CORONAVIRUS PROGRAM | NOV 2020

SARS-CoV-2 Main protease or MPro proteolyticallycleaves the overlapping viral pp1a and pp1ab
polyproteins into functional proteins. This is a
critical step during viral replication. Replicationessential enzymes such as RdRp or nsp13 cannot
fully function without prior proteolytic release,
positioning MPro as a key enzyme in the viral
replication cycle. Consequently, its inhibition canstall the production of infectious viral particles andthus alleviate disease symptoms.
Capitalizing on knowledge gained fromstructures and inhibitors of MPro from the closely
related SARS-CoV and MERS-CoV, MPro is one of
the most attractive viral targets for anti-viral drug
discovery against SARS-CoV-2 and future variantsof the virus. The high degree of structuralsimilarity of the active site between related
viruses might prove valuable for thedevelopment of pan-coronaviral drugs.

ACE2 TMPRSS2
Endosomal entry
Exocytosis
genomic RNA

Translation

Virion assembly

Replication
Proteolysis
pp1a/abM P roP L P roTranscription

ERGIC

RTC

Structural proteins

Translation
ERnspsIN BRIEF | Excellent progress in design of inhibitors to fight SARS-CoV-2 and related human coronaviruses
TARGETING CORONAVIRUSES WITH SBDDTARGET PRODUCT PROFILE

Primary objective: Design synthetic compounds that have thepotential for optimization to an oral agent suitable for development asa treatment of COVID-19.
Secondary objective: Leverage highly conserved structure of MProprotease to design oral agents to treat disease caused by infection bya broader range of coronaviruses and other related viruses.

Once or twice daily oral agent fortreatment of SARS-CoV-2 viral infection
dosed immediately after a positive test
result and for up to 2 weeks thereafter,with potential for broader application
for intervention of associated humancoronavirus and related viral infections.

DRUG DISCOVERY
We sought to use our Structure Based Drug Design (SBDD) capabilities
to design inhibitors of the MPro protease and focused on 3 chemicalseries. Here, we describe Series 3, which is currently most advanced.
This work has been done in close collaboration with Syngene
International which has supported chemical synthesis, enzyme
inhibition screening and characterization of pharmacokinetic
properties of key compounds. Sosei Heptares scientists havesupported in silico drug design, protein production and X-ray
structure solution to support SBDD and biophysical characterization ofcompound binding. This and additional series are progressing throughan international network of collaborators.

PROGRAM STAGE
Excellent progress has been made inthree distinct chemical series ofinhibitors, since project initiationin April 20.
Lead Compound identified suitable forfurther optimization to an oral drug.

NEXT STEPS
Identify a collaboration partner toaccelerate progress into and throughhuman clinical trials.

PROGRAM COLLABORATORS© 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.

KEY RESULTS
Series 3 compound SH-580 ismore than 100-fold morepotent in vitro thanBoceprevir as an inhibitor of
the SARS-CoV-2 MPro viralprotease, making it a muchbetter start point for further
optimization

IC50: 5.33 µM

100

IC50: 0.02 µM% Inhibition

806040Boceprevir

20SH-580

0-20-4-3-2-1012Log [Compound] (µM)

Chloroquine

SH-59412012010080229E

60

MRC540200-200.1

110OC43100

OC43% of live cells

Cell-based anti-viral assay
development completed• Initial data in hand for HCoVOC43, NL63 and 229E assays,
demonstrating excellent
potency• Testing of key compounds inSARS-CoV2 replication
inhibition assays planned120% of live cells

Enzyme assays rapidly
established for SARS-CoV2-MProand related proteases throughcollaborators• Assays benchmarked with key
literature / approved proteaseinhibitors• Boceprevir (HCV proteaseinhibitor) is used as an assay