Enlivex Ltd. · NASDAQ:ENLV
Enlivex — Enlivex Therapeutics — Investor Presentation (December 2022)
61 slides from Enlivex's investor presentation, December 2022
Slide 1: Off-the-shelf, universal, macrophage reprogramming cell therapies
Off-the-shelf, universal, macrophage reprogramming cell therapies for life- threatening diseases NASDAQ Ticker: ENLV
Slide 2: The problem: patients do not respond to existing therapies
The problem: The primary reason: Too many patients with life- The most prevalent life- threatening diseases do not threatening diseases involve respond to existing therapies multiple pathways of the immune system, making them highly evasive 2
Slide 3: Sepsis is the 3rd leading cause of death in the U.S. and Europe
Sepsis is the 3rd leading cause of death in the U.S. and Europe There are currently no FDA/EMA approved drugs for the treatment of sepsis United States Europe Each year, at least 1.7 million adults in America Each year, at least 3.4 million adults in Europe develop sepsis. Nearly 270,000 Americans d
Slide 4: More than 19 million new annual cases of cancer
More than 19 million new annual cases of cancer, and more than 50% mortality Source: American Cancer Society Journals, Global Cancer Statistics 2020 4
Slide 5: 70-80% of cancer patients do not respond to approved immunotherapies
Specifically with the most difficult tumors, 70-80% of cancer patients do not respond to approved cancer immunotherapies Source: FDA label 5
Slide 6: Enlivex: next-generation, differentiated cell therapies
Enlivex: next-generation, differentiated cell therapies PAST FUTURE • Autologous • Off-the-shelf • Not scalable • Scalable • High COGS • Low COGS & • Engineered T-cells • New cell modalities • NKs • Gamma-delta • Macrophages 6
Slide 7: Immune system balance: macrophages are key player
Immune system balance: macrophages are key player PAST are primary immune cells that • Macrophages FUTURE regulate immune activity • They are the first-responders to pathogenic challenge, engulf infected cells, cancer cells, and increase/decrease overall immune activity in response to these various
Slide 8: Macrophage homeostasis implies proper function for its tissue
Macrophage homeostasis implies proper function for its specific tissue, environment and challenge Reprogramming imbalanced macrophage populations can lead to disease resolution Sepsis, COVID-19 ARDS, Macrophage population homeostasis ARF post heart surgery Pro-homeostasis Pro-inflammatory Pro-organ
Slide 9: Allocetra
AllocetraTM • First-ever cell therapy designed to restore macrophage homeostasis, overall immune rebalancing • Provide a highly-differentiated new modality that may offer effective treatment to sepsis and cancer patients who do not respond to standard-of-care
Slide 10: Allocetra for macrophage reprogramming: the manufacturing process
Allocetra™ for macrophage reprogramming: the manufacturing process Proprietary, universal, off-the-shelf, frozen-formulation, macrophage-reprogramming cells Allocetra™ characteristics Allocetra™ delivery into macrophages via engulfment Allocetra™ cell “eat me” signals PtdSer • Mononuclear cells coll
Slide 11: Allocetra for macrophage reprogramming pipeline
Allocetra™ for macrophage reprogramming Pipeline of reprogrammable macrophage-modulated indications Potential support Global for EU Conditional Post EU Marketing Indication Pre-Clinical Phase Ib Phase IIb Market Size Marketing Approval US Phase 3 Submission Organ failure associated with Top-line dat
Slide 12: Allocetra clinical track record in infectious diseases and solid tumors
