ACTOBIOTICS, MICROBE-BASED BIOPHARMACEUTICALS - ActoBio Therapeutics

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ACTOBIOTICS, MICROBE-BASED BIOPHARMACEUTICALS - ActoBio Therapeutics
© 2019 ActoBio Therapeutics, Inc. All rights reserved.

                                                                       ACTOBIOTICS®, MICROBE-BASED BIOPHARMACEUTICALS
                                                                      for expression and local delivery of therapeutics at disease sites
                                                                           including the intestine, the mouth and the nasopharynx.

                                                         1   Corporate presentation - Pieter Rottiers, PhD, Chief Executive Officer, Director – JAN 2019
ACTOBIOTICS, MICROBE-BASED BIOPHARMACEUTICALS - ActoBio Therapeutics
FORWARD-LOOKING STATEMENTS

                                                             Some of the statements made in this presentation are forward-looking statements.
                                                             These forward-looking statements are based upon our current expectations and
                                                             projections about future events and generally relate to our plans, objectives and
                                                             expectations for the development of our business.
© 2019 ActoBio Therapeutics, Inc. All rights reserved.

                                                             Although management believes that the plans and objectives reflected in or suggested
                                                             by these forward-looking statements are reasonable, all forward-looking statements
                                                             involve risks and uncertainties and actual future results may be materially different from
                                                             the plans, objectives and expectations expressed in this presentation. All information in
                                                             this presentation is as of the date marked on the cover page, and ActoBio Therapeutics™
                                                             undertakes no duty to update this information unless required by law.

                                                             © 2018 ActoBio Therapeutics, Inc. All rights reserved. ActoBio Therapeutics is sharing the following materials for informational purposes only. Such materials do not constitute an
                                                             offer to sell or the solicitation of an offer to buy any securities of ActoBio Therapeutics™. Any offer and sale of Intrexon’s securities will be made, if at all, only upon the registration and
                                                             qualification of such securities under all applicable federal and state securities laws or pursuant to an exemption from such requirements. The attached information has been
                                                             prepared in good faith by Intrexon. However, ActoBio Therapeutics makes no representations or warranties as to the completeness or accuracy of any such information. Any
                                                             representations or warranties as to ActoBio Therapeutics shall be limited exclusively to any agreements that may be entered into by ActoBio Therapeutics and to such
                                                             representations and warranties as may arise under law upon distribution of any prospectus or similar offering document by ActoBio Therapeutics .

                                                             Trademarks
                                                             Intrexon, ActoBio Therapeutics, ActoBiotics, Powering the Bioindustrial Revolution with Better DNA, and Better DNA are trademarks of Intrexon and/or its affiliates. Other names may
                                                         2   be trademarks of their respective owners.
ACTOBIOTICS, MICROBE-BASED BIOPHARMACEUTICALS - ActoBio Therapeutics
ACTOBIO THERAPEUTICS™ - KEY INVESTMENT HIGHLIGHTS

                                                                                                                                       PRODUCT
                                                                                     PLATFORM                                                                                       EXPERIENCE
                                                                                                                                       PORTFOLIO
© 2019 ActoBio Therapeutics, Inc. All rights reserved.

                                                             •   ActoBiotics® is a fully integrated, cost-    •   Two Clinical stage programs in Phase       •   Straightforward and reliable
                                                                 effective & unique food microbe-based            IIb and Phase Ib, with other programs          cGMP manufacturing process
                                                                 delivery platform for therapeutics, with         close to clinical stage                    •   IP portfolio across the technology
                                                                 potential for superior efficacy and safety   •   Broad therapeutic application across a         platform:
                                                                 through oral or local targeted delivery          wide set of diseases with strong growth           •   >250 granted patents
                                                             •   Designed to perform specific biological          dynamics.                                         •   >50 pending patent applications
                                                                 interventions                                •   Target the (gut) mucosal immune system     •   Extensive regulatory acceptance of
                                                             •   Accelerates development and validated            for:                                           platform and applications
                                                                 regulatory path for new IND candidates:             • Mucosal healing and decreasing        •   Experienced leadership team with
ACTOBIOTICS, MICROBE-BASED BIOPHARMACEUTICALS - ActoBio Therapeutics
ACTOBIOTICS® - AN INTEGRATED MICROBIAL DRUG PLATFORM

                                                                                                               L. lactis
                                                                                                                                           Therapeutic gene inserted
                                                                                                               essential
                                                                                                               gene
                                                                                                               removed
                                                                                                                                                       GENETIC                                     SCALABLE
                                                                                      SAFETY
                                                                                                                                                       ENGINEERING                                 MANUFACTURING
© 2019 ActoBio Therapeutics, Inc. All rights reserved.

