NON – CONFIDENTIAL

Sosei Heptares R&D Day
October 2022 | Sosei Group Corporation (TSE:4565)

Disclaimer
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unforeseen safety issues resulting from the administration of our products in patients, uncertainties related to product manufacturing, the lack of market acceptance of our products, our inability to manage growth, thecompetitive environment in relation to our business area and markets, our inability to attract and retain suitably qualified personnel, the unenforceability or lack of protection of our patents and proprietary rights, ourrelationships with affiliated entities, changes and developments in technology which may render our products obsolete, and other factors. These factors include, without limitation, those discussed in our public reports filedwith the Tokyo Stock Exchange and the Financial Services Agency of Japan. Although the Company believes that the expectations and assumptions reflected in the forward-looking statements are reasonably based on
information currently available to the Company's management, certain forward looking statements are based upon assumptions of future events which may not prove to be accurate. The forward looking statements in thisdocument speak only as at the date of this presentation and the company does not assume any obligations to update or revise any of these forward statements, even if new information becomes available in the future.
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References to "FY" in this presentation for periods prior to 1 January 2018 are to the 12-month periods commencing in each case on April 1 of the year indicated and ending on March 31 of the following year, and the 9 month
period from April 1 2017 to December 31 2017. From January 1 2018 the Company changed its fiscal year to the 12-month period commencing in each case on January 1. References to "FY" in this presentation should beconstrued accordingly.
© Sosei Group Corporation. Sosei Heptares is the corporate brand and trademark of Sosei Group Corporation. Sosei, Heptares, the logo and StaR® are trademarks of Sosei Group companies.

2

AgendaThursday 22 October 2022 15:30 to 17:30

1. Business Overview and Update
Chris Cargill, CEO

2. Key Partnered Programs and Platform Technologies
Dr. Matt Barnes, President of Heptares and Head of UK R&D

3. Priority Wholly-owned Programs
Dr. Rie Suzuki, Senior Director, Translational Biology

4. Q&A3

1
Business Overview and Update
Chris Cargill, CEO

4

The vision for Sosei Group
LONG-TERM
FOCUS

NEAR-MID TERM
FOCUS

WORLD-LEADING SCIENCE
LIFE-CHANGING MEDICINESWESTERN INNOVATIONWorld-class scientific platform,
discovering life-changing
medicines

5

JAPANESE QUALITY
Science-led development
and engagement,delivering innovative medicines
to patients

Clear and transparent objectives to drive the business forward
1

MID-TERM
FOCUS

NEAR-TERM
FOCUS

TRANSFORM
TO TRANSLATIONAL MEDICINE-LED,
PROGRAM-CENTRIC R&D

3

LONG-TERM
FOCUS

ACTIVATE
THE JAPAN PHARMA
BUSINESS UNIT

ENHANCEGROUP STRUCTURE AND
OPERATIONAL EFFICIENCY✓ SCIENCE-LED✓ PATIENT-FOCUSED✓ PROGRAM-ORIENTED

LONG-TERM
FOCUS

EXPAND
TO NEW GEOGRAPHIC
MARKETSWorld-leading science. Life-changing medicines.

6

2

4

What do we mean by transforming to TM-led R&D?

1

Choosing
the right target

Discoveringa therapeutic agent

Conducting
the right patient studies•

Will modulating the target
affect disease?

•

Identifying a modulator withthe appropriate profile•

Demonstrating the value ofthe agent in treating disease•

Can a good modulator of thetarget be found?

•

Differentiating fromcompetitors (if any)•

Utilizing biomarkers to
support patient stratification

The Right Target

The Right Asset

The Right Therapeutic Hypothesis

Driven by programs, and requiring close interaction of internal and external subject matter experts

7

NEAR-TERM
FOCUS

Transforming to TM-led R&D to enhance value and successTraditional

1

Scarcityof drug
discovery

Preclinicaldevelopment

Phase II

FED

FHD

CS

Quick win, Fast fail

Phase I

Phase IIIPD

Launch

•••••Traditional approach (10+ years)
Increasingly unproductive
Capital intensive, billions of $ wasted
Focus on “keeping the program alive”
Low probability of success••

Increase critical information earlier
Shift program attrition to earlier,cheaper phase
Faster attrition drives reinvestment in
R&D ‘sweet spot’ for new programs•
Abundanceof drug
discovery

Preclinicaldevelopment

POC

Confirmation,dose finding

Higher p(TS)
PD

CS

FHD

Translational Medicine
R&D ‘Sweet Spot’

Launch•••••Venture Capital approach
Highly productive, “quick-win/fast-fail”
Optimized use of capital
Focus on “testing the hypothesis”
Higher probability of technical success

Quick-win/fast-fail approach may enhance value by improving the probability of technical success
Source: Adapted from Owens et al. (2015), Nature Reviews Drug Discovery

8

NEAR-TERM
FOCUS

NEAR-TERM
FOCUS

Transforming to TM-led R&D to transact at higher values

1

CORPORATE VALUEPARTNERSHIP VALUE
Program-centricTranslational
Medicine(“TM”)TS + ClinDev
Drug
Discovery
StaR®

