Research & Development Webinar5 June 2020

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© 4D pharma plc

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2

AN INTEGRATED, END-TO-END MICROBIOME PLAYER3

Platform&

Research

Development &

Manufacturing

ClinicalDevelopment

Unique end-to-end capability and expertise

cGMP certified

Production for 4 clinical trials in parallel

MicroRx® platform - focus on functionality

Research collaboration with in vaccines

Sector-leading IP estate

4 clinical-stage candidates across multiple TAs

Clinical collaboration with in I-O

Positive early signals for MRx0518 + Keytruda®

4D pharma is a leader in the development of single strain Live Biotherapeutics, a novel class of drug derived from the human gut microbiome

The Company © 4D pharma plc

CLINICAL UPDATE: ONCOLOGY & COVID-194

© 4D Pharma plc

Immuno-oncology

MRx0518Combination with Keytruda

in patients with acquired resistance to ICI*

Clinical

Phase I/IIPart A (n=12) completeExcellent safety profile25% clinical benefit*

Mechanism

ImmunostimulatoryTLR agonism

Increases tumour immune infiltration

COVID-19

MRx-4DP0004To prevent or reduce hyper-

inflammation associated with severe disease

Clinical

Phase IIFirst patient dosing expected June 2020

Data expected Q4 2020

Mechanism

ImmunomodulatoryDramatic reduction in lung

inflammation in vivo

*all enrolled patients as of 03/06/2020*Immune checkpoint inhibitor

© 4D pharma plc

Research & Development Webinar:Immuno-oncology

MRx0518 – IMMUNO-ONCOLOGY OVERVIEW6

© 4D Pharma plc

Ongoing clinical studies• Phase Ib neoadjuvant biomarker study (UK)• Phase I/II combination study with anti-PD-1 (US)• Phase I combination study with hypofractionated radiation therapy in resectable

pancreatic cancer (US)

Efficacy in vivo• As a monotherapy: reduction of tumour volume in different syngeneic cancer models• In combination: boosts efficacy of checkpoint inhibition

MRx0518• Gram-positive, motile, anaerobic bacterium of the

Enterococcus genus• Selected for immunostimulatory host response

profile, relevant for immunotherapy

Mechanism of action• Increases tumour NK, CD4+, CD8+ cell count; decreases CD8+/Treg ratio• Immune stimulation through action of bacterial flagellin on TLR5

MRx0518

MRx0518 MONOTHERAPY INHIBITS TUMOUR GROWTH7

© 4D Pharma plc

MRx0518 showed efficacy as a monotherapy in mouse syngeneic tumour models of breast, kidney and lung cancer

3 6 9 12 15 18 21 240

100

200

300

400

500

600

Kidney adenocarcinoma (RENCA)

Days post tumour induction

Mea

n tu

mou

r vol

ume

(mm

3 ) Untreated

Vehicle

MRx0518

anti-CTLA-4 +anti-PD-L1

****

********

3 6 9 12 15 18 21 24 27 300

250

500

750

1000

1250

1500

Breast carcinoma (EMT6)

Days post tumour induction

Mea

n tu

mou

r vol

ume

(mm

3 )

******

Untreated

Vehicle

MRx0518

anti-CTLA-4

3 6 9 12 15 18 21 240

500

1000

1500

2000

Lung carcinoma (LLC1)

Days post tumour induction

Mea

n tu

mou

r vol

ume

(mm

3 )

Untreated

Vehicle

MRx0518

anti-CTLA-4

******

Breast carcinoma (EMT6) Kidney carcinoma (RENCA) Lung carcinoma (LLC1)

MRx0518 – Immuno-oncology

T/C – tumour volume / control (untreated or vehicle) tumour volume

MRx0518 ACTIVATES INNATE AND ADAPTIVE ANTI-TUMOUR IMMUNE RESPONSE

8

© 4D Pharma plc

Oncology Response Summit July 2019

Lauté-Caly et al., Scientific Reports 2019

• MRx0518 increases NK cells, T cells and cytotoxic cells in breast (EMT6) and kidney (RENCA) cancer models

