Life-saving immunomodulating cell therapies
November 2019
FORWARD-LOOKING STATEMENTS
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These slides and the accompanying oral presentation contain forward-looking statements and information. Forward-looking statements are subject to known and unknown risks, uncertainties, and other factors that may cause our or our industry’s actual results, levels or activity, performance or achievements to be materially different from those anticipated by such statements. The use of words such as “may”, “might”, “will”, “should”, “could”, “expect”, “plan”, “anticipate”, “believe”, “estimate”, “project”, “intend”, “future”, “potential” or “continue”, and other similar expressions are intended to identify forward looking statements. For example, all statements we make regarding (i) the initiation, timing, cost, progress and results of our preclinical and clinical studies and our research and development programs, (ii) our ability to advance product candidates into, and successfully complete, clinical studies, (iii) the timing or likelihood of regulatory filings and approvals, (iv) our ability to develop, manufacture and commercialize our product candidates and to improve the manufacturing process, (v) the rate and degree of market acceptance of our product candidates, (vi) the size and growth potential of the markets for ourproduct candidates and our ability to serve those markets, and (vii) our expectations regarding our ability to obtain and maintain intellectual property protection for our product candidates, are forward looking. All forward-looking statements are based on current estimates, assumptions and expectations by our management that, although we believe to be reasonable, are inherently uncertain. All forward-looking statements are subject to risks and uncertainties that may cause actual results todiffer materially from those that we expected. Any forward-looking statement speaks only as of the date on which it was made. We undertake no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events or otherwise, except as required by law. This presentation is not, and nothing in it should be construed as, an offer, invitation or recommendation in respect of our securities, or an offer, invitation or recommendation to sell, or a solicitation of an offer to buy, any of our securities in any jurisdiction. Neither this presentation nor anything in it shall form the basis of any contract or commitment. This presentation is not intended to be relied upon as advice to investors or potential investors and does not take into account the investment objectives, financial situation or needs of any investor.
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We develop intelligent immunomodulating cell therapies to rebalance life-threatening hyperimmune responses,
in indications previously considered untreatable.
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Enlivex, Executive Summary
Paradigm shifting
immunotherapy
Multi-billion dollar
underserved markets
Advanced
clinical-stage pipeline
Short regulatory
approval pathwayCash balanceStrong leadership
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For complex, life-threatening
indications without therapies
Bone-Marrow Transplantations
Sepsis | Solid Tumors
with promising Phase IIa results,
initiating Phase II/III studies
Specialized
life-threatening regulation in
Europe potentially enabling post-
Phase II/III marketing approval;
FDA & EU orphan designations
$35 Million invested; Cash
balance supporting
multiple clinical milestone
within 12-18 months
Previously founded and
managed PROLOR Biotech, a
$560M exit event; Signed
partnership with Pfizer, $295
Million down payment
Ticker: ENLV
Fundamentals
$10.1MM shares outstanding
Market cap: ~$75MM
Stock price: ~$7.5
Immune System Fundamentals
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And release signals to recruit special forcesMacrophage & dendritic cells activated
Macrophages & dendritic cells
“eat” the dying cells
The more dying cells they “eat”,
the less alert signals they release
Immune system triggered
Immune system
relaxed
Immune system
relaxing
Alert & relax signalingthe role of macrophages and dendritic cells
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A normal immune response
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Bacterial or viral
invasionIntrusion is detected Immune system triggered
Kill infected cells
Bacteria infects cells
Special forces arriveDying cells are cleared
from the body
Immune system relaxed
Signals to recruit special
forces are stopped
Signals released to
recruit special forces
Immune system relaxed
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Immune system
out-of-control
Immune-triggered organ failures result in increased morbidity & mortality during sepsis and BMTfailure of macrophages and dendritic cells to relax triggers attacks of immune cells on healthy organs, and may result in organ damage, failure and mortality
Macrophages & dendritic cells release
signals to recruit special forces
