cell and gene therapy for cli: update on current evidence ...€¦ · safety profile of plx-pad in...
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Cell and Gene therapy for CLI:
Update on current evidence and ongoing projects
Professor Sigrid Nikol
Clinical and Interventional Angiology
Asklepios Klinik St. Georg
Hamburg, Germany
Disclosures
Consulting/Steering Committee
- Genyzme
- Sanofi
- Pluristem
Placebo 259 217 196 184 173
NV1FGF 266 211 193 179 169
Number at Risk Months since randomization
0
5
10
15
20
25
30
35
40
0 3 6 9 12
NV1FGF
Placebo
Placebo
N=259
NV1FGF
N=266
Hazard ratio
(95% CI)P
Major amputation
or death
86
(33.20%)
96
(37.07%)
1.11
(0.83, 1.49)0.48
Prim
ary
ou
tco
me e
ve
nt ra
te (
%)
Belch J, Hiatt WR, Baumgartner I, Driver IV, Nikol S, Norgren L, Van Belle E;
Lancet. 377(9781):1929-37, 2011
TAMARIS Phase III angiogenesis gene therapy trial
Primary Endpoint: amputation-free survival
Cell therapy as opposed to Gene therapy:
Effect via multiple growth factors released by host cells
Human EPCs were
transplanted into immuno-
compromised nude mice,
and the levels of cytokines
were measured by both
human- and mouse-specific
primers and probes.
Cho HJ J Exp Med. 204:3257-3269, 2007
Teraa M et al. Circulation. 2015 ; 131, 851
Meta-analysis on RCTs using autologous bone marrow cells:
no benefit !
Randomized RCTs
Randomized placebo-controlled RCTs
Autologous Vs. Allogeneic Treatments
Autologous Allogeneic
Donor Sick, rel. old Healthy, rel. young
Cell Availability Limited Immediate availability
“off-the-shelf”
Cell Quantity Limited Unlimited
Cell Quality & Standardization Inconsistent Consistent
(also consistent dosing)
More strict quality control
possible
Immunological Issues No rejection Possible but immuno-
privileged
Procedure to obtain cells Invasive (BM, adipose) Non-invasive for patient
Zhou et al. Aging Cell. 2008 June; 7(3): 335–343.
Effect of Donor Age on MSC Growth
Production of growth factors decreases with age
1
10
100
1000
10000
100000
IL-1b
Il-1ra
IL-2
IL-4
IL-5
IL-6
IL-7
IL-8
IL-9
IL-10
IL-12
IL-13
IL-15
IL-17
Eotaxin
FGF basic
G-C
SF
GM-CSF
IFN-g
IP-10
MCP-1 (MCAF)
MIP-1a
MIP-1b
PDGF bb
RANTES
TNF-a
VEGF
pg
/ml
90 years 79 years 68 years 51 years 50 years
Altaner, et al.2011
IMPAIRED FUNCTIONALITY OF STEM CELLS WITH AGE
• Off the shelf placental expanded cells
Placenta-derived cells - Pluristem
PLX-PAD support endothelial cells proliferation and migration and
recruit precursors required for formation of new blood vessels
PLX-PAD restore blood flow
in a dose and distance dependent manner
Injection of 1*10^6 to the operated limb shows a higher blood flow compared the contralateral limb which was
injected with the same amount of PLX PAD cells
Placebo
PLX-PAD
treated
Blood flow measurements are expressed as
the ratio of the flow in the ischemic limb to
that of the normal limb
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
90.0
day 1 day 7 day 14 day 21 day 28
Blo
od
flo
w
1x106 cellsoperated
Placebooperatedlimb
Live Cellvizio imaging following IV
administration of FITC-labeled Dextran
PLX-PAD Increased blood flow in the tibia
Angiogenesis
• Most frequent AEs based on >150 patients
administered with PLX-PAD in clinical trials:
• Local Injection-site reactions
• Systemic allergic reactions
• Transient bad breath odor and body skin odor related to DMSO
• Immunological testings:
• No evidence for PLX-PAD specific humoral or T-cell allo-sensitization
• No evidence for over immunosuppression
• No long-term safety concern to date
Safety profile of PLX-PAD in patients
Ongoing Phase II in patients suffering from mild
to moderate intermittent claudication
(n=172 recruited)
PACE: Phase III, Randomized, Double-Blind,
Multicenter, Placebo-Controlled, Parallel-Group Study
in CLI Rutherford 5, n=246, recruitment starting Q2 2017
Arm 2: Placebo, twice at an 8-week interval (n=82)
Enrolment
Randomization
(up to Day -7)
Screening
(-35d to d0)
Arm 1: PLX-PAD 300×106, twice at an 8-week interval (n=164)
End of study or
Reached 36 months FU
PLX-PAD/placebo
(1st) Day 0
PLX-PAD/placebo
(2nd) Month 2
Dosage and administration
• PLX-PAD/placebo will be
administered via 30 IM
injections (0.5 mL each)
delivered into the index leg.
Each subject will be treated
twice, with an interval of
8 weeks between
treatments.
• Arm 1: PLX-PAD 300×106
cells (20×106 cells/mL)
• Arm 2: Placebo (without cells
- 10% DMSO, 5% human
serum albumin, and
Plasma-Lyte)
Study efficacy endpoints
Primary Efficacy Endpoints:
Amputation-free survival
Time to occurrence of major amputation of the index leg or death
Secondary Efficacy Endpoints:
• Time to first occurrence of any of the following single events:
– Major amputation of the index leg.
– Revascularization due to worsening of CLI in the index leg.
– Doubling of total wound area from baseline in the index leg.
– De novo gangrene in the index leg.
– All-cause mortality.
Company Cell source Comparability Status
Celgene Placenta allogeneic Phase II in DFU in
PAD patients
Caladrius CD34+ allogeneic Phase II in CLI
Cesca Therapeutics Bone marrow autologous Phase III in CLI
Vericel Bone marrow autologous Phase III in CLI early
terminated (REVIVE-
CLI)
Hemostemix Blood autologous Phase II in CLI
Reneuron Neuronal allogeneic Phase I in CLI
OTHER CURRENT CELL THERAPY TRIALS
Cell and Gene therapy for CLI:
Update on current evidence and ongoing projects
Professor Sigrid Nikol
Clinical and Interventional Angiology
Asklepios Klinik St. Georg
Hamburg, Germany