September 21, 2021

VectivBio R&D Day

CONFIDENTIAL

R&D Day

This presentation contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 that reflect the current beliefs, expectations and assumptions of VectivBio Holding

AG (the “Company,” “we” or “our”) regarding the future of its business, its future plans and strategies, clinical results, future financial condition and other future conditions. All statements other than statements of

historical facts contained in this presentation, including statements regarding future results of operations and financial position, business strategy, product candidates, planned preclinical studies and clinical trials,

results of clinical trials, research and development costs, regulatory approvals, timing and likelihood of success, as well as plans and objectives of management for future operations, are forward-looking statements.

The words “may,” “will,” “expect,” “anticipate,” “aim,” “estimate,” “intend,” “plan,” “believe,” “is/are likely to,” “potential,” or “continue” or the negative of these terms or other similar expressions are intended to identify

forward-looking statements, although not all forward-looking statements contain these identifying words. These forward-looking statements are subject to a number of risks, uncertainties and assumptions, including,

among other things: the ability of our clinical trials to demonstrate acceptable safety and efficacy of our product candidate; the timing, progress and results of clinical trials for our product candidate, including

statements regarding the timing of initiation and completion of studies or trials and related preparatory work, the period during which the results of the trials will become available, and our research and development

programs; the timing, scope and likelihood of regulatory filings and approvals; our ability to obtain marketing approvals of our product candidate and to meet existing or future regulatory standards or comply with

post-approval requirements; our expectations regarding our ability to fund our operating expenses and capital expenditure requirements with our cash and cash equivalents and net proceeds of this offering; future

milestone or royalty payments to our licensing partners or other third-parties, and the expected timing of such payments; our expectations regarding the potential market size and the size of the patient populations for

our product candidate, if approved for commercial use; our expectations regarding the potential advantages of our product candidate over existing therapies for SBS-IF and our expectations regarding potential uses

of our product candidate to treat other indications; the success of development and commercialization of the CoMET platform; our ability to develop new product candidates using the CoMET platform; developments

and projections relating to our competitors and our industry, including competing therapies; the impact of COVID-19 on our business, operations and prospects and on our clinical trials; our potential to enter into new

collaborations; our expectations with regard to our ability to develop additional product candidates or leverage our current product candidate for other indications, and our ability to identify additional products, product

candidates or technologies with significant commercial potential that are consistent with our commercial objectives; our ability to develop, acquire and advance additional product candidates into, and successfully

complete, clinical trials; the commercialization and market acceptance of our product candidate; our marketing and manufacturing capabilities or those of third parties with which we contract; our ability to operate our

businesses without infringing the intellectual property rights and proprietary technology of third parties; the scope of protection we are able to establish and maintain for intellectual property rights covering our product

candidates; estimates of our expenses, future revenue, capital requirements, our needs for additional financing and our ability to obtain additional capital; regulatory development in the United States, Europe and

other jurisdictions; and other risks described in the “Risk Factors” section of our Registration Statement on Form F-1 declared effective by the Securities and Exchange Commission (SEC) on April 8, 2021 and our

other subsequent filings with the SEC.

The forward-looking statements in this presentation represent our views as of the date of this presentation. Although we believe the expectations reflected in such forward-looking statements are reasonable, we can

give no assurance that such expectations will prove to be correct. Accordingly, readers are cautioned not to place undue reliance on these forward-looking statements. Except as required by applicable law, we do

not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise. No representations or

warranties (expressed or implied) are made about the accuracy of any such forward-looking statements. New risk factors and uncertainties may emerge from time to time, and it is not possible to predict all risk

factors and uncertainties.

We file Current Reports on Form 6-K, Annual Reports on Form 20-F, and other documents with the SEC. You should read these documents for more complete information about us. You may obtain these documents

for free by visiting EDGAR on the SEC website at www.sec.gov.

This presentation concerns products that are under clinical investigation and which have not yet been approved for marketing by the relevant regulatory authorities. They are currently limited by federal law to

investigational use, and no representation is made as to their safety or effectiveness for the purposes for which they are being investigated.

Disclaimer and Forward-Looking Statements

2

Luca Santarelli, M.D.CEO & Founder

Introduction

R&D Day

Building a Fully Integrated Global Rare Disease CompanyApraglutide in SBS-IF: an underserved market demanding better products with >$2B potential

*Gattex® (teduglutide), known as Revestive® outside the U.S.

SBS-IF: Short Bowel Syndrome Intestinal Failure; SOC: Standard of Care; MOA: Mechanism of Action

• Designed to address previously

intractable Inherited Metabolic

Diseases and prevent clinical

progression of IMDs

• Modular chemistry designed to

restore fundamental cellular

metabolism

• 4 programs in research, plans to enter the clinic in 18 months

• Apraglutide, a differentiated drug candidate for Short Bowel Syndrome

• >$2B market potential, severely underserved

• Gattex®*, only approved product with several shortcomings and limited penetration

• Apraglutide offers a next generation profile and the potential to establish a new SOC

• MOA and approval path are validated

• Multiple life-cycle opportunities

• Successful rare disease track record in R&D, Commercial and Business Development

• Expertise across multiple disease areas and modalities

• Strong focus on execution and discipline in asset selection

Transformative CoMET platform

SuccessfulTeam

Compelling Ph3 Asset

4

R&D Day

Raised $154M* in Nasdaq IPO (VECT) on April 9, 2021

Cash and Cash Equivalents as of June 30, 2021: $144.6M**

Accomplishments in 2021

Apraglutide: • Ph3 programs started in SBS –

• STARS trial initiated in January

• STARS Extend trial initiated in July

• STARS Nutrition trial initiated in June

• ODD status obtained in GVHD - Ph2 trial in preparation

Pipeline expansion:• CoMET platform acquired – 4 programs added to the pipeline

5

VectivBio: 2021 accomplishments to date

* Includes $146.6M in gross proceeds from Initial Public Offering and $7.5M pursuant to a simple agreement for future equity (SAFE) with an existing shareholder; net proceeds after underwriting discount, commissions and fees of $140.5M

** Unaudited; Cash balance on December 31st, 2020: $40.2M

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Our Pipeline

1. Our planned pediatric SBS-IF and acute graft versus host disease clinical trials rely on clinical trial data from our completed healthy volunteer Phase 1 and adult SBS-IF patient Phase 2 clinical trials.

To date, we have not completed any dedicated clinical trials in pediatric SBS-IF and acute graft versus host disease.

Indication(s) Stage of Development Upcoming Milestone(s)

Adult SBS-IF

Pediatric SBS-IF1 • Intend to initiate Ph 3 in 2023

Acute Graft Versus Host Disease1 • Intend to initiate Ph 2 in Q1 2022

Preclinical Phase 1 Phase 2 Phase 3

Apraglutide

Discovery

• First readout: H1 2022

• Top-line results: H2 2023

• OLE

VB-1197

VB-1200

VB-1300

VB-1400

CoMET

Malonic and Propionic Acidemia

Other Organic Acidemias

VB-1197 • Intend to initiate Ph 1 by Q1 2023

Urea Cycle Disorders

Fatty Acid Oxidation Disorders

Amino Acidopathies

6

7 R&D Day

Program & Speakers

Luca Santarelli, M.D.Founder and CEO

Omar Khwaja, M.D., Ph.D.Chief Medical Officer

Nader Youssef, M.D., MBA, FACGSVP, Global Medical Affairs & GI Therapeutic

Area Head

Kishore Iyer, MBBS, FRCS, FACSDirector of Adult and Pediatric Intestinal Rehabilitation

& Transplantation at Mount Sinai Medical Center

Robert Zeiser, M.D.Head of Tumor Immunology and Immune Modulation

at the University Medical Center Freiburg

Introduction to VectivBio

ApraglutideShort Bowel Syndrome with Intestinal Failure

ApraglutideAcute Graft-versus-Host-Disease

CoMET – Coenzyme Metabolism PlatformInherited Metabolic Diseases

Conclusion

Question & Answer

7

SBS-IF

R&D Day

SBS-IF Represents a Significant Opportunity

* We estimate that the addressable global market opportunity for apraglutide, if approved, in SBS-IF, could exceed $2 billion per year through significant growth in the number of eligible patients receiving a GLP-2 analog, potentially improved compliance and persistency, and geographic expansion beyond where teduglutide is approved today.