• Cell types associated with improved response to therapy and clinical outcomes

• MRx0518 induces a strong innate immune response in vitro

• MRx0518 induces a strong CD4+ and CD8+ adaptive immune response in vitro

• Mice dosed with MRx0518 show increased frequency of systemic immune cell populations associated with anti-tumour immunity

• MRx0518 flagellin activates TLR5, induces IL-8 secretion• Bacterial effector molecule that mediates immunostimulatory effects

described above

MRx0518 – Immuno-oncology

MRx0518-I-002: COMBINATION STUDY WITH KEYTRUDA®9

NCT03637803

© 4D pharma plc

• Open-label Phase I/II study assessing MRx0518 combined with Keytruda® in patients with NSCLC, RCC, urothelial carcinoma and melanoma

• Patients must have had clinical benefit from and then subsequently progressed on a prior anti-PD-1 or anti-PD-L1 immune checkpoint inhibitor (ICI)

• Primary Endpoints:• Safety and tolerability

• Secondary and Other Endpoints:• Tumour response, overall survival, immunological biomarkers, microbiome profile

MRx0518 – Immuno-oncology

MRx0518-I-002: COMBINATION STUDY WITH KEYTRUDA®10

NCT03637803

© 4D pharma plc

Refractory patient population with a high unmet medical need• Eligible patients have secondary/acquired resistance to ICI as defined by an initial

response with subsequent progression meeting the following criteria:• Have received ≥ 2 doses of an anti-PD1 or anti-PD-L1 ICI• Progression within 12 weeks of last dose of the prior ICI• Progression confirmed by 2 radiological scans ≥ 4 weeks apart (in the absence

of rapid clinical progression)• Patients have no appropriate therapeutic options remaining known to provide clinical

benefit• The expected response rate of this patient population is very low

MRx0518 – Immuno-oncology

MRx0518-I-002: OVERVIEW OF PART A11

NCT03637803

© 4D pharma plc

• 12 subjects treated with MRx0518 and Keytruda® (pembrolizumab) combination therapy• 5 subjects remain on treatment• 7 subjects withdrawn from treatment due to progression or progression-related

adverse events• The safety review committee for the study has evaluated the data from Part A of the

study and determined it is safe to proceed to Part B• Part B now open to recruitment of an additional 30 patients per tumour type included in

the study – four additional investigational sites will be opened• Part A data to be submitted to a peer-reviewed publication & conferences

MRx0518 – Immuno-oncology

MRx0518 + KEYTRUDA® – PHASE I/II PART A OVERVIEW12

© 4D Pharma plc* First scheduled radiographic restaging scan at 9 weeks

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62

01-018

01-017

01-016

01-015

01-013

01-011

01-008

01-007

01-006

01-004

01-003

01-002

All Patients (N=12): Duration of Treatment (weeks)*

PD

PD

PD

SD

PD

PD

PD

SD

SD

PD

Clinical response startClinical responseDurable Benefit (≥ 6 months)Remains on studyWithdrawn – radiological assessment prior to week 9Withdrawn – no radiological assessment

RCC NSCLC

PR

PR

Weeks from start of treatment

39%

13% 10% 10% 6% 4% 0%

-24%

-51%

-74%-80%

-60%

-40%

-20%

0%

20%

40%

60%RCC RCC NSCLC RCC RCC RCC RCC RCC NSCLC RCC

% C

hang

e fr

om B

asel

ine

at B

est R

espo

nse

Best Tumour Response (All Evaluable Patients, N = 10*)

MRx0518 + KEYTRUDA® COMBINATION SHOWS CLINICAL EFFICACY IN BOTH RCC & NSCLC

13

© 4D Pharma plc

Evaluable Patients

All ORR: 2/10 – 20%DCR: 5/10 – 50%

RCC ORR: 1/8 – 13%DCR: 4/8 – 50%

NSCLC ORR: 1/2 – 50%DCR: 1/2 – 50%

ORR: Overall Response RateDCR: Disease Control Rate

(CR + PR + SD, in patients that underwent a radiographic restaging scan)

