mobilized cd34+ cells for refractory angina:

$: Mobilized CD34+ Cells for Refractory Angina:$
Mobilized CD34+ Cells for Refractory Angina:

Design and Rationale for the RENEW Study

Thomas J. Povsic, MD, PhDon behalf of the RENEW Investigators

All Rights Reserved, Duke Medicine 2007

Disclosure Statement of Financial Interest

• Grant/Research Support• Grant/Research Support

• Baxter Healthcare Corporation• Revalesio Inc.

Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below.

Affiliation/Financial Relationship Company


Scope

• Estimated that 600,000 – 1.8 million Americans suffer from refractory angina

• 50,000 – 100,000 new cases per year• Increasing incidence• Poor QOL• Variable outcomes• Poor success of novel therapeutics


Treatment effect of bone marrow cells implantation on total exercise time on treadmill test.

Tse H et al. Eur Heart J 2007;28:2998-3005

PROTECT-CAD Trial


Treatment effect of bone marrow cells implantation on left ventricular ejection fraction as determined by cardiac magnetic resonance imaging.

Tse H et al. Eur Heart J 2007;28:2998-3005

PROTECT-CAD Trial


van Ramshorst, J. et al. JAMA 2009;301:1997-2004

Double Blind Placebo Controlled Trial of Treatment of Refractory Angina with BM MNCs


Original Description of Endothelial Progenitor Cells (EPC) in Adults•CD34+ cells isolated•Cultured on fibronectin•Grew into colonies resembling embryonic blood islands

Asahara et al. Science 1997;275:964-7


Treatment Groups 1) PBS: 100 µl 2) Low 34: 5X103 cells/ rat kg 3) Mid 34: 5X105 cells/ rat kg 4) Mid MNC: 5X105 cells/ rat kg 5) High MNC: tMNCs containing Mid EPC dose n=8~10 in each group

PreClinical Models


0

10

20

30

40

50 *

**

PBSLow34

MidMNC

Mid34

High MNC

Fractional Shortening (%)

16

20

24

28

PBS Low34

MidMNC

Mid34

**

Regional Wall Motion Score

HighMNC

* *

Human CD34 Transplant Improves Left Ventricular Function Post-MI

Kawamoto et al, Circulation (2006) 114:2163Less fibrosis, more endothelial markers with CD34+ cells


1 x 105 CD34+ cells/kg


Endomyocardial Mapping and Injection with NOGAIsolex selected CD34+ cells / Placebo Rx

Cell Mobilization (GCSF 5mcg/kg/d x 5d)Apheresis on Day 5

Follow-up Safety and Efficacy Assessments:1,2, 4 weeks and 2, 3, 6, 9, and 12 months; ETT at 3, 6, 12 months

MRI at 6 months, SPECT at 6 & 12 months

Screening and Baseline Visits

Placebo

Randomization

Phase 1 Randomized, Double-Blind, Placebo Controlled Dose-Escalation Trial of Autologous CD34+ Cell Therapy for Refractory Myocardial Ischemia

Subject population (n=24)

• CCS class III or IV Angina• Attempted “best” medical

therapy• Non-candidate for

Surgical/Perc. revasc.• Ischemia on SPECT• 1-6 min. Bruce protocol with

angina or anginal equivalent at baseline

• AICD or LifeVest



Phase I: The Dose Range is Feasible

1.00

10.00

100.00

ControlNo cells

Group 1 5 X 104 cells

Group 21 x 105 cells

Group 3 5 X 105 cells A

uto-

CD 3

4+ C

ell D

ose/

kg x

104

(

log

scal

e)

Actual Auto-CD 34+ Cell Dose Delivered / kg (n = 6 / dose group)

Losordo D W et al. Circulation 2007;115:3165-3172


3 6 12-20

-15

-10

-5

0

5

10

ControlCD34+ Cell

Angina Episodes per week

(Change from Baseline)

Phase I: Angina FrequencyEpisodes per Week

12 month control data is not represented due to control patient cross-over after 6 months

Months

+6.5

-11.6**

-4.5

-12.6-15.6

**p=0.053 ANOVA between treatment groups Losordo D W et al. Circulation 2007;115:3165-3172


1 x 10^5 CD34+ cells/kg (n = 55)

5 x 10^5 CD34+ cells/kg (n = 56)

Endomyocardial Mapping and Injection with NOGAIsolex selected CD34+ cells / Placebo Rx

Cell Mobilization (GCSF 5mcg/kg/d x 5d)Apheresis on Day 5

Follow-up Safety and Efficacy Assessments:1 - 7 days, and 1, 3, 6, and 12 months; ETT at 3, 6, 12 months