Source: Custom market research commissioned by VectivBio, Nov 2019; internal estimates.

Rest of World Opportunity

~ 1,000 SBS-IF patients in Japan

China

Other Markets

5,000

7,500

2,500

7,500

U.S. Market Opportunity

EU Market Opportunity

We Believe There is a >$2 Billion Peak Market Potential Opportunity*

Est. Peak SBS-IF Patients Treated

with GLP-2

U.S. and EU Market Opportunity

Est. SBS-IF Patients

9

R&D Day

Significant Unmet Medical Needs Remain with Gattex

PS, parenteral support (includes parenteral nutrition and/or intravenous fluid)

1. Gattex® (teduglutide) for injection. Prescribing Information; 2. Revestive® Summary of Product Characteristics; 3. Gattex® (teduglutide) Instructions for Use; 4. Jeppesen PB, et al. Gastroenterology. 2012; 5. Jeppesen PB et al. Clin. Nutr. 2013; 6. Jeppesen PB, et al. Gastroenterology. 2018; 7. CRA Market Research, Nov 2019 (U.S. and EU5); 8. Symphony Health, PatientSource®, Dec 2015–Jan 2019 (analysis period of claims); patient cohort: U.S. patients starting Gattex who have had an SBS diagnosis and at least 180 days of parenteral nutrition prior to receiving Gattex and who could be followed for at least 24 months; patients are considered discontinued if they have a gap in therapy >90 days; patients are considered persistent until first event of discontinuation.

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Gattex® / Revestive®

(only GLP-2 analog approved for SBS-IF since 2021)1,2

Limitations of Gattex

• 2hr half life, daily subcutaneous injections1

• Lengthy and complex administration procedure3

• Only partially addresses the needs of

SBS-IF patients:

• Adverse events: injection site reactions and abdominal pain1,4

• No demonstrated impact on patients’ quality of life5

• Colon-in-continuity patients treated with Gattex did not exhibit a

significant reduction in PS volume as compared to placebo-treated

patients in Phase 3 trial6

• Gattex is predominantly used in stoma/high PS SBS-IF patients7

Gattex 24-Month Persistency, U.S. (n=194)8

74%

62%

48%

34%

0%

20%

40%

60%

80%

100%

0 1 2 3 4 5 6 7 8 9 101112131415161718192021222324Months

Despite significant limitations, Gattex revenue was >$600M in FY20

Increases intestinal absorption and reduces the volume of parenteral support*

Limited/niched use, sub-optimal persistency

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Apraglutide Has the Potential to Establish a New Standard of Care

*Management expectations, based on clinical trials to date.

1. Martchenko SE et al. J Pharmacol Exp Ther. 2020; 2. Hargrove DM et al. J Pharmacol Exp Ther. 2020; 3. Eliasson J et al. Clinical Nutrition ESPEN 40 (2020), 459; 4. Eliasson J et al. Clinical Nutrition ESPEN 40 (2020), 436.

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Enhanced Value Proposition

Differentiated Apraglutide Target Profile*

• Convenient administration

• Weekly dosing3,4

• Developing pre-filled syringe

• Demonstrated robust pharmacology

• Improved intestinotrophic effects in preclinical models1,2

• Enhanced energy absorption in SBS patients in Phase 23

• Differentiated clinical and regulatory strategy in Phase 3

• Takes into account remnant bowel anatomy when weaning PS and assessing benefits from GLP-2 treatment

• Focuses on clinically meaningful effects, including enteral autonomy and quality of life measurements

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We Believe Apraglutide Can Significantly Expand the Market to >$2BThere are multiple drivers that can establish apraglutide’s best-in-class value proposition

GL

P-2

Re

ve

nu

e

2019

GLP-2 RevenuePeak

GLP-2 Revenue

FY 2020

Market

of ~$609M

Potential

Peak Market

of >$2.0BDrivers of

Market Growth

Drivers of

Apraglutide UseImproved convenience with weekly dosing

Greater reduction in PS & enteral autonomy

Consideration of remnant bowel anatomy

Enhanced QoLImproved persistency

(50% pts off Gattex @ 12 mos)

Increased use in untreated patients(< ½ stoma and ¼ CIC pts on therapy)

Expanded use outside the U.S.(only ~15% of sales ex-US)

Global strategy

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Short Bowel Syndromewith Intestinal Failure (SBS-IF)

Nader Youssef, M.D., MBA, FACGSVP, Global Medical Affairs & Therapeutic Area Head, GI

R&D Day

Short Bowel Syndrome with Intestinal Failure

Short Bowel Syndrome (SBS)

SBS-Intestinal Failure

(SBS-IF) • Requires intravenous supplementation

of parenteral nutrition to maintain life

• Standard of care includes PN, symptom management teduglutide

• Significant unmet need

• Improve nutrient and fluid absorption

• Reduce PN dependence and serious complications

• Achieve enteral autonomy from PNIBD, inflammatory bowel disease

Pironi L et al. Clin Nutr. 2015 Apr;34(2):171-8014

• Loss of significant length of bowel

due to disease or surgical resection

• Causes include: IBD, trauma,

mesenteric infarction, bariatric

surgery, etc.

• Patients may require short-term

intravenous parenteral nutrition (PN),

or permanent PN and become SBS-IF

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SBS-IF is Associated with Significant Burden

SBS-IF, intestinal failure associated with short bowel syndrome; SBS, short bowel syndrome; PS, parenteral support (includes parenteral nutrition and/or intravenous fluid); GI, gastrointestinal; QoL, quality of life

1. Parrish CR et al. Gastroenterol Hepatol (N Y). 2017 Oct;13(10):600-608; 2. Billiauws L et al. J Visc Surg. 2018 Sep;155(4):283-291; 3. Schalamon J et al. Best Pract Res Clin Gastroenterol. 2003 Dec;17(6):931-42; 4. Howard L. Gastroenterology. 2006 Feb;130(2 Suppl 1):S52-9; 5. Ballinger R et al. ISPOR 2019; 6. Piamjariyakul U et al. Nurs Econ. 2010 Jul-Aug;28(4):255-63.

