Synthetic mRNA Encoding VEGF-A in Patients Undergoing Coronary Artery Bypass Grafting: Design of a Phase 2a Clinical Trial

Vesa Anttila, Antti Saraste, Juhani Knuuti, Pekka Jaakkola, Marja Hedman, Sara Svedlund, Maria Lagerström-Fermér, Magnus Kjaer, Anders Jeppsson, Li-Ming Gan, Vesa Anttila, Antti Saraste, Juhani Knuuti, Pekka Jaakkola, Marja Hedman, Sara Svedlund, Maria Lagerström-Fermér, Magnus Kjaer, Anders Jeppsson, Li-Ming Gan

Abstract

Therapeutic angiogenesis may improve outcomes in patients with coronary artery disease undergoing surgical revascularization. Angiogenic factors may promote blood vessel growth and regenerate regions of ischemic but viable myocardium. Previous clinical trials of vascular endothelial growth factor A (VEGF-A) gene therapy with DNA or viral vectors demonstrated safety but not efficacy. AZD8601 is VEGF-A165 mRNA formulated in biocompatible citrate-buffered saline and optimized for high-efficiency VEGF-A expression with minimal innate immune response. EPICCURE is an ongoing randomized, double-blind, placebo-controlled study of the safety of AZD8601 in patients with moderately decreased left ventricular function (ejection fraction 30%-50%) undergoing elective coronary artery bypass surgery. AZD8601 3 mg, 30 mg, or placebo is administered as 30 epicardial injections in a 10-min extension of cardioplegia. Injections are targeted to ischemic but viable myocardial regions in each patient using quantitative 15O-water positron emission tomography (PET) imaging (stress myocardial blood flow < 2.3 mL/g/min; resting myocardial blood flow > 0.6 mL/g/min). Improvement in regional and global myocardial blood flow quantified with 15O-water PET is an exploratory efficacy outcome, together with echocardiographic, clinical, functional, and biomarker measures. EPICCURE combines high-efficiency delivery with quantitative targeting and follow-up for robust assessment of the safety and exploratory efficacy of VEGF-A mRNA angiogenesis (ClinicalTrials.gov: NCT03370887).

Keywords: ▪▪▪.

© 2020 The Authors.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Study Flow Chart aScreening and randomization visits can be combined provided that 15O-water PET and CFVR assessments are carried out on separate days. bThe 14-day time-window before surgery on day 0 can be reduced if the pre-operative conference, randomization, and delivery of AZD8601/placebo can be accommodated within a shorter period. cIncludes CFVR in the left anterior descending artery (for sites able to assess CFVR). dKansas City Cardiomyopathy Questionnaire, Seattle Angina Questionnaire, and NYHA classification. eIncludes high-sensitivity troponin T and NT-proBNP. fOptional digital assessments via mobile phone app. X, assessment times; XXXXX, daily assessments during stay in hospital; 6MWT, 6-min walking test; CFVR, coronary flow velocity reserve; CT, computed tomography; MCWS, maximum continuously walked steps; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; PET, positron emission tomography; TC, teleconference; VEGF-A, vascular endothelial growth factor.
Figure 2
Figure 2
Sentinel and Sequential Ascending-Dose Cohorts Sequential low-dose and high-dose cohorts each include 12 participants, with 8 randomized to AZD8601 and 4 randomized to placebo. Each dose cohort includes 3 sequential sentinel sub-cohorts: the first and second sub-cohort each include 2 participants, randomized to AZD8601 (n = 1) or placebo (n = 1), and the third sentinel cohort includes 8 participants, randomized to AZD8601 (n = 6) or placebo (n = 2). Safety data at 1 month is reviewed before initiation of the next cohort or sub-cohort.