Evaluable patients defined as those patients who had a restaging scan at any point after starting treatment. Based on the best response from any radiological evaluation following the start of treatment using RECIST 1.1 criteria.* 2 non-evaluable patients withdrawn prior to any restaging scan due to SAEs non-related to treatment† Patient remains on study‡ Confirmed response of over 6 months╘ Patient withdrawn following disease-related SAE and early first restaging scan before 9 weeks

SD† SD† SD† PR† ‡ PR† ‡PD╘ PD PD╘ PD╘ PD

MRx0518 – Immuno-oncology

Partial Response (PR)

Stable Disease (SD)

Progressive Disease (PD)

PATIENT 01004: DURABLE PARTIAL RESPONSE OF METASTATIC CLEAR CELL RENAL CARCINOMA (mccRCC)

14

© 4D pharma plc

• 70 year old male, diagnosed with Stage IV mccRCC 4th

April 2016• ECOG score of 1 and Stage IV disease at enrolment• Best response to prior anti-PD-1 ICI (nivolumab) was

stable disease• Discontinued after 44 weeks due to confirmed

progressive disease• Now on study for 58 weeks (cycle 20) with a continuing

partial response for 32 weeks• Complete absence of one of two target lesions• No serious adverse events

MRx0518 – Immuno-oncology

% change combined target tumour volume from baseline

-100

-75

-50

-25

0

25

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21Treatment cycle

%

-66%

2016 2017 2018 2019 2020

A M J J A S O N D J F M A M J J A S O N D J F M A M J J A S O N D J F M A M J J A S O N D J F M A M

Sunitinib PD

Nivolumab SD

Axitinib SD

MRx0518 + pembrolizumab PR

PATIENT 01007: DURABLE PARTIAL RESPONSE OF METASTATIC NON-SMALL CELL LUNG CARCINOMA (NSCLC)

15

© 4D pharma plc

• 62 year old female, diagnosed with Stage IV mNSCLC with EGFR mutation on 15th June 2016

• ECOG score of 1 and Stage IV disease at enrolment• 7 prior therapies at enrolment - best response to prior anti-

PD-1 immune checkpoint inhibitor was stable disease (SD)• Discontinued due to confirmed progressive disease

after 24 weeks• Now on study for 49 weeks with a continuing partial

response for 31 weeks• No serious adverse events

2016 2017 2018 2019 2020J A S O N D J F M A M J J A S O N D J F M A M J J A S O N D J F M A M J J A S O N D J F M A M

Whole brain radiation

Erlotinib PDCisplatin + pemetrexed SD

Pemetrexed PDNivolumab SDDocetaxel PD

Osimertinib PDMRx0518 + pembrolizumab PR

-100

-75

-50

-25

0

25

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16Treatment cycle

%

% change combined target tumour volume from baseline

-49%

CONFIDENTIALMRx0518 – Immuno-oncology

MRx0518-I-002 – PRELIMINARY RESPONSE SUMMARY16

© 4D Pharma plc

RECIST 1.1 Response Criteria

Renal Cell Carcinoma

Non-Small Cell Lung Carcinoma All Patients

N 9 3 12 100%

PR 1 1 1 2 17%

SD (≥ 6 months) 1 0 1 8%

SD (≤ 6 months) 2 2 0 2 17%

PD 5 2 7 58%

Clinical Benefit:3/12 = 25%

• Duration of treatment (months): median 2.6 (0.4 – 13.5)• Responders: median 10.3 (2.9 – 13.5), all responses ongoing• Non-Responders: median 0.8 (0.4 – 3.2)

• Updated analysis of clinical benefit (CR + PR + SD ≥ 6 months) will be announced when all patients have completed at least 6 months of treatment or discontinued

• All responses (PR and SD) are ongoing. SD responses may improve over time• Clinical benefit analysis includes all patients, including 5 that were withdrawn due to clinical

progression before undergoing the first scheduled restaging scan at 9 weeks• In the 7 patients who had a restaging scan following 3 cycles of therapy clinical benefit is 43%

1 Subject 01007 has EGFRmut NSCLC2 Subject 01017 demonstrated a 24% tumour volume reduction at first control

MRx0518 – Immuno-oncology

MRx0518-I-002 – CONCLUSIONS17

© 4D Pharma plc

• The study addresses a population highly refractory to immune checkpoint inhibitors with high unmet medical need and no standard treatment options