15

• 30% mortality after 5 years SBS patients on home PS3

• PN Complications impact long-term survival3Increased Mortality1,3

• Central venous access complications1,2

• Organ damage1,2

• GI complications1,2

Significant Morbidity1,2

• Significant reductions in patient QoL:4

• Negative QoL impact on caregivers5

Reduced Quality of Life1,4,5

• Average annual costs of chronic PS is $185-594k6

• Significant indirect costs from disability & lost productivity

Burden to the Healthcare System6

1

2

3

4

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• Decreased bacterial infection

• Decreased gut injury in chemically induced enteritis

• Modulation of intestinal microbiome

GLP-2 Pharmacological ActionsAn enteroendocrine tissue hormone produced by intestinal L cells

Actions are mediated by a distinct GLP-2 receptor expressed on subsets of enteric nerves and enteroendocrine cells in the stomach and small and large intestine

Preclinical data

GLP-2, Glucagon-like peptide 2; GI, gastrointestinal

Drucker DJ. Gastroenterology. 2002

• Improved intestinal adaptation after bowel resection

• Promoted nutrient and fluid absorption via expansion of the mucosal epithelium

↑ Enterocyte Proliferation

↑ Intestinal Barrier Function & ↓ Epithelial Damage

• Decreased meal-stimulated gastric acid secretion and GI motility

Enterocytes

GLP-2

Villus

Crypt

L-cells

Intestinal Stem Cells

Paneth Cells

Subepithelial Myofibroblasts

Enteric Nerves

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↑ Intestinal Blood Perfusion

↓ GI Motility

• Vascular-ischemia reperfusion injury, and dextran sulfate-induced colitis

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Apraglutide Rationally Designed to Have Enhanced PK/PDComparative peptide sequence of apraglutide to teduglutide and glepaglutide

PK, pharmacokinetic; PD, pharmacodynamic; GLP-2, Glucagon-like peptide 2; DPP-IV, dipeptidyl peptidase IV; SC, subcutaneous

Adapted from K Wisńiewski et al., J. Med. Chem. 2016, 59, 3129−3139

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Molecular class: Peptide, chemically synthesized

Chemical name: [Gly2, Nle10, D-Phe11, Leu16]hGLP-2 (1-33)-NH2

Structural formula: H-His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Nle-D-Phe-Thr-Ile-Leu-Asp-Leu-Leu-Ala-Ala-Arg-Asp-Phe-Ile-

Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-NH2 (Sodium salt)

The sequence of apraglutide contains one D stereoisomer-amino acid (D-phenylalanine) and two achiral amino acids (glycine).

All other amino acids are of L-configuration. Apraglutide is synthesized as a single enantiomer with all stereo-centers of defined chirality

Replacement of two asparagines, Asn11 by D-Phe11 and Asn16 by Leu16, causes a significant change in plasma protein binding and corresponding remarkable decrease in totalclearance. (K Wisńiewski et al.)

Replacement of Met10 by Nle10 provides enhanced chemical stability. (K Wisńiewski et al.)

The lower charge due to the amide group is thought to result in a more limited solubility, thereby slowing down the absorption from the SC injection site intothe circulation and increasing the terminal half-life.

Gly2 eliminates enzymaticcleavage by DPP-IV enzyme.(K Wisńiewski et al.)

AA Pos. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33

Native GLP-2 H A D G S F S D E M N T I L D N L A A R D F I N W L I Q T K I T D

Teduglutide H G D G S F S D E M N T I L D N L A A R D F I N W L I Q T K I T D

Glepaglutide H G E G T F S S E L A T I L D A L A A R D F I A W L I A T K I T D K

Apraglutide H G D G S F S D E Nle D-Phe T I L D L L A A R D F I N W L I Q T K I T D

Chemical

Name and

Structure

34+

OH

OH

K K K K K K NH2

NH2

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Apraglutide Possesses Differentiated Pharmacology (Half-Life)Pharmacokinetic comparisons vs. teduglutide and glepaglutide1

PK, pharmacokinetic; hGLP-2, human glucagon-like peptide 2

1. Hargrove et al. J Pharmacol Exp Ther. 2020 May;373(2):193-203; 2. Bolognani F et al. ESPEN 2020.

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Human

Rat

1

10

1,000

10,000

90 120

Pla

sm

aC

on

ce

ntr

ati

on

(ng

/ml)

60Time (min)

hGLP-2

Teduglutide

Glepaglutide

Apraglutide

100

300

Apraglutide

Half Life (T1/2) 70–72 hours2

Manufacturing Synthetic

PK supports weekly dosing

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Apraglutide Possesses Differentiated Pharmacology (Intestinotrophic)Greater efficacy on intestinal growth in head-to-head preclinical studies in rats

* = p< 0.05 vs corresponding vehicle control.

^ = p< 0.05 vs. corresponding apraglutide treatment group.

Hargrove et al. J Pharmacol Exp Ther. 2020 May;373(2):193-203

19

Daily Injection (24 hrs. Dosing Interval)Intestine weight 96 hours post 1st injection

Single InjectionIntestine weight 72 hours post injection

60

50

40

30

20

10

0

30 nmol/kg 300 nmol/kg

Sm

all

Inte

stin

e W

etW

eig

ht

(% in

cre

ase o

ve

rve

hic

le)

*

* ^ * ^

* ^

* ^

*

-10

0

10

20

30

30 nmol/kg 300 nmol/kg

Sm

all

Inte

stin

e W

etW

eig

ht

(% incre

ase o

vervehic

le)

*

^ ^ ^

* ^

*

Apraglutide Teduglutide Glepaglutide

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GLP-2 Activation by Apraglutide Significantly Increased Intestinal Mucosal Mass and Length

GLP-2, Glucagon-like peptide 2

1. Slim GM et al. JPEN J Parenter Enteral Nutr. 2019 Sep;43(7):891-898; 2. Data on File. VectivBio. Basel, Switzerland.

20

Saline Apraglutide

lnte

stin

ele

ng

th(c

m)

20

15

10

5

0

-5

-10

-15

Representative samples of jejunum from JC piglets (magnification = 20X)

ApraglutideVehicle

Mu

co

sa

l Ma

ss

(mg

/cm

)

210

190

170

150

130

110

90

Change in Intestinal Length

Change in Mucosal Mass

Histological observations of the jejunum in apraglutide-treated jejunostomy

piglets demonstrated elongated villi compared to control

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Methodology for Phase 2 Studies in SBSThe effects of GLP-2 on output assessed while input is maintained constant

SBS, short bowel syndrome; GLP-2, Glucagon-like peptide 2

21

Phase 2

Baseline 4 Weeks

Phase 3

Baseline 4 WeeksBaseline 4 Weeks Baseline 6 Months

Stable External Fluids

surface area

fluid absorption

Phase 2

Baseline 4 Weeks

Phase 3

Baseline 4 WeeksBaseline 4 Weeks Baseline 6 Months

Stable External Fluids

surface area

fluid absorption

After 4 Weeks

Phase 2

Baseline 4 Weeks

Phase 3

Baseline 4 Weeks

Urine Output

Stoma Bag Volume & Calories

Baseline

Phase 2

Baseline 4 Weeks

Phase 3

Baseline 4 Weeks

Stoma Bag Volume& Calories

Low Urine Output

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Apraglutide Phase 2: Once-Weekly Proof of Concept Achieved in SBSClinically relevant pharmacodynamic effects observed in ALL subjects at 5 mg/week

SBS, short bowel syndrome; SEM, standard error of mean

Eliasson J et al. Oral presentation at the American Society for Parenteral and Enteral Nutrition (ASPEN) Nutrition Science and Practice Conference on March 20-23, 2021. Virtual meeting. Abstract # 944900

22

Urinary Output Wet Weight Absorption Energy Absorption

0

200

400

600

800

1,000

Baseline End of Treatment

Ch

an

ge

fro

m B

as

eli

ne

, g

/da

y

Mean +/- SEM

0

200

400

600

800

1,000

Baseline End of Treatment

Ch

an

ge

fro

m B

as

eli

ne

, g

/da

y

Mean +/- SEM

0

250

500

750

1,000

1,250

1,500

Baseline End of Treatment

Ch

an

ge

fro

m B

as

eli

ne

, k

J/d

ay

Mean +/- SEM

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Apraglutide Studied in a Metabolic Balance TrialApraglutide demonstrated statistically significant increases in energy absorption with weekly dosing

