DISCLOSURESBAXTER SAB MEMBER

BDSLICENSINGAGREEMENT

CYTORI SAB MEMBER

THEROX INVESTOR

LISTOFPHASEIII POSITIVETRIALS

TRIALS2015REFRACTORY ANGINA

BAXTER CD34 PHASE III, TERMINATEDCYTORI PHASE II, TERMINATED

REFRACTORY CHFCUPID NEGATIVEMESOBLAST, TEVA ONGOINGSDF1, NEGATIVEAASTROM PHASE II CONCLUDEDCYTORI, TERMINATED

POST MIALLSTAR CARDIOSPHERE PHASE II COMPLETEDANGIOBLAST (OUS AMICI PHASE II, REVASCOR)AMORCYTE PHASE II, CONCLUDED

ROGUECLINICS

THE HITMAN͟

YOU CAN’TMAKETHISUPGionisSentenced to 5 Yearsfor WayneAttack : Court: The judgesays theex-husband ofJohn Wayne'sdaughter hasa 'dangerouscombination . . . of no remorseand a need tocontrol.'July 07, 1992|MARK I. PINSKY | TIMESSTAFF WRITERSANTA ANA — Theex-husband of John Wayne'sdaughter wassentenced Monday to fiveyears in prison for masterminding an attack that a judgesaid went "way beyond what anormal husband would do in adivorcesituation."Dr. ThomasGionis, 38, appeared calm ashewassentenced for soliciting thebeating inwhich two hired thugsbound AissaWayne, 36, and slammed her face into agarage f looron Oct. 3, 1988. Gionisand Waynewere locked in abitter custody battleat thetime.Theattackersalso bound Wayne's then-boyfriend, Roger Luby, pistol-whipping him andslashing hisAchillestendon during theattack at Luby's Newport Beach estate.In addition to theprison sentence, Superior Court JudgeTheodoreE. Millard fined thePomomaphysician $10,000 and ordered him to serve threeyears' probation aftercompleting hisprison sentence. The judgeestimated that, with work credits, Gioniscould be free in as litt leas2 1/2 years.

CELLULARREGENERATIONTISSUE REPAIR

TISSUE GROWTH

MESENCHYMAL CELL LINES

PATIENTPOPULATIONSREFRACTORY ANGINA

REFRACTORY CHF

POST MI REMODELING

CELLTHERAPYOPTIONSAUTOLOGOUSCELLS

UNFRACTIONATED BONE MARROW

ADIPOSE DERIVED STEM CELLS

CARDIOSPHERES

TMR + PRP

SKELETAL MYOBLAST

IPS

ALLOGENIC CELLS

ANGIOBLAST (MESENCHYMAL)

CARDIOSPHERES

SDF

ISSUESWHYHASITTAKEN SOLONG?

EARLYTRIALSNEGATIVE

POORSTUDYDESIGN

POORPATIENT SELECTION

END POINT CHAOS

DOSING CHAOS

WRONGAGENT

DELIVERYCATHETER/TECHNIQUE ISSUES

FINANCIAL FAILURE

BAD LUCK

QUESTIONS1998HOW BEST DELIVER

DOSE

WHERE DO THEY GO

DO THEY GRAFT

DO THEY REPLICATE

DO THEY SURVIVE (LOW OXYGEN)

DO THEY REALLY DzWORKdz

DELIVERYINTRACORONARY

INTRA MYOCARDIAL

EPICARDIAL

INTRAVENOUS

CORONARY SINUS

PERICARDIAL

ENDPOINTCHAOSANGINA

SUBJECTIVECCS

NTG USE

SELF REPORTING (IVRS)

SAQ

OBJECTIVEETT TIME *

TIME TO ST CHANGE

TIME TO ANGINA

SPECT (SSS)

