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Effect of the BET Protein Inhibitor, RVX-208, on Progression of Coronary Atherosclerosis: Results of the Phase 2b, Randomized, Double-Blind, Multicenter, ASSURE Trial

  • Original Research Article
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Abstract

Background

Bromodomain and extra-terminal (BET) proteins regulate transcription of lipoprotein and inflammatory factors implicated in atherosclerosis. The impact of BET inhibition on atherosclerosis progression is unknown.

Methods

ASSURE was a double-blind, randomized, multicenter trial in which 323 patients with angiographic coronary disease and low high-density lipoprotein cholesterol (HDL-C) levels were randomized in a 3:1 fashion to treatment with the BET protein inhibitor RVX-208 200 mg or placebo for 26 weeks. Plaque progression was measured with serial intravascular ultrasound imaging. Lipid levels, safety, and tolerability were also assessed.

Results

During treatment, apolipoprotein (apo)A-I increased by 10.6 % with placebo (P < 0.001 compared with baseline) and 12.8 % with RVX-208 (P < 0.001 compared with baseline), between groups P = 0.18. HDL-C increased by 9.1 % with placebo (P < 0.001 compared with baseline) and 11.1 % with RVX-208 (P < 0.001 compared with baseline), between groups P = 0.24. Low-density lipoprotein cholesterol (LDL-C) decreased by 17.9 % with placebo (P < 0.001 compared with baseline) and 15.8 % with RVX-208 (P < 0.001 compared with baseline), between groups P = 0.55. The primary endpoint, the change in percent atheroma volume, decreased 0.30 % in placebo-treated patients (P = 0.23 compared with baseline) and 0.40 % in the RVX-208 group (P = 0.08 compared with baseline), between groups P = 0.81. Total atheroma volume decreased 3.8 mm3 in the placebo group (P = 0.01 compared with baseline) and 4.2 mm3 in the RVX-208 group (P < 0.001 compared with baseline), P = 0.86 between groups. A greater incidence of elevated liver enzymes was observed in RVX-208-treated patients (7.1 vs. 0 %, P = 0.009).

Conclusion

Administration of the BET protein inhibitor RVX-208 showed no greater increase in apoA-I or HDL-C or incremental regression of atherosclerosis than administration of placebo.

Trial Registration

ClinicalTrials.gov identifier—NCT01067820.

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Acknowledgments

Data Safety Monitoring Board: Peter Ganz (Chair), Eva Lonn, Gregory Schwartz, Danielle Brennan.

Intravascular Ultrasound Core Laboratory Staff: William Magyar, Jordan Andrews, Eva Balazs, Anne Colagiovanni, Teresa Fonk, Karilane King, Erin Mayock, Roman Poliszczuk, Rhiannon Regal, Jill Rusticelli.

Additional contributions: We thank Craig Balog, BS, C5Research statistical support. Helen Street and Kim Nguyen at Resverlogix and Deirdre Albertson and Alla Sharorodskaya at inVentiv for their role in study coordination.