*p=0.0374, **p=0.0150, ***p=0.0236

CFB, change from baseline; GLP-2, Glucagon-like peptide 2

1. Eliasson J et al. Clinical Nutrition ESPEN 40 (2020), 459; 2. Jeppesen PB et al. Gut. 2005 Sep;54(9):1224-31; 3. Naimi RM et al. EBioMedicine. 2019 Aug;46:444-451

23

Apraglutide1

5 mg ONCE-WEEKLY

Urinary Output (% CFB) 39.1%*

Wet Weight Absorption (CFB) 740.7 g/day**

Energy Absorption (CFB) 1,094.8 kj/day***

• Only GLP-2 to demonstrate robust absorption

enhancements after weekly dosing

• Only GLP-2 to demonstrate statistically

significant enhancement in energy absorption

in Phase 22,3

• Enhanced energy absorption could result in

better outcomes in patients

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SBS is Heterogeneous Based on Remnant Bowel AnatomyStoma and CIC patients have different responses to Gattex1

*As compared to placebo at six months in the phase 3 study

SBS, short bowel syndrome; PS, parenteral support

1. Jeppesen PB et al. Gastroenterology. 2018 Mar;154(4):874-885; 2. Company Phase 3 feasibility and CRA Market Research, Nov 2019 (U.S. and EU5).

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Stoma Colon-in-Continuity (CIC)

Prevalence2 ~45% of Patients ~55% of Patients

Anatomy No functional colon ≥50% of colon remaining

Absorption deficits Limited oral absorption of fluids Sufficient oral absorption of fluids

PS requirements Require large volume of PS consisting of fluids &

nutrientsRequire lower PS volume to deliver nutrients

• Stoma patients require more fluids in their PS because they cannot absorb water

• CIC patients require mainly ‘additional calories’ with an overall lower PS volume

Duodenum

Jejunocolonic

Anastomosis

Jejunum

Colon

Duodenum

Jejunum

Stoma(on abdominal surface)

Stoma Bag Adapted from: Jeppesen P et. al., Gastroenterology, 2018

Kishore Iyer, MBBS, FRCS, FACSDirector of Adult and Pediatric Intestinal Rehabilitation

& Transplantation at Mount Sinai Medical Center

SBS-IFLessons Learned in the GLP-2 Era:

Can We Improve Outcomes Further?

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• Scientific advisor (Pharma):

‒ VectivBio

‒ Zealand

‒ Takeda

‒ Hanmi

• Investigator (Pharma):

‒ VectivBio

‒ Takeda

‒ Zealand

• Grant support (Pharma):

‒ Takeda

‒ Zealand

Disclosure

26

R&D Day

*Based on N=85 (Gattex® (teduglutide) for injection. Prescribing Information)

PS, parenteral support

Jeppesen PB, et al. Gastroenterology. 2012;143:1473-1481

Teduglutide Phase 3 STEPS Study Design & Patient Characteristics

N=86

Remnant Bowel Anatomy n (%)*

Stoma

Colon-in-continuity

38 (45)

47 (55)

PS Dependence, mean (SD)

PS dependence, years

PS volume, L/week

PS infusion, days/week

6.3 (6.0)

12.9 (7.6)

5.8 (1.6)

PS stabilization

Teduglutide 0.05 mg/kg/day

Placebo

PS optimization

4–8 weeks0–8 weeks

Urine volume 1–2 L/day

24 weeks

27

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PS, parenteral support

Jeppesen PB, et al. Gastroenterology. 2012;143:1473-1481

Teduglutide Phase 3 STEPS Study Significant effect in Responder Rate analysis (primary endpoint)

Responders defined as patients with ≥20%reduction from baseline in weekly PS volume at Weeks 20 and 24

63%*

30%

0

10

20

30

40

50

60

70

Placebo (n=43)

Teduglutide 0.05 mg/kg/day(n=43)

Resp

on

ders

, % *P=0.002 vs placebo

Cochran-Mantel-Haenszel Test

• Primary endpoint defined as ≥20% reduction in weekly PS volume from baseline at both Weeks 20 and 24:

‒ Clinically meaningful to patients and physicians

‒ Reflects increased intestinal absorption

• Potential for 1 additional day off PS

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Teduglutide STEPS Phase 3 Retrospective Analysis (i)Response was driven by effects on PS volume reduction in stoma patients only

a. n=14 with data available; b. n=6 with data available; c. n=13 with data available.

TED, teduglutide; PBO, placebo; PS, parenteral support; SD, standard deviation; CIC, colon in continuity

Jeppesen PB et al, Gastroenterology. 2018 Mar;154(4):874-885

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Group 1

• Stoma anatomy • 0% colon remaining

Group 2

• Colon in continuity • ≥50% colon remaining• No stoma

Parameter TED (n=17)a PBO (n=16) TED (n=18) PBO (n=20)

PS volume % change from baselinemean (SD)

–40.3 (18.26) –18.8 (29.10)c –23.3 (15.84) –23.8 (22.23)

• While the study met its primary endpoint, the results were mostly driven by patients with stoma and high PS volume requirements at baseline

• 55.6% of patients treated with teduglutide had CIC, however, benefits in these patients were minimal

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Teduglutide STEPS Phase 3 Retrospective Analysis (ii)An increase in PS days off was observed in CIC patients

a. n=14 with data available; b. n=6 with data available; c. n=13 with data available.

CIC, colon in continuity; TED, teduglutide; PBO, placebo; PS, parenteral support

Jeppesen PB et al, Gastroenterology. 2018 Mar;154(4):874-885

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Additional days off PS per weekn (%)

Group 1

• Stoma anatomy • 0% colon remaining

Group 2

• Colon in continuity • ≥50% colon remaining• No stoma

TED (n=17)a PBO (n=16) TED (n=18) PBO (n=20)

≥1-day reduction at Week 24 6 (42.9) 2 (15.4)c 10 (55.6) 6 (30.0)

• CIC patients have higher likelihood of achieving clinically meaningful days off compared to stoma patients

‒ Days off PS and enteral autonomy are important to patients

• Enteral absorption must be considered along with urine volume in CIC patients

R&D Day

• 11/18 patients achieved enteral autonomy

‒ 1/3 (33%) stoma patients

‒ 10/15 (67%) CIC patients

Single Center Experience1

(N=18)

• 13/54 achieved enteral autonomy

‒ 2/19 (11%) stoma patients

‒ 11/35 (31%) CIC patients

French National Cohort Study2

(N=54)

Real-world data of GLP-2 in SBS-IF patientsEvidence that CIC patients could achieve higher rates of enteral autonomy with GLP-2 treatment

GLP-2, Glucagon-like peptide 2; CIC, colon in continuity

1. Lam K et al. JPEN J Parenter Enteral Nutr. 2018 Jan;42(1):225-230; 2. Joly F et al. Clin Nutr. 2020 Sep;39(9):2856-2862

31

R&D Day

Single-Center US Experience in Adult PatientsReal-world data supports benefit of GLP-2 in CIC patients achieving enteral autonomy

GLP-2, Glucagon-like peptide 2; CIC, colon in continuity; PS, parenteral support

Lam K et al. JPEN J Parenter Enteral Nutr. 2018 Jan;42(1):225-230

32

Baseline Characteristics of Patients on teduglutide

N = 18

Stoma 3

CIC 15

Median (range)

Age, years 47 (20–81)

Time between last bowel resection and

initiation of teduglutide, years4 (1–13)

Time on PS prior to teduglutide, months 36 (4–96 )

Weekly PS volume prior to teduglutide, L 9.9 (2.7–30)

PS calories prior to teduglutide, kcal/day 682 (0–1823)

Small bowel length, cm 55 (6–180)