MORTALITY

CHFSUBJECTIVE

NYHA

MINN HF

OBJECTIVEV02 MAX

EF

PV LOOPS

REPEATHOSPITALIZATION

MORTALITY

DEFIB EVENTS

NEGATIVETRIALSVIVA TRIAL: VEGF I PROTEIN

FIRST TRIAL: FGF PROTEIN

GENASISTRIAL: VEGF II GENE

AGENT TRIAL: FGF GENE/VECTOR

DzPLACEBO WORKSPRETTY GOOD!dz

SCRIPPSTRIALS, COMPLETEDBAXTER PHASE II

AMORCYTE PHASE II

AASTROM PHASE II

CYTORI PHASE II

TWOYEARFOLLOW UP

ANGINA RELIEF

ETTRESULTS

ACT34 MACE

CADUCEUSTRIALCARDIOSPHERES

25 PATIENTSPHASE I

RANDOMIZED DOUBLE BLIND 2:1

POST STEMI 1.5-3 MONTHSPOST

BIOPSY DERIVED CDC VSSOC

PRIMARY ENDPOINT

6 MONTH MACE

SECONDARY ENDPOINT

MRI SCAR, WMA, VOLUMES

CADUCEUSMRI RESULTS

CADUCEUSMRI RESULTS

CARDIOSPHERES

PHASE II

30 PATIENTS

POST ANTERIOR/ INFERIOR STEMI PCI

EF < 55%

UP TO 1YEAR POST STEMI

ALLOGENIC CELLS!

PRIMARY ENDPOINT

INFARCT SIZE BY MRI

• Adipocytes

• Adult stem cells

• Endothelial cells

• Vasc. smooth muscle cells

• Tissue resident macrophages

• Perivascular cells

• …… ..

p g

Adipose Derived Regenerat iveCel ls• Adipocytes

• Adult stem cells

• Endothelial cells

• Vasc. smooth musclecells

• Tissue resident macrophages

• Perivascular cells

• …… ..

Adipose Tissue

Liposuction

Processing

Adipose Tissue

Was hing media

Liquid fa t

Collagen/Adipocytes /Debris

Ce ll pe lle t/e rythroc ytes

Enzyme Digestion +Centrifugation

Right picture from TulaneUniversity

ADRCs

g y

Cell Type Frequency

Endothelial cell 7%

Smooth musclecell 9%

Blood cell 22%

Tissue Macrophage 23%

CD34+/CD31-/CD45- 38%

Stem Cells (CFU-F) 1-5%

CYTORIATHENATRIAL

150 PT PHASE II

CHRONIC ICM/CHF/ANGINA

EF< 45%

RANDOMIZED DOUBLE BLIND 2:1

LIPOSUCTION ADRC VSPLACEBO

PRIMARY ENDPOINT

MVO2 AT 6 MONTHS

SECONDARY ENDPOINTS

MRI/SPECT/ANGINA RELIEF

ETT

ATHENAPROTOCOLLIPOSUCTION INPATIENT

CELLSPROCESSED IN 1HOUR

NOGA MAP/ INJECTION 2-4 HOURS

D/C IN 24 HOURS

TERMINATED FOR 3 STROKES

AASTROM TRIAL15O PATIENTSPHASE II

CHRONIC ISCHEMIC CHFBUT YOU DON’T HAVE TO BE ISCHEMIC!

EF < 35%

RANDOMIZED 1:1

ABM (IXMYELOCELL) VSPLACEBO

PRIMARY ENDPOINT

HOSPITAL ADMISSIONS OVER 12 MONTHS

SECONDARY ENDPOINTS

MVO2 MAX

TEVATRIALRANDOMIZED DOUBLE BLIND

1700 PATIENTS52 SITES

ISCHEMIC AND NON ISCHEMIC

<45% EF

ALLOGENIC CELLS

NOGA DELIVERY

Greenberg B. et al. Presented at ESC, London. Sept 1, 2015

CUPID

(Time to recurrent HF-related hospitalizationsand ambulatoryworseningHF)

Greenberg B. et al. Presented at ESC, London. Sept 1, 2015

• 232 total recurrentevents: 128 in placebogroup, 104 inAAV1/SERCA2a

• AAV1/SERCA2a fai ledto improve the rate ofrecurrent events (HR0.93p = 0.81)