Platform

2007 – 20142015 – 2022

Avg. Total Future "Biobuck" Value
Avg. Upfront Cash Receipt

Drug
Discovery

$400m

9

$100m+$180m

Platform$5 – 10m

2022 – 2030

Discovery$10 – 20m

Pre-Clin/Phase I

Building our Translational Medicine capability to support the next 10 years of growth
Source: Management figures$1–3bnPh II/POC

Transforming to program-centric R&D to drive productivity

1

PROGRAMCENTRIC

Function

Empowered leaders and team structureswith aligned incentives

Programs accountable for R&D budget, risk
management & project plans
Functions exist to support programs

Traditional functional reporting lines structures kill productivity. Program-centricity drives productivity

10NEAR-TERM
FOCUS

Enhance the group structure and operational efficiency more
rapidly by building a disruptive virtual infrastructure2

Traditional pharma model

MID-TERM
FOCUS

Disruptive, “virtual infrastructure” pharm model (illustrative)

Pharma company
R&D (incl. CMC, Pre-clinical& Clinical operations)
Regulatory & pharmacovigilance
Pricing and market accessGovernment affairs
Medical
Sales
MarketingCommercial
Supply Chain

BD
HR
IT
Legal

Source: Management

11

CSO
CRO

CRO

MedicalR&D (incl. CMC, Pre-clinical& Clinical operations)
Regulatory &pharmacovigilance

CSO
3PL

Sales & Marketing(Commercial)
HQ function(BD, HR, IT, Legal)

3PL
Supply chain• Big pharma companies often havehigh in-house infrastructure and fixed
costs• Higher reliance for mid to small
pharma to leverage externalorganizations

CSO or Strat.
partnership w/
pharmaFunctional leads from
R&D, Medical, Sales & marketing,Commercial, P&MA

Consultancies
Pricing and market accessGovernment affairs

CDMO
Manufacturing
Traditional “core” capabilities
that can be virtualizedCollaboration with Weatherden is enhancing efficiency byenabling us to flexibly access scientific and strategic services

2

MID-TERM
FOCUS

Weatherden Science & Strategy Services
Focused on translation into patients

Scientific strategy

Indication selection
Asset positioning
Competitive
landscape

12

Clinical development

Trial design
Patient Stratification
Early Efficacy signals

Regulatory expertise

Regulatory strategy
Lead/support regulatory
meetings (e.g. EMA, MHRA,
FDA)
Orphan Drug Designation
Paediatric Investigation Plans

Scientific advisory boards

World-leading experts
Key questions
Clear advice

Long-term plan to activate a late-stage pipeline that will
benefit Japanese patients living with unmet need3

PRECLINICALEARLY CLINICALLATE STAGE CLINICAL

UK

Advance selected
HTL programs forJapan patients

Japan

P

P

LONG-TERM
FOCUS

COMMERCIALPP

Retain Japan
territory rights

GlobalPartners/“SpinCos”

When we partner…

In-license innovative medicines in areasof high unmet need from global partners

We are a Japanese company with a priority to deliver innovative medicines to patients in Japan and globally
Source: Sosei management

13Several key factors support our long-term plan to activate a
disruptive pharma business in Japan

3

1

Second largest pharma market globally (ex-China) and
expected to remain large

2

Large, ageing population driving sustained demand andability-to-pay

3

Universal health care system sets a certain level of prices

4

Stable and pro-innovation market driven by innovative
specialty drugs

5

Weak incumbents creating opportunities for insurgents6

Attractive market for disruptors validating existence ofopportunities

Source: L.E.K. analysis

14

There is room in Japan to be a
disruptive player:
1 Focusing on underserved,
specialty TAs/DAs
2 Adopting a lean, rational
development andcommercial model
3 Building a core in Japan thatmaximizes value from acrossthe broader APAC region

LONG-TERM
FOCUS

Expand to new geographies in APAC which consist ofdeveloped and developing markets with a critical mass of patients

LONG-TERM
FOCUS

4Pharmaceutical market size of APAC and major markets(2021)
Billions of USD

580
85

Overall APAC (ex-China) pharma market
size is c. $70 B, comparable to a major
market if treated as a singular market

69
65

42
37

14
4
PH

7

VN

9

ID

7

6

TH

2

1

MY

SG

Note: *China and small APAC markets are not included
Source: BMI; IQVIA; World Bank; Taiwan Ministry of Health and Welfare

15

18

AU

KR

TW

APAC*

US

JP

DE

FR

UK

2
Key Partnered Programs andPlatform Technologies
Dr. Matt Barnes, President of Heptaresand Head of UK R&D
16

2-1
R&D Key Events Summary

17

Key event summary - March -> September 2022
March
Strategic Collaboration with
Weatherden announced

April
May

Kallyope collaboration announced

R&D expansion to the Cori BuildingMay
BD BIO International Conf – San Diego

June
Scientific Advisory Board

June
CRUK EP4 Ant agreement signed

July*FDA accepted IND for M4 Ag –progressing into Ph2

AugustAbbVie multi-target
neuroscience collaboration

AugustInforma Pharma Intelligence Awards Japan –Transaction of the Year and Executive of the Year

September
October

18

Sosei Heptares Confirms Senior Leadership Changes to
Drive the Company Through the Next Stage of its
Evolution