MRI at 6 months, SPECT at 6 & 12 months


Placebo (n = 56)

Randomization

Randomized, Double-Blind, Placebo Controlled Trial of Autologous CD34+ Cell Therapy for Refractory Myocardial Ischemia

Subject population (n=167)

• 21-80 yrs• CCS class III or IV Angina• Attempted “best” medical

therapy• Non-candidate for

Surgical/Perc. revasc.• Ischemia on SPECT• 3-10 min. mod. Bruce

protocol with angina or anginal equivalent at baseline


Change in Angina Counts


Change in Angina – 12 months


Change in Exercise Capacity


Control 1x105

CD34+cells/kg5x105

CD34+cells/kgp-

value*Death 3(5.4%) 0(%) 0(%) 0.107

MI 7 (12.5%)

3(5.5%) 3(5.4%) 0.305

Death, MI 10(17.9%)

3(5.5%) 3(5.4%) 0.058

Death, MI, Urgent Revasc

11(19.6%)

5(9.1%) 4(7.1%) 0.106

Death, MI, Urgent Revasc,

Worse CHF, ACS

15(26.8%)

7(12.7%) 7(12.5%) 0.093

Pts with MACE events from start of mobilization thru 12 mo in injected pts; *= Fisher’s Exact Test

Major Adverse Cardiac Events (12 Months)


Control 1x105

CD34+cells/kg5x105

CD34+cells/kgp-

value*Death 7(12.5%) 1(1.8%) 2(3.6%) 0.081

MI 10 (17.9%)

9(16.4%) 6(10.7%) 0.587

Death, MI 15(26.8%)

10(18.2%) 6(10.7%) 0.096

Death, MI, ACS

Hospitalization

17(30.4%)

10(18.2%) 8(14.3%) 0.101

Death, MI, ACS or Worse

CHF Hospitalizatio

n

19(33.9%)

12(21.8%) 9(16.1%) 0.078

Pts. with MACE events from start of mobilization thru 12 mo in injected pts.; *= Fisher’s Exact Test

Major Adverse Cardiac Events (24 Months)


Efficacy Comparison: Change in ETT

0

20

40

60

80 7080

23.8

45.9

2416

35

Δ Ex

erci

se T

ime


CD34-6 Month

CD34-12 Month

Ranexa CARISA EECP

-6

-5

-4

-3

-2

-1

0

Change in Angina Episodes per Week

Cha

nge

inN

umbe

rs o

f Ang

inal

Epis

odes

Per

Wee

k


RENEW:

A Prospective, Randomized, Double-Blinded, Active-controlled Study to Determine the Efficacy and Safety of Targeted Intramyocardial Delivery of G-CSF Mobilized Autologous CD34+ Cells For the Improvement In Total Exercise Time in Subjects with Refractory Angina and Chronic Myocardial Ischemia

• RENEW is the first trial of cell therapy for CV disease designed to fulfill requirements for US regulatory approval

• Powered to demonstrate efficacy on clinical endpoints• Largest planned US trial in cell therapy• Largest currently enrolling cell therapy trial in CV disease• RENEW represents a landmark study in the field, setting

benchmarks for development of other cell therapies for CV disease.


RENEW Efficacy and Safety Endpoints• Primary Efficacy Endpoint

– Change in total exercise duration using a standardized Modified Bruce Protocol ETT at 12 months

• Secondary Efficacy Endpoints– Change in angina frequency at 12 months– Change in exercise duration and angina frequency at 6

months• Exploratory Endpoints

– Incidence of MACE* and SAEs in all subjects

* MACE: all death, non-fatal MI, CVA, Cardiac rehosp


1 x 105 CD34+ cells/kg (n = 200)

Unblinded Standard of Care (n = 100)

Cell Mobilization (G-CSF 5 mg/kg/d x 4d)Apheresis on Day 5


Active Control(n = 100)

Randomization

Safety Assessments during 24 month follow-up: AEs,

SAEs, MACE

RENEW Study Design

Inclusion Criteria:• 21-80 yrs• CCS class III or IV Angina• Attempted “best”

medical therapy• Non-candidate for Surgical/Perc. revasc.• Ischemia w/stress• 3-10 min. mod. Bruce