• No benefi t insecondary orexploratory events

y

Sanz-RuizR. Eur Heart J2015. doi:10.1093/eurheartj/ ehv258

p

Penn M. et al. Circ Res2013:112,816

Primary safety (MACE) endpoint wasmet

Chung M. et al. Eur Heart 2015: doi:10.1093/eurheartj/ehv254

Characteristic Placebo 15 mg 30 mg

Demographics Patients (n) 31 32 30

Sex (%male) 90 88 90

NYHAClassIII (%) 69 61.3 70

Yearssince Last MI 13 + 11 10 + 7 10 + 9

Comorbidities Diabetic (%) 48.3 35.5 46.7

Age 67 +9 64 +11 64 +7

BMI 30 +5 29 +4 32 +7

LV Structure LVESV(ml) 158 +64 161 +63 183 +71

LVEDV(ml) 219 +68 228 +75 222 +76

LVEF(%) 30 +7 28 +8 26 +8

Clinical Status NTproBNP(pg/ml) 1259 +1373 1144 +1005 952 +802

6MWD(meters) 284 +98 295 +96 308 +73

MLWHFQ 56 +17 49 +18 47 +22

Baseline Therapy ACE-I/b-blocker/MRA(%) 84/94/48 78/91/62 80/93/63

Bi-V pacemaker (%) 54.8 53.1 43.3

Chung M. et al. Eur Heart 2015: doi:10.1093/eurheartj/ehv254

• Primary endpointwas not met

• Safety endpointmet

• Placebo effect seen

• No signi f icantdi fference in LVEF,LVESV orNTproBNP witht reatmentcompared toplacebo

Chung M. et al. Eur Heart 2015: doi:10.1093/eurheartj/ehv254

Why did pSDF 1 fail in STOPHF?

Timothy D. Henry, Carl J. Pepine, Charles R. Lambert, Jay H. Traverse,Richard Schatz, Marco Costa, Thomas J. Povsic, R. David Anderson,

Steven Kesten, JamesT. Willerson, Emerson C. Perin

PRECISETRIALStudy Design

Double-blind, randomized, parallel group, placebo-controlledin 27 (21ADRC, 6 placebo) ischemic cardiomyopathy patientsin Europe

Procedure

EMM (NOGASTAR®Diagnostic Def lectableTip Catheter)

≤ 15 IM injections [ADRCs(n=21, median dose = 42 x 106 cells]

Resul ts

Suggested improvement in symptoms, MVO2 and areductionin reversible ischemia

Perin et al Adipose-derived regenerativecells in patientswith ischemiccardiomyopathy: ThePRECISETrial. Am Heart J2014; doi:10.1016/ j.ahj.2014.03.022.

Return cells to thesame patient

Collect donortissue

1½hours

Separate andprocessADRCs

(Celution®)

ATHENA: Study Design

61

0

10

20

30

40

50

60

baseline 3 Month 6 Month 12 Month

ADRC

Placebo

p=0.154p=0.038

p=0.54

p=0.25

16 14 15 13 14 1314 16

Number

(%)

Month 6 Month 12

ADRC Placebo ADRC Placebo

Improved 8 (62) 3 (27) 8 (67) 3 (27)

Same 4 (31) 8 (73) 4 (33) 8 (73)

Worsened 1 (8) 0 (0) 0 (0) 0 (0)

y p g

Number

(%)

Month 6 Month 12

ADRC Placebo ADRC Placebo

Improved 7 (47) 4 (31) 8 (57) 2 (15)

Same 6 (40) 6 (46) 4 (29) 8 (62)

Worsened 2 (13) 3 (23) 2 (14) 3 (23)

NYHA CCS

6 months

*p<0.05

12 months

Changes from baseline in the ADRC (n=15) and placebo (n=13) groups

-15

-10

-5

0

5

10

15

20

25

30

35

PF RP BP GH V SF RE MH PC MC

*

*

**

-15

-10

-5

0

5

10

15

20

25

30

35

PF RP BP GH V SF RE MH PC MC

*

*

*

mVO2 and LVEF

65

-20

-10

0

10

20

30

40

50

ADRC Placebo

mV

O2

(mL

/min

)