They keep on
releasing alert signals
(cytokines)
More special
forces arrive
Start killing
healthy cells and organs
Immune system
triggeredKill infected cellsSpecial forces arrive
Macrophages & dendritic cells
“Eat” the dying cells, but thatis not enough to relax them
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Immune System Fundamentals
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ALLOCETRATM
A challenge to current therapeutic paradigms
Cytokine storms involve:
An acute multifactor problem cannot be overcome with a single drug for a single target…Requires a major shift in therapeutic approach
Dozens of cytokine types Multiple biological processes
Allocetra™
Billions of semi-apoptotic (dying)
ALLOCETRA cells
ready to be infused
Matched or unmatched
(off-the-shelf) donor
blood
Selection of
mononuclear cells ONLY
B cells | T cells | NK cells
Chemically inducing
programmed cell death
of the selected cells
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Rebalancing the immune responses
Cytokine Storm1 Allocetra™ infusion2 Macrophage feeding3 Alert signals decrease4 Normal immune state 5
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Corporate Overview
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Therapeutic product pipeline of live-saving therapies for out-of-control immune indications
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Indication Global Market
Size
Pre Clinical
Phase Ib Phase II/III EU Conditional Marketing Approval
Post EU Marketing US Phase 3
Prevention of post-Bone Marrow Transplantations (BMT)complications
$3B
Adjunctive treatment for prevention of cytokine storms and organ dysfunction in Sepsis
$33B
Treatment of post-BMT complications for steroid refractory patients
$1.3B
Solid tumor “immune checkpoint” microenvironment modulation
$4BSeekingPartner
IIa CompletedII/III Initiation
Q1 2020
Phase II/III InitiationQ1 2020
Phase II InitiationQ2 2021
Phase IbCompleted Recruitmen
t
Preventing & Treating Complications Post Bone-Marrow
Transplantations
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Preventing & treating
complications post bone-marrow transplantations
Bone marrow transplants (BMT) are susceptible to GvHD and other material complications that may lead to non-relapse mortality
Graft-vs-host disease (GvHD), a hyperimmune response,
occurs when the donor T-cells register the host body's
tissues and organs as foreign antigens and initiate an
attack. Other complications such as Hepatic veno-
occlusive disease, Severe endothelial leakage syndrome,
Pneumonitis and Hepato-renal failure are also highly
correlated with cytokine storms (Schots et al Leukemia 2003)
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POST TRANSPLANTATION ALL CAUSE MORTALITY
Complications43%
Primary Cancer
57%
40%
27%
22%
11%
0ther Infection Organ Failure GvHD
Phase IIa clinical data – prevention of complications Preventing GvHD, leading to expedited hospital discharge overall improved outcomes
Hadassah Hospital BMT unit Low Doses of Allocetra, n=7Cohorts 1+2 low doses 35-70mm cells/kg
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High Doses of Allocetra, n=6Cohorts 3+4 high doses 140-210mm cells/kg
50%
43%
0%0%
10%
20%
30%
40%
50%
60%
AC
UTE
GV
HD
GR
AD
E II
-IV
(%
)
0%
GvHD
grade
II-IV
4139
22
0
10
20
30
40
50
60
DAY
S TO
DIS
CH
AR
GE
50%
time to
hospital
discharge28%
16%
0%0%
10%
20%
30%
40%
50%
60%
NO
N R
ELPA
SEM
OR
TALI
TY 2
00 D
AYS
0%
deaths
due to
transplant
complications
TNFR
I Rat
io
IL-6
co
nce
ntr
atio
n (
pg/
ml)
Days
Upper-threshold of
“normal” range
Days
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
-2 18 38
TNFRI Ratio in patientswho received HIGH DOSE(210mm cells/kg) ofAllocetra
TNFRI Ratio in patientswho received MEDIUMDOSE (140mm cells/kg) ofAllocetra
TNFRI Ratio in patientswho received LOW DOSE(35mm - 70mm cells/kg)of Allocetra
0
50
100
150
200
250
300
-2 18 38
IL-6 levels in patients who receivedLOW Dose (35mm - 70mmcells/kg) of Allocetra
IL-6 levels in patients who receivedMEDIUM DOSE (140mm cells/kg)of Allocetra
IL-6 levels in patients who receivedHIGH DOSE (210mm cells/kg) ofAllocetra
Cytokine profile post bone-marrow transplantation in 7
patients with ALL, 5 with AML, 1 with CML
UNCONTROLLED
UNCONTROLLED
Phase IIa clinical data - immune activityPreventing uncontrolled signaling levels (cytokine storm)
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Phase II/III endpoints vs Phase IIa data
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Endpoints 30-Day Engraftment6-Months GvHD-Free Survival
(GFS)
Historical averages1 94.4% 30%
Phase IIa(study results2)
100% 100% (n=6)
Phase II/III (required to show statistical significance3)
>=95%
>= 50% (n=54)>= 60% (n=25)>= 70% (n=15)= 100% (n=8)
1 Al-Kadhimi et al., 2014; Gooley et al., 2010, matched related/unrelated donor population; O. Ringden et al. 2013, matched and unmatched donor population
2 Data in matched-related donor population3 Study in matched-unrelated donor population. GFS rates and the number of patients to show statistical significance.