Allocetra™: clinical track record in infectious diseases and application to solid tumors Infectious & inflammatory diseases Solid tumors No SAEs or drug related AEs to date • Favorable safety and tolerability profile of • Phase I/II Allocetra + chemotherapy (on-going, AllocetraTM in 3 completed clin
Slide 13: Reprogramming macrophages responsible for organ failure in sepsis
AllocetraTM Reprogramming macrophages responsible for organ failure in sepsis
Slide 14: Cytokine/Chemokine network in sepsis
Cytokine/Chemokine network in sepsis: the impossible task of resolving sepsis with inhibition of a certain cytokine or signaling pathway Ghrelin G-CSF MΦ: Macrophages GM-CSF TREM-1 sTNFR1 Activation Inhibition Gro-α/β MCP-1 Chemotaxis Bacterial TNFα infection Downregulated in most of the patients IL
Slide 15: Phase Ib clinical trial in sepsis patients
AllocetraTM Phase Ib clinical trial of macrophage reprogramming in sepsis patients
Slide 16: Reprogrammed macrophages return to homeostatic state (1)
Reprogrammed macrophages in sepsis patients return to homeostatic state (1) Phase Ib clinical trial data, change from screening, pro-inflammatory cytokines A 5000 IL-6 B 150 TNF-a C 20 IL-1b 3000 100 15 10 1000 50 5 900 50 5 700 40 4 TNF-⍺ pg/ml pg/ml IL-1-β pg/ml 500 IL-6 300 30 3 100 20 2 100 50 1
Slide 17: Reprogrammed macrophages return to homeostatic state (2)
Reprogrammed macrophages in sepsis patients return to homeostatic state (2) Phase Ib clinical trial data, change from screening, anti-inflammatory cytokines IL-10 IL-1R⍺ G-CSF E F G 50 IL-10 40000 IL-1Ra 1000 G-CSF 30 800 20000 600 10 10 10000 300 8 250 pg/ml pg/ml pg/ml 7500 6 200 5000 150 4 100 2
Slide 18: Sequential Organ Failure Assessment (SOFA) Score
Sequential Organ Failure Assessment (SOFA) Score The sequential organ failure assessment score (SOFA score), previously known as the sepsis-related organ failure assessment score, is used to track a person's status during the stay in an intensive care unit (ICU) to determine the extent of a person's
Slide 19: High degree of matching: treated vs controls
High degree of matching: treated vs controls Treated (n=10) Matched Controls (n=37) Average age 71.5 (51-83) 71.25 (50-83) Male/female 80/20 80/20 Average diagnosis SOFA 3.4 (2-6) 3.47 (2-7) Average diagnosis Apache II score 12.3 (8-21) 14.25 (5-24) Sepsis source Pneumonia 50% 53% Biliary infections
Slide 20: Day 28 treatment outcomes
Allocetra™ macrophage reprogramming leads to improved outcomes for sepsis patients Alive and organs recovered on day 28: 100% vs 41% 120% Day 28 treatment outcomes Day 28, Mortality 100% 100% Day 28 mortality 80% Day 28 still with organ failures 60% 41% 40% 32% Hospital discharge 27% 20% 0% 0% 0% Al
Slide 21: Improved outcomes: SOFA scores vs matched controls
Allocetra™ macrophage reprogramming leads to improved outcomes for sepsis patients Statistically significant improvement in hospitalization and SOFA vs. matched controls Time to ICU discharge Average SOFA score during 28 days Drastic difference in organ failure resolution 5 4.4 4.1 4.1 4.0 4 3.47 Av
Slide 22: Clinical summary of macrophage reprogramming in sepsis Phase Ib
Clinical summary of macrophage reprogramming in sepsis Phase Ib: complete recovery from any organ failure for all 10 patients and 100% 28-day survival Sepsis clinical characteristics and organ recovery Organ Dysfunction Each patient had at least 2 organ dysfunctions, maximum of 5 Kidney 3/9 patients
Slide 23: Allocetra Phase IIb clinical plan in sepsis