• 16/18 decreased PS

‒ 11/18 (61%) patients achieved enteral

autonomy

▪ Total median duration of teduglutide

therapy prior to achieving enteral

autonomy was 10 months (range: 3–36)

▪ 10/11 patients with CIC

‒ 2/18 decreased PS volume by 50%

‒ 2/18 decreased PS volume by 20%

Results

R&D Day

French Real-world Experience

* Includes patients with ≥50% and <50% of colon in continuity

SBS, short bowel syndrome; PS, parenteral support; CIC, colon in continuity

Joly F et al. Clin Nutr. 2020 Sep;39(9):2856-2862

33

• Open-label, observational study (N=74)

‒ 15 sites in France allowed to prescribe teduglutide

‒ Retrospective analysis at 6 months

• Objective: To evaluate in a “real world setting” SBS cohort, predictive factors for response & weaning off PS

• Of 74 patients who initiated teduglutide treatment, 54 received ≥6 months of teduglutide treatment

Baseline Characteristics N = 54

Age, year (range) 52.3 (22–84)

Gender 22 F 32 M

Remnant Bowel Anatomy, n (%)

Stoma

CIC*

19 (35)

35 (65)

PS Duration, year (range) 9.8 (0.5–31)

Infusion per Week, days (range) 4.3 (2–7)

Volume of PS, L/week (range) 11.1 (2–38.5)

Energy from PS, Kcal/ week (range) 6747 (0–16800)

Remnant Bowel Length, cm (range) 61 (0–200)

R&D Day

French Real-world Experience with TeduglutideThe majority of patients weaned off PS had CIC anatomy

* Includes patients with ≥50% and <50% of colon in continuity

PS, parenteral support; SD, standard deviation; CIC, colon-in-continuity

Joly F et al. Clin Nutr. 2020 Sep;39(9):2856-2862

34

• 11/13 patients who weaned from PS had CIC

• Patients who weaned off PS had:

‒ Less PS volume requirement at baseline

‒ More oral intake at baseline

Analysis of predictive factors associated with weaning off PS at 24 weeks

among SBS-IF patients who received ≥6 months of teduglutide (N=54)

Weaned

n=13

Non-weaned

n=41

Bowel anatomy

Stoma, n (%)

CIC, n* (%)

2/13 (15)

11/13 (85)

17/41 (42)

23/41 (56)

Intestinal failure features

Basal PS volume, mean mL/day (SD)

Basal oral intake, mean kcal/day (SD)

738 (272)

2845 (787)

1867 (1253)

2294 (657)

R&D Day

Key Learnings from Past SBS ExperienceOpportunity to improve outcomes by considering an individual’s remnant bowel anatomy

SBS, short bowel syndrome; CIC, colon in continuity

1. Jeppesen PB et al, Gastroenterology. 2018 Mar;154(4):874-885; 2. Joly F et al. Clin Nutr. 2020 Sep;39(9):2856-2862

35

• Diuresis is a good marker of response in stoma patients

• Diuresis alone proved insensitive1 in CIC patients; enteral absorption must be considered2

Establishing Clinical Relevance

DiuresisEnteral

absorption

Consider individual remnant bowel anatomy

Diuresis

Stoma Colon-in-Continuity

Evaluating Efficacy

• PS volume reduction has greatest

therapeutic relevance in stoma patients

• Days off and enteral autonomy are the

therapeutic goals in CIC

R&D Day

Key Learnings for Future Apraglutide Study Design

GLP-2, Glucagon-like peptide 2; PS, parenteral support; SBS-IF, intestinal failure associated with short bowel syndrome

36

SBS is heterogeneous and encompasses a spectrum of anatomical diversity: stoma and CIC

Current experience with GLP-2 analogues focuses mostly on patients with stoma and high PS volume requirements

Post-hoc analysis and real-world data from teduglutide suggests remnant anatomy should be considered when assessing response to GLP-2 analogues

There is opportunity to individualize GLP-2 treatment and improve outcomes by considering an individual’s remnant bowel anatomy

Patients with CIC need to be better characterized

Goal of the apraglutide studies are designs that allow for more clinically meaningful results and captures responses in CIC patients

Nader Youssef, M.D., MBA, FACGSVP, Global Medical Affairs & Therapeutic Area Head, GI

SBS-IFSTARS Clinical Trials

R&D Day

STARS Study Design

Enrollment of 144 SBS-IF patients

Week 24

Primary endpoint: PS volume reduction

Secondary endpoints collected across all patients and by anatomy

Week 48

Secondary endpoints

collected by anatomy

Apraglutide (96 patients)

Placebo (48 patients) 2:1 randomization

Anatomy-specific randomization

Two dose arms: weekly placebo and apraglutide(2.5 or 5 mg depending on body weight)

Primary endpoint (week 24):PS volume reduction in overall population

Secondary endpoints (week 24 and 48):Common and anatomy-specific

Anatomy-specific PS reduction algorithm to best adapt PS requirements

1

2

3

4

5

6

First patient dosed January 2021; Topline results anticipated in 2H2023

Pivotal Phase 3 study in SBS-IF patients

Regulatory alignment obtained from FDA, EMA and PMDA on critical design elements

38

R&D Day

STARS Nutrition Study Design Metabolic Balance Study in SBS-IF patients with CIC anatomy

39

Up to 10 SBS-IF patients with CIC

Open label, baseline controlled

Weekly apraglutide (2.5 or 5 mg depending on body weight)

Primary objective: Calorie absorption increases at week 4 and 48

Secondary endpoint: PS volume reduction/enteral autonomy at week 48

1

2

3

4

5

0-1 4 28 52

MB MB MB

Week

Metabolic Balance

ObjectiveIntestinal

Absorption PS reduction and wean off

Apraglutide Treatment

OLE48

First patient dosed June 2021; Data from first 4 weeks of treatment anticipated in 1H2022

R&D Day

Apraglutide Potential Advantages

40

Improved:

• Efficacy

• Tolerability

• Convenience

Longer half-life

Potent intestinotrophic effects

Weekly dosing

Increased energy absorption

Pre-filled syringe

Omar Khwaja, M.D., Ph.D.Chief Medical Officer

Graft Versus Host Disease (GvHD)

R&D Day

• Emerges within the first 100 days post-transplant1,2

• Predominantly affects the skin, GI tract, and liver3,4

• Secretory and bile salt diarrhea, severe abdominal pain, increasing severe nausea1,3,4

• Malabsorption, weight loss, and need for parenteral support6

• Maculopapular skin rash1

• 30% mortality at 12-months in steroid refractory patients is driven by the severity of GI symptoms5

• Grades II, III, and IV have ~80%, ~25%, and ~5% survival rates, respectively7

Gastrointestinal GvHD is one of the leading causes of morbidity and mortality

Diagnosis

Symptoms

Outcomes

GI, gastrointestinal; GvHD, graft versus host disease

1. Goker H et al. Exp Hematol. 2001 Mar;29(3):259-77; 2. Filipovich AH et al. Biol Blood Marrow Transplant. 2005 Dec;11(12):945-56; 3. MacMillan ML et al. Biol Blood Marrow Transplant. 2002;8(7):387-94; 4. RowlingsPA et al. Br J Haematol. 1997 Jun;97(4):855-64; 5. Dignan Fl et al. Br J Haematol. 2012;158(1):30-45; 6. Naymagon S et al. Nat Rev Gastroenterol Hepatol. 2017 Dec;14(12):711-726; 7. Cahn JY et al. Blood. 2005 Aug 15;106(4):1495-500

Acute GvHD is a Life-Threatening Condition Resulting From Allogeneic Hematopoietic Stem Cell Transplant (HSCT)

Erosion/ulceration in patients with acute GI-GvHD7

© 2018 Ohwada et al.