0

1

2

3

4

5

ADRC PlaceboLV

EF

(%)

mVO2 LVEF

Change from baseline to 6 months

p=0.495p=0.433

Baseline (B) and 6 months (6) [ADRC n=15, Placebo n=12]

0

10

20

30

40

50

60

70

80

90

100

Fixed Reversible Stress

ADRC-B

ADRC-6

Placebo-B

Placebo-6

%LV

Type of Defect

p=0.44

p=0.40

p=0.07

Safety Total (n=31) ADRC (n=17) Placebo (n=14) p-value

SeriousAdverse Events 18 (58.1%) 9 (52.9%) 9 (64.3%) 0.66

MACE 9 (29.0%) 6 (35.3%) 3 (21.4%) 0.46

Cardiac Death* 2 (6.5%) 2 (11.8%) 0 (0%) 0.49

MI 1 (3.2%) 1 (5.9%) 0 (0%) 1.0

Stroke/TIA 3 (9.7%) 2 (11.7%) 1 (7.1%) 1.0

Heart Failure

Hospital.5 (16.1%) 2 (11.7%) 3 (21.4%) 0.47

*decompensation of heart failure – day 291, myocardial ischemia – day 2 post-procedure

ConclusionsSmall volume fat harvest, followed by automated localprocessing, and intramyocardial delivery of autologousADRCs is feasible

Symptom-based outcomes indicated beneficial trends:MLHFQ, SF-36, NYHA and CCS, HF Hosp, MVO2

No beneficial effect on LVEF

Observed cerebrovascular effects indicate need for patientselection and peri-procedure diligence

Although thesample issize is limited, the findingssupport feasibility and scalability for useof ADRCs fortreatment of ischemic heart disease

Timothy D. Henry, ThomasJ. Povsic, Jay Traverse, F David Fortuin, Gary L Schaer,Dean J. Kereiakes, Richard A. Schatz, AndreasM. Zeiher, Christopher J. White,

Duncan J. Stewart, E. Marc Jolicoeur, Theodore Bass, David A. Henderson, PatriciaDignacco, Xianqiong Gu, Hussein R. Al-Khalidi, Candice Junge, Adel Nada, Andrea

Hunt, DouglasW. Losordo, on behalf of the RENEW Investigators

ACT34 Study Design

70

Subjec t popula tion

(n=167)

• 21-80 yrs

• CCS clas s III or IV Angina

• Attempted “bes t”medical

therapy

• Non-candidate for

Surgica l/Perc . revas c .

• Is chemia on SPECT

• 3-10 min. mod. Bruce

protocol with angina or

anginal equiva lent a t bas e line

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

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

Endomyocardia l Mapping and Injec tion with NOGAIs olex s e lec ted CD34+ cells / P lacebo Rx

Cell Mobiliza tion (GCSF 5mcg/kg/d x 5d)Apheres is on Day 5

Follow-up Safe ty and Efficacy As s es s ments :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

Screening and Bas eline Vis its

P lacebo(n = 56)

Randomization

y yEndpoints

Primary Efficacy Endpoint

Change in tota l exercise dura tion us ing a s tandardized

Modified Bruce Protocol ETT at 12 months

Secondary Efficacy Endpoints

Change in angina frequency at 12 months

Change in exercise dura tion and angina frequency a t 6

months

Explora tory Endpoints

Incidence of MACE* and SAEs in a ll subjects

72

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

Statistical PlanSample Size

400 completed subjects

90% power to detect 60 seconddifference in mean change frombaseline in total exercise time