Sosei Heptares to host R&D Day

2-2
R&D Operations Update

19World leading drug discovery targeting GPCRs
There were lower number of milestone events until end of June, compared with FY21
World leader in
GPCR drug discovery
and early development

EVOLVING WITH A SPECIALISTTHERAPEUTIC FOCUS
Advancing a broad and deep
pipeline of over 40 partneredand in-house programs acrossmultiple therapeutic areas:

Proprietary GPCR-targeted
StaR® technology and SBDD
platform capabilities

Neurology
Immunology
Gastroenterology
Other

Japan-anchored biotech, withstate-of-the-art R&D centre in
Cambridge, UK
Listed on Tokyo Stock Exchange(4565-JP)

8%
34%
29%

200+

350+

500+

20+

$800M+EMPLOYEESWORLDWIDESTRUCTURESSOLVED

GLOBALPATENTSWORLD-LEADINGPARTNERSPARTNER REV.
RECEIVED TO DATE1

1 Includes upfront and milestone payments, royalties and R&D funding received from active, inactive and completed partnerships from 2005 to 2021.

20

29%

Stabilized Receptor (StaR®) platform
We are driving a new era of GPCR Structure-Based Drug Design

Unstable
nativereceptor

DRUG TARGET PROFILESCREENING

ITERATIVE MUTAGENESISBIOPHYSICSTHERMOSTABILITYSTRUCTURE

PHARMACOLOGY
CHARACTERIZATION• GPCR drug discovery remains challenging
•

•

•

21

Low expression levels – often withcomplicated expression and secretion
pathways
Difficult purification – lose structural integrity
outside the membrane

Heterogeneity – inherently flexible; changing
conformation depending on the bound ligand

StaR®
protein

INTERPRETATION

Hit ID

LIGAND OPTIMIZATION• We introduce point mutations into a
GPCR which leads to increased
thermostability• The receptor is trapped in a relevant
conformation to match the drug
product profile• The Stabilized Receptor (StaR®) can beextracted from the membrane andpurified with function retained

70+ Stabilized
Receptors
generated in agonist
and/or antagonist
conformations

Structure-Based Drug Design (SBDD) platform
StaR® technology plus SBDD is a powerful tool for GPCR drug discovery

Unstable
GPCR Structure

DRUG TARGET PROFILEPHARMACOLOGYHOMOLOGY MODELCADDSTRUCTURE

STRUCTURE

BIOPHYSICSHIT SELECTION• GPCR focused SBDD
•

•

•

22

Hit Identification – Virtual Screening,
Biochemical and Biophysical assays
Structure Determination – characterizebinding modes
Pharmacology – understanding mode ofaction and signalling

Medicinal
Chemistry

BIOPHYSICS

Candidate
Selection

OPTIMIZATION• Medicinal Chemistry working closelywith Computer Aided Drug Design(CADD)• Establish detailed Screening Cascadeand progression criteria• Typically 2 year process from starting
the target screening to entering
Candidate Selection phase25+ Preclinical
Candidates
identified forin-house andcollaboration
pipelineTranslating world-leading science into life-changing therapeutics
Focus areas to build on our global leadership position for the next generation of growth
PLATFORMGROWTHTARGET
BIOLOGY

Build on the strength of
our industry leading
SBDD platform, drug
discovery and early
development position

Entrench target biology
into all projects for agreater understanding of
disease processes

Lead the next wave ofgrowth throughexpansion beyond GPCRs
and adding newtechnology capabilities

Defining a robust,
testable hypothesis
linking target, cell,mechanism and site ofaction to clinical efficacy

TRANSLATIONALMEDICINE

Fully integrate ourpreclinical and clinicalcapabilities to support atranslational medicine
approach, which is fit for
purpose and bestpractice

PROGRAMCENTRICPATIENT
FOCUS

Empowered and aligned
team structures withaligned incentives

Continually strive todeliver innovative,
quality drugs to patients
fasterProjects accountablefor R&D budget, Risk
Management & Project
Plans. Functions exist
to support projects.

Recognise thatpartnering someprojects can deliverclinical validation earlier

OPERATIONAL EXCELLENCE
Complement our world leading science with operational best practiceIncrease efficiency, Probability of Success (Pos) & Return on Investment (ROI). Employ Project Managers into Enterprise Portfolio Management Office(EPMO). Provide more accurate information to senior management, store data in a format that facilitates external communication faster.

23

PLATFORM GROWTH

Strengthening our world leading GPCR platform
Expanding on complementary technologies
Pre-Disc. / Discovery

Preclinical studies

Target ID

Structure

Hit ID

StaR®

SBDD

(Stabilized Receptor)(Structure-Based Drug Design)

CryoEM

Chemogenomic GPCR
Library Screening

Protein Binder Toolkit

DEL Screening

Core

Clinical studies

Technologies
Expansions to
our platform

24(DNA Encoded Library)

Commercialization

Lead Optimization

PLATFORM GROWTH

Strengthening our world leading GPCR platform (cont'd)
Combining with our StaR/SBDD, 4 new technologies makes our platform better and faster

Cryo-EM

Protein
BinderToolkit25• Early adopters of Cryo-EM with continued growth (c.f. Richard
Henderson - Nobel prize -2017)• Routine Cryo-EM structure determination to support SBDD.
• 45+ structures of 15+ unique GPCRs determined by Cryo-EM at
Sosei Heptares including Family A, Family B and Family F receptors
by both X-ray crystallography and cryo-EM to enable SBDD.

