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Lessons learned from Phase 1 trial of heart-derived stem Lessons learned from Phase 1 trial of heart-derived stem

Lessons learned from Phase 1 trial of heart-derived stem - PowerPoint Presentation

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Lessons learned from Phase 1 trial of heart-derived stem - PPT Presentation

Lessons learned from Phase 1 trial of heartderived stem c ells as we move into Phase 2 Eduardo Marbán MD PhD Director CedarsSinai Heart Institute Los Angeles CA Disclosure founder amp stockholder Capricor Inc ID: 770520

cells cdcs stem heart cdcs cells heart stem scar mass amp treatment post regeneration effect 2012 viable allogeneic months

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Lessons learned from Phase 1 trial of heart-derived stem cells as we move into Phase 2 Eduardo Marbán, M.D., Ph.D.Director, Cedars-Sinai Heart InstituteLos Angeles, CA Disclosure: founder & stockholder, Capricor Inc.

re·gen·er·a·tion n. “Regrowth of lost or destroyed parts or organs.” The American Heritage® Dictionary of the English Language, Fourth Edition ©2000 How do we want to use stem cells? To achieve true regeneration in the injured heart Criteria for regeneration growth of new healthy cardiac tissue improvement of function reduction of scar (bonus)

Types of stem cells Embryonic stem cells* or iPS cells#Can evolve into all tissuesTumorsImmune reactions limit use without cloning*Ethically problematic*Imprinting, genetic modification#Adult stem cellsSkeletal myoblastsBone marrow stem cellsAutologous (BMCs, EPCs) or allogeneic (MSCs) Cardiac-derived cells

100 m m 3 How we harvest and grow CDCs R. Smith et al., Circulation 115: 896 – 908, 2007 200 m m 1 Explants (1) Biopsy 200 m m 5 Cardiospheres (5) 4 % of cell total c-Kit+ CD90 + CD105 + CD133 + 0 20 40 60 80 100 Cardiosphere -forming cells (4) 50 m m 6 Cardiosphere- derived cells (CDCs, 6) 2,3 2 200 m m Yield: 30M CDCs in 3-5 weeks

Properties of CDCs CD105+/CD45- cells1,2 of intrinsic cardiac origin3<25% CD90+ (unlike MSCs)1<2% DDR2+/SMA+ (unlike fibroblasts or myofibroblasts)TnI / TnT/MHC/α-SA- (unlike cardiomyocytes)4 Shrink scar and increase viable myocardium1,2,4-8Functionally superior to other clinically-applied cells5 Multipotent & clonogenic,4 but long-term engraftment & differentiation not necessary for benefit6-8~20μ diameter (max safe dose i.c. = 350,000 CDCs/kg) 9 1 . RR Smith et al, Circ 2007; 2. Makkar et al., Lancet 2012; 3. A White et al., EHJ 2011; 4. D Davis PLoS One 2010; 5. T-S Li et al, JACC 2012; 6. I. Chimenti et al, Circ Res 2010; 7. K. Malliaras et al, Circ 2012; 8. K. Malliaras et al., EMBO Mol Med 2012; 9. P Johnston et al, Circ 2010

CADUCEUS(CArdiosphere -Derived aUtologous Stem CElls to Reverse ventricUlar dySfunction) Makkar et al., Lancet 2012 Post-MI (<30d @screening) & LV dysfunction (EF <45%) Fully randomized (8 controls:17 CDCs), safety & preliminary efficacy study ( MRI) Intracoronary infusion of autologous CDCsNo safety concerns (including arrhythmia/SCD) First therapeutic modality to ↓scar & ↑viable tissue

0005-CDC01-002 Control 0005-CDC01-014 CDC-treated baseline 6m Regenerative efficacy in CADUCEUS: Representative MR images

All bars represent +/- 1 SEM p=0.001 p:0.02 p:0.01 p=0.001 Δ scar mass Δ viable mass 6 mos 12 mos 6 mos 12 mos CDC therapy reduces scar and increases healthy heart muscle in CADUCEUS n=8 n=15 n=8 n=15 n=7 n=8 n=7 n=8

r=-0.59 p<0.001 Reductions in scar mass mirror increases in viable mass, consistent with true regeneration (g, 6 months and 12 months minus baseline, pooled CDC group) Viable mass treatment effect (g) Scar mass treatment effect (g)

P=0.02 P=0.001 CDCs n=83 (14) Peak Ecc strain (%) in treated segments @ 6 months Systolic wall thickening (%) in treated segments @ 6 months Meanwhile, regional function improves in CDC-treated patients relative to controls controls n=42 (7) CDCs n=83 (14) controls n=48 (8) All bars represent +/- 1 SEM

Limitations of autologous therapy Timing constraints (3-5 weeks for CDCs)ExpenseRiskHarvesting procedureManufacturing failureSuboptimal QA/QCInterpatient variability in cell potencyIs allogeneic therapy safe and effective?

LV function in post-MI rats: syn = allo K. Malliaras et al., Circ 2012 Fractional Area Change Ejection Fraction D0 3wks 3mos 6mos D0 3wks 3mos 6mos % % Fractional Shortening % Treatment effect Δ FAC (%) 3 weeks post injection D0 3wks3mos6mos Syngeneic Allogeneic Control WKY Control BN Xenogeneic* ** * ** * ** * * ***** * * * *

Intracoronary allogeneic CDCs regenerate the infarcted pig heart Scar size treatment effect Viable mass treatment effect Ejection Fraction treatment effect * * * All bars represent +/- 1 SEM. Unpublished data baseline 2 months K. Malliaras , H. Kanazawa, M. Kreke, R.R. Smith, L. Marbán , E. Marbán , unpublished

Summary Autologous CDCs produce therapeutic regeneration in humans post-MIAllogeneic CDCs without immunosuppression safe, promote cardiac regeneration and improve heart function via stimulation of endogenous repairThis work motivates the testing of allogeneic human CDCs as a potential off-the-shelf product for cellular cardiomyoplasty: ALLSTAR trial

Proprietary & Confidential: CAPRICOR IncALLogeneic heart STem cells to A chieve myocardial Regeneration PIs: Tim Henry, Raj Makkar EF: < 50%, IS > 15% (MRI)Stratified patient recruitment ( 274 pts total) 30-90 days post MI (healing) > 90 days post MI (chronic) Double-blind randomized placebo-controlled20 sites (US) Phase I/II study (funded by NIH and CIRM grants to Capricor ) Allogeneic CDCs Intracoronary infusion of CDCs

Acknowledgments Cedars-Sinai Heart Institute Raj Makkar Kostas Malliaras Rachel R. Smith Ke Cheng Linda Marbán Daniel Berman Eugenio Cingolani Mohamed Aminzadeh Eleni Tseliou Hideaki Kanazawa James Dawkins Capricor Michelle Kreke John Terrovitis Funding NIH (NHLBI SCCT) California Institute for Regenerative Medicine (Disease Team 1) Board of Governors, Cedars-Sinai Medical Center Johns Hopkins University Gary Gerstenblith Peter Johnston Al Lardo EMMES Corporation Adam Mendizabal