MatchedRelated/Unrelated
Haploidentical
US - -
EU -Zalmoxis(revoked)
Regulatory Approvals
Zalmoxis Reimbursed Pricing
BMT Market
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- $180,000
CompanyRisk Of Cancer
RelapseNon-Relapse
Mortality
Estimated Pricing & TAM
$150,000 x 20,000 Patients PA (global)
=$3.0 Billion TAM
!
!
!
!
! !
!
Phase II/III: prevention of post BMT complications
Addressable global market $3 Billion
Type Open-label, compared to historical controls
Patients 40-60 (Phase II/III, EU Submission)
Duration 1 year / patient
Recruitment 18 months
End-points2 endpoints: (i) 30-day engraftment; (ii) 6-Months GFS (GvHD Free Survival)
Secondary Duration of hospitalization, various others
Study initiation Q1/2020
Prevention of BMT complications Phase II/III Planning
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AllocetraTM
Adjunctive therapy for the Prevention of multiple organ failure & mortality in Sepsis
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AllocetraTM
Adjunctive therapy for the prevention of sepsis-related cytokine storms & organ dysfunction
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50%50% Organ Damage
Mortality
Severe25%
Mild orModerate
75%
OUTCOME
SEPSIS CATEGORIES
Sepsis is the 3rd leading cause of death in the U.S.#1 Cardiovascular #2 Cancer
SEPSIS is a body’s overwhelming, life-threatening response to infection, involving hyper activity
of the immune system. It can lead to tissue damage, organ failure, and death.
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Sepsis severity & cytokine storm
Viral/Bacterial Problem Zone
Cytokine Storm Problem Zone
Magnitude
Time
TreatmentAnti-Viral/AntibioticsFluids, Vasopressors
TreatmentUnmet medical needOrgan
Failure Zone
Recovery Zone
Death Zone
Pro-inflammatory cytokines Anti-inflammatory cytokines
The only pharmacologic treatments currently used, without success, for sepsis
are antibiotic agents, fluids, and vasopressors.
an adjunctive therapy for preventing cytokine storms and organ dysfunction in Sepsis, in combination with existing antibiotics agents.
Designed to offer a true paradigm shift in the quest to solve a complex healthcare challenge.
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Allocetra™
1 Ertapenem (an antibiotic drug by Merck) is a highly effective antibiotic agent commonly used for the treatment of severe or high-risk bacterial infections.This drug is usually reserved for known or suspected multidrug-resistant (MDR) bacterial infections. It is standard of care for Sepsis identified from urinary or abdominal infections.