• CryoEM structure determination often benefits from theintroduction of additional protein domains.
• These include domains fused to the StaR or introduced during
expression or purification.
• Clear benefits in structure determination for other non-GPCR
membrane protein classes.
• Internal Protein Binder platform is included as part of Cambridge
site lab expansion.

2D class averages

nanobody

StaR

Mini G
proteinPLATFORM GROWTH

Strengthening our world leading GPCR platform (cont'd)
Combining with our StaR/SBDD, 4 new technologies makes our platform better and faster

DEL
Screening(DNA Encoded
Library)

Chemogenomic
GPCR
Library
Screening26• Alternative strategy for Hit identification in early drug discovery.
• 15 billion to >1 trillion compound libraries allowing access tounprecedented levels of diversity.
• StaR proteins can be panned with known tool molecules to identify
new binding sites• 10+ StaR proteins have now been utilized in DEL screens• Chemogenomic GPCR library screening (WT protein)• ~50k compound set based on proprietary GPCR structural
chemogenomics & pharmacology knowledge• Contains GPCR diversified ligand sets covering 390+ GPCR-ligand
modality combinations• 10+ GPCR targets screened

PLATFORM GROWTH

Future innovations
Investing in non-GPCR membrane drug target exploratory research

Choosing the right target

Sosei Heptares Core Technologies
StaR®

SBDD

CryoEM

DEL Screening

Protein Binder Toolkit

Chemogenomic GPCR
Library Screening

Discoveringa therapeutic
agent
Partner CoreTechnologies

Partners with complementary technologies / expertise in non-GPCR
membrane target classes

27

•
•
•
•

Ion Channels
Transporters
Integrins
Oral SME alternatives
to biologics•

Technical Feability of nonGPCR membrane target
classes
Choosing Targets with low
Biological Risk•

World leading
SBDD
Platform for
Membrane
ProteinsTARGET BIOLOGYTranslational Medicine & Target Biology

TRANSLATIONALMEDICINE

Greater emphasis required on Translational Medicine & Target Biology

Choosing
the right target•

Will modulating the target
affect disease?

•

Identifying a modulator withthe appropriate profile•

Demonstrating the value ofthe agent in treating disease•

Can a good modulator of thetarget be found?

•

Differentiating fromcompetitors (if any)•

Utilizing biomarkers to
support patient stratification

The Right Target

28

Conducting
the right patient studies

Discoveringa therapeutic agent

The Right Asset

The Right Therapeutic Hypothesis

Instill a project centric focus throughout the organization

PROJECTCENTRIC

Portfolio Management ensure project strategies arealigned to business deliverables and ROI

Effective, transparent Governance enabling timely decision
making

Function

Project Leaders accountable for Asset Generation and
Therapeutic Hypothesis aspects of projectCore Team model overseeing project deliverablesSpecialist Project Managers drive operational best practice
Budgets aligned to projects
Functions exist to serve projects
Empowered and accountable team structures with aligned
incentives

29

PATIENT FOCUS

Focus on clear unmet medical need
Target product profiles & treatment algorithms
TARGET PRODUCT PROFILE30

TREATMENT ALGORITHMS

2-3
R&D Portfolio & Projects

31Overview of major pipeline
Pre-Disc. / Discovery

Preclinical studies

Multi-target

Multi-target

GI and otherMultiple

Multi-target

Multi-target

Inflammatory and Neurology

Multiple

Phase 1

M1M4 ag.

GLP-1 ag.

Neurology

T2DM/Obesity

M1 ag.

Phase 2M4 ag. NBI’568

Marketed
Ultibro® Breezhaler®

Schizophrenia

COPD

CCR6 ant.

A2a ant. combo(s)1Seebri® Breezhaler®

Neurology

IBD

mCRPC

COPD

GPR35 ag.

MC4 ant.

Enerzair® Breezhaler®

IBD

Anorexia

AsthmaPartnered

Co-dev /Profitshare

Oravi®

Neurology

Mouth candidiasis

CXCR4 mAb
TPD

Antibody

Gut-brain axis

PAR2 peptide

Ion channel

AI-driven

AI-driven

AI-driven

Co-owned
companies

In-house /Not yetpartnered

CGRP ant.

10+ other programs

Immuno-oncology

OX2 ag.

OX2 ag.

Narcolepsy(Oral)

Narcolepsy(Intranasal)

SARS-CoV-2 MPro
Coronaviruses

GPR52 ag.

H4 ant.

Neurology

Atopic Dermatitis

PAR2 mAb

EP4 ag.

EP4 ant.

Atopic Dermatitis

IBD

Immuno-oncology

mGlu5 NAM

Substance abuse

Note: Seebri®, Ultibro®, Enerzair® and Breezhaler® are registered trademarks of Novartis AG.) 1AstraZenenca have removed the A2a program from their clinical pipeline as at Q3 2021

32

Partnered Program
In-house ProgramOverview of major pipeline
Pre-Disc. / Discovery

Preclinical studies

Multi-target

Multi-target

GI and otherMultiple

Multi-target

Multi-target

Inflammatory and Neurology

Multiple

Phase 1

M1M4 ag.