Sepsis AllocetraTM macrophage reprogramming Phase IIb clinical plan Sepsis Phase IIb Addressable global market $33 Billion market (severe Sepsis only) Type Controlled, randomized, multi-country, multi-center Patients 80-160, SOFA < 10, Source: pneumonia, biliary, urinal tract, and peritoneal infecti
Slide 24: Phase Ib & II Clinical Trials in COVID-19
AllocetraTM Phase Ib & II Clinical Trials in COVID-19 Patients in Severe or Critical Condition
Slide 25: COVID-19 business opportunity is de-prioritized
Despite strong clinical results, COVID-19 business opportunity is de-prioritized • Primary reasons: • Availability of therapeutics for mild/moderate patients • Dominance of Omicron variants, who seem to cause less severe disease in most patients • Regulators “step-back” and reluctance to provide eme
Slide 26: Positive Phase Ib and top line Phase II results in COVID-19
TM Allocetra : Positive Phase Ib and top line Phase II results in COVID-19 Hospitalization Clinical Outcome # Patients Post Administration of AllocetraTM Clinical Trial Disease Severity enrolled Recovered Mortality Discharged Duration Day 28 Day 28 Day 28 (days, avg.) Phase Ib 5 2 Severe, 3 Critical
Slide 27: Macrophage reprogramming in solid tumor microenvironment
AllocetraTM Macrophage reprogramming in solid tumor microenvironment Unique & differentiated value proposition
Slide 28: Tumor-associated macrophages: pro-tumor, immunosuppressive activities
Tumor-associated macrophages: pro-tumor, immunosuppressive activities Immunosuppressive functions1 • inhibit T cell, DC and NK cell activation • suppress anti-tumor T cell functions through inhibitory Direct pro-tumor functions • Promote resistance to therapy, angiogenesis, tumor cell survival and m
Slide 29: Effective solid cancer therapy requires changes to macrophages in the TME
Effective solid cancer therapy requires changes to macrophages in the TME Multiple strategies to kill or reprogram non-homeostatic, pro-tumor macrophages (TAMs)1 Kill or inhibit recruitment of TAMs Reprogram TAMs SIRPa inhibitors Trabectedin SIRP1a Immune checkpoints PD-L1 inhibitors Caspase 8 Bisph
Slide 30: The Enlivex differentiation: resident vs infiltrating macrophages
The Enlivex differentiation: Balance of resident macrophages vs bloodborne infiltrating macrophages and the effect on anti-tumor activity Cancer-induced changes to macrophage sub-populations: • Elimination of resident macrophages • Accumulation of pro-tumor TAMs originating from infiltrating macroph
Slide 31: Preclinical data
AllocetraTM Macrophage reprogramming in solid tumor microenvironment Preclinical data
Slide 32: Studies evaluating Allocetra + anti-cancer drugs
Studies for evaluating the synergistic effect of Allocetra™ + anti-cancer drugs in solid tumors Model Anti-cancer drug used Syngeneic peritoneal mesothelioma 1. Anti-CTLA4 (AB12) in immunocompetent mice Syngeneic peritoneal mesothelioma 2. Anti-PD1 (AB12) immunocompetent mice Syngeneic peritoneal me
Slide 33: Allocetra + anti-CTLA4 in peritoneal mesothelioma
Synergistic effect of Allocetra™ + anti-CTLA4 in peritoneal mesothelioma solid tumor 33
Slide 34: Allocetra + anti-CTLA4 in peritoneal mesothelioma
Synergistic effect of Allocetra™ + anti-CTLA4 in peritoneal mesothelioma solid tumor Legend Initial cancer spread advanced cancer spread mouse dead mouse alive Mortality 100% 75% 71.5% 33% 0% Survival 0% 25% 28.5% 67% 100% Complete 0% 25% 28.5% 67% 100% cure IVIS imageing, AB12-137 study 34
Slide 35: Allocetra + anti-CTLA4: clinical score
Synergistic effect of Allocetra™ + anti-CTLA4 in peritoneal mesothelioma solid tumor • Clinical score observations support superior clinical and survival effect of the anti-CTLA4+Allocetra combinations 18 PBS 15 Mesothelioma (no treatment, n=16) 12 Mesothelioma + Anti-CTLA4 (n=16) Clinical score 9 M
