Effects of Reestablishing SDF-1 Expression in Chronic Heart Failure

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1 Effects of Reestablishing SDF-1 Expression in Chronic Heart Failure Marc S. Penn, MD, PhD, FACC Skirball Laboratory for Cardiovascular Cellular Therapeutics Director of Research, Summa Cardiovascular Institute Summa Health System Professor of Medicine and Integrated Medical Sciences Northeast Ohio Medical

2 Disclosures Company Name Juventas Therapeutics Cleveland Heart Lab, LLC Oakwood Medical Ventures Foundation Medical Partners Athersys, Inc. SDG, Inc. MPI Research NIH, Heart Failure Network BIOMET, Inc. VBL, Inc. Current Relationship Founder, CSO, Equity, Inventor Founder, CMO, Equity, Inventor Venture Partner Clinical Partner Sponsored Research Sponsored Research Consultant DSMB Member DSMB Member DSMB Member 03/2009

3 Evidence for Stem Cell Therapy in Chronic Heart Failure Autologous bone marrow in CHF Perin group Improved clinical parameters Hare group Improved remodeling Zeiher & Dimmeler Improved outcomes and definition of target population

4 Chemokine/GF MSC Exogenous BMMNC

5 Stem Cell Based Tissue Repair We proposed several years ago that: Stem cell based repair of ischemic tissue in mammals is a natural process but clinically inefficient due to dysregulation or short term expression of key molecular signals

6 SDF-1 Mediates Stem Cell Homing following MI Stromal Cell-Derived Factor 1 Time after MI: Transplantation: SDF-1 GAPDH Hours Days RT-PCR of 500 ng of total RNA for 40 cycles

7 Stromal Cell-Derived Factor-1 (SDF-1) Chemokine receptor CXCR4/CXCR7 Induces stem cell homing to bone marrow Lethal knockout secondary to abnormal hematopoietic trafficking SDF-1:CXCR4 blocks apoptotic cell death

8 Exogenous BMMNC

9 Stem Cell Based Tissue Repair We and others have shown: SDF-1 is responsible for stem cell homing to myocardial tissue in AMI Re-establishment of SDF-1 expression in ischemic cardiomyopathy induces stem cell homing Increases vascular density recruits cardiac stem cells improves cardiac function Patient response to BMMNC cell infusion in AMI correlates with cellular responsiveness to SDF-1

10 Is SDF-1 Important in Stem Cell Based Repair? Zeiher & Dimmeler Demonstrated patient response to BM infusion post-ami is predicted by preps response to SDF-1 in in vitro migration assay Is SDF-1 required in vivo?

11 Expression Hypothesis: Cell Therapy Induces Myocardial Repair by Temporally Aligning the SDF-1: CXCR4 axis SDF-1 CXCR4 Time after Ischemic Injury

12 Expression Hypothesis: MSC Engraftment Temporally Aligns the SDF-1: CXCR4 Axis SDF-1 with MSC delivery CXCR4 Time after Ischemic Injury

13 CXCR4 is not required for Cardiac Myocyte Development or Function MCM-Cre: CXCR4f/f MLC-2v: CXCR4f/f No VSD No differences in EF, radial strain or circumferential strain compared to littermates lacking MLC-2v

14 Expression Hypothesis: MSC Engraftment Temporally Aligns the SDF-1: CXCR4 Axis SDF-1 SDF-1 CXCR4 Time after Ischemic Injury

15 Expression Hypothesis: MSC Engraftment Temporally Aligns the SDF-1: CXCR4 Axis SDF-1 with MSC SDF-1 with MSC CXCR4 Time after Ischemic Injury

16 CM-CXCR4 is Required for CM Preservation and Functional Response to Mesenchymal Stem Cells Ejection Fraction (%) 100 CTRL CM-CXCR4 Null CTRL+ MSC CM-CXCR4 Null +MSC *# Baseline 21 d after AMI

17 Conceptual Evolution of CV Regenerative Medicine Cell Therapy SKMB, MSC, MAPC Paracrine Factors with or without Cells Embryonic Stem Cells or ips

18 JVS-100 (hsdf-1 plasmid) Non-viral DNA plasmid Encodes for hsdf-1 (CXCL12) Driven by CMV promoter with enhancer elements (RU5)

19 BioCardia Helical Infusion Catheter Delivers therapeutics via endomyocardial injection Used to deliver biologics in over 100 clinical cases 1,2 CE marked 1 Williams AR. Circ Res. 2011;108: ; 2 de la Fuente LM. Am Heart J Jul;154(1):79.e1-7.

20 SDF-1 Plasmid for NYHA Class III CHF Phase I trial Sponsor: Juventas Therapeutics, Inc. Northwestern University Columbia University Princeton Baptist Rush Memorial Open Label Dose Escalation Study PI Doug Losordo

21 Phase I clinical trial design summary Enrollment completed in Q Open-label dose-escalation trial Class III heart failure EF < 40%, post-mi 5 mg (n=4); 15 mg (n=6); 30 mg (n=7) JVS-100 delivery 15 injections (1 ml each) of JVS-100 Using BioCardia Helical Infusion Catheter Primary Endpoints Major Adverse Cardiac 1 mo 4 months Cohort Cohort Cohort Follow-up Month Participating Centers Principal Investigator: Doug Losordo, M.D. Cardiology P.C (Birmingham, AL), Columbia (New York, NY), Northwestern (Chicago, IL), Rush Memorial (Chicago, IL) 21