42

R&D Day

More than 27,000 Allogeneic HSCT take place in US and Europe yearlyAcute GVHD occurs in 50% of patients of whom half will become steroid-refractory

* Calculated based on 50% of allogeneic transplants developing aGvHD

HSCT, hematopoietic cell transplants; 1. Gratwohl A et al. Lancet Haematol. 2015 Mar;2(3):e91-100; 2. World Health Organization. https://www.who.int/transplantation/hsctx/en/. Accessed on Dec 18, 2020; 3. D'Souza A et al. Transplant. 2020 Aug;26(8):e177-e182; 4. Baldomero H et al. EBMT activity survey 2018; 5. Jacobsohn DA, Vogelsang GB. Orphanet J Rare Dis. 2007 Sep 4;2:35; 6. Martin PJ et al, Biol Blood Marrow Transplant 2004; 10:320–327; 7. Martin PJ et al. Biol Blood Marrow Transplant. 2012;18(8):1150-1163; 8. Dignan FL et al . J Haematol. 2012;158(1):30-45; 9. MacMillan ML et al. Biol Blood Marrow Transplant. 2002;8(7):387-394; 10. Schoemans HM et al Bone Marrow Transplant. 2018;53(11):1401-1415.

43

R&D Day

SR aGvHD is Associated with High Mortality Durable overall responses and failure-free survival remain areas of unmet medical need

Figures adapted from R Zeiser et al. N Engl J Med 2020;382:1800-1810.

SR aGVHD steroid refractory acute graft versus host disease

Ruxolitinib for Glucocorticoid-Refractory

Acute Graft-versus-Host Disease

N Engl J Med 2020; 382:1800-1810

Robert Zeiser, M.D., et al., for the REACH2 Trial Group*

44

Prof. Dr. Robert ZeiserHead of Tumor Immunology and Immune Modulation

at the University Medical Center Freiburg

GvHDA Potential New Approach for GvHD:

Modulation of GI GvHD with GLP-2

R&D Day

• Tissue damage mediated by donor T cell responses and inflammatory cytokine

• Recipient intolerance of donor cell due to downregulation or inhibition of recipient Treg cell and upregulation of the recipient TEFF cell

• Immune activation due to dysfunction in recipient antigen-presenting cells

Compromised intestinal epithelium

Immune dysregulation leads to compromised:

• intestinal stem cells• Paneth cells• goblet cells

Gut Microbiota Imbalances

Altered microbiota composition due to:

• conditioning regimens• broad-spectrum antibiotics• immunosuppressants• foreign grafted lymphocytes

Mucosal Barrier Disturbance

Leads to failure of fluid resorption, particularly in the ileum and bacterial

translocation into the systemic circulation

• Osmotic diarrhea due to mucosal cell destruction, compromised brush border tight junctions, and substantial mucosal protein loss

• Bile salt diarrhea due to inflammatory-cell-mediated destruction of apical bile salt transporters in the ileal brush border and bile acid malabsorption

GI Tract is One of the Primary Tissue Systems Damaged in Acute GvHDPlays a major role in the initiation and amplification of systemic immunological reaction driving GvHD

GvHD, graft versus host disease; Treg , regulatory T cell; TEFF, effector T cell

Ghimire et al. Front Immunol. 2017 Mar 20;8:79

• Loss of microbiome diversity early after HSCT has been recognized as a new risk factor for GvHD and HSCT-related complications

46

R&D Day

Pathophysiology of Acute GvHDDamage to the host tissues leading to release of inflammatory cytokines

GvHD, graft versus host disease

Ghimire et al. Front Immunol. 2017 Mar 20;8:79

• Conditioning regimen cause profound

damage to the host tissues leading to

release of inflammatory cytokines,

activating host antigen-presenting cells

(APCs)

• Loss of microbial diversity and

metabolites leads to loss of epithelial

and immune homeostasis.

• Host APCs activate mature donor T

cells present in stem cell inoculum

• T cells proliferate and differentiate

• Activation of CD4 cytotoxic T

lymphocyte (CTL), CD8 CTL, and

natural killer cells that mediate tissue

damage

• Effector T cells & pro-

inflammatory cytokines attack

the epithelial cells of skin, liver,

lung, and GI

• Damage is further supported by

the lipopolysaccharide (LPS)

that has leaked through

damaged intestinal mucosa

• Myeloid cells recruited to

further produce pro-

inflammatory cytokines and

thus enhance the cytokine

storm

47

R&D Day

Proinflammatory events and intestinal repair mechanisms in GvHD

GvHD, graft versus host disease

Zeiser R, Blazar BR. N Engl J Med. 2017;377(22):2167-2179

48

R&D Day

Histologic Severity of Clinical GvHD in the GI Tract Categorized by the Degree of Crypt Damage

GvHD, graft versus host disease; GI, gastrointestinal

1. Salomao M et al. J Clin Pathol. 2016 May;145(5):591-603; 2. Ferrara JLM, Chaudhry MS. Hematology Am Soc Hematol Educ Program. 2018;2018(1):221-227

• The lamina propria inflammatory infiltrate is typically sparse and consists primarily of mononuclear cells, although scattered eosinophils and neutrophils may be seen1

• Identification of this focal periglandular inflammation in the colon may be helpful in directing the search for apoptotic bodies1

Grade Degree of Crypt Damage

1 Isolated apoptotic epithelial cells, without crypt loss

2 Loss of isolated crypts, without loss of contiguous crypts

3 Loss of 2 or more contiguous crypts

4 Extensive crypt loss with mucosal denudation

49

R&D Day

L-Cells are a Target of GvHDChemotherapy, total body irradiation, and GvHD affect L-cells

GvHD, graft versus host disease; GLP-2, glucagon-like peptide 2

1. Sale et al. Am J Surg Pathol. 1979; 2. Epstein et al. Gastroenterology. 1980; 3. Eriguchi et al. Biol Blood Marrow Transplant. 2013; 4. Hanash et al. Immunity. 2012.

Mucosal growth

Reduction of Intestinal inflammation

Reduce apoptosis of enterocytes

L-Cells produces GLP-2 which

Promotes:Chemotherapy or total body irradiation

GvHD

Enterocytes

Villus

Crypt

L-cells

Intestinal Stem Cells

Paneth Cells

Enteric Nerves

50

R&D Day

Role of Paneth Cells in Maintaining Barrier and Antimicrobial FunctionPaneth cells compromised with GvHD

GvHD, graft versus host disease; GLP-2, glucagon-like peptide 2

Serody J. Blood. 2012 Jul 5;120(1):6-7

1. Paneth cells generate antimicrobial peptides in response to bacterial products

2. T-cell immune response leads to loss of Paneth cells, inhibiting antimicrobial peptide

generation leading to bacterial translocation across the mucosa into the systemic

circulation

3. Paneth cell destruction leads to the release of RegIII, which serves as a marker for the

presence of GvHD

Paneth Cell

Antimicrobial Peptides

Systemic Circulation

Crypt Lumen

Bacteria

BacterialProducts

Enterocytes

Villus

Crypt

L-cells

Intestinal Stem Cells

Paneth Cells

Enteric Nerves

51

R&D Day

Results suggested potential use of GLP-2s in the treatment of steroid-resistant aGvHD

Teduglutide, reduced de novo acute GvHD and steroid-refractory GvHD, with no compromising effects on graft-versus-leukemia, an important finding to support clinical studies

