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Michael JB Kutryk, MD PhD Terrence Donnelly Heart Centre, St Michael’s Hospital,

The NORTHERN Trial: A Prospective, Randomized, Double Blind Placebo-Controlled Evaluation of Intramyocardial VEGF 165 Plasmid Gene Transfer in Patients with Refractory Angina. Michael JB Kutryk, MD PhD Terrence Donnelly Heart Centre, St Michael’s Hospital, University of Toronto,

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Michael JB Kutryk, MD PhD Terrence Donnelly Heart Centre, St Michael’s Hospital,

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  1. The NORTHERN Trial:A Prospective, Randomized, Double Blind Placebo-Controlled Evaluation of Intramyocardial VEGF165 Plasmid Gene Transfer in Patients with Refractory Angina Michael JB Kutryk, MD PhD Terrence Donnelly Heart Centre, St Michael’s Hospital, University of Toronto, Ontario, Canada Duncan J Stewart, MD Ottawa Health Research Institute, The Ottawa Hospital, University of Ottawa, Ontario, Canada on behalf of the NORTHERN investigators

  2. Disclosure Statement of Financial Interest Within the past 12 months, I have had a financial interest/ arrangement or affiliation with the organization(s) listed below. Affiliation/Financial RelationshipCompany Grant/Research support Johnson & Johnson

  3. Introduction Angiogenesis represents a potential novel therapy for patients with refractory angina due to chronic coronary artery disease Despite the promise of the preclinical and early clinical trials, larger “proof-of-concept” studies have failed to show convincing benefit – but, previous studies have limitations: Use of unstable protein factors – FIRST, VIVA Delivery strategies (i.e. intracoronary administration) – AGENT trials Lack of blinding – REVASC Suboptimal gene “dose” – EURO-INJECT-1

  4. The NORTHERN trial The NORTHERN trial was designed to overcome these limitations by: Intramyocardial gene transfer to achieve a high level of local cardiac VEGF165 expression Percutaneous navigational and mapping injection catheter (NOGA, Cordis – Biosense, Webster) to allow double blind trial design Delivery of an “optimal dose” of plasmid DNA equivalent to preclinical studies

  5. NORTHERN Trial • Montreal • Heart Institute • - Dr. L. Bilodeau • Dr. S. Doucet • Ms. N. St.Jean Quebec City Laval -Dr. G. Proulx -Dr. E. Larose -Mr. G. Rossignol 7 “NOGA” sites across Canada • Toronto • St. Michael’s Hospital • Dr. M. Kutryk • Dr. M. Freeman • Dr. H. Leong-Poi • Dr. D. Fitchett • Ms. R. Dunne • Ms. N. Camack • Sunnybrook Health SC • Dr. S. Radhakrishnan • Dr. A. Dick • -Ms. I. Taibert • Ms. L. Balleza • Edmonton • U of Alberta • Dr. J. Burton • Dr. W. Tymchak • Ms. L. Lindholm • Ms. N. Hogg • Victoria • Heart Institute • Dr. D. Hilton • Dr. P. Klinke • Dr. A. Della Siega • Ms. N. Lounsbury Mt. Sinai Hospital -Dr. A. Barolet -Ms. D. Locke • VEGF165 plasmid DNA (2,000 mg total dose) vs. saline – 10 injections targeted to ischemic region • Io EP: persantine sesta MIBI SSS at 3 and 6 months • Secondary EPs: SDS, ETT, CCS class, SAQ, SF-36

  6. Group 2 (n=21) - Single vessel disease: diffuse in-stent restenosis or single occlusion NORTHERN Study Flow Chart Group 1 (n=72) – “no option” patients: severe, advanced CAD; CCS Class III or IV NOGA Catheter Mapping Randomization Active VEGF165 DNA NOGA Injection (n=48) Sham (saline) NOGA Injection (n=45) 7 day F/U: ECG, Office visit 30 day F/U: ECG, Office Visit, CCSA score SAQ, AE 3 and 6 months Exercise test/Sestamibi CCS/SAQ/SF-36 Primary Outcome Assessment

  7. Baseline Characteristics VEGF 165 Placebo n=48 (%) n=45(%) P-value Age 63±7 64±8 0.58 Male sex 40 (83%) 42 (93%) 0.20 Hyperlipidemia 46 (96%) 41 (91%) 0.43 Cardiac RFs Hypertension 35 (73%) 33 (73%) 1 DM 18 (38%) 14 (31%) 0.66 Smoking 18 (38%) 13 (29%) 0.51 MI 41 (85%) 38 (84%) 1 CABG 42 (88%) 39 (87%) 1 Past Medical History PCI 30 (63%) 33 (73%) 0.28 Stroke 7 (15%) 3 ( 7%) 0.32 TIA 3 ( 6%) 3 ( 7%) 1 PVD 12 (25%) 12 (27%) 1 P-value from Fisher’s Exact Test

  8. Myocardial Perfusion by SPECT imaging Summed Difference Score Summed Stress Score 30 18 P=0.78 P=0.19 P=0.87 16 25 14 20 12 10 15 8 10 6 4 5 2 38 45 47 42 40 42 0 0 Base 3M 6M Base 3M 6M Placebo VEGF165 P=0.26 P=0.48 P=0.8 38 45 47 42 40 42 P-value from Wilcoxon Test