• Strong safety profile for MRx0518 with no specific signals so far• No drug-related SAEs, no treatment-related drug discontinuation• No increase of immune-related adverse events as seen with ICIs

• A clear signal of therapeutic clinical benefit in RCC:• 1 partial response (PR), 3 stable disease (SD) (1 > 6 months) in 9 patients

• Durable partial response in a NSCLC patient with EGFRmut• 1 PR in 3 NSCLC patients

• Long duration of response:• PRs of 32 and 31 weeks, SD at 44, 15 and 12 weeks, all responses are still ongoing

These results demonstrate proof-of-concept for the synergy between a single-strain Live Biotherapeutic and an immune checkpoint inhibitor in patients with advanced renal cell carcinoma who have exhausted other therapeutic options

NEXT STEPS WITH MRx051818

© 4D Pharma plc1 GlobalData; 2 Zhange et al., Oncotarget 2016; 3 Hastings et al., Annals of Oncology 2019; 4 Reck et al., Lancet Resp Med 2019; 5 Grimm et al., J Clin Med 2020; 6 Rini et al., NEJM 2019

1) Explore expedited approval pathways based on proof-of-concept clinical data• End of Line therapy for immune checkpoint inhibitor refractory patients – no approved

therapeutic options known to provide clinical benefit:

2) Explore the use of MRx0518 in alternative tumour types, combinations and settings in the treatment pathway

Metastatic RCC• ~22,000 diagnoses of mRCC in US in

2019 alone 1

• ICIs have become standard first-line treatment 5

• Up to ~17% of patients receiving ICI therapy for RCC are expected to develop secondary resistance 6

Metastatic NSCLC• ~122,000 diagnoses of mNSCLC in US in

2019 alone 1

• ICIs have become standard first-line treatment

• Includes ~25% of US NSCLC patients with EGFRmut – lower response to ICIs & commonly excluded from clinical studies 2,3

• Up to ~33% of patients are expected to develop secondary resistance 4

Patient populations expected to grow significantly with increased ICI use in NSCLC & RCC

© 4D pharma plc

Research & Development Webinar:COVID-19

PREVENTING HYPERINFLAMMATORY RESPONSE IN COVID-1920

© 4D Pharma plcAdapted from Siddiqi K.H et al., J Heart Lung Transplant 2020

4D recognised the potential of MRx-4DP0004 to reduce inflammatory response to COVID-19 infection and prevent progression to hyperinflammatory state and severe disease

MRx-4DP0004 HAS A UNIQUE IMMUNOMODULATORY PROFILE21

© 4D Pharma plc

COVID-19 (Observed Immune Response) MRx-4DP0004 (Preclinical models) 6

• Uncontrolled activation of the immune system 1 • Reduced production of key pro-inflammatory cytokines in the lungs in preclinical asthma model

• High neutrophil count emerging as an indicator of disease severity 2,3

• Reduced lung production of chemokines involved in neutrophil trafficking

• Reduced airway neutrophil infiltration

• Acute respiratory distress is the leading cause of COVID-19 mortality 4

• Reduced lung immune infiltration results in dramatic improvement in lung histopathology

• Lower levels of regulatory T cells, and to a greater extent in severe cases 3 • Increases Tregs in vitro and in vivo

• Broad immunosuppression (e.g. anti-IL-6/IL-6R mAbs) may dampen adaptive immune response, delaying viral clearance and symptomatic recovery

• Regulates innate hyperactivation without suppressing adaptive response involved in anti-viral clearance

• Follicular helper T cells (Tfh) and CD19+ B cells important for symptomatic recovery 5

• Increased frequency of Tfh cells & activated CD19+ B cells

• More severe cases of COVID-19 are associated with systemic hyperinflammation, not limited to the lungs

• Efficacy models of other inflammatory diseases including MS and arthritis

1 Mehta et al., Lancet 2020; 2 Mo et al., Clin Infec Dis 2020 ; 3 Qin et al., Clin Infec Dis 2020; 4 Ruan et al., Intens Care Med 2020; 5 Thevarajan et al., Nat Med 2020; 6 Raftis et al., Scientific Reports 2019