                                                             •   L. lactis has a long history of safe use in     •       Construction strategy allows for
                                                                 human nutrition                                         minimum genetic modifications
                                                             •   Non-colonizing, non-human commensal             •       Engineered through chromosomal
                                                                 species allowing for control of dosage                  integration of single or multiple genetic
                                                                 and timing of exposure                                  elements through precise, targeted
                                                             •   No known pathogenicity                                  double homologous recombination
                                                             •   Oral delivery platform demonstrated             •       Host is engineered for environmental                     •   Industrial microorganism used for
                                                                 safe for use in humans                                  containment¹, preventing accumulation                        large scale food production
                                                                                                                         of bacteria outside the body                             •   cGMP manufacturing process
                                                                                                                 •       Engineering process established in-                          established
                                                                                                                         house to allow for continual creation of                 •   Following fermentation, the modified
                                                                                                                         new drug candidates                                          bacteria are freeze-dried and packaged

                                                         4
                                                                                                                     ¹ Steidler et al., 2003. Nature Biotechnology 21: 785-789.
ACTOBIOTICS, MICROBE-BASED BIOPHARMACEUTICALS - ActoBio Therapeutics
DELIVERY OF ACTOBIOTICS® THERAPEUTICS
© 2019 ActoBio Therapeutics, Inc. All rights reserved.

                                                             1. Genetically engineered             2. Capsule opens and              3. Bacterium releases the
                                                             bacterium freeze dried and            releases the bacterium directly   therapeutic agent locally at
                                                             inserted into enteric coated          at the disease target             target site (e.g. in GI tract)
                                                             capsule

                                                         5
ACTOBIOTICS, MICROBE-BASED BIOPHARMACEUTICALS - ActoBio Therapeutics
ACTOBIOTICS COMPARED TO EXISTING TREATMENTS

                                                             ActoBiotics                                                                                             Classic Protein Biologics
                                                             •   Can be delivered in an oral capsule or in a topical solution                                        •     Intravenous administration
                                                             •   No known toxicity or immunogenicity observed                                                        •     Systemic toxicity, immunogenicity observed
                                                             •   Targeted delivery to mucosa                                                                         •     Limited tissue penetration (notably in the gut)
© 2019 ActoBio Therapeutics, Inc. All rights reserved.

                                                             •   Simultaneous delivery of multiple proteins                                                          •     Single protein administration

                                                                                        Treatment with              ROA                                                              Purified                               50,000
                                                                       Indication         Biologicals            (Biological)     ActoBiotics ROA
                                                                                                                                                      ActoBiotics                    (topical)

                                                                 Oral Mucositis     Palifermin (HSCT)        Injected           Buccal rinse
                                                                 IBD                Anti-TNF                 Injected           Oral capsule
                                                                                                                                                     are as effective as          ActoBiotics               32

                                                                 Type 1 Diabetes                             Injected           Oral capsule        injected biologicals
                                                                                    Insulin (Replacement)                                                                                        1               1,000
                                                                                                                                (Immunotherapy)
                                                                                                                                                      even at 1/1000th
                                                                 Chronic                                     Injected           Nasal spray                                                      TFF1 dose (ng) delivered
                                                                 Rhinosinusitis
                                                                                    Anti-IL5 / anti-IL4R                                                  the dose                                     for efficacy
                                                                 Celiac Disease     -                        -                  Oral capsule

                                                         6
© 2019 ActoBio Therapeutics, Inc. All rights reserved.

7
                                 PIPELINE
                               ACTOBIOTICS
                               CLINICAL AND
                               DEVELOPMENT
ACTOBIO THERAPEUTICS KEY MILESTONES

                                                                                1Q18           2Q18            3Q18         4Q18     1Q19        2Q19         3Q19       4Q19      1Q20      2Q20        3Q20         4Q20

                                                                                                                                                Metabolic
                                                          Target selection                       IBD                                 Allergy     Disease
                                                                                                                                               Skin Disease
© 2019 ActoBio Therapeutics, Inc. All rights reserved.