Investigators: Argentina: Sanatorio Allende Hipolito, Córdoba (E. Moreyra, MD), Hospital Privado, Córdoba (M. Ballarino, MD), Instituto de Cardiología de Corrientes, Corrientes Capital (J. Baccaro, MD), Sanatorio Parque S. A. Privado,Córdoba (H. Luquez, MD), Instituto de diagnóstico y tratamiento de afecciones cardiovasculares, La Plata (D. Grinfeld, MD), ICBA Instituto Cardiovascular de Buenos Aires, Ciudad de Buenos Aires (L. Padilla, MD), Instituto DAMIC SRL, Córdoba (A. Lorenzatti, MD), Sanatorio San Lucas, San Isidro (G. Marchetti, MD), Clinica Chutro SRL, Córdoba (H. Jure, MD), Sanatorio Güemes,Ciudad de Buenos Aires (M. Bettinotti, MD); Belgium: Universitair Ziekenhuis Antwerpen, Edegem (C. Vrints, MD), Ziekenhuis Oost Limburg, Genk (M. Vrolix, MD), Universite Catholique de Louvain, Brussels (J. Renkin, MD), Centre Hospitalier Universitaire de Charleroi, Charleroi (J. Lalmand, MD); Brazil: Instituto do Coração do Triângulo Mineiro, Uberlândia (R. Vieira Botelho, MD), Hospital Cardiológico Costantini, Curitiba (Costantino Roberto Costantini Frack, MD), Instituto do Coração, São Paulo (P. Lemos, MD), Santa Casa de Misericórdia de Porto Alegre, Porto Alegre (V. Correia deLima, MD), Hemodinâmica Meridional, Cariacica (B. Moulin Machado, MD), Centro de Pesquisa em Cardiologia da Via Médica, Goiânia (W. Kunz Sebba Barroso de Souza, MD), Hospital do Coração do Brasil, Brasília (A. Gomes Taques Fonseca, MD), Instituto Dante Pazzanese de Cardiologia, São Paulo (J. de Ribamar Costa Junior, MD); Hungary: Szent-Györgyi Albert Klinikai Központ, Szeged (I. Ungi, MD), Semmelweis Egyetem Kardiológiai Közpon, Budapest (B. Merkely, MD), Pécsi Tudományegyetem, Pécs (I. Horvath, MD), Fővárosi Önkormányzat Bajcsy-Zsilinszky Kórház, Budapest (B. Nagybaczoni, MD), Honvédkórház - Állami Egészségügyi Központ, Budapest (R. Kiss, MD), Budai Irgalmasrendi Kórhá, Budapest (A. Zsoldos, MD); Netherlands: Onze Lieve Vrouwe Gasthuis, Amsterdam, (J. P. Herrman, MD), Isala Klinieken, Zwolle (M. Gosselink, MD), St. Antonius Ziekenhuis, Niewegein (B. Rensing, MD), Catharina Ziekenhuis, Eindhoven (C. Joost Botman, MD), Maasstad Ziekenhuis, Rotterdam (P. Smits, MD), Maastricht Universitair Medisch Centrum, Maastricht (A. Moens, MD), Canisius Wilhelmina Ziekenhuis, Nijmegen (A. J. M. Oude Ophuis, MD), Medisch Spectrum Twente, Enschede (C. Von Birgelen, MD), Medisch Centrum Alkmaar, Alkmaar (A. A. C. M. Heestermans, MD); Poland: Samodzielna Pracownia Hemodynamiki, Krakow (D. Dudek, MD), Klinika Kardiologii Inwazyjnej, Warszawa (R. Gil, MD), Zakład Kardiologii Inwazyjnej, Katowice (A. Ochala, MD), Oddział Strukturalnych Chorób Serca Samodzielny Publiczny Szpital Kliniczny, Katowice (G. Smolka, MD), Instytut Kardiologii, Warszawa (A. Witkowski, MD); Russia: Acad. V. I. Shumakov, Moscow (V. Chestukhin, MD), St. Petersburg State Healthcare Institution, Saint Petersburg (L. Shcheglova, MD),