Figure 3
Figure 3
Example Individualized Injection Map for Targeting Ischemic but Viable Myocardium The individualized injection map is based on a hybrid image showing 3D-rendered coronary anatomy (coronary CT angiography) and left ventricular myocardial blood flow during adenosine stress (15O-water PET). Green or blue shading indicates stress myocardial blood flow < 2.3 mL/g/min. The red overlay on the left panel indicates the target region of the left coronary artery territory for epicardial injections of AZD8601 (stress myocardial blood flow < 2.3 mL/g/min and resting myocardial blood flow > 0.6 mL/g/min). Treatment is focused on the largest ischemic area, with any remaining injections used for partial treatment of the second-largest area. White arrows, left anterior descending coronary artery; yellow arrows, left circumflex coronary artery branches; red arrows, right coronary artery.

References

    1. Moran A.E., Forouzanfar M.H., Roth G.A., Mensah G.A., Ezzati M., Flaxman A., Murray C.J., Naghavi M. The global burden of ischemic heart disease in 1990 and 2010: the Global Burden of Disease 2010 study. Circulation. 2014;129:1493–1501.
    1. Foglia M.J., Poss K.D. Building and re-building the heart by cardiomyocyte proliferation. Development. 2016;143:729–740.
    1. Ryan M.J., Perera D. Identifying and managing hibernating myocardium: what’s new and what remains unknown? Curr. Heart Fail. Rep. 2018;15:214–223.
    1. Hughes G.C., Annex B.H. Angiogenic therapy for coronary artery and peripheral arterial disease. Expert Rev. Cardiovasc. Ther. 2005;3:521–535.
    1. Johnson T., Zhao L., Manuel G., Taylor H., Liu D. Approaches to therapeutic angiogenesis for ischemic heart disease. J. Mol. Med. (Berl.) 2019;97:141–151.
    1. Ylä-Herttuala S., Baker A.H. Cardiovascular gene therapy: past, present, and future. Mol. Ther. 2017;25:1095–1106.
    1. Giacca M., Zacchigna S. VEGF gene therapy: therapeutic angiogenesis in the clinic and beyond. Gene Ther. 2012;19:622–629.
    1. Gaffney M.M., Hynes S.O., Barry F., O’Brien T. Cardiovascular gene therapy: current status and therapeutic potential. Br. J. Pharmacol. 2007;152:175–188.
    1. Ahmadi H., Baharvand H., Ashtiani S.K., Soleimani M., Sadeghian H., Ardekani J.M., Mehrjerdi N.Z., Kouhkan A., Namiri M., Madani-Civi M. Safety analysis and improved cardiac function following local autologous transplantation of CD133(+) enriched bone marrow cells after myocardial infarction. Curr. Neurovasc. Res. 2007;4:153–160.
    1. Ang K.L., Chin D., Leyva F., Foley P., Kubal C., Chalil S., Srinivasan L., Bernhardt L., Stevens S., Shenje L.T., Galiñanes M. Randomized, controlled trial of intramuscular or intracoronary injection of autologous bone marrow cells into scarred myocardium during CABG versus CABG alone. Nat. Clin. Pract. Cardiovasc. Med. 2008;5:663–670.
    1. Katayama Y., Takaji K., Shao Z.Q., Matsukawa M., Kunitomo R., Hagiwara S., Moriyama S., Kawasuji M. The value of angiogenic therapy with intramyocardial administration of basic fibroblast growth factor to treat severe coronary artery disease. Ann. Thorac. Cardiovasc. Surg. 2010;16:174–180.
    1. Mocini D., Staibano M., Mele L., Giannantoni P., Menichella G., Colivicchi F., Sordini P., Salera P., Tubaro M., Santini M. Autologous bone marrow mononuclear cell transplantation in patients undergoing coronary artery bypass grafting. Am. Heart J. 2006;151:192–197.
    1. Patel A.N., Geffner L., Vina R.F., Saslavsky J., Urschel H.C., Jr., Kormos R., Benetti F. Surgical treatment for congestive heart failure with autologous adult stem cell transplantation: a prospective randomized study. J. Thorac. Cardiovasc. Surg. 2005;130:1631–1638.