Prophylaxis and Treatment Evidence

GLP-2: a potential new approach that aims at protecting and regenerating Paneth cells and intestinal stem cells GLP-2 have promising preclinical rationale to suggest a role in the prevention or treatment of aGvHD

GLP-2, glucagon-like peptide 2; aGvHD, acute graft versus host disease; allo-HSCT, allogeneic hematopoietic stem cell transplant

Norona et al. Blood 2020

Mice treated with teduglutide on day -3 to +3 relative to allo-HSCT demonstrated a lower

GvHD-related mortality vs controls

GLP-2 protected and promoted regeneration of Paneth Cells and intestinal stem cells, which enhanced production of antimicrobial peptides and caused microbiome changes

Mice treated with teduglutide + prednisolone showed lower severity of aGvHD

GLP-2 expanded intestinal organoids and reduced expression of apoptosis-related genes

52

R&D Day

GvHD Results in Decreased Endogenous GLP-2 LevelGLP-2 is an enteroendocrine tissue hormone produced by intestinal L cells

GLP-2, glucagon-like peptide 2; GLP-2+ L-cell, L-cells containing endogenous GLP-2; syn-HCT, syngeneic hematopoietic cell transplantation

Norona et al. Blood 2020

• The number of GLP-2+ L-cell was significantly lower:

‒ When mice developed acute GvHD

‒ In mice that received allo-HCT vs. syn-HCT indicating that the

decrease in L-cell numbers was due to GvHD

‒ In mice developing acute GvHD after chemotherapy conditioning

Mice Colon Sections on Day 10

53

R&D Day

GLP-2 Treatment Reduces GvHD-induced Loss of Paneth Cells

GLP-2, glucagon-like peptide 2; GvHD, graft versus host disease; allo-HSCT, allogeneic hematopoietic stem cell transplant

Norona et al. Blood 2020

• Paneth cells are a target of GvHD

‒ Lysozyme1 Paneth cells

decrease upon GvHD induction

• Paneth cell preserved when mice

were treated with teduglutide

Representative immunohistochemistry staining for the Paneth cell marker, lysozyme (red), in small intestine from allo-HCT BALB/c mice on day 10. Mice treated with vehicle or teduglutide were compared with untreated controls. Mice were treated with teduglutide or vehicle.

54

R&D Day

Initial Clinical Proof-of-Concept Achieved With GLP-2Clinical signs of intestinal GvHD improved in all 6 patients with a decline in diarrhea frequency

GLP-2, Glucagon-like peptide 2; aGvHD, acute graft versus host disease

1. Norona et al. European Society for Blood and Marrow Transplantation Conference, March 2021, Abstract OS9-1 and oral presentation.

Clinical Findings of GLP-2 in aGvHD1

Methods:

• N=6

• Steroid-refractory aGvHD

• Failed multiple therapies – 5 of 6 patients on ruxolitinib + steroids

• Once daily dosing of teduglutide for 10 days

Findings:

• Clinical signs of intestinal GvHD improved in all 6

patients with a decline in the frequency of diarrhea

• Serum albumin levels increased in all patients, a

parameter indicating a positive impact on patients’

nutritional status

Change in Stools Per Day Change in Albumin

Normal range:3.5 – 5.5 g/dL

55

GvHDApraglutide Development in aGvHD

Omar Khwaja, M.D., Ph.D.Chief Medical Officer

R&D Day

Apraglutide, a Novel Regenerative Medicine ApproachCompelling preclinical data support the therapeutic potential in aGvHD

Source: Data on file. VectivBio. Basel, Switzerland.TBI: Total Body Irradiation; BMT: Bone Marrow Transplant; Gy: Gray (unit)

0

20

40

60

80

100

5 6 7 8 9 10 11 12 13 14

Su

rviv

al

(%)

Days Post-Transplant

TBI Only

TBI/BMT + Vehicle

TBI/BMT + apraglutide

Apraglutide Reduced Mortality Apraglutide Prevented GI Damage

TBI (8.5 Gy)/BMT + vehicle TBI (8.5 Gy)/BMT + apraglutide

TBI-BMT Model (7.0 Gy)

5/5

4/10

0/10

Preclinical Findings of Apraglutide

57

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Apraglutide in Animal Model of Melphalan-Induced Intestinal DamageThe addition of apraglutide preserved plasma level of citrulline at normal level

Data on File. VectivBio

58

• Increased weight of duodenum, ileum, and jejunum were observed

• In surviving animals treated with apraglutide, examination revealed the absence of melphalan-induced morphological changes of the small intestine

• There was a marked difference of the intestinal morphology between early-euthanized and surviving animals, suggesting that the improvement of survival of the mice was tightly linked to the preservation of the physical integrity and overall function of the intestinal mucosa

Species: BALB/c miceMelphalan: 17.5 mg/kgApraglutide: 3.3 mg/kg

R&D Day

Apraglutide in Animal Model of Cytarabine-Induced Intestinal DamageMaintenance of serum citrulline level suggested protective effect of apraglutide on intestinal

structure

Data are shown as treatment group Mean±SEM. N=3 per treatment group

Data on File. VectivBio

59

• In parallel to the decrease of the body weight, animals treated only with cytarabine/vehicle showed a significant decrease in serum citrulline

• When the animals also received apraglutide, a significantly smaller serum citrulline level decrease was observed suggesting a protective effect of apraglutide on intestinal structure

Species: Balb/c miceCytarabine: 30 mg/kg BIDApraglutide: 0.11 to 1.1 mg/kg

* Significant difference relative to vehicle only control animals

# Significant difference relative to the cytarabine/vehicle-treated animals

R&D Day

VectivBio GvHD ProgramPhase II dose-finding study in patients with steroid-refractory acute GvHD on best available therapy

*best available therapy defined as glucocorticoids and ruxolitinib

60

First patient dosed Q1 2022 Interim data Q4 2022

Dose level 1

Dose level 2

Apraglutide

up to 90 days treatment

External control

Study Objectives

Safety and Tolerability; PK; Response at days 28, 56, 90 and 180• Double-blind externally-

controlled dose-dose

finding study

• Patients aged 12 years

and older

• Steroid-refractory acute

GI-GvHD

• on best available therapy*

Follow up to 2 years

CoMETInherited Metabolic Diseases

Omar Khwaja, M.D., Ph.D.Chief Medical Officer

R&D Day

• Genetic loss of key enzymes required for cellular metabolism

• Failure of energy production and accumulation of toxic metabolites

• 1 in 800 births

• Diagnosed in infancy

• Recurrent metabolic crises

• Coma and high risk of death

• Progressive organ damage

• Brain

• Heart

• Kidney

• Liver

• Impaired growth and severe neurodevelopmental delay

Inherited Metabolic Diseases Are Severe, Life-threatening Genetic DisordersEnzymatic defects result in common pathophysiology and clinical presentation

Yang, L., Guo, B., Li, X. et al. Brain MRI features of methylmalonic acidemia in children: the relationship between neuropsychological scores and MRI findings. Sci Rep 10, 13099 (2020).