Slide 36: Allocetra + anti-CTLA4: survival
Synergistic effect of Allocetra™ + anti-CTLA4 in peritoneal mesothelioma solid tumor • Superior survival of the anti-CTLA4+Allocetra combinations, dose response demonstrated • Weak, although statistically-significant, survival effect of stand-alone anti-CTLA4, Allocetra 120 100 PBS p=**** <0.0001 Me
Slide 37: Allocetra + anti-PD1 in peritoneal mesothelioma
Synergistic effect of Allocetra™ + anti-PD1 in peritoneal mesothelioma solid tumor ⍺PD1 (125µg/250µg) 37
Slide 38: Allocetra + anti-PD1 in peritoneal mesothelioma
Synergistic effect of Allocetra™ + anti-PD1 in peritoneal mesothelioma solid tumor 1 Day before treatment 3 Days after 4th treatment 38
Slide 39: Allocetra + anti-PD1: day 53 post treatment
Synergistic effect of Allocetra™ + anti-PD1 in peritoneal mesothelioma solid tumor Day 53 post treatment 39
Slide 40: Allocetra + anti-PD1: survival
Synergistic effect of Allocetra™ + anti-PD1 in peritoneal mesothelioma solid tumor 100 80 % Survival 60 % 40 20 0 0 30 40 50 60 70 80 Days 40
Slide 41: Allocetra + cisplatin in peritoneal mesothelioma
Synergistic effect of Allocetra™ + cisplatin in peritoneal mesothelioma solid tumor 41
Slide 42: Allocetra + cisplatin: day 54 post treatment
Synergistic effect of Allocetra™ + cisplatin in peritoneal mesothelioma solid tumor Day 54 post treatment X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X 42
Slide 43: Allocetra + cisplatin: survival
Synergistic effect of Allocetra™ + cisplatin in peritoneal mesothelioma solid tumor 100 80 % Survival 60 % 40 20 0 Days 10 20 30 40 50 60 43
Slide 44: Allocetra + anti-PD1 in ovarian cancer model
Synergistic effect of Allocetra™ + anti-PD1 in ovarian cancer solid tumor model Immunocompetent ⍺PD1 (1.25 mg/kg) C57BL/6 ±Allocetra/vehicle Injection IP Injection ip 44
Slide 45: Allocetra + anti-PD1 in ovarian cancer, Yale study
Synergistic effect of Allocetra™ + anti-PD1 in ovarian cancer (study conducted in collaboration with Yale Cancer Center) Ovarian Cancer ID8 Study – Survival Probability 100% • Superior overall survival, 90% Allocetra 20M monotherapy survival duration and lower rate 80% 70% of tumor progression with
Slide 46: Reprogramming of peritoneal pro-tumor macrophages
Allocetra™: reprogramming of peritoneal pro-tumor macrophages Preclinical study model: solid tumor engineered to express CD19, making it potentially responsive to CD19 CAR-T Macrophage reprogramming effect measured via single cell analysis SCID Survival/Histology 1 6 12 18 24 30 40 Days 0 10 20 30 4
Slide 47: Allocetra macrophage reprogramming synergistic with CD19 CAR-T
Allocetra™ macrophage reprogramming synergistic with CD19 CAR-T D89* Allocetra (opsonized, not engulfed by macrophages) has no programming nor clinical effect 120 HeLaCD19 100 HeLa-CD19 + CAR-T HeLa-CD19 + CAR-T + Allocetra-OTS 80 HeLa-CD19 + CAR-T + D89E_Allocetra-OTS % Survival 60 Complete remissi
Slide 48: Resident vs infiltrating macrophages and anti-tumor activity
Balance of resident macrophages vs bloodborne infiltrating macrophages and the effect on anti-tumor activity Peritoneal fluid myeloid cells populations pre/post induction of peritoneal cancer, SCID-bg mice Large peritoneal resident Healthy mice macrophages (anti-tumor) Day 23 post Pro-tumor TAMs can
Slide 49: CAR-T restores resident macrophage populations
CAR-T treatment restores resident macrophage populations, and depletes pro-tumor infiltrating macrophages Peritoneal fluid myeloid cells populations pre/post induction of peritoneal cancer, SCID-bg mice Large peritoneal resident macrophages (anti-tumor) Pro-tumor TAMs Small peritoneal resident macro