    1. Stamm C., Kleine H.D., Choi Y.H., Dunkelmann S., Lauffs J.A., Lorenzen B., David A., Liebold A., Nienaber C., Zurakowski D. Intramyocardial delivery of CD133+ bone marrow cells and coronary artery bypass grafting for chronic ischemic heart disease: safety and efficacy studies. J. Thorac. Cardiovasc. Surg. 2007;133:717–725.
    1. Trifunović Z., Obradović S., Balint B., Ilić R., Vukić Z., Šišić M., Kostić J., Rusović S., Dobrić M., Ostojić G. Functional recovery of patients with ischemic cardiomyopathy treated with coronary artery bypass surgery and concomitant intramyocardial bone marrow mononuclear cell implantation--a long-term follow-up study. Vojnosanit. Pregl. 2015;72:225–232.
    1. Losordo D.W., Vale P.R., Symes J.F., Dunnington C.H., Esakof D.D., Maysky M., Ashare A.B., Lathi K., Isner J.M. Gene therapy for myocardial angiogenesis: initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia. Circulation. 1998;98:2800–2804.
    1. Ylä-Herttuala S., Bridges C., Katz M.G., Korpisalo P. Angiogenic gene therapy in cardiovascular diseases: dream or vision? Eur. Heart J. 2017;38:1365–1371.
    1. Robich M.P., Chu L.M., Oyamada S., Sodha N.R., Sellke F.W. Myocardial therapeutic angiogenesis: a review of the state of development and future obstacles. Expert Rev. Cardiovasc. Ther. 2011;9:1469–1479.
    1. Grönman M., Tarkia M., Stark C., Vähäsilta T., Kiviniemi T., Lubberink M., Halonen P., Kuivanen A., Saunavaara V., Tolvanen T. Assessment of myocardial viability with [15O]water PET: A validation study in experimental myocardial infarction. J. Nucl. Cardiol. 2019 doi: 10.1007/s12350-019-01818-5. Published online July 17, 2019. 31317328.
    1. Hartikainen J., Hassinen I., Hedman A., Kivelä A., Saraste A., Knuuti J., Husso M., Mussalo H., Hedman M., Rissanen T.T. Adenoviral intramyocardial VEGF-DΔNΔC gene transfer increases myocardial perfusion reserve in refractory angina patients: a phase I/IIa study with 1-year follow-up. Eur. Heart J. 2017;38:2547–2555.
    1. Murthy V.L., Bateman T.M., Beanlands R.S., Berman D.S., Borges-Neto S., Chareonthaitawee P., Cerqueira M.D., deKemp R.A., DePuey E.G., Dilsizian V., SNMMI Cardiovascular Council Board of Directors. ASNC Board of Directors Clinical Quantification of Myocardial Blood Flow Using PET: Joint Position Paper of the SNMMI Cardiovascular Council and the ASNC. J. Nucl. Med. 2018;59:273–293.
    1. Chien K.R., Zangi L., Lui K.O. Synthetic chemically modified mRNA (modRNA): toward a new technology platform for cardiovascular biology and medicine. Cold Spring Harb. Perspect. Med. 2014;5:a014035.
    1. Karikó K., Muramatsu H., Keller J.M., Weissman D. Increased erythropoiesis in mice injected with submicrogram quantities of pseudouridine-containing mRNA encoding erythropoietin. Mol. Ther. 2012;20:948–953.
    1. Karikó K., Muramatsu H., Welsh F.A., Ludwig J., Kato H., Akira S., Weissman D. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol. Ther. 2008;16:1833–1840.
    1. Kormann M.S., Hasenpusch G., Aneja M.K., Nica G., Flemmer A.W., Herber-Jonat S., Huppmann M., Mays L.E., Illenyi M., Schams A. Expression of therapeutic proteins after delivery of chemically modified mRNA in mice. Nat. Biotechnol. 2011;29:154–157.
    1. Warren L., Manos P.D., Ahfeldt T., Loh Y.H., Li H., Lau F., Ebina W., Mandal P.K., Smith Z.D., Meissner A. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell. 2010;7:618–630.
