluated apabetalone in 2,425 people with Type 2 diabetes and coronary artery disease on a primary outcome of number of major cardiovascular events. The trial included a cognitive substudy of 467 participants age 70 or older, who took the Montreal Cognitive Assessment (MoCA) at baseline, annually thereafter, and when the study ended (Ray et al., 2019). Its outcomes included whether apabetalone slowed cognitive decline over a two-year period.
The trial was completed in November 2019. According to results presented at the 2019 CTAD conference in December, it missed its primary endpoint. Apabetalone reduced cardiovascular events compared to placebo, but the difference did not reach statistical significance. The main study results were subsequently published (Ray et al., 2020).
In the cognitive substudy, 469 participants had test results at baseline, one year and a final visit, which averaged 27 months. They were split into three groups based on baseline MoCA scores, corresponding to cognitively normal (MoCA of 26 or higher), MCI (22-25), or MCI to AD (below 22). Treatment had no effect in the cognitively normal or MCI groups, whose MoCA scores declined slightly or remained stable. The 97 participants in the MCI to AD subgroup improved an average of 3 points on the MoCA, compared to one point for placebo. The investigators plan to measure AD biomarkers in plasma samples from the study, to learn if a benefit occurred in AD or vascular dementia, or both (Dec 2019 conference news).
Apabetalone is also being evaluated in pulmonary artery hypertension, kidney failure, and Fabry disease. For all trials of apabetalone, see clinicaltrials.gov.
Last Updated: 30 Apr 2020
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- Ray KK, Nicholls SJ, Ginsberg HD, Johansson JO, Kalantar-Zadeh K, Kulikowski E, Toth PP, Wong N, Cummings JL, Sweeney M, Schwartz GG. Effect of selective BET protein inhibitor apabetalone on cardiovascular outcomes in patients with acute coronary syndrome and diabetes: Rationale, design, and baseline characteristics of the BETonMACE trial. Am Heart J. 2019 Nov;217:72-83. Epub 2019 Aug 9 PubMed.
- McLure KG, Gesner EM, Tsujikawa L, Kharenko OA, Attwell S, Campeau E, Wasiak S, Stein A, White A, Fontano E, Suto RK, Wong NC, Wagner GS, Hansen HC, Young PR. RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist. PLoS One. 2013;8(12):e83190. Epub 2013 Dec 31 PubMed.
- Wasiak S, Tsujikawa LM, Halliday C, Stotz SC, Gilham D, Jahagirdar R, Kalantar-Zadeh K, Robson R, Sweeney M, Johansson JO, Wong NC, Kulikowski E. Benefit of Apabetalone on Plasma Proteins in Renal Disease. Kidney Int Rep. 2018 May;3(3):711-721. Epub 2017 Dec 8 PubMed.
- Gilham D, Tsujikawa LM, Sarsons CD, Halliday C, Wasiak S, Stotz SC, Jahagirdar R, Sweeney M, Johansson JO, Wong NC, Kalantar-Zadeh K, Kulikowski E. Apabetalone downregulates factors and pathways associated with vascular calcification. Atherosclerosis. 2019 Jan;280:75-84. Epub 2018 Nov 14 PubMed.
- Wasiak S, Gilham D, Tsujikawa LM, Halliday C, Calosing C, Jahagirdar R, Johansson J, Sweeney M, Wong NC, Kulikowski E. Downregulation of the Complement Cascade In Vitro, in Mice and in Patients with Cardiovascular Disease by the BET Protein Inhibitor Apabetalone (RVX-208). J Cardiovasc Transl Res. 2017 Aug;10(4):337-347. Epub 2017 May 31 PubMed.
- Haarhaus M, Ray KK, Nicholls SJ, Schwartz GG, Kulikowski E, Johansson JO, Sweeney M, Halliday C, Lebioda K, Wong N, Brandenburg V, Beddhu S, Tonelli M, Zoccali C, Kalantar-Zadeh K. Apabetalone lowers serum alkaline phosphatase and improves cardiovascular risk in patients with cardiovascular disease. Atherosclerosis. 2019 Nov;290:59-65. Epub 2019 Sep 17 PubMed.