Slide 50: Allocetra's MOA under characterization, single cell analysis
Allocetra’s MOA under characterization, single cell analysis • Peritoneal fluid myeloid cells populations post induction of CD19+ peritoneal cancer in SCID-bg mice and treatment with either (A) CD19 CAR-T stand-alone, or (B) CD19 CAR-T + Allocetra Large peritoneal resident macrophages (anti-tumor) P
Slide 51: Clinical programs in solid tumors
AllocetraTM Macrophage reprogramming in solid tumor microenvironment Clinical programs
Slide 52: Phase I/II Allocetra + Chemotherapy in Peritoneal Metastases
Phase I/II Clinical Trial Evaluating Allocetra™ + Chemotherapy in Patients with Peritoneal Metastases Arising from Solid Tumors Phase I/II (ClinicalTrials.gov Identifier: NCT05431907) Addressable global market $4 Billion market Type Open-label, single center Patients 12, all-comers with peritoneal m
Slide 53: Phase I/II Allocetra + anti-PD1 in Solid Tumors
Phase I/II Clinical Trial Evaluating Allocetra™ + anti-PD1 in Patients with Solid Tumors Phase I/II (ClinicalTrials.gov Identifier: NCT05581719) Addressable global market $4 Billion market Type Open-label, multi-center Patients 36-48, ~all-comers with solid tumors Duration 90 days / patient Expected
Slide 54: Allocetra macrophage reprogramming research collaborations
Allocetra macrophage reprogramming research collaborations Collaborations aim to evaluate the potential of Allocetra™ in combination with immune-checkpoint inhibitors in solid cancer patients that do not respond to stand-alone checkpoint inhibitor therapies 54
Slide 55: Planned milestones (24 months)
Planned milestones (24 months) Q1 2022 Q4 2022 Q1/2 2023 Q3/4 2023 Completion of development Initiation of Phase I/II in Interim data Top line data macrophage of frozen formulation advanced-stage solid tumors macrophage reprogramming sepsis AllocetraTM patients with peritoneal reprogramming sepsis P
Slide 56: Experienced leadership team of Enlivex (I)
Experienced leadership team of Enlivex (I) “ I founded my former Biotech company, named PROLOR Biotech, to help children who suffer from growth-hormone deficiencies, and need to inject growth hormone every night for years. We started as a garage-startup but were able to develop a long-acting growth
Slide 57: Experienced leadership team of Enlivex (II)
Experienced leadership team of Enlivex (II) “ As Opko Biologics GM, I was part of the leading team that worked closely with Pfizer for 5 years to complete the advanced-stage development of our long-acting growth hormone. I was involved and led many aspects of the development including non-clinical,
Slide 58: Financial Summary
Financial Summary NASDAQ GS ENLV Cash $54MM (Sep 30, 2022) Debt None Shares Outstanding 18.2 MM Funded Through Q3 2024 58
Slide 59: Management
Management Founder and President of PROLOR Biotech through a $560mm sale in 2013. Lead product Shai Novik partnered to Pfizer, $295 million down payment, $275 upon FDA & other regulatory approvals. Executive Chairman Now named Ngenla® by Pfizer, received marketing authorizations starting 2022 in Aus
Slide 60: Board Of Directors
Board Of Directors Shai Novik Founder and President of PROLOR Biotech, Sold in 2013 ($560mm transaction). Lead product partnered to Pfizer, Executive Chairman $295 million down payment, $275 upon FDA & other regulatory approvals. BLA filed by Pfizer late 2020. Former Worldwide Head of Licensing and
Slide 61: Thank You
Thank You
Enlivex Therapeutics — Investor Presentation (December 2022) on 6ix