Inherited Metabolic Diseases (IMDs)

Clinical Presentation

• No approved treatments

• Intensive care, supportive and dietary management, liver or kidney transplant in selected cases

62

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IMDs Fall into Groups that Share Common Affected Pathways Enzyme deficits impair substrate metabolism and coenzyme A (CoA) functionality,

with widespread downstream impact

OTC: ornithine transcarbamylase

MCAD: medium chain Acyl-CoA dehydrogenase

PK: pyruvate kinase

63

R&D Day

Intracellular Delivery of Stabilized Pantetheine with CargoCargo addresses deficiency in specific cluster of metabolic disorders such as MMA and PA

Provide key intermediates to Kreb’s cycle and

fuel energy production

Prevent compensatory

catabolism

Provide CoA for multiple essential

metabolic pathways

Restore correct processing and

avoid build up of toxic metabolites

3

4

Cargo

Pantetheine/Free CoA

Cargo-CoA

Pantetheine + Cargo

1

2

64

R&D Day

• Can enter cells and replenish CoA

• Unstable

• Rapidly cleaved by Vanin-1 to generate toxic cysteamine

• Enhanced stability with systemic exposure

• Labelled molecule integrates into CoA biosynthesis

• Can carry conjugated cargos into cells

CoMET Platform Designed to Address Clusters of IMDs by Providing CoA Precursor and Disease-relevant CargosProprietary chemistry based on a stabilized pantetheine backbone

P1, P2: Proprietary protective/stabilization modifications

Can carry up to 3 conjugated cargos per pantetheine backbone

PantetheineStabilized CoA

precursor backboneCargo Molecule Targeted IMDs

Succinate VB-1197 Organic acidemias

Undisclosed VB-1200 Urea cycle disorders

Undisclosed VB-1300Fatty acid oxidation disorders

Undisclosed VB-1400 Amino acidopathies

P1 P2 Broad Intellectual Property portfolio with projected

Composition of Matter protection to at least 2040

65

R&D Day

Methylmalonic and Propionic Acidemia are IMDs with Very High Unmet NeedInherited, life-threatening or fatal disorders of branched chain amino acid metabolism

66

Reduced Succinyl-CoA production

impairs Kreb’s cycle function

Reduced Acetyl-CoA impairs metabolic

flux

Toxic organic acid build upCompensatory GABA and glutamine

catabolism impairs CNS function

• Prevalence 15 in 100,000 newborns

• Infantile form:

• fulminant metabolic acidosis

• hyperammonemia,

• liver and bone marrow failure

• encephalopathy and coma

• Chronic intermittent form:

• recurrent life-threatening crises

• developmental delay,

• neurocognitive impairment

• impaired growth

• kidney failure

• Mortality of 40% before age 18 years

• Major disability in adult survivors

• Treatment supportive, strict dietary management, liver and kidney

transplantation

MMA and PA

1

2

2

3

4

4

1

2

3

4

R&D Day

Simple primary screen can identify compounds capable of restoring metabolic processesAssay measures increase in cellular respiration in disease-relevant patient fibroblasts

Source: Data on file. VectivBio. Basil, Switzerland.

Patient derived fibroblast cells (1. Methylmalonic acidemia; 2. Propionic acidemia; 3. Glutaric aciduria type 1) were treated with 10 uM of VB compounds and assayed using the Seahorse XF assay protocol

Respiration in MMA Patient

Fibroblasts1

Strong Potentiation of Cellular Respiration Across Patient Cells from Multiple Organic Acidemias

67

R&D Day

CoMET Platform Demonstrated Restoration of Intracellular Metabolism after Systemic Administration Incorporation and correction of biochemical abnormalities in animal models

Source: Data on file. VectivBio. Basil, Switzerland.

1. Stabilized pantetheine was labelled with deuterium to and administered to Vitamin B5 deprived WT mice (n=4-5/treatment group) either IV or PO. Whole organs were harvested and labelled vs. endogenous CoA was measured via mass spectrometry

2. MMUT knock-in mice (Forny P et al; J Biol Chem. 2016 Sep 23; 291(39): 20563–20573) were used as a model of MMA. Mice (n=2-4/treatment group) were administered VB-1056 (1, 10, 50 mpk) for 113 days (QD) via intraperitoneal injection. Whole organs were harvested and metabolites were measured via mass spectrometry

D6 labelled stabilized

pantetheine in vivo1

Endogenous CoA

Labelled CoA

Improvement in liver

metabolism in mouse model

of Methyl Malonic Acidemia

(MMA) with stabilized

panthetheine + cargo2

Compounds

incorporated

Into all relevant

organs

Compounds

correct metabolic

defects

Increases Levels of Functional CoA Decreases Levels of Toxic Metabolites

Liver Acetyl-CoA Liver MMA

Liver Heart Brain (Cerebellum)

68

R&D Day

Addressing Unmet Needs of Patients Suffering from IMDsCoMET platform has potential to deliver effective systemic therapies for many patients

Desired Goal Organ Transplant Gene Therapy Vision for CoMETPlatform

Broad patient eligibility

Highly selected patients Specific to one genetic defectNo pre-existing immunity to vector

Efficacy across diseases with similar metabolic deficits

Systemic benefit Transplanted organ only Targeted tissues only Systemic efficacy

SafetyImmunosuppression, infection risk

Integration, immunogenicity Large therapeutic index

Sustained efficacy Lasting effect for life of organDuration of effect unknownImmunogenicity prevents re-use

Efficacy maintained by chronic oral or subcutaneous therapy

• Current management aims to manage and prevent metabolic crises through general supportive measures

and strict dietary control

• An ideal therapy would address intracellular metabolic defects in all tissues and for all patients

69

R&D Day

CoMET Platform Aims to Transform the Treatment of IMDsModular approach to address a broad range of severe metabolic disorders

a. Villani GR et al. Clin Exp Med. 2017 Aug;17(3):305-323; b. Brusilow SW, Horwich AL. Urea cycle enzymes. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds.). The Metabolic and Molecular Bases of Inherited Disease, 8th ed., New York: McGrawHill, 2001:1909–1963; c. Marsden D et al. Genet Med. 2021 May;23(5):816-829; d. Wasim M et al. Biochem Genet. 2018 Apr;56(1-2):7-21

Patients in US & EU

26,000a

26,000b

16,000c

8,000d

FIH Q1 2023

Discovery Preclinical Phase 1

Methyl Malonic and Propionic Acidemia

Other Organic Acidemias

Urea Cycle Disorders

Fatty Acid Oxidation Disorders

Amino Acidopathies

Molecule

VB-1197

VB-1200

VB-1300

VB-1400

Strong development synergies support a potentially transformative, fast-to-patient portfolio

• Modular platform to deliver series of molecules that each address multiple IMDs

• Common pathophysiology and clinical endpoints allow for umbrella and basket trials

• Diagnosis through newborn screening and supported by existing clinical guidelines

• Biochemical endpoints allow rapid biomarker-enabled drug development with small, seamless trials

• Patients treated at specialist metabolic medicine units with center-of-excellence model for delivery and care

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Conclusion

Luca Santarelli, M.D.CEO & Founder

R&D Day

Building a Fully Integrated Global Rare Disease CompanyMultiple near-term catalysts

Transformative CoMET platform

Designed to address pre-

viously intractable IMDs

4 programs in research, plans to enter the clinic in 18 months

ExperiencedTeam

Apraglutide,a Compelling Phase 3 Asset

SBS-IF, an underserved >$2B market opportunity

Significant life-cycle potential starting with GVHD

Strong track record of success

2021 2022 2023

Key Catalysts

Adult SBS-IF:

-Phase 3 Start: Jan

-Phase 2 Start: Q2

CoMET

-Entry into human trials: Q1

Adult SBS-IF

-Phase 3 Top-Line Results: H2

Pediatric SBS-IF

-Trial Initiation: 2023

Adult SBS-IF CIC

-STARS Nutrition Results: H1

Acute GVHD

-Phase 2 Start: Q1

-Interim POC read out: H2

✓

✓

BD transaction-

achieved

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VectivBio AGAeschenvorstadt 364051 BaselSwitzerlandIR@vectivbio.com

Thank You

We are on a mission to build a leading, fully integrated global rare disease company using our patient-centric approach to

identify and develop transformative medicines for the treatment of severe rare diseases.