    1. Zangi L., Lui K.O., von Gise A., Ma Q., Ebina W., Ptaszek L.M., Später D., Xu H., Tabebordbar M., Gorbatov R. Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction. Nat. Biotechnol. 2013;31:898–907.
    1. Sun N., Ning B., Hansson K.M., Bruce A.C., Seaman S.A., Zhang C., Rikard M., DeRosa C.A., Fraser C.L., Wågberg M. Modified VEGF-A mRNA induces sustained multifaceted microvascular response and accelerates diabetic wound healing. Sci. Rep. 2018;8:17509.
    1. Carlsson L., Clarke J.C., Yen C., Gregoire F., Albery T., Billger M. Biocompatible, purified VEGF-A mRNA improves cardiac function after intracardiac injection 1 week post-myocardial Infarction in swine. Mol. Ther. Methods Clin. Dev. 2018;9:330–346.
    1. Pehrsson S., Hölttä M., Linhardt G., Danielson R.F., Carlsson L. Rapid production of human VEGF-A following intradermal injection of modified VEGF-A mRNA demonstrated by cutaneous microdialysis in the rabbit and pig in vivo. BioMed Res. Int. 2019;2019:3915851.
    1. Gan L.M., Lagerström-Fermér M., Carlsson L.G., Arfvidsson C., Egnell A.C., Rudvik A., Kjaer M., Collén A., Thompson J.D., Joyal J. Intradermal delivery of modified mRNA encoding VEGF-A in patients with type 2 diabetes. Nat. Commun. 2019;10:871.
    1. Kajander S.A., Joutsiniemi E., Saraste M., Pietilä M., Ukkonen H., Saraste A., Sipilä H.T., Teräs M., Mäki M., Airaksinen J. Clinical value of absolute quantification of myocardial perfusion with (15)O-water in coronary artery disease. Circ. Cardiovasc. Imaging. 2011;4:678–684.
    1. Danad I., Uusitalo V., Kero T., Saraste A., Raijmakers P.G., Lammertsma A.A., Heymans M.W., Kajander S.A., Pietilä M., James S. Quantitative assessment of myocardial perfusion in the detection of significant coronary artery disease: cutoff values and diagnostic accuracy of quantitative [(15)O]H2O PET imaging. J. Am. Coll. Cardiol. 2014;64:1464–1475.
    1. Gan L.M., Svedlund S., Wittfeldt A., Eklund C., Gao S., Matejka G., Jeppsson A., Albertsson P., Omerovic E., Lerman A. Incremental value of transthoracic doppler echocardiography-assessed coronary flow reserve in patients with suspected myocardial ischemia undergoing myocardial perfusion scintigraphy. J. Am. Heart Assoc. 2017;6:6.
    1. Blomster J.I., Svedlund S., U Westergren H., Gan L.M. Coronary flow reserve as a link between exercise capacity, cardiac systolic and diastolic function. Int. J. Cardiol. 2016;217:161–166.
    1. Green C.P., Porter C.B., Bresnahan D.R., Spertus J.A. Development and evaluation of the Kansas City Cardiomyopathy Questionnaire: a new health status measure for heart failure. J. Am. Coll. Cardiol. 2000;35:1245–1255.
    1. Spertus J.A., Winder J.A., Dewhurst T.A., Deyo R.A., Prodzinski J., McDonell M., Fihn S.D. Development and evaluation of the Seattle Angina Questionnaire: a new functional status measure for coronary artery disease. J. Am. Coll. Cardiol. 1995;25:333–341.
    1. The Criteria Committee of the New York Heart Association . Ninth Edition. Little, Brown & Co.; Boston: 1994. Nomenclature and criteria for diagnosis of diseases of the heart and great vessels.
    1. Hedman M., Hartikainen J., Syvänne M., Stjernvall J., Hedman A., Kivelä A., Vanninen E., Mussalo H., Kauppila E., Simula S. Safety and feasibility of catheter-based local intracoronary vascular endothelial growth factor gene transfer in the prevention of postangioplasty and in-stent restenosis and in the treatment of chronic myocardial ischemia: phase II results of the Kuopio Angiogenesis Trial (KAT) Circulation. 2003;107:2677–2683.