Russian Cardiology Research-and-Production Complex, Moscow (V. Kukharchuk MD, M. Ruda, MD, and F. Ageev, MD), 3 Central Military Clinical Hospital, Moscow (V. Ivanov, MD), Tyumen Department of South-Ural Scientific Center of RAMS, Tyumen (S. Shalaev, MD), A. N. Bakulev of RAMS Cardiosurgery Institution, Moscow (S. Matskeplishvili, MD), Scientific Research Cardiology Institute of Sibirian Branch of RAMS,Tomsk (O. Koshelskaya, MD), FSI Federal Center of Heart, Blood and Endocrinology, St. Petersburg (M. Karpenko, MD), FSI State Scientific Research Center of Preventive Medicine of Rosmedtechnologies, Moscow (V. Mazaev, MD), Orenburg State Medical Academy of Roszdrav, Orenburg (R. Sayfutdinov, MD); Spain: Hospital de Meixoeiro, Vigo (A. Iniguez, MD), Hospital Clinico Universitario Virgen de la Victoria, Málaga (J. Maria Hernandez, MD), Hospital de Cabueñes, Gijón (J. Rondan, MD), Hospital Universitari Germans Trias i Pujol, Barcelona (J. Mauri, MD), Hospital Universitario La Paz, Madrid (R. Moreno, MD), Hospital de Galdakao-Usansolo, Galdakao (J. Ramon Rumoroso, MD), Hospital General Universitario Santa Lucia, Cartagena (F. Pico, MD), Hospital Universitari de Bellvitge, Barcelona (A. Cequier, MD), Hospital Clinico Universitario San Carlos, Madrid (F. Alfonso, MD), Hospital Clínico Universitario de Santiago, Santiago de Compostela (R. Trillo, MD), Hospital Vall d’Hebrón, Barcelona (B. Blanco, MD), Hospital Universitario Marqués de Valdecilla, Santander (J. Zueco, MD).

Author contributions

Drs. Nicholls and Nissen and the Cleveland Clinic Coordinating Center for Clinical Research had full and independent access to all of the data in the study. Dr. Nicholls takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs. Nicholls and Nissen and Ms. Wolski and Borgman were responsible for study concept and design. Drs. Nicholls, Puri, Uno, Herrman, Merkely, and Kataoka and Ms. Borgman take responsibility for data acquisition. Drs. Nicholls, Nissen, Ballantyne, Barter, Brewer, Kastelein, Puri, Uno, Kataoka, Hu, Herrman, and Merkely and Ms. Wolski and Ms. Borgman analysed and interpreted the data. Drs. Nicholls and Nissen and Ms. Wolski drafted the manuscript. Drs. Nicholls, Nissen, Ballantyne, Barter, Brewer, Kastelein, Puri, Uno, Kataoka, Hu, Herrman, and Merkely and Ms. Wolski and Ms. Borgman provided critical revision of the manuscript for important intellectual content. For the purpose of the academic interpretation of the study, Ms. Wolski and Dr. Hu performed all primary statistical analyses of the study that were used for the manuscript. Ms. Wolski is an employee of the Cleveland Clinic Coordinating Center for Clinical Research. Dr. Hu is a faculty member within the Department of Quantitative Health Sciences at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. Drs. Nicholls and Nissen obtained funding for the study. Ms. Borgman provided administrative support.

Author information

Authors and Affiliations

  1. South Australian Health and Medical Research Institute, PO Box 11060, Adelaide, SA, 5001, Australia

    Stephen J. Nicholls & Yu Kataoka

  2. Department of Cardiovascular Medicine and Cleveland Clinic Coordinating Center for Clinical Research, Cleveland Clinic, Cleveland, OH, USA

    Rishi Puri, Kathy Wolski, Bo Hu, Kiyoko Uno, Marilyn Borgman & Steven E. Nissen

  3. Section of Cardiovascular Research, Baylor College of Medicine and the Methodist DeBakey Heart and Vascular Center, Houston, TX, USA

    Christie M. Ballantyne

  4. University of New South Wales, Sydney, NSW, Australia

    Philip J. Barter

  5. Medstar Research Institute, Hyattsville, MD, USA

    H. Bryan Brewer

  6. Department of Vascular Medicine, Academic Medical Center, University of Medicine, Amsterdam, The Netherlands

    John J. P. Kastelein

  7. Department of Cardiology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands

    Jean-Paul R. Herrman

  8. Heart and Vascular Center, Semmelweis University, Budapest, Hungary

    Bela Merkely

Authors
  1. Stephen J. Nicholls
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  2. Rishi Puri
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  3. Kathy Wolski
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  4. Christie M. Ballantyne
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  5. Philip J. Barter
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  6. H. Bryan Brewer
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  7. John J. P. Kastelein
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  8. Bo Hu
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  9. Kiyoko Uno
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  10. Yu Kataoka
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  11. Jean-Paul R. Herrman
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  12. Bela Merkely
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  13. Marilyn Borgman
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  14. Steven E. Nissen
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Corresponding author

Correspondence to Stephen J. Nicholls.