                                                           Clinical strain                                                                                      IBD
                                                          selection & GMP                       AG017           AG018                             PKU
                                                                                            Celiac Disease     CRSwNP                                          Allergy
                                                             production

                                                                                AG019           AG019                                AG017                     AG018                                                   IBD
                                                              IND/CTA             T1D            T1D                                 Celiac                   CRSwNP                                       PKU
                                                                                 (IND)          (CTA)                                Disease                                                                          Allergy

                                                                                                                                                 AG017
                                                          First patient in                                      AG019                            Celiac                   AG018
                                                               study                                             T1D                             Disease                 CRSwNP

                                                                                                AG013                                 AG019                              AG013     AG019     AG017
                                                         DSMB review/data
                                                                                                 OM                                    T1D                               OM#        T1D*      CeD
                                                         primary endpoint                      (DSMB)                                (DSMB)
                                                                                                                                                                         Interim   Interim   Interim
                                                                                                                                                                         EOP2b     EOP2a     EOP1b
                                                         Last patient out of                                                                                                                           AG019/ AG013
                                                               study                                                                                                                                    T1D** OM##

                                                                               #1  month Follow-up; ## 1 year Follow-up
                                                                               * 6 months Follow-up, ** 1 year Follow-up
                                                         88
© 2019 ActoBio Therapeutics, ActoBio
                     © 2019Inc.        Therapeutics,
                                All rights reserved. Inc. All rights reserved.

                                 ActoBio Therapeutics™ in
                              Autoimmune & Allergic Diseases
STRATEGY BUILT ON RESEARCH FOUNDATION
© 2019 ActoBio Therapeutics, Inc. All rights reserved.

                                                              Huibregtse et al. J. of Immunol. 2009               Takiishi et al. JCI 2012

                                                         10
THE BURDEN OF AUTOIMMUNE DISEASES

                                                                A QUICK AUTOIMMUNE DISEASE                                                      CHALLENGES & OPPORTUNITIES
                                                                        BREAKDOWN
                                                              The National Institutes of Allergy and Infectious
                                                                   Diseases (NIAID) has estimated that:                                         Top Challenges to Antigen-Specific Immune Tolerance Therapies
                                                                                                                                                • Identification, validation and targeting of key antigens
© 2019 ActoBio Therapeutics, Inc. All rights reserved.

                                                                                                                                                • Complex clinical heterogeneity: < 100 autoimmune diseases
                                                                                  $100BN                                                        • Achieving durable tolerance while ensuring safety and efficacy
                                                                             Estimated cost
                                                               of treating autoimmune diseases in the US
                                                                                                                                                Top Opportunities in Antigen-Specific Immune Tolerance Therapies
                                                                                                                                                • Rapid identification and validation of key antigens
                                                                                      50M                                                       • Developing combined therapies to target multiple antigens in complex disease
                                                                          Estimated number
                                                               of Americans with an autoimmune disease                                          • Achieving specific tolerization of self-reactive immune cells without altering host immunity
                                                                                                                                                • Reducing development and production costs compared to traditional antibody or immune
                                                                                                                                                  transplant approaches
                                                                 AND THAT'S WITHOUT TAKING INTO
                                                                    ACCOUNT TYPE 1 DIABETES!

                                                                       Source:
                                                                       Infographic THE BURDEN OF AUTOIMMUNE DISEASES created by 2nd Antigen-Specific Immune Tolerance Drug Development – March 26-28, 2019 Boston, USA www.as-immunetolerance.com
                                                         11
OPPORTUNITIES IN AUTOIMMUNITY / ALLERGY WITH ORAL ACTOBIOTICS

                                                                                                 Mucosal immune system                 Pancreas – T1D   AG019   GI-tract - CeD    AG017
                                                                                          (Intestinal, Buccal, Gingival, Sublingual)

                                                                                             •   Targeted delivery at mucosal                                                    GI-tract
                                                                    Buccal                       immune system                                                                    food
© 2019 ActoBio Therapeutics, Inc. All rights reserved.

