0400 cell therapy 2016 - promedica international · 2019. 5. 24. · d/cin 24 hours terminated...
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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