• ETT reproducible <20%• 7 angina/wkExclusion Criteria:• Recent hospitalization• Other angiogenic trials• Must be willing to forgo other

angiogenic/experimental txt x 2 years

Pre-Qual Committee Central Review


Auto-CD34+ Cell Product: Centralized Processing

Mobilization, apheresis, and shipment to centralized manufacturing facility

Apheresis at Clinical

Site

ISOLEX CD34+ cell selection, syringe preparation, release testing, and shipment to clinical sites

Cell Processing

at Centralized

Facility

Receive product, NOGA mapping and injection in catheter lab

Injection at Clinical

Site

Auto CD34+ Cell Product

<48 hrs

<48 hrs


1 x 105 CD34+ cells/kg (n = 200)

Unblinded Standard of Care (n = 100)

Intramyocardial Mapping and Injection with NOGA

ISOLEX selected CD34+ cells / Placebo

Cell Mobilization (G-CSF 5 mg/kg/d x 4d)Apheresis on Day 5

Efficacy Assessments during 12 month follow-up: ETT, angina frequency, and QoL

(SF-36)Safety Assessments during 24 month

follow-up: AEs, SAEs, MACE


Active Control(n = 100)

Randomization

Safety Assessments during 24 month follow-up: AEs,

SAEs, MACE

RENEW Study Design

Inclusion Criteria:• 21-80 yrs• CCS class III or IV Angina• Attempted “best”

medical therapy• Non-candidate for Surgical/Perc. revasc.• Ischemia w/stress• 3-10 min. mod. Bruce


• ETT reproducible <20%• 7 angina/wkExclusion Criteria:• Recent hospitalization• Other angiogenic trials• Must be willing to forgo other

angiogenic/experimental txt x 2 years

Pre-Qual Committee Central Review


Monitoring Committees• Steering Committee

– Responsible for oversight of study, data interpretation, protocol and amendments, publications

– Oversee country activities• Data Safety Monitoring Board

– Will be un-blinded and will oversee safety and integrity of study– Recommend changes in study arms– Meetings after 10, 25, 50, 100, 200 and 300 patients

• Clinical Events Committee– Blindly adjudicate clinical events

• Pre-Qualification Committee

27


Study Population: Main Inclusion Criteria

• Male or female subjects who are 21 to 80 years of age• CCS class III or IV chronic refractory angina• On maximal tolerated doses of anti-anginal drugs

– At least 2 of 4 classes recommended• Unsuitable for conventional revascularization as determined at site and confirmed by

an independent pre-qualification committee• Objective evidence of inducible ischemia in the potential injection target zone, using

clinically accepted assessment of ischemia within 1 year of screening provided the subject has remained clinically stable

• LVEF ≥25% at screening.• Minimum average of 7 angina or angina-equivalent episodes per week• Able to complete a minimum of 3 minutes but no more than 10 minutes on a treadmill

using the Modified Bruce Protocol during 2 ETTs performed during screening period with ≤ 20% variability

• Subject must experience angina or angina-equivalent symptoms at each of the 2 ETTs


Comparator ArmsBlinded Active Control Unblinded Standard of Care

Advantages

Only true double-blind design Blinding minimizes both subject and

assessor bias Impact of placebo effect on safety

endpoints allows for more rigorous comparisons

Allows for assessment of efficacy of the cell product

Regulatory Considerations (combo product)

Safety of Auto-CD34+ cell therapy versus SOC may be assessed

Eliminates potential impact of intervention on cardiac outcomes

Subjects will reflect those of general refractory angina population

Regulatory Considerations

Challenges Potential periprocedural safety risks due to minimal apheresis & femoral artery access

Utility of clinical comparison

May negatively impact subject enrollment and retention (issues with differential retention)

No placebo effect: subjects may have a poorer perception of overall health.

Patients may seek out other options

No reasonable efficacy assessment


Statistical Plan• Sample Size

– 400 completed subjects– 90% power to detect 60 second

difference in mean change from baseline in total exercise time

• Statistical Approach– Closed form testing procedure on

primary and secondary efficacy endpoints

– Allows for potential inclusion of secondary efficacy endpoints in product label


Conclusions

• RENEW is the first trial of cell therapy for CV disease designed to fulfill requirements for US regulatory approval

• Powered to demonstrate efficacy on clinically important endpoints

• Largest planned US trial in cell therapy• Largest currently enrolling cell therapy trial in CV

disease• RENEW represents a landmark study in the field,

setting benchmarks for development of other cell therapies for CV disease.

mobilized cd34+ cells for refractory angina:

Documents

duke medicine

cd34 cellsall rights

5x105 cells rat

5x103 cells rat

bm mncsall rights

cad trialall rights

treatment groups

human cd34 transplant