                                                              (Sublingual/rinse)                                                                                                 allergy
                                                                                             •   Efficacy at lower amounts vs. oral
                                                                                                 purified protein
                                                                                             •   Co-delivery of multiple
                                                                                                 antigens/allergens                       ANTIGEN-SPECIFIC
                                                              Oral                           •   Co-delivery of antigen/allergen          TREGS MIGRATE TO                   Joints - RA
                                                              ActoBiotics                        with cytokines                            INFLAMED TISSUE
                                                                                             •   Reduction of local & systemic
                                                                                                 response
                                                                 Intestinal
                                                                                             •   Proof of concept demonstrated in                                            Respiratory
                                                                 (capsule)
                                                                                                 autoimmune and allergic models                                                  tract
                                                                                                                                                                            Asthma/Rhinitis

                                                                                                                                               CNS - MS
                                                                                                  Oral Immune Tolerance
                                                         12
                                                                                                      Desensitization
ORAL TOLERANCE INDUCTION WITH ORAL ACTOBIOTICS

                                                         Oral L. lactis Secreting Ovalbumin Induces Ovalbumin-Specific Immune Tolerance2 – Superior efficacy versus purified protein
© 2019 ActoBio Therapeutics, Inc. All rights reserved.

                                                                                                                          •   Treatment is accompanied by a local and systemic
                                                                                                                              OVA-specific increase in IL-10 production
                                                                                                                          •   Treatment suppresses OVA-specific CD4+ T cell
                                                              •   Oral Ovalbumin (OVA) secreting L. lactis proved to be       proliferation mediated by T-reg cells
                                                                  very efficient in suppressing OVA-induced DTH
                                                                                                                          •   Induced Treg cells following LL-OVA Treatment
                                                                  •   Indicate suppression of systemic T cell responses       can transfer OVA tolerance in vivo
                                                         13   •   Superior efficacy versus oral purified OVA
                                                                                                                                      2 Huibregtse   et al., Gastroenterology 2007.
© 2019 ActoBio Therapeutics, Inc. All rights reserved.

14
            Case Study
                          ActoBiotics® in Type 1 Diabetes
AG019 IN TYPE 1 DIABETES - OPPORTUNITY

                                                                     CURRENT TREATMENT                          ACTOBIOTICS OPPORTUNITY                              GLOBAL MARKET
                                                                                                                                                                   SIZE/EPIDEMIOLOGY
                                                                 • Exogenous insulin                          • Value Proposition
                                                                 • Diet and lifestyle modification               •   First disease-modifying treatment
                                                                                                                     that can prevent, delay or reverse
                                                              • Disadvantages
                                                                                                                     T1D
© 2019 ActoBio Therapeutics, Inc. All rights reserved.

                                                                 •    Lifelong treatment with
                                                                      exogenous insulin required
                                                                                                              • Mode of Action
                                                                      for survival                               •   Induction of antigen-specific Treg
                                                                                                                     cells will re-establish long-lasting      2018 Addressable Population:
                                                                 •    Impact on quality of life due
                                                                      to fear of hypoglycemia and                    immunological tolerance to                 > 70,000 newly diagnosed
                                                                      day-to-day management                          islet-antigens aiming to maintain               children per year
                                                                                                                     functional β-cell mass
                                                              • Unmet Need                                                                                         United States: 36,133
                                                                                                                 •   Enhance efficacy by combination
                                                                                                                                                                    European Union: 40,046
                                                                 •    No disease-modifying treatment                 with broad immunoregulatory
                                                                      available                                      agents (e.g. anti-CD3)

                                                                                                                                                            Target Patient     Clinical recent-onset T1D
                                                                                                                                                            Demographic                  patients

                                                         15
AG019 IN TYPE 1 DIABETES - OPPORTUNITY

                                                                                     89% of new-onset T1D in animals cured by AG019 plus low-dose anti-CD34

                                                                                                                              10-25%
                                                                                                                                                                                                  Enrollment criteria
© 2019 ActoBio Therapeutics, Inc. All rights reserved.