GLP-1 ag.

Neurology

T2DM/Obesity

M1 ag.

Phase 2M4 ag. NBI’568

Marketed
Ultibro® Breezhaler®

Schizophrenia

COPD

CCR6 ant.

A2a ant. combo(s)1Seebri® Breezhaler®

Neurology

IBD

mCRPC

COPD

GPR35 ag.

MC4 ant.

Enerzair® Breezhaler®

IBD

Anorexia

AsthmaPartnered

Co-dev /Profitshare

Oravi®

Neurology

Mouth candidiasis

CXCR4 mAb
TPD

Antibody

Gut-brain axis

PAR2 peptide

Ion channel

AI-driven

AI-driven

AI-driven

Co-owned
companies

In-house /Not yetpartnered

CGRP ant.

10+ other programs

Immuno-oncology

OX2 ag.

OX2 ag.

Narcolepsy(Oral)

Narcolepsy(Intranasal)

SARS-CoV-2 MPro
Coronaviruses

GPR52 ag.

H4 ant.

Neurology

Atopic Dermatitis

PAR2 mAb

EP4 ag.

EP4 ant.

Atopic Dermatitis

IBD

Immuno-oncology

mGlu5 NAM

Substance abuse

Note: Seebri®, Ultibro®, Enerzair® and Breezhaler® are registered trademarks of Novartis AG.) 1AstraZenenca have removed the A2a program from their clinical pipeline as at Q3 2021

33

Partnered Program
In-house ProgramMuscarinic M4 agonist (NBI-1117568)
Collaboration with Neurocrine, announced IND of Ph2 study trigger $30 million milestone

Source: Neurocrine Biosciences Announces Conference Call and Webcast of Second Quarter 2022 Financial Results
https://www.neurocrine.com//assets/2022/08/NBIX-Q2-2022-Earnings-Presentation-Final-08.04.22.pdf

34

GLP-1 agonist (PF-07081532)
Pfizer recently presented potentially best-in-class data at EASD (19-23 September)

Source: Pfizer Analyst and Investor call to review Oral GLP-1 Data – EASD meeting Sep 2022
https://s28.q4cdn.com/781576035/files/doc_presentation/2022/09/2022-EASD-IR_Presentation_FINAL.pdf

35

Overview of major pipeline
Pre-Disc. / Discovery

Preclinical studies

Multi-target

Multi-target

GI and otherMultiple

Multi-target

Multi-target

Inflammatory and Neurology

Multiple

Phase 1

M1M4 ag.

GLP-1 ag.

Neurology

T2DM/Obesity

M1 ag.

Phase 2M4 ag. NBI’568

Marketed
Ultibro® Breezhaler®

Schizophrenia

COPD

CCR6 ant.

A2a ant. combo(s)1Seebri® Breezhaler®

Neurology

IBD

mCRPC

COPD

GPR35 ag.

MC4 ant.

Enerzair® Breezhaler®

IBD

Anorexia

AsthmaPartnered

Co-dev /Profitshare

Oravi®

Neurology

Mouth candidiasis

CXCR4 mAb
TPD

Antibody

Gut-brain axis

PAR2 peptide

Ion channel

AI-driven

AI-driven

AI-driven

Co-owned
companies

In-house /Not yetpartnered

CGRP ant.

10+ other programs

Immuno-oncology

OX2 ag.

OX2 ag.

Narcolepsy(Oral)

Narcolepsy(Intranasal)

SARS-CoV-2 MPro
Coronaviruses

GPR52 ag.

H4 ant.

Neurology

Atopic Dermatitis

PAR2 mAb

EP4 ag.

EP4 ant.

Atopic Dermatitis

IBD

Immuno-oncology

mGlu5 NAM

Substance abuse

Note: Seebri®, Ultibro®, Enerzair® and Breezhaler® are registered trademarks of Novartis AG.) 1AstraZenenca have removed the A2a program from their clinical pipeline as at Q3 2021

36

Partnered Program
In-house ProgramMulti-target collaboration partners
Making excellent progress with new and long-term partnered programs
Partner

Execution

Therapeutic Area

Stage

Progress

November 2015

Multiple

Phase 1x3 clinical stage assets achieved in 6 years
and clinical development is ongoing

July 2019

Multiple

Discovery

x5 milestones achieved in 3 years withtargets for small and large molecule drugs

August 2019

Multiple(Initial focus on
Gastrointestinal)

Discovery

Early Discovery milestones achieved
June 2020
August 2022

37

Inflammatory,
Autoimmune and
Neurology

Discovery

Sosei Heptares and AbbVie collaboration
Multi-target collaboration announced – upfront payment of $40 million

Source: https://soseiheptares.com/uploads/news/id785/2022.08.02%20Neu%20Highland%20_vF.pdf df

38

Overview of major pipeline
Pre-Disc. / Discovery

Preclinical studies

Multi-target

Multi-target

GI and otherMultiple

Multi-target

Multi-target

Inflammatory and Neurology

Multiple

Phase 1

M1M4 ag.

GLP-1 ag.

Neurology

T2DM/Obesity

M1 ag.

Phase 2M4 ag. NBI’568

Marketed
Ultibro® Breezhaler®

Schizophrenia

COPD

CCR6 ant.