The CLP model is a highly aggressive sepsis model causing widespread infection that results in 90%-100% mortality within 100 hours
Post induction survival, severe sepsis model (pre-clinical)
0
20
40
60
80
100
0 25 50 75 100 125 150 175 200
% S
urv
ival
Hours post CLP (Sepsis Induction)
CLP (cecum ligation and puncture) only
CLP + Ertapenem + vehicle
CLP + Ertapenem + Allocetra-OTS
n= 16
n= 20 p< 0.001
n= 15
Survival rate 10X higherthan antibiotics alone
60%Survival
6%Survival
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Low clinical score, severe sepsis model (pre-clinical)
0.0
2.0
4.0
6.0
8.0
10.0
12.0
14.0
16.0
18.0
20.0
0 3 23 30 32 48 51 55 73 97 120 126 145 168
Clin
ica
l Sco
re
Hours post CLP
Cecal ligation and puncture (CLP) only
CLP + Ertapenem + Hartmann
CLP + Ertapenem + Allocetra-OTS
High Clinical Score
Means Clinical
Deterioration
Clinical Score Correlates to Survival in CLP-induced Sepsis Models
60%SURVIVAL
6%SURVIVAL
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Immune activity profile, severe sepsis model (pre-clinical)
1,284
20
1,167
366
0
200
400
600
800
1,000
1,200
1,400
1,600
pre-CLP 24h
TNFα
(pg/
ml)
TNFα
5,469
50
4,649
247
0
1,000
2,000
3,000
4,000
5,000
6,000
7,000
pre-CLP 24h
IL-6
(p
g/m
l)
IL-6
CLP CLP + Ertapenem CLP + Ertapenem + OTS-ALLOCETRA
5XINCREASE
110XINCREASE 64X
INCREASE
18XINCREASE
ALLOCETRA™ prevents uncontrolled signaling levels (cytokine storm) post sepsis induction, leading to increased survival
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AllocetraTM
Adjunctive therapy for the Prevention of multiple organ failure & mortality in Sepsis
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AllocetraTM
Phase Ib Clinical TrialInterim Results
Severe Sepsis PatientsOff-The-Shelf Universal Product
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Time 0Sepsis diagnosis
Prevention of Sepsis-related Organ DysFunction with Allocetra-OTS (P-SOFA-1) Clinical Trial
Main Inclusion Criterion• Meet Sepsis 3 criteria: the
presence of organ dysfunction as identified by a presence of SOFA score > 2 over baseline
Day 1Allocetra Infusion140mm cells/kg
6 Patients
Cohort 1
Day 1Allocetra Infusion140mm cells/kg
4 Patients
Cohort 2
Day 3Allocetra Infusion140mm cells/kg
+
10 Patients
Total
Primary endpointSafety at 28 days
Open-label, compared to matched historical controls at the same hospital
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High Degree of Matching• Age distribution• Gender matching• SOFA score at admission• Source of Sepsis• Admission years: 2016-2019
Treated
Non-Treated
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50-60 61-70 71-80 81-90
ALL Patients, Age Distribution
Patients Characteristics – Matched Controls, All Cases 2016-2019, Hadassa Hospital, Jerusalem, Israel
0%
10%
20%
30%
40%
50%
60%
1 2 3 4 5 6 7 8 9
Per
cen
t o
f P
atie
nts
SOFA Score At Admission
ALL Patients, SOFA at Admission
0%
20%
40%
60%
80%
100%
Treated (n=6) Matched Controls (n=37)
Pneumonia
MRSA
UTI
All Patients, Source of Sepsis
Comparative Interim Data: SOFA At Admission & Sepsis-Associated Mortality
For The Matched-Controls Group, Mortality Associated Mostly With Low SOFA Scores At Admission
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9%
0%
27%
45%
0%
18%
0% 0% 0%0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
1 2 3 4 5 6 7 8 >=9
Pe
rce
nt
of
Tota
l Mo
rtal
itie
s
SOFA At Admission
All Patient Mortalities Within Matched Controls Group As Function Of SOFA at Admission
Non-Treated Mortality DistributionAcross Initial SOFA
Comparative Interim Data: Recovery From Sepsis
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0%
20%
40%
60%
80%
100%
0 1 2 3 4 5 6 8 10 12 14 21 23 25 27
Days To Sespis Cure
Non-Treated (n=37) Treated (n=6)
ALLOCETRA is highly effective in treatment of Sepsis Swiftly After Admission
All Subjects, % Patients With Complete Organ Failure Recovery By Days From Admission
49%
100%
0%
20%
40%
60%
80%
100%
120%
Non-Treated (n=37) Treated (n=6)
ALL Subjects, % Patients With Complete Organ Failure Recovery During 28 days
Comparative Top-Line Data: Recovery From Sepsis, Mortality, ICU Hospitalization
ALLOCETRA is highly effective in prevention of Sepsis-associated mortality
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After 6 Days, Only 43% Of ALL Matched Controls Released From ICU
Compared With 100% Of Treated
0%
20%
40%
60%
80%
100%