                                                                                                                                                                                                  predict therapeutic
                                                                                                                                                                                                    success (89% of
                                                                                                                               60%                                                                      mice cured)

                                                                                            •   AG019 (LL-[PINS] + IL-10) +
                                                                                                anti-CD3 mAb most effective
                                                                                            •   60% of diabetic mice
                                                                                                 •   Reverted to normal blood sugar levels
                                                                                                                                                   •   Treatment effective in 89% of mice treated at the
                                                              Takiishi et al. 2012               •   Preserved residual β-cell function                early stage of diabetes
                                                                                                 •   Halted insulitis progression                        •     Starting glycemia and insulin autoantibody (IAA+)
                                                                                                 •   Treatment induced specific FoxP3+ Treg                    positivity at study entry predicted therapeutic success
                                                                                                     cells for long-term disease suppression
                                                                                                 •   Normoglycemia remained stable for the least
                                                         16                                          15 weeks post-treatment that was followed         4 Takiishi   et al., 2017. Diabetes.
AG019 IN TYPE 1 DIABETES - OPPORTUNITY

                                                              PINS-specific FoxP3+ Treg cells accumulate and proliferate in the pancreatic & peripheral lymph nodes

                                                                                                                            #; &: respectively
© 2019 ActoBio Therapeutics, Inc. All rights reserved.

                                                                                                                            vs. week 6 and 14 CT;
                                                                                                                            1 symbol: p
AG019 IN TYPE 1 DIABETES - EXECUTIVE SUMMARY

                                                              • L. lactis delivering hPINS and hIL-10 – Capsule formulation

                                                              • Intended for the treatment of clinical recent-onset T1D in patients with residual functional β-cell mass

                                                              • High efficacy when combined with low dose systemic anti-CD3
© 2019 ActoBio Therapeutics, Inc. All rights reserved.

                                                                   •    Treatment effective in 89% of mice treated at the early stage of diabetes

                                                                   •    Superior efficacy compared to monotherapy (AG019 or anti-CD3 alone)

                                                              • PK, safety pharmacology and Repeat Dose Toxicity (RDT) studies completed

                                                              • cGMP production of AG019 DS/DP completed

                                                              • IND open; CTA submitted (Belgium)

                                                              • First Patient Dosed in October 2018

                                                              • Interim End Of Phase Ib/IIa data – Q1 2020

                                                         18
AG019 – PHASE IB/IIA – STUDY DESIGN

                                                              • STUDY TITLE: A prospective, multi-center, Phase Ib/IIa study to assess the safety and tolerability of different doses of AG019 administered
                                                                alone or in association with teplizumab [anti-CD3] in patients with clinical recent-onset Type 1 Diabetes Mellitus (T1D)

                                                              • INDICATION: Clinical recent-onset T1D in patients with residual functional β-cell mass

                                                              • STUDY OBJECTIVES:
                                                                   •    The primary objective of this study is to assess the safety and tolerability of different doses of AG019 alone (monotherapy) as well as
© 2019 ActoBio Therapeutics, Inc. All rights reserved.

                                                                        AG019 in association with teplizumab (co- administration therapy).
                                                                   •    The secondary objectives of this study are to obtain pharmacodynamic data of AG019 alone as well as AG019 in association with
                                                                        teplizumab; and to determine the potential presence of AG019 in systemic circulation and the presence of L. lactis bacteria in fecal
                                                                        excretion (pharmacokinetic profile).

                                                              • STUDY DESIGN:
                                                                   •   The Phase Ib (AG019 monotherapy) part of the study will enroll 4 sequential AG019 cohorts of 4-6 patients, in ascending dose cohorts
                                                                       and descending age cohorts. All patients in these cohorts will be treated with AG019 in an open label fashion.
                                                                   •   The Phase IIa (AG019 combination therapy) part of the study will evaluate 2 cohorts of patients administered AG019 and teplizumab.
                                                                       The first 2 patients will be treated with double active treatment in an open label fashion. Patients 3-12 will be randomized (4:1) to receive
                                                                       double active treatment or double placebo in a double-blind fashion.

                                                              • STUDY POPULATION: 8 single dose patients
                                                                (treatment for 1 day) and up to 48 repeat dose patients
                                                                (treatment for 8 weeks) aged 12-40 years will be enrolled in up to 25 sites in USA and Belgium
                                                         19
                                                                                                                     ClinicalTrials.gov Identifier: NCT03751007
© 2019 ActoBio Therapeutics, Inc. All rights reserved.

20
                ActoBiotics® in
           Gastrointestinal Diseases
STRATEGY BUILT ON RESEARCH FOUNDATION
© 2019 ActoBio Therapeutics, Inc. All rights reserved.