22 Inclusion Criteria NYHA Class III secondary to ischemic cardiomyopathy** No ACS within 6 months LVEF less than or equal to 40% by echocardiography* No left ventricular wall thickness less than 0.5 cm by echocardiography* Mitral regurgitation of 0-2+ (inclusive) by echocardiography Implanted, functional ICD 18 years of age Stable optimal pharmacological treatment ** One patient with NYHA Class II and six-minute walk distance <400 m was granted a waiver

23 Exclusion Criteria Diabetes related Patients with uncontrolled diabetes defined as HbA1c >9.0% Electrophysiology related Persistent atrial fibrillation BIV pacemaker/icd implant within the last 3 months Patients with 40% RV uiniventricular pacing Angiogenic Factor-Related History of cancer (with exception of basal cell carcinoma) Cardiac structure related History of Aortic Valve Regurgitation>2* Moderate/Severe Aortic stenosis Aortic aneurysm >3.8 cm* Other risk factors egfr < 30 ml/min Abnormal liver function test (LFT) Previous organ transplant LV thrombus* Clinical testing related Inability to undergo SPECT imaging Standard No planned revascularization in ensuing 30 days Life expectancy < 1 year Participation in another clinical trial History of drug abuse HIV+, Hepatitis B/C +

24 Baseline data Parameter Full Trial (n=17) Cohort 1 (n=4) Cohort 2 (n=6) Cohort 3 (n=7) Age (yrs.) 65.8± ± ± ±10.6 Sex (M/F) 12/5 4/0 4/2 4/3 6 Min. Walk (m) 290±91 336± ±51 224±51 Bi-V Pacing 24% 50% 16.67% 14.3% Time from last MI (yrs)* 7.3± ± ± ±2.7 QoL 54±21 53±9 55±28 55±21 LVESV (ml) 109±35 112±55 125±17 91±30 LVEF (%) 33±5.5 35±4 30±4 34±6 Data are Mean ± SD * 5 patients unknown time of MI

25 Serious Adverse Event Summary 1 SAE Possibly Related to Drug HF Decompensation* 3 SAE Probably Related to Study Procedure/Device Hematoma in Groin Anemia* Pericardial Effusion** 8 SAE Probably/Possibly Related to Underlying Disease Systemic Lupus Erythematosus Worsening Angina Failure to Thrive Worsening Failure to Thrive *** Renal Insufficiency Unwitnessed Cardiac Arrest *** Orthostatic Hypotension Acute on Chronic HF Exacerbation Primary safety endpoint was met. No SAE has been classified as likely related to drug. Data strongly suggests JVS-100 is safe. *Also reported as probably related to underlying disease **Also reported as possibly related to underlying disease *** Outcome of death Red denotes MACE

26 Median Change from Baseline Median Change from Baseline JVS-100 promotes clinically relevant improvements in QOL and 6MWD at 4 months 0 Quality of Life (QOL) (10 pt change is clinically relevant) 45 6-Min Walk Distance (6MWD) (30 m change is clinically relevant) p= p= Cohort 1 (5 mg) Cohort 2 (15 mg) Cohort 3 (30 mg) Cohort 2 & 3 0 Cohort 1 (5 mg) Cohort 2 (15 mg) Cohort 3 (30 mg) Cohort 2 & 3 P-value relates to change from baseline

27 Median change from baseline JVS-100 stabilizes cardiac remodeling at 4-months 5 0 Parameter (Direction of Improvement) LVESV (ml, ) -5 5 Δ=7%, p< LVEF (%, ) & 3 Cohort

28 JVS-100 Promotes Significant Improvement in NYHA Class 0,0 50% Parameter (Direction of Improvement) Mean change NYHA Class ( ) % Patients Improved -0,1-0,2-0,3-0,4-0,5-0,6-0,7 25% 40% 50% 45% p= & 3 Cohort

29 Summary SDF-1:CXCR4 axis is involved in stem cell homing and tissue repair JVS-100 is well tolerated at all doses tested and primary safety endpoint has been met with no adverse events likely related to drug Defining the molecular mechanisms associated with endogenous stem cell repair identifies targets with therapeutic potential Re-establishment of SDF-1 expression late in patients with chronically remodeled myocardium and symptoms of chronic heart failure leads to improvement in clinical status

30 hsdf-1

31 Acknowledgements Investigators PI - Doug Losordo, MD Farrell Mendelsohn, MD Gary Schaer, MD Warren Sherman, MD Mary Jane Farr, MD Northwestern University Princeton-Baptist, Birmingham, AL Rush Memorial, Chicago Columbia University Columbia University DSMC Les Miller, MD University of South Florida Amit Patel, MD University of Utah Jay Traverse, MD Minneapolis Heart Institute Corey Goldman, MD, PhD Tulane University

32 Acknowledgements Maritza Mayorga, PhD Feng Dong, MD, PhD Indu Deglurkar, MD Niladri Mal, MD Samuel Unzek, MD Jing Bian, PhD Soren Schenk, MD Nikolai Vasilyev, MD Ming Zhang, MD, PhD Mazen Khalil, MD Yu Peng, MD Dominik Wiktor, MD Udit Agarwal, PhD Amanda Finan Nikolai Sopko, PhD Peter Lee, PhD Srividia Sundararaman, PhD Zoran Popovic, MD Farhad Forudi, BS Matthew Kiedrowski, BS Kristal Weber, BS Juventas Therapeutics Rahul Aras, PhD Joe Pastore, PhD Ruth Clemens, RN SironRx Therapeutics Tim Miller, PhD Biocardia Didier Rouy Cheryl Wong Po Foo MPI Research