Sta tis tica l Approach

Closed form tes ting procedure onprimary and secondary efficacyendpoints

Allows for potentia l inclus ion ofsecondary efficacy endpoints inproduct label

74

CD34+

n=57

Consented n=297

Randomized n=112

ACn=27

SOCn=28

ITT Population

CD34+ n=54AC n=30

3patients with inadequatestudy product substituted with placebo

2 ptn pt

AC n=28

Not injectedn=6

CD34+ n=50AstreatedPopulation

y p

D Mixed Model Range P-value

3-months 42.1 -20.6, 104.8 0.19

6-months 34.7 -37.7, 107.0 0.34

12-months 20.4 -68.9, 109.6 0.65

76

ITT Population

Population asTreated

D Mixed Model Range P-value

3-months 61.0 -2.9, 124.8 0.06

6-months 46.2 -28.0, 120.4 0.22

12-months 36.6 -56.1, 129.2 0.43

Primary Endpoint asTreated

MEAN MEDIAN

MEAN MEDIAN

As Treated

0.63 P=0.05

79

6 months Relative Risk

ITT

0.58 P=0.02

Results: 2-Year MACE

80

Standard ofCare

(n=28)

Act iveCont rol(n=28)

CD34+ Cel lTxt (n=50)

StartedMobi l izat ion

but NotInjected

(n=6)Pat ients wi thMACE

19 (67.9%) 12 (42.9%) 23 (46.0%) 2 (33.3%)

Death2 (7.1%) 3 (10.7%) 2 (4.0%) 0

MI2 (7.1%) 3 (10.7%) 5 (10.0%) 2 (33.3%)

Perforat ion0 0 2 (4.0%) 1* (16.7%)

Stroke- - - -

CVhospi tal izat ion

18 (64.3%) 9 (32.1%) 21(42.0%) 2 (33.3%)

Vent r iculararrhythmias

1(3.6%) 2 (7.1%) 1(2.0%) -

MACE <2 weeks0 0 3 (6.0%) 2 (33.3%)

MACE dur ingfol low-up

19 (67.9%) 12 (42.9%) 21(42.0%) 2 (33.3%)

ConclusionsTrial stopped prematurely for strategic/ financialreasons

Positive improvements in angina, exercise timeandmortality consistent with Phase 2 data

Standard of carearm did very poorly

Utility of CD34+ cells for refractory angina remainsvery promising but incompletely defined

82

SSO2 Therapy Devices

83

IVTubing

OxygenChamber

Blood MixingChamber

Pressure Transducer

Draw Tubing

Piston Chamber

Fluid Manifold

IV Tubing

PistonChamber

OxygenChamber Blood

MixingChamber

FluidManifold

PressureTransducer

Draw Tubing

Return Tubing

DownStream System

DownStream Cartridge

SSO2 DeliveryCatheter

Clinical Outcomes

84

Schomig A et al. N Engl JMed 2000;343:385-91

Reducing Infarct Size by 5% Improves Clinical Outcomes

Size Results

85

Med

ian

Infa

rct

Siz

e(%

LV)

0

5

10

15

20

25

30

26.5%

20.0%

25.0%

18.5%

Control SSO2 Therapy

72 209 124 258 18

9.6%

INFARCTSIZEANDSURVIVAL

NEW TRIALSCARDIOAMP

CHF

CHART 3

CHF

RECARDIO

CHF

COMBINATION THERAPY

GCSF

FACTOR X

CONCLUSIONSGENE THERAPY IS DEADSTEM CELLS ARE ALIVE AND WELLPHASE I-II TRIALS POSITIVEPHASE III ONGOINGRECRUITMENT VERY DIFFICULTSTILL QUESTIONS REMAIN

BEST CELL?DOSE?DELIVERY?STUDY DESIGN?CHF VS ANGINA?

FDAAPPROVAL 7-10 YEARS?

KEEPITSIMPLE!

THANKYOUDR JIM MASON

DR BILL MILLER

HEMATOLOGY STAFF

BM TRANSPLANT SERVICE

DR ROSSRUDOLPH

THANKYOUGEORGE AND NORMA PLEWES

JIM NEWMAN

SID AND JENNY CRAIG

DR ERIC TOPOL

DR LARRY KLINE

ADRCs: Mechanism of Action

93

Note: Thegrowth factorsand cell types listed here are by way of exampleand are not an exhaustive list of thecellsand factors involved