cell and gene therapy for cli: update on current evidence ...€¦ · safety profile of plx-pad in...

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

Thank-you

s.nikol@asklepios.com

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