                                                                                                                       Vandenbroucke et al. Gastroenterology 2004

                                                              Steidler et al. Science 2000                             Vandenbroucke et al. Mucosal Immunol. 2010

                                                         21
OPPORTUNITIES IN GASTROINTESTINAL DISEASES WITH ORAL ACTOBIOTICS

                                                                        Oro-Gastrointestinal mucosal                 Oral cavity - OM   AG013
                                                                                 receptors
                                                                        •   Oral capsules offer better patient
                                                                            compliance
                                                                        •   Targeted delivery to mucosal
© 2019 ActoBio Therapeutics, Inc. All rights reserved.

                                                                            tissues without systemic exposure                                   GI-tract - IBD     AG020
                                                                        •   Efficacy through localized release at
                                                                            the (inflamed) intestinal mucosa           COMBINATION
                                                                        •   No evidence of problems                 THERAPY TO TARGET
                                                                            demonstrated with systemic therapy      MULTIPLE MUCOSAL
                                                                        •   No known immunogenicity                 DISEASE PATHWAYS

                                                                        •   POC demonstrated superior efficacy
                                                                                                                                                      GI-tract –
                                                                            in experimental IBD models
                                                                                                                                                      Mucositis
                                                                        •   Can deliver combinations of                                                GvHD
                                                                            bioactive proteins                                                          CRC

                                                                                                                           Liver -
                                                                            Mucosal Immunotherapy                   Metabolic/inflammatory
                                                         22                                                               diseases
ACTOBIOTICS ACTIVE DELIVERY OF THERAPEUTIC AGENTS AT SITE OF INFLAMMATION

                                                               Outcome of PK studies with oral L. lactis in mice with chronic colitis3 - Targeted delivery to mucosa
© 2019 ActoBio Therapeutics, Inc. All rights reserved.

                                                                                                 L. lactis locates to the inflamed gut tissue as seen in confocal and
                                                                                                 electron microscopic analysis

                                                                                                 Immunohistochemistry analysis demonstrated active delivery of anti-
                                                                                                 TNF antibodies at the intestinal mucosa

                                                                                                  3 Waeytens   et al., 2007. Infl Bowel Dis.; Vandebroucke et al., 2010. Mucosal Immunol.
                                                         23
EFFECT OF ACTOBIOTICS TREATMENT ON COLITIS IN MOUSE MODEL

                                                                  Oral L. lactis secreting IL-10 (LLmIL10) significantly reduces colitis4 - Targeted delivery to mucosa

                                                              A                                                          B
© 2019 ActoBio Therapeutics, Inc. All rights reserved.

                                                                                                                    Treatment daily for 2 or 4 weeks efficiently:

                                                                                                                               •     (A) Cured colitis in chronic DSS model
                                                                                                                               •     (B) Prevented onset of colitis in IL-10-/- mice
                                                                                                                               •     With ActoBiotics LLmIL10, a 10,000-fold lower dose was as
                                                                                                                                     effective as injected mIL10
                                                                                                                               •     Demonstrates local delivery of therapeutic agents at disease site

                                                                                                                LLmIL10 = L. lactis secreting mIL-10
                                                                                                                Bars represent the mean ± SEM. *P < 0.025; **P = 0.0151
                                                         24                                                     4 Steidler   et al., 2000. Science.
STRATEGY BUILDS ON STRONG FOUNDATION OF PRIOR RESEARCH

                                                                                                                             Oral L. lactis Secreting anti-TNF Demonstrate Efficacy in Chronic Colitis5

                                                                                                     Superior efficiency of
                                                                                                       oral vs systemic
                                                                                                       Purified anti-TNF                 *P < 0.05 compared to mock & LL-pTREX1
                                                                                                                                                                                     •   Assessment of oral L. lactis anti-TNF and purified anti-
                                                                                                                                 6.0                                   5.6
© 2019 ActoBio Therapeutics, Inc. All rights reserved.

                                                                                   7.0
                                                                                             5.4                                                         5.5                             TNF (oral and systemic) for efficacy in established
                                                                                   6.0                                                     4.4
                                                                                                                                                                                         chronic enterocolitis
                                                              Histological Score

                                                                                   5.0                          3.1
                                                                                   4.0                                                                                               •   Proof of concept demonstrated in mouse colitis
                                                                                   3.0
                                                                                                                                                                                         models with oral ActoBiotics :
                                                                                   2.0
                                                                                   1.0                                                                                                   •   Superior efficacy versus purified anti-TNF (oral and
                                                                                   0.0                                                                                                       systemic): ActoBiotics represents a nearly ~50%
                                                                                                                LL-MT1-MT1