4D recognised the potential of MRx-4DP0004 to reduce inflammatory response to COVID-19 infection and prevent progression to hyperinflammatory state and severe disease

ANTI-INFLAMMATORY ACTIVITY DEMONSTRATED IN MODEL OF SEVERE NEUTROPHILIC ASTHMA

© 4D pharma plc

22

• Measurement of inflammatory mediators in lung tissue

• Quantification and characterisation of airway infiltrating immune cell types

• Lung histology

• HDM-specific IgG1 and IgG2a production

• Sensitisation of animals with Complete Freund’s Adjuvant (CFA) and HDM skews inflammatory phenotype towards neutrophilic

• MRx-4DP0004 dosed prophylactically (D-14 to D7) OR therapeutically (D7 to D17)

• Anti-IL-17 mAb as positive control

Model summary Experimental readouts

Therapeutic MRx-4DP0004

CFASensitisation

CFASensitisation

SacrificeAnti-IL17

HDM challenge

D-14 D0 D7 D18D14 - 17

Steroid-resistant model of severe neutrophilic asthma

Prophylactic MRx-4DP0004

MRx-4DP0004 REDUCES CYTOKINES AND CHEMOKINES23

© 4D Pharma plc

High mortality rate of COVID-19 may be due to hyper-inflammatory response and cytokine storm syndrome caused by uncontrolled activation of the immune system

• House dust mite (HDM) model of severe steroid-resistant asthma

• Oral administration of MRx-4DP0004 reduces production of key pro-inflammatory cytokines in the lungs, including IL-1α and IL-1β

• Also reduces production of chemokine CXCL2, a key neutrophil trafficking signal

IL-1α IL-1β CXCL2

Raftis et al., Sci Rep 2018

MRx-4DP0004: COVID-19

MRx-4DP0004 REGULATES EXCESSIVE INNATE ACTIVATION WITHOUT SUPPRESSING ADAPTIVE IMMUNE RESPONSE

24

© 4D pharma plc

Maintenance of an appropriate anti-viral adaptive immune response is key to viral clearance and disease resolution

• MRx-4DP0004 induces Tregs and significantly reduces innate hyperactivation

• However, the number of adaptive immune CD4+ and CD8+ T cells in MRx-4DP0004 treated mice is comparable to untreated

• MRx-4DP0004 significantly increases the activation status of CD4+ CD44+ memory T cells

Raftis et al., Sci Rep 2018

MRx-4DP0004: COVID-19

Adaptive immune cellsCD4+ CD8+ CD4+ CD44+

MRx-4DP0004 DRAMATICALLY REDUCES NEUTROPHILS25

© 4D Pharma plc

High neutrophils increasingly understood to be a key driver of COVID-19 symptom pathology and emerging as an indicator of disease severity

• MRx-4DP0004 induces strong and significant reduction in BALF neutrophils in a mouse model of severe asthma

• Activity was demonstrated in both prophylactic and therapeutic settings

Prophylactic dosing Therapeutic dosing

Raftis et al., Sci Rep 2018

MRx-4DP0004: COVID-19

MRx-4DP0004 SIGNIFICANTLY REDUCES IMMUNE INFILTRATION AND PROTECTS LUNG HISTOLOGY

26

© 4D Pharma plc

Reduced immune infiltration is associated with strong reduction in peribronchiolar and perivascular immune infiltration, and improved lung histopathology

House dust might model of severe, steroid-resistant, neutrophil-high asthma

• MRx-4DP0004 treatment strongly reduced peribronchiolar and perivascular infiltrate

• Lung histopathology scores of MRx-4DP0004-treated animals were not significantly different from the scores of control healthy animals

Total inflammatory score Lung histopathology

MRx-4DP0004: COVID-19

Raftis et al., Sci Rep 2018

SYSTEMIC IMMUNOMODULATORY ACTIVITY OF MRx-4DP0004 IS NOT LIMITED TO LUNGS

27

© 4D Pharma plc

More severe cases of COVID-19 are associated with systemic hyperinflammation

Experimental autoimmune encephalitis (MS)