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Days In ICU
ALL Patients, % Still In ICU Post Admission
Matched Controls (n=37)
Treated (n=6)
ALLOCETRA is highly effective in expediting recovery
0% No Mortality
29%
23%
0%
5%
10%
15%
20%
25%
30%
35%
Treated (n=6) Non-Treated Literature
ALL Subjects, % Patients Mortality
Comparative Interim Data: Organ Dysfunction & Failure
ALLOCETRA prevents organ dysfunction and failure
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4.50 4.503.97
8.11
0.00
2.00
4.00
6.00
8.00
10.00
12.00
14.00
Avg Baseline SOFA Avg MAX SOFA
ALL Subjects, Avg Baseline SOFA & Maximum SOFA
Treated (n=6)Matched Controls (n=37)
Median values similar to averages:Treated baseline: 4.5 Treated Max: 4.5Non-Treated baseline: 4 Non-Treated Max: 8
0%
78%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
Treated (n=6) Non-Treated (n=37)
ALL Subjects, % Patients With SOFA Increase From Time Of Admission
Comparative Interim Data: Organ Dysfunction & Failure
Prevention of SOFA increase by 4 or more points is critical to prevent mortality
ALLOCETRA prevents SOFA increase by 4 or more points
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57%
0%
10%
20%
30%
40%
50%
60%
Treated (n=6) Non-Treated (n=37)
% of Patients With SOFA Increase >= 4
Treated (n=6) Non-Treated (n=37)
52%
0%
10%
20%
30%
40%
50%
60%
Treated (n=6) Non-Treated (n=37)
% Mortality of Patients With SOFA Increase >= 4
Treated (n=6) Non-Treated (n=37)
0% No Increase
0% No Mortality
Sepsis Phase II/III
Addressable global market $33 Billion market (severe Sepsis only)
Type Controlled, randomized
Patients 60 (40 treated, 20 control)
Duration 28 days / patient
Recruitment 12 Months
End-points Composite organ damage/failure (SOFA) score max vs baseline in 28 days
Secondary Mortality
First patient dosed Q1/2020
Sepsis- Phase II/III clinical plan
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Solid Tumor Treatment
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Solid Tumor Treatment
Solid tumors’ micro-environment modulation
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Enlivex discovered a proprietary
“immune checkpoint” pathway
for solid tumors, which is
activated by the engulfment of
Allocetra™ by tumor-associated
macrophages, rendering the solid
tumor microenvironment
“tumor negative”
TUMOR
80% 20%
BLOOD CANCERS SOLID CANCERS
OVERALL RESPONSE TO THERAPY
SCID-Bg mice were injected intra-peritoneally with human HeLa-CD19-luciferase cells, followed by CD19-CAR T cells, with or without apoptotic cells (Allocetra-OTS), or opsonized apoptotic cells (D89E_Allocetra-OTS).
Opsonized apoptotic cells are NOT engulfed by resident macrophages, while Allocetra-OTS is engulfed by resident macrophages surrounding the tumor
0
10
20
30
40
50
60
70
80
90
100
110
0 20 40 60 80 100 120 140 160
% S
urv
ival
Days To Mortality
HeLaCD19
HeLa-CD19 + CAR-T
HeLa-CD19 + CAR-T + Allocetra-OTS
HeLa-CD19 + CAR-T + D89E_Allocetra-OTS
Substantial increase in complete remission & survival, solid tumor model (pre-clinical)
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ALLOCETRA™ has received FDA & EU orphan drug designations for GVHD
USA conditional approval (RMAT)
Phase II
Open-label
Single arm
Small # of patients
Initiate post-marketing phase III
Initiate USA sales
Accelerated regulatory pathways for life-saving, unmet medical need indications
EU conditional approval
Phase II
Open-label
Single arm
Small # of patients
Initiate post-marketing phase III
Initiate EU sales
Q1/19 Q2/19 Q3/19 Q4/19 Q1/20 Q2/20 Q3/20 Q4/20 Q1/21 Q2/21 Q3/21 Q4/21 Q1/22 Q2/22 Q3/22 Q4/22
Phase Ibstudy initiation (ISR)
Phase II/III initiation
Phase II/III full data
EU conditional marketing application filed
Phase II/III study initiation (EU/ISR)
EU conditional marketing application granted
Full 6-months GCFS efficacy data
Full 12-months mortality data
Prevention of GvHD & Transplant Complications
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Clinical milestones planned timeline
Prevention of organ failure & mortality in Sepsis
Phase II interim30 patients clinical data
10 Sepsis patients clinical data
# Patients:patients’ interim clinical data30-Day engraftment & 6M GFS endpoints
173 4030
Full 30-day engraftment efficacy endpoint data
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Thank You
www.enlivex.com
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