A2a ant. combo(s)1Seebri® Breezhaler®

Neurology

IBD

mCRPC

COPD

GPR35 ag.

MC4 ant.

Enerzair® Breezhaler®

IBD

Anorexia

AsthmaPartnered

Co-dev /Profitshare

Oravi®

Neurology

Mouth candidiasis

CXCR4 mAb
TPD

Antibody

Gut-brain axis

PAR2 peptide

Ion channel

AI-driven

AI-driven

AI-driven

Co-owned
companies

In-house /Not yetpartnered

CGRP ant.

10+ other programs

Immuno-oncology

OX2 ag.

OX2 ag.

Narcolepsy(Oral)

Narcolepsy(Intranasal)

SARS-CoV-2 MPro
Coronaviruses

GPR52 ag.

H4 ant.

Neurology

Atopic Dermatitis

PAR2 mAb

EP4 ag.

EP4 ant.

Atopic Dermatitis

IBD

Immuno-oncology

mGlu5 NAM

Substance abuse

Note: Seebri®, Ultibro®, Enerzair® and Breezhaler® are registered trademarks of Novartis AG.) 1AstraZenenca have removed the A2a program from their clinical pipeline as at Q3 2021

39

Partnered Program
In-house Program

Aim

How

Why

To support the identification andvalidation of new drug GPCR targets
across our core therapeutic areas (GI,immunology, immuno-oncology andneuroscience)

By leveraging top-end external company
omics platforms/databases andvalidation capabilities
To add exciting novel GPCR targets toour pipeline which have evidence of adirect involvement in a disease /mechanism process to fuel partnering
activity and higher value creation

AI / Machine Learning

New Target Identification and Validation (TIV) framework to give us
the next generation of GPCR targets
Bioinformatics

Proteomics

SBDD
platform

Transcriptomics

Small Molecule
Discovery

Genomics

Clinical Trials

Clinical/Patient Data

Continuously expanding our know-how and SBDD platform to maintain our leadership position in GPCR drug discovery

40Strategic collaboration partners
Identification and validation of novel GPCR targets for new discovery programs
2021~

2022~

AI drug discovery (Target)••

Discovery collaboration combining
InveniAI’s AI-powered platform fortarget discovery with SH’s GPCR
SBDD and early development
capabilities
Collaboration aims to identify new
therapeutic product concepts for
immune diseases and generate
novel compounds that could
improve responses to existing
immunotherapies

Immunology/Multi-target

41

2022~

AI drug discovery (Target)

Gut-brain axis platform (Target)•

Research collaboration combining
Verily’s immune profilingcapabilities and SH’s StaR® platform
and SBDD capabilities•

Strategic research collaboration
leveraging Sosei Heptares
capabilities with Kallyope’s gutbrain axis platform•

Collaboration aims to identify
GPCRs expressed in immune cells,
enhance our understanding of theirfunctional relevance and prosecuteas potential drug targets inimmune-mediated diseases•

Collaboration aims to identify,
prioritize and validate novel GPCR
targets with a goal of creating new
drug discovery programs in the areaof gastrointestinal (GI) diseases

Immunology/Multi-target

Gastroenterology/Multi-target

Overview of major pipeline
Pre-Disc. / Discovery

Preclinical studies

Multi-target

Multi-target

GI and otherMultiple

Multi-target

Multi-target

Inflammatory and Neurology

Multiple

Phase 1

M1M4 ag.

GLP-1 ag.

Neurology

T2DM/Obesity

M1 ag.

Phase 2M4 ag. NBI’568

Marketed
Ultibro® Breezhaler®

Schizophrenia

COPD

CCR6 ant.

A2a ant. combo(s)1Seebri® Breezhaler®

Neurology

IBD

mCRPC

COPD

GPR35 ag.

MC4 ant.

Enerzair® Breezhaler®

IBD

Anorexia

AsthmaPartnered

Co-dev /Profitshare

Oravi®

Neurology

Mouth candidiasis

CXCR4 mAb
TPD

Antibody

Gut-brain axis

PAR2 peptide

Ion channel

AI-driven

AI-driven

AI-driven

Co-owned
companies

In-house /Not yetpartnered

CGRP ant.

10+ other programs

Immuno-oncology

OX2 ag.

OX2 ag.

Narcolepsy(Oral)

Narcolepsy(Intranasal)

SARS-CoV-2 MPro
Coronaviruses

GPR52 ag.

H4 ant.

Neurology

Atopic Dermatitis

PAR2 mAb

EP4 ag.

EP4 ant.