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Financial support

The study was funded by Resverlogix Corporation.

Role of the Sponsor

The sponsor, Resverlogix Corporation, participated actively in designing the study, developing the protocol, and providing logistical support during the trial. Monitoring of the study was performed by a contract research organization, inVentiv Health Inc., under contract with the sponsor. The sponsor maintained the trial database. Statistical analysis was performed by statisticians employed by inVentiv, although the analysis employed by the manuscript represent those performed by the academic statisticians (Ms. Wolski, Dr. Hu). After completion of the trial, as specified in the study contract, a complete copy of the database was transferred to the Cleveland Clinic Coordinating Center for Clinical Research, where analyses were verified by independent statisticians, Kathy Wolski, MPH and Bo Hu, PhD. The manuscript was prepared by the corresponding author and modified after consultation with co-authors. The sponsor was permitted to review the manuscript and suggest changes, but the final decision on content was exclusively retained by the academic authors.

Financial disclosures

The study was sponsored by Resverlogix Corporation. SJN reports receiving research support from AstraZeneca, Novartis, Eli Lilly, Anthera, LipoScience, Roche, and Resverlogix and has received honoraria or been a consultant for AstraZeneca, Roche, Esperion, Abbott, Pfizer, Merck, Takeda, LipoScience, Omthera, Novo-Nordisk, Sanofi-Aventis, Atheronova, Anthera, CSL Behring, and Boehringer. HBB is a consultant for Merck, AstraZeneca, Eli Lilly, Roche, Amgen, and Sanofi. CMB has received research support from Abbott, Amarin, Amgen, Eli Lilly, GlaxoSmithKline, Genentech, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi-Synthelabo, Takeda, the National Institutes of Health, and the American Heart Association, is a consultant for Abbott, Aegerion, Amarin, Amgen, Arena, Cerenis, Esperion, Genentech, Genzyme, Kowa, Merck, Novartis, Omthera, Pfizer, Resverlogix, Regeneron, Roche, and Sanofi-Synthelabo and serves on the speaker’s bureau for Abbott. PJB has received research grants from Merck and Pfizer, received honoraria from Amgen, AstraZeneca, ISIS, Kowa, Merck, Novartis, Pfizer, and Roche and serves on advisory boards for AstraZeneca, CSL Behring, Kowa, Eli Lilly, Merck, Novartis, Pfizer, and Roche. JJPK has received research support from the Dutch Heart Foundation (2010T082) and has received honoraria or has been a consultant for AstraZeneca, Novartis, Eli Lilly, Anthera, Roche, Resverlogix, Pfizer, Merck, Omthera, Sanofi-Aventis, Regeneron, Amgen, AtheroNova, CSL Behring, Boehringer Ingelheim, Aegerion, the Medicines Company, Isis Pharmaceuticals, Genzyme, Amarin, Xenon Pharma, Servier, and Cerenis. SEN has received research support from AstraZeneca, Eli Lilly, Pfizer, Takeda, Sankyo, and Sanofi-Aventis. He has consulted for a number of pharmaceutical companies without financial compensation. All honoraria, consulting fees, or any other payments from any for-profit entity are paid directly to charity, so that neither income nor any tax deduction is received. No assistance in the preparation of this article is to be declared. RP, KU, YK, MB, JRH, BM, BH, and KW have no potential conflicts to disclose.

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Nicholls, S.J., Puri, R., Wolski, K. et al. Effect of the BET Protein Inhibitor, RVX-208, on Progression of Coronary Atherosclerosis: Results of the Phase 2b, Randomized, Double-Blind, Multicenter, ASSURE Trial. Am J Cardiovasc Drugs 16, 55–65 (2016). https://doi.org/10.1007/s40256-015-0146-z

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