    1. Zhao Q., Sun Y., Xia L., Chen A., Wang Z. Randomized study of mononuclear bone marrow cell transplantation in patients with coronary surgery. Ann. Thorac. Surg. 2008;86:1833–1840.
    1. Schumacher B., Stegmann T., Pecher P. The stimulation of neoangiogenesis in the ischemic human heart by the growth factor FGF: first clinical results. J. Cardiovasc. Surg. (Torino) 1998;39:783–789.
    1. Ruel M., Laham R.J., Parker J.A., Post M.J., Ware J.A., Simons M., Sellke F.W. Long-term effects of surgical angiogenic therapy with fibroblast growth factor 2 protein. J. Thorac. Cardiovasc. Surg. 2002;124:28–34.
    1. Ruel M., Beanlands R.S., Lortie M., Chan V., Camack N., deKemp R.A., Suuronen E.J., Rubens F.D., DaSilva J.N., Sellke F.W. Concomitant treatment with oral L-arginine improves the efficacy of surgical angiogenesis in patients with severe diffuse coronary artery disease: the Endothelial Modulation in Angiogenic Therapy randomized controlled trial. J. Thorac. Cardiovasc. Surg. 2008;135:762–770, 770.e1.
    1. Pätilä T., Lehtinen M., Vento A., Schildt J., Sinisalo J., Laine M., Hämmäinen P., Nihtinen A., Alitalo R., Nikkinen P. Autologous bone marrow mononuclear cell transplantation in ischemic heart failure: a prospective, controlled, randomized, double-blind study of cell transplantation combined with coronary bypass. J. Heart Lung Transplant. 2014;33:567–574.
    1. Noiseux N., Mansour S., Weisel R., Stevens L.M., Der Sarkissian S., Tsang K., Crean A.M., Larose E., Li S.H., Wintersperger B. The IMPACT-CABG Trial: A Multicenter, Randomized Clinical Trial of CD133(+) Stem Cell Therapy During Coronary Artery Bypass Grafting for Ischemic Cardiomyopathy. J Thorac Cardiovasc Surg. 2016;152:1582–1588.e1582.
    1. Nasseri B.A., Ebell W., Dandel M., Kukucka M., Gebker R., Doltra A., Knosalla C., Choi Y.H., Hetzer R., Stamm C. Autologous CD133+ bone marrow cells and bypass grafting for regeneration of ischaemic myocardium: the Cardio133 trial. Eur. Heart J. 2014;35:1263–1274.
    1. Menasché P., Alfieri O., Janssens S., McKenna W., Reichenspurner H., Trinquart L., Vilquin J.T., Marolleau J.P., Seymour B., Larghero J. The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation. Circulation. 2008;117:1189–1200.
    1. Kilian E.G., Sadoni S., Vicol C., Kelly R., van Hulst K., Schwaiger M., Kupatt C., Boekstegers P., Pillai R., Channon K. Myocardial transfection of hypoxia inducible factor-1α via an adenoviral vector during coronary artery bypass grafting. - A multicenter phase I and safety study - Circ. J. 2010;74:916–924.
    1. Hu S., Liu S., Zheng Z., Yuan X., Li L., Lu M., Shen R., Duan F., Zhang X., Li J. Isolated coronary artery bypass graft combined with bone marrow mononuclear cells delivered through a graft vessel for patients with previous myocardial infarction and chronic heart failure: a single-center, randomized, double-blind, placebo-controlled clinical trial. J. Am. Coll. Cardiol. 2011;57:2409–2415.
    1. Hendrikx M., Hensen K., Clijsters C., Jongen H., Koninckx R., Bijnens E., Ingels M., Jacobs A., Geukens R., Dendale P. Recovery of regional but not global contractile function by the direct intramyocardial autologous bone marrow transplantation: results from a randomized controlled clinical trial. Circulation. 2006;114(1, Suppl):I101–I107.

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