Atopic Dermatitis

IBD

Immuno-oncology

mGlu5 NAM

Substance abuse

Note: Seebri®, Ultibro®, Enerzair® and Breezhaler® are registered trademarks of Novartis AG.) 1AstraZenenca have removed the A2a program from their clinical pipeline as at Q3 2021

42

Partnered Program
In-house ProgramAdvancing four wholly-owned programs
Advancing priority programs into early clinical studies, including collaboration with CRUKIndication andtargetTargetProduct
ProfileClinical starttarget43

Schizophrenia
and Psychosis

AtopicDermatitis

Immunosuppression
in solid tumors

Inflammatory
Bowel Disease

GPR52 agonist

H4 antagonist

EP4 antagonist

EP4 agonist• Once daily oral
small molecule• 24hr target engagement

H1 2023• Once daily oral small
molecule• To be used as amonotherapy or in
combination

H1 2023• Once daily oral small
molecule• To be used in combo withcheckpoint inhibitors• Collaboration with CRUK

H1 2023• Oral GI restricted• Good potency andselectivity• Minimal GI systemic
exposure

End of 2023

3
Priority Wholly-owned Programs(EP4 antagonist and EP4 agonist)
Dr. Rie Suzuki, Senior Director,
Translational Biology
44EP4 receptor: GPCR with multiple therapeutic opportunities
EP4 is a key receptor for PGE2

Inflammatory bowel
disease45

Immuno-oncology

Potent anti-inflammatory action

https://doi.org/10.15252/emmm.202012798

EP4 Antagonist
Antagonist

Project Hypothesis:
Restore immune
surveillance andenhance efficacy ofcheckpoint inhibitors

EP4 Agonist
Project Hypothesis:
Dampeninflammation, restore
gut homeostasis andaccelerate mucosal
healingCancer is the leading cause of premature death in highdevelopment index countries
National Ranking of Cancer as a Cause of Death at Ages
<70 Years in 2019.

National Ranking of Cancer as a Cause of Death at Ages <70 Years in 2019.
The numbers of countries represented in each ranking group are includedin the legend. Source: World Health Organization.

Sung et al (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA CANCER J CLIN 2021;71:209–249
https://ganjoho.jp/public/qa_links/report/statistics/2021_en.html

46

Current treatments

Immunotherapy offers improved survival in some patients – butroom for improved efficacy
Immunotherapy provides lasting remission for somepatients

Only <20% patients eligible for Checkpoint inhibitors
respond to treatment

Combination

2nd gen immunotherapy
1st gen immunotherapy
Conventional chemotherapy

Haslam & Prasad (2019); JAMA Network Open; 2(5): e192535
First generation immunotherapies: anti-CTLA-4 ipilimumab and the therapeutic vaccine Sipuleucel-T
Second generation immunotherapies target PD-1/PD-L1 and deliver effective responses in up to 40% of patients across many clinical trials

47

EP4 Antagonist and role in cancer
PGE2 and COX2 is elevated in tumour microenvironmentand contributes to poorer prognosis in cancer

How do EP4 antagonists provide therapeutic benefits?

Tumour microenvironment (TME)

PGE2 &
COX2 in TME

Cancer cell survival
Migration & invasion
Angiogenesis
Immunosuppression

Poorerprognosis

Block of PGE2-EP4 signalling will lead to:
Reduced immune
suppression of the
TME

48

Enhanced antigen
presentation

Activation of T andNK cells

Inhibition of
tumor
proliferation/
metastasis

EP4 Antagonist target molecule profile
Early chemistry H2L inspired from extensive literature ligand mining
EP4 Antagonist Competitor Landscape

EP4 Antagonist Chemistry Strategy• Goal: Identify potent, EP4 selective antagonist
targeting high receptor cover (Cmin > IC90 over
24 hrs) from a low oral dose (<100 mg)

E7046 +/- Pembrolizumab (Phase 1b)
Grapiprant +/- Pembrolizumab (Phase 1 & 1b/2)
BMS-986310/ONO-4578 +/- Nivolumab (Phase 1 & 1b/2a)• Utilise SBDD approach to identify best-in-classagent• Wealth of published prostanoid structures andinternal StaR mutagenesis work facilitateddevelopment of homology models• Multi-series approach driven by deep
literature/patent mining to design novel
ligands

49

TPST-1495 +/- Pembrolizumab (Phase 1)
HTL0039732
PRECLIN

Ph 1

Ph 2

Sosei Heptares EP4 Antagonist molecule profile: HTL0039732
Sosei Heptares EP4 antagonist molecule Profile

HTL0039732 displays synergy with aPD1 mAb✓

High potency

Blockade of EP4 in PGE2 high tumours will restore immune
surveillance facilitating enhanced efficacy of checkpoint
inhibitors✓

High selectivity vs EP2 agonism

Day -7

Day 0

Day 1

Day 28HTL0039732 QD PO✓

Excellent in vitro safety profile

aPD1 mAb 2QW IP
HTL0039732 + aPD1 mAb
Vehicle✓Excellent in vitro ADME properties✓

Excellent PK profile across 3 sp. (low Cl, long T1/2)✓

High free fold cover at low doses

Tumour volume50

Summary and future directions• Sosei Heptares (SH) has successfully
utilised the Proprietary StaR® platform
and Structure based drug design todevelop novel, high potency EP4
antagonist, HTL0039732.
• HTL0039732 has broad potential use intreatment of solid tumours incombination with immune checkpoint
inhibitors (CPI), with targeted therapies
and with chemotherapy andradiotherapy

51• Under the Clinical Trial and Licence Agreement (CTLA), Cancer Research
UK’s Centre for Drug Development will sponsor, design and execute a
Phase I/IIa clinical trial of HTL00397322, a novel selective EP4antagonist.
• HTL0039732 has been proposed for a range of cancers including
microsatellite stable3 colorectal, gastroesophageal, head and neck andcastrate resistant prostate cancer.

Opportunities for EP4 Agonist for the treatment of IBD
What is IBD?

