Michael JB Kutryk, Michael JB Kutryk, MD PhDMD PhD

Terrence Donnelly Heart Centre, Terrence Donnelly Heart Centre, St Michael’s Hospital, St Michael’s Hospital, University of Toronto, University of Toronto,

Ontario, CanadaOntario, Canada

on behalf of the NORTHERN investigatorson behalf of the NORTHERN investigators

Duncan J Stewart, Duncan J Stewart, MDMD

Ottawa Health Research Institute, Ottawa Health Research Institute, The Ottawa Hospital, The Ottawa Hospital, University of Ottawa, University of Ottawa,

Ontario, CanadaOntario, Canada

The NORTHERN Trial:A Prospective, Randomized, Double Blind

Placebo-Controlled Evaluation of Intramyocardial VEGF165 Plasmid Gene

Transfer in Patients with Refractory Angina

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 Relationship Company

Grant/Research support Johnson & Johnson

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

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

NORTHERN TrialQuebec City

Laval -Dr. G. Proulx-Dr. E. Larose

-Mr. G. Rossignol TorontoSt. 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

EdmontonU of Alberta

-Dr. J. Burton-Dr. W. Tymchak-Ms. L. Lindholm

-Ms. N. Hogg

VictoriaHeart Institute

-Dr. D. Hilton -Dr. P. Klinke

-Dr. A. Della Siega-Ms. N. Lounsbury

MontrealHeart Institute - Dr. L. Bilodeau- Dr. S. Doucet- Ms. N. St.Jean

• VEGF165 plasmid DNA (2,000 g 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

7 “NOGA” sites across Canada7 “NOGA” sites across Canada

Mt. Sinai Hospital -Dr. A. Barolet -Ms. D. Locke

NOGA Catheter Mapping

Group 1 (n=72) – “no option” patients: severe,

advanced CAD;CCS Class III or IV

7 day F/U: ECG, Office visit

3 and 6 monthsExercise test/Sestamibi

CCS/SAQ/SF-36

Primary Outcome Assessment

30 day F/U: ECG, Office Visit, CCSA score SAQ, AE

Randomization

Sham (saline) NOGA Injection (n=45)

NORTHERN Study Flow ChartNORTHERN Study Flow Chart

Active VEGF165 DNA NOGA Injection (n=48)

Group 2 (n=21) - Single vessel disease: diffuse in-stent restenosis or single

occlusion

Baseline Characteristics

P-value from Fisher’s Exact Test

CardiacRFs

Past MedicalHistory

VEGF 165 Placebon=48 (%) n=45(%)

Age 63±7 64±8 0.58

Male sex 40 (83%) 42 (93%) 0.20

Hyperlipidemia 46 (96%) 41 (91%) 0.43

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

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

Myocardial Perfusion by SPECT imaging

Summed Stress Score

0

5

10

15

20

25

30

Base 3M 6M

Placebo

VEGF165

P=0.26 P=0.48 P=0.8

P-value from Wilcoxon Test

38 45 47 42 40 42

Summed Difference Score

02468

1012141618

Base 3M 6M

P=0.78 P=0.19 P=0.87

38 45 47 42 40 42

Change in Myocardial Perfusion by SPECT imaging – the Primary analysis

Placebo

VEGF165

3M 6M 3M 6M

Summed Stress Score

-2.5

-2

-1.5

-1

-0.5

0

Summed Difference Score

P=0.98 P=0.95 P=0.16 P=0.93

P-value from Wilcoxon Test

-3

-2.5

-2

-1.5

-1

-0.5

0

††††

VEGF vs. placebo VEGF vs. placebo

†

† p=0.08 vs. baseline†† p=0.01 vs. baseline

Baseline Characteristics

CardiacRFs

Past MedicalHistory

AgeMale sex

HyperlipidemiaHypertensionDMSmoking

MICABGPCIStrokeTIAPVD

Group 1 Group 2n=72 (%) n=21 (%)

63±7 63±9 0.9965 (90%) 17 (81%) 0.26

67 (93%) 20 (95%) 152 (72%) 16 (76%) 0.7927 (38%) 5 (24%) 0.3024 (33%) 7 (33%) 1

59 (82%) 20 (95%) 0.2964 (89%) 17 (81%) 0.4649 (68%) 14 (67%) 18 (11%) 2 ( 10%) 15 ( 7%) 1 ( 5%) 1

19 (26%) 5 (24%) 1

P-value

Change in SSS and SDS:Group 1 and Group 2

Placebo VEGF165

-8

-6

-4

-2

0

Group 1 Group 26 months

SS

S

-6

-4

-2

0

SD

S

(31) (6)(35) (9)(N)

-6

-4

-2

0

*

(31) (6)(35) (9)(N)

SD

S

* = p<0.05; Wilcoxon sum-rank

3 months

-6

-4

-2

0

Group 1 Group 2

SS

S

Exercise treadmill Time (ETT)

Placebo

VEGF165

Change in ETT

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

(min

ute

s)

3M 6M

ETT

0

1

2

3

4

5

6

7

8

Base 3M 6M

(m

inu

tes)

†

†

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

CCS Functional Class

Placebo

100%

0%

20%

40%

60%

80%

Base 3M 6M

VEGF165 CCS Class

I

II

III

IV

P=1.0

3M 6M

P=0.23 P=0.48VEGF vs. Placebo:

†† †† †† ††

P values from Fisher’s Exact Test †† P<0.001 vs. baseline

Base

Adverse Events

* basal cell carcinomasP-value from Fisher Exact Test

VEGF 165 Placebon=48 (%) n=45 (%) P-value

Liver enzyme rise 4 (8%) 3 (7%) 0.68Headache 5 (10%) 8 (18%) 0.54Pericardial 7 (15%) 3 (7%) 0.32GI related 15 (31%) 11 (24%) 0.62Dizziness 6 (13%) 5 (11%) 1Dermatological 12 (25%) 11 (24%) 0.86Retinal 2 (4%) 1 (2%) 0.44Peripheral 9 (19%) 7 (16%) 0.89Muskuloskeletal 21 (44%) 11 (24%) 0.04Neurological 7 (15%) 9 (20%) 0.68Inflammation 5 (10%) 4 (9%) 1Hypotension 4 (8%) 3 (7%) 0.73Cancer* 1 (2%) 1 (2%) 1

0

1

2

3

4

5

6

7

8

Death/MI/Revascularization*

Ischemicevent

Cardiovascular Events - Major

Nu

mb

er

of p

atie

nts

P=0.16 P=0.49

Placebo n=45 VEGF165 n=48

P-value from Fisher Exact Test

* 2 deaths: 1 VEGF; 1 Placebo

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

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).

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

This trial was supported by:Canadian Institutes of Health ResearchHeart & Stroke Foundation of Ontario

St. Michael’s Hospital FoundationJohnson & Johnson

Acknowledgements

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

Change SSS and SDS in VEGF Group Troponin +ve vs. Troponin –ve

Positive

Negative

P-value from Wilcoxon Test

-4

-3

-2

-1

0

1

2

3 Months 6 Months

Summed Difference Score

(37) (34)(7) (7)(N)

P=0.16 P=0.93

(37) (34)(7) (7)(N)-3

-2.5

-2

-1.5

-1

-0.5

0

0.5

1

3 Months 6 Months

Summed Stress Score

P=0.98 P=0.95