                                                                                                                                                         PBS
                                                                                                                                           MT1-MT1
                                                                                              LL-pTREX1

                                                                                                                                 Mock

                                                                                                                                                                       MT1-MT1-AR1
                                                                                                                                                                                             decrease in intestinal inflammation versus ~25% and ~5%
                                                                                                                                                                                             with oral and systemic purified anti-TNF, respectively
                                                                                                                                                                                         •   No immunogenicity issues in contrast with systemic
                                                                                                                                                                                             purified anti-TNF
                                                                                                              Oral Treatment                         Systemic Treatment                  •   Activity restricted to intestine - No interference with
                                                                                   LL-pTREX1: L. lactis Empty Vector Control  LL-MT1-MT1: L. lactis-Secreting Anti-mTNF                      systemic bacterial infections
                                                                                   MT1-MT1(-AR1): Purified Anti-mTNF (50mg/kg oral; 25mg/kg systemic)

                                                         25              5 Vandebroucke              et al., Mucosal Immunol. 2010
© 2019 ActoBio Therapeutics, Inc. All rights reserved.

                                                              ActoBiotics® in Inflammatory Bowel Disease
                                                                                Case Study

                                                         26
AG020 – MULTIPLE EFFECTORS IN INFLAMMATORY BOWEL DISEASE

                                                                       DISEASE SNAPSHOT                   CURRENT TREATMENT PARADIGM                       GLOBAL MARKET SIZE/EPIDEMIOLOGY

                                                              • Risk Factors:                            • Current Treatment Pathway:
                                                                 • Complex interactions between             •   Aminosalicylates
                                                                   genetics, environment and gut
                                                                                                            •   Corticosteroids
© 2019 ActoBio Therapeutics, Inc. All rights reserved.

                                                                   microbiota
                                                                                                            •   Immunomodulators (AZA, 6-MP,
                                                                                                                anti-TNF, etc.)
                                                              • Symptoms:                                • Disadvantages of Current Treatments:
                                                                 • Vary depending on the location and                                                               2019 Addressable Population:
                                                                                                            •   Systemic administration with risks for
                                                                   severity of inflammation, but may            infections, cancer, immunogenicity
                                                                   include diarrhea, bleeding ulcers,                                                               US: 52,000 (UC) / 44,000 (CD)
                                                                                                            •   Lack of full remission and loss of                   EU: 94,00 (UC) / 62,000 (CD)
                                                                   abdominal pain, weight loss, anemia
                                                                                                                response                                            Japan: 8,600 (UC) / 2,800 (CD)
                                                                   and extra-intestinal manifestations
                                                                                                         • Unmet Need:
                                                                                                            •   Efficacious drugs or drug
                                                                                                                combinations without side-effects
                                                                                                                and more convenient administration
                                                                                                                                                                                       1L Mild / Moderate CD
                                                                                                                                                         Target Patient Demographic
                                                                                                                                                                                       2L Mild / Moderate UC

                                                         27
AG020 – MULTIPLE EFFECTORS IN INFLAMMATORY BOWEL DISEASE

                                                              • ActoBiotics® demonstrated therapeutic efficacy in animal models of IBD.
                                                                   •   When orally delivered by ActoBiotics, the anti-inflammatory cytokine IL-10, mucosal healing trefoil factors (TFF) 1, 2 and 3, and
                                                                       antibodies against TNFα, each individually showed an initial level of reduction of inflammation in mice models of disease.

                                                              • ActoBiotics® have also been demonstrated to be safe and tolerated in human Phase 1 clinical trials.
© 2019 ActoBio Therapeutics, Inc. All rights reserved.

                                                              • Seek to improve upon these positive results by combining multiple treatments in a single dosage, targeting
                                                                established as new disease pathways identified by recent research. Development strategy based on:
                                                                   •   Oral therapy
                                                                   •   High efficacy through topical delivery
                                                                   •   Novel mechanisms/combination approaches to improve efficacy
                                                                   •   Superior efficacy/safety to systemic biologicals
                                                                   •   Favorable safety/cost profile allows for sustained treatment over years vs. days/weeks

                                                              • Test this multiple effector approach in validated animal disease models and then enter human clinical trials.