Untreate

d

Vehicl

e

MRx000

4

Dexam

ethas

one0

50

100

150

200

250

Spinal Cord Inflammatory Foci

Spin

al C

ord

Infla

mm

ator

y Fo

ci/M

ouse

**

********

Untreate

d

Vehicl

e

MRx000

4

Dexam

ethas

one0.0

0.5

1.0

1.5

2.0

2.5

Tregs % CD4+ in the Spleen

CD4+

CD25

+Fo

xP3+

(% o

f CD4

+Ce

lls)

Vehicl

e

MRx000

40

1

2

3

4

Inflammation Scores

Infla

mm

atio

n S

core

s

**

Vehicl

e

MRx000

40

2

4

6

8

10

Total Scores 1

Tota

l Sco

res

**

Type II collagen-induced arthritis

VehicleGrade 9 - extensive joint and bone destruction, inflammation & fibrosis extending to periarticular soft tissues

MRx-4DP0004Grade 0 - normal joint

Joint histology

1 Bone, joint and inflammation

MRx-4DP0004: COVID-19

MRx-4DP0004 has demonstrated in vivo efficacy in additional models of inflammatory disease

MRx-4DP0004 PHASE II COVID-19 RCT APPROVED (NCT04363372))28

© 4D pharma plc

Results of initial pilot study will support regulatory fast-tracked engagement on:• Potential accelerated approval; and/or• Design and endpoints of pivotal study

Randomised, double-blind, placebo-controlled study enrolling up to 90 patients with COVID-19

MHRA Study Approval Press Release

• Ethics committee and HRA approval received• Clinical site selection and initiations underway• First patient dosing expected June 2020• Preliminary data expected Q4 2020

Size and design of study chosen to rapidly generate meaningful signal of clinical benefit• 2:1 randomisation to receive MRx-4DP0004 or placebo B.I.D + standard of care, for up

to 14 days• Primary Endpoint: Mean clinical status score change (WHO Ordinal Scale for Clinical

Improvement)• Secondary Endpoints: requirement and duration of ventilation, time to discharge,

mortality, safety and tolerability

Positive data in COVID-19 would indicate potential in other inflammatory viral diseases

© 4D pharma plc

Summary

CLINICAL UPDATE: ONCOLOGY & COVID-1930

Clinical PoC

MRx0518Proof of concept in RCCPotential to expand into additional tumour types

Safety

Clinical demonstration of expected excellent safety

profile

Validation

Positive clinical data validates our to single strain LBP approach

© 4D Pharma plc

Immuno-oncology

COVID-19Mechanism

MRx-4DP0004Relevant mechanism of

action for COVID-19Clinical safety data from Phase I/II asthma study

Clinical operations

Rapid response to urgent public health issue

< 4 weeks from programme ideation to MHRA approval

Platform

Enabled by MicroRx®

platform, mechanistic understanding and

preclinical data package

SUMMARY31

© 4D pharma plc

4D continues to deliver clinical data across multiple programmes, validating our Live Biotherapeutics approach

Leading microbiome therapeutics innovation• Diverse pipeline and sector-leading IP estate powered by unique discovery

platform MicroRx®

• Established cGMP-certified, scalable manufacturing facility

Building on clinical proof-of-concept data• Strong signals generated in renal cell carcinoma and potentially non-small

cell lung cancer• Consistently favourable safety profiles across clinical candidates

Delivering first-in-class Live Biotherapeutics medicines• Exploring expedited regulatory approval pathways for lead indications• Readouts across multiple therapeutic areas in 2020/2021 offering key value

inflection points to our shareholders

© 4D pharma plc

Supplementary Data

MRx0518 INDUCES A STRONG INNATE IMMUNE RESPONSE IN VITRO

34

© 4D Pharma plc

IL-6IL-22 IFN-γ

CXCL10

GM-CSF

CXCL1TNF-a

CCL5CCL3

CCL4

CXCL2CCL2

CCL7IL-17

AIL-18 IL-2

0

200

400

600

800

Con

cent

ratio

n (p

g/m

l) UntreatedYCFAMRx0518

***

TNFa

CXCL1

CXCL3

CCL20 IL8

CXCL10 IL29

NFKBIATLR7

TNFAIP3

NFKBIZBIRC3

IRF1IL17

C0

4080

120160200400800

12001600

Fold

cha

nge

GM

-CS F

IL-1

0

IL-1

2 p 7 0IL

-1β

IL-2

3IL

-6

T N F α

C X C L 9

C X C L 1 0

V E GF

0

5 0 0 0

1 0 0 0 0

1 5 0 0 0

2 0 0 0 0

Co

nc

en

tra

tio

n (

pg

/mL

)