  9. Change in Myocardial Perfusion by SPECT imaging – the Primary analysis Summed Stress Score Summed Difference Score 3M 6M 3M 6M 0 0 -0.5 -0.5 -1 -1 -1.5 -1.5 -2 † †† †† -2 -2.5 -2.5 -3 P=0.98 P=0.95 P=0.16 P=0.93 VEGF vs. placebo VEGF vs. placebo P-value from Wilcoxon Test Placebo † p=0.08 vs. baseline †† p=0.01 vs. baseline VEGF165

  10. Baseline Characteristics Group 1 Group 2 n=72 (%) n=21 (%) P-value Age 63±7 63±9 0.99 Male sex 65 (90%) 17 (81%) 0.26 Hyperlipidemia 67 (93%) 20 (95%) 1 Hypertension Cardiac RFs 52 (72%) 16 (76%) 0.79 DM 27 (38%) 5 (24%) 0.30 Smoking 24 (33%) 7 (33%) 1 MI 59 (82%) 20 (95%) 0.29 CABG 64 (89%) 17 (81%) 0.46 Past Medical History PCI 49 (68%) 14 (67%) 1 Stroke 8 (11%) 2 ( 10%) 1 TIA 5 ( 7%) 1 ( 5%) 1 PVD 19 (26%) 5 (24%) 1

  11. Change in SSS and SDS:Group 1 and Group 2 3 months 6 months Group 2 Group 1 Group 2 Group 1 0 0 -2 -2 SSS SSS -4 -4 -6 -6 -8 0 0 -2 -2 SDS SDS -4 * -4 -6 -6 (N) (31) (35) (6) (9) (N) (31) (35) (6) (9) Placebo VEGF165 * = p<0.05; Wilcoxon sum-rank

  12. Exercise treadmill Time (ETT) ETT Change in ETT 8 1.6 7 1.4 6 1.2 5 1 (minutes) (minutes) 4 0.8 3 0.6 2 0.4 1 0.2 0 0 3M 6M Base 3M 6M Placebo VEGF165 P=0.46 P=0.74 P=0.78 P=0.49 P=0.96 †† † † † P-value from Wilcoxon Test † p<0.05 vs. baseline ††p<0.01 vs. baseline

  13. CCS Functional Class 3M 6M 3M 6M P=0.23 P=0.48 Placebo VEGF165 CCS Class †† †† †† †† 100% I 80% II 60% III 40% 20% IV 0% Base Base VEGF vs. Placebo: P=1.0 P values from Fisher’s Exact Test ††P<0.001 vs. baseline

  14. Adverse Events VEGF 165 Placebo P-value n=48 (%) n=45 (%) Liver enzyme rise 4 (8%) 3 (7%) 0.68 Headache 5 (10%) 8 (18%) 0.54 Pericardial 7 (15%) 3 (7%) 0.32 GI related 15 (31%) 11 (24%) 0.62 Dizziness 6 (13%) 5 (11%) 1 Dermatological 12 (25%) 11 (24%) 0.86 Retinal 2 (4%) 1 (2%) 0.44 Peripheral 9 (19%) 7 (16%) 0.89 Muskuloskeletal 21 (44%) 11 (24%) 0.04 Neurological 7 (15%) 9 (20%) 0.68 Inflammation 5 (10%) 4 (9%) 1 Hypotension 4 (8%) 3 (7%) 0.73 Cancer* 1 (2%) 1 (2%) 1 * basal cell carcinomas P-value from Fisher Exact Test

  15. Placebo n=45 VEGF165n=48 Cardiovascular Events - Major P=0.16 P=0.49 8 7 6 5 Number of patients 4 3 2 1 0 Death/MI/ Revascularization* Ischemic event * 2 deaths: 1 VEGF; 1 Placebo P-value from Fisher Exact Test

  16. Summary Intramyocardial plasmid VEGF165 gene transfer did not result in any improvement in myocardial perfusion, exercise tolerance or anginal symptom class compared with placebo Similar and significant improvement was seen in both the treatment and placebo groups in all endpoints: 2 point decrease in SDS by SPECT imaging ~1 minute improvement in total ETT 40-50% of patients improved by at least 1 CCS symptom class

  17. Conclusion Intramyocardial plasmid VEGF165 gene transfer was ineffective for the treatment of refractory angina in patients who were not candidates for traditional revascularization procedures (Group 1) or for whom bypass surgery was deemed not appropriate (Group 2).

  18. Discussion The improvement in myocardial perfusion in both placebo and treatment groups raises the possibility of spontaneous development of collaterals, which supports the biological plausibility pro-angiogenic therapeutic strategies despite the lack of efficacy of simple VEGF gene transfer This study suggests that more sophisticated strategies will be required in order to enhance collateralization in patients with severely symptomatic coronary disease Combinations of genes or sequential delivery Cell or combined cell and gene therapies

  19. Acknowledgements This trial was supported by: Canadian Institutes of Health Research Heart & Stroke Foundation of Ontario St. Michael’s Hospital Foundation Johnson & Johnson

  20. Study Limitations Limited power due to termination prior to reaching target enrolment of 110 patients Given the lack of any trend in favor of VEGF, it is unlikely that additional patients would have changed the result Transfection efficiency due to use of plasmid rather than viral vector Cannot rule out that higher levels of transfection might have been effective

  21. Change SSS and SDS in VEGF Group Troponin +ve vs. Troponin –ve Summed Stress Score Summed Difference Score 6 Months 3 Months 6 Months 3 Months P=0.98 P=0.95 P=0.16 P=0.93 2 1 0.5 1 0 0 -0.5 -1 -1 -1.5 -2 -2 -3 -2.5 -3 -4 Positive (N) (37) (7) (34) (7) (N) (37) (7) (34) (7) Negative P-value from Wilcoxon Test

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