                                                         28
A unique delivery platform precisely tailored for specific disease modification
                                                                     ACTOBIOTICS®,
                                                                    MICROBE-BASED                         Specifically designed to target disease areas with high unmet need
                                                               BIOPHARMACEUTICALS
                                                                                                          Rapid development of new candidates
                                                                for expression and local
                                                              delivery of therapeutics at                 Targeted delivery via oral capsule, oral rinse or topical solution
                                                              disease sites including the
                                                               intestine, the mouth and
© 2019 ActoBio Therapeutics, Inc. All rights reserved.

                                                                                                          Demonstrated safety and tolerability
                                                                    the nasopharynx
                                                                                                          Robust and scalable manufacturing process

                                                                                             Feel free to contact us for more information:
                                                                                                    communications@actobio.com

                                                                               Our factsheet can be downloaded in the investors section on actobio.com

                                                         29
KEY PUBLICATIONS

                                                              Clinical
                                                              • Limaye SA, et al. Phase 1b, multicenter, single blinded, placebo-controlled, sequential dose escalation study to assess the safety and tolerability of topically applied AG013 in subjects with locally
                                                                  advanced head and neck cancer receiving induction chemotherapy. Cancer. 2013;119(24):4268-4276.
                                                              • Braat H, et al. A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn's disease. Clinical Gastroenterology and Hepatology. 2006;4:754-759.

                                                              Preclinical
                                                              • Takiishi T, et al. Reversal of diabetes in NOD mice by clinical-grade proinsulin and IL-10-secreting Lactococcus lactis in combination with low-lose anti-CD3 depends on the Induction of Foxp3-
                                                                  Positive T cells. Diabetes. 2017;66(2):448-459.
© 2019 ActoBio Therapeutics, Inc. All rights reserved.

                                                              • Robert S, et al. Oral delivery of glutamic acid decarboxylase (GAD)-65 and IL10 by Lactococcus lactis reverses diabetes in recent-onset NOD mice. Diabetes. 2014;63(8):2876-2887.
                                                              • Takiishi T, et al. Reversal of autoimmune diabetes by restoration of antigen- specific tolerance using genetically modified Lactococcus lactis in mice. Journal of Clinical Investigation. 2012 May
                                                                  1;122(5):1717-25
                                                              • Caluwaerts S, et al. AG013, a mouth rinse formulation of Lactococcus lactis secreting human Trefoil Factor 1, provides a safe and efficacious therapeutic tool for treating oral mucositis. Oral
                                                                  Oncology. 2010 Jul;46(7):564-70.
                                                              • Vandenbroucke K, et al. Orally administered L. lactis secreting an anti-TNF Nanobody demonstrate efficacy in chronic colitis. Mucosal Immunology. 2010 Jan;3(1):49-56.
                                                              • Huibregtse IL, et al. Induction of antigen-specific tolerance by oral administration of Lactococcus lactis delivered immunodominant DQ8-restricted gliadin peptide in sensitized nonobese
                                                                  diabetic ABo DQ8 transgenic mice. Journal of Immunology. 2009 Aug 15;183(4):2390-6.
                                                              •    Vandenbroucke K, et al. Active delivery of trefoil factors by genetically modified Lactococcus lactis prevents and heals acute colitis in mice. Gastroenterology. 2004;127:502-513.

                                                              Platform
                                                              • Rottiers P, De Smedt T and Steidler L. Modulation of gut-associated lymphoid tissue functions with genetically modified Lactococcus lactis. International Reviews of Immunology. 2009;28:465-
                                                                  486.
                                                              • Huibregtse IL, et al. Induction of ovalbumin-specific tolerance by oral administration of Lactococcus lactis secreting ovalbumin. Gastroenterology. 2007;133:517-528.
                                                              • Steidler L, et al. Biological containment of genetically modified Lactococcus lactis for intestinal delivery of human interleukin 10. Nature Biotechnology. 2003;21:785-789.
                                                              • Steidler L, et al. Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science. 2000;289:1352-1355.
                                                              • Steidler L, et al. Mucosal delivery of murine interleukin-2 (IL-2) and IL-6 by recombinant strains of Lactococcus lactis co-expressing antigen and cytokine.
                                                                  Infection and Immunity. 1998;66:3183-3189.
                                                              • Steidler L, et al. Secretion of biologically active murine interleukin-2 by Lactococcus lactis subsp. lactis. Applied and Environmental Microbiology.
                                                                  1995;61(4):1627-1629.
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