Typical course of disease progression in IBD:

Disease cycles through episodes of active
flare & remission
Uncontrolled inflammation
Bowel resection

Goal oftherapyLong term remission anddeep mucosal healing52Current SOC primarily target the immune axis: opportunity for
differentiation
Unmet need remains in IBD despite biologic therapy
Remicade

HumiraSimponi

Entyvio

Stelera

Manufacturer

Janssen/Merck

AbbvieJanssen/Merck

TakedaJanssenMechanism

Anti-TNF

Anti-TNF

Anti-TNF

Anti-a4b7

Anti IL12/IL23

Rate ofremission:
Induction

Placebo

15%

9.3%

9.5%

5.4%

7%

Active39% (W8)

16.5% (W8)17.8% (W6)

16.9%

19%

Rate ofremission:
Maintenance

Placebo

17%

8.5%

15.4%

15.9%

26%

Active35% (W54)

17.3% (W52)

28.6% (W52)

41.8%

45%

Boxed
warning

Boxed warning

Boxed warning

Warning
for PML

Warning forinfections,malignancies,
RPLS, pneumonia

Key safety
information

PML = Progressive Multifocal Leukoencephalopathy; RPLS = Reversible posterior leukoencephalopathy syndrome53

Proposed benefits of EP4 Agonist in IBD
Target hypothesis
EP4 Agonist produces potent anti-inflammatory
activity and enhances barrier repair & regeneration

Gut barrier

EP4 Agonist

EP4 Agonist•

EP4 agonist represents a novel MOA targeting a
differentiated axis to current SOC.

•

Opportunity to enhance efficacy in IBD via combination
therapy (e.g. anti-TNF)

Immune cells
Anti-TNF
Steroids

54

ONO4819-CD EP4 agonist in patients with mild to moderate UC
Disease activity index and histological scores following ONO-4819 or placebo treatment• Randomised Placebo controlled PhII trial• Mild to moderate UC patients refractory to 5aminosalicylates

Early signs of histological benefit demonstrated in ONO-4819CD group after 2 weeks treatment
Nakase et al (2010); Inflamm Bowel Dis, 16; 731

55

Sosei Heptares GI restricted EP4 Agonist program
EP4 Agonist Chemistry strategy

Sosei Heptares Chemistry and Differentiation• Goal: Identify potent, oral GI restricted EP4
selective agonist with minimal systemic exposure• SBDD driven design to optimise molecules tominimise oral absorption• Identification of novel EP4 agonists with excellent
in vitro pharmacological activity and selectivity•

Superior EP selectivity compared to KAG308• Excellent physicochemical and DMPK properties
aligned to minimal systemic exposure profile•

Clear differentiation in terms of systemic exposure andluminal drug distribution

Competitor status:
KAG308 (Kaken Pharmaceuticals): UC• Status: Inactive*• RoA: Oral
ONO-4819CD (Ono Pharmaceuticals): UC• Status: Discontinued• RoA: IV* Source: Global Data

56

Sosei Heptares GI restricted EP4 agonist offers a novel approach totarget IBD disease
Sosei
Heptares
EP4

KAG308Luminal drugconcentration:

Mucosal repair
Minimal absorption

Upper GI

KAG
308

SH

High

High

Route

ONO4819

KAG308

Sosei EP4
Agonist

IV

Oral

Oral

Permeable

Low

Permeability
Systemic exposure

Yes

Yes

Minimalabsorption

Potency

+

+++

+++

+

+++

+

+++

EP Selectivity
Oral bioavailability
Colon tissue
concentration✓
Cardiovascular effect
Colon

Low

High

+

Successful design of a novel, GI restricted EP4 agonist:
High affinity, potent full agonist, good EP receptor selectivity
Low permeability, minimal oral absorption
Good in vivo efficacy
Favourable in vitro safety profile57

EP4 agonists improve barrier function and colitis in vivo
Mouse organoid
EP4

Swelling

Mouse intestinal organoid

58

EP4 agonist shows protective effects on the intestinal
barrier and shows potent anti-inflammatory effects

Improved GI permeability in
NSAID model of GI damage

Anti-inflammatory effects in
DSS colitis modelSummary• Sosei Heptares has successfully developed 2 high quality lead assets with high potency, selectivity
and excellent physchem properties.
• Application of Sosei Heptares StaR platform to support Structure based drug design• EP4 represents an exciting GPCR target with opportunities in different therapeutic areas.

• EP4 Antagonist for Immune-oncology:• Successful partnership established with Cancer Research UK (2022).
• HTL0039732 is a high affinity EP4 antagonist molecule anticipated to have class matching efficacy and low
predicted oral daily dose• EP4 Agonist for GI inflammatory disease (IBD):• Successful design of a novel, gut restricted EP4 agonist• Opportunity to promote epithelial repair and reduce immune mediated damage in the inflamed gut.

⎻ Differentiation from current SOC.

59

4
Q&A

60

Locations
SOSEI HEPTARESPMO Hanzomon 11F

Steinmetz Building

North West House

2-1 Kojimachi, Chiyoda-ku

Granta Park, Cambridge

119 Marylebone RoadTokyo 102-0083

CB21 6DG

London NW1 5PU

Japan

United Kingdom

United Kingdom