U n tre a ted

M R x0518

* * * *

* * *

* * * *

* **

• MRx0518 increases the production of a cytokine/chemokine signature that includes IL-8, IFN-γ, IL-6, TNF-α, IL-1β, IL-23, CCL20, CXCL1, CXCL3, CXCL9 and CXCL10

Caco-2THP-1

GM

-CS F

IL-1

0

IL-1

2 p 7 0IL

-1β

IL-2

3IL

-6

T N F αIF

N Y

C X C L 9IL

-2IL

-8

C X C L 1 0

V E GF

0

5 0 0 0

1 0 0 0 0

1 5 0 0 0

2 0 0 0 0

Co

nc

en

tra

tio

n (

pg

/mL

)

U n tre a ted

M R x0518

****

****

****

****

PBMCs

THP-1

Splenocytes

Caco-2

MRx0518 – Immuno-oncology

MRx0518 INDUCES A STRONG CD4+ AND CD8+ ADAPTIVE IMMUNE RESPONSE IN VITRO

35

© 4D Pharma plc

Treg differentiation assay PBMC co-culture assay

CD8+ cells

CD4+ cells

• MRx0518 increases % CD8+ T cells and activated IFN+ CD8+ T cells (Fig.1)

• MRx0518 increases % CD4+ T cells and activated IFN+ Th1 CD4+T cells (Fig.2)

• MRx0518 reduces differentiation of CD4+CD25+FoxP3+ Tregs (Fig.3)

CD3/CD28, IL-2 and TGF-βCD3/CD28

1

2

3Tregs

MRx0518 – Immuno-oncology

MRx0518 INCREASES CYTOTOXIC CELL, T-CELL AND NK CELL POPULATIONS IN TUMOURS

36

© 4D Pharma plc

Ileum immune populations

Untreate

d

Vehicl

e

MRx051

8

NK CD56dimcellsCD8 T cells

Exhausted CD8DC

Cytotoxic cellsMacrophages

T-cellsMast cells

NeutrophilsB-cells

NK cellsCD45

Th1 cells

Z-score

-0.5

0

0.5

Tumour immune populations Ascending colon immune populations

• Increased NK cells, T cells and cytotoxic cells in the tumour• Increases NK cells, T cells and cytotoxic cells in the ascending colon• Few changes in ileal immune populations

Untreate

d

Vehicl

e

MRx051

8

NK CD56dim cells

Exhausted CD8

DC

Cytotoxic cells

Macrophages

T-cells

Mast cells

Neutrophils

B-cells

NK cells

CD45

Z-score

-0.5

0

0.5

Untreate

d

Vehicl

e

MRx051

8

NK CD56dim cells

Exhausted CD8

DC

Cytotoxic cells

Macrophages

T-cells

Neutrophils

B-cells

NK cells

CD45

Th1 cells

Z-score

-0.5

0

0.5

MRx0518 – Immuno-oncology

NF-κB TLR5

MRx0518 FLAGELLIN ACTIVATION OF TLR5 MEDIATES IMMUNOSTIMULATORY EFFECTS

37

Dose-response with recombinant flagellins

• Purified recombinant flagellins activate TLR5

• MRx0518 flagellin is more potent than the reference flagellin at low concentrations

NF-κB activation in response to SN

• Little to no NF-κB/TLR5 activation when flagellin gene is knocked out (fliC)

• Supernatant of the reference strain does not activate TLR5

• (HKLM & FLA-ST +ve controls)

Recombinant MRx0518 flagellin is more potent than that of a reference strain

Flagellin in MRx0518SN activates NF-κB and TLR5 signalling

TLR5NF-κB

© 4D pharma plc

Lauté-Caly et al., Sci Reps 2019

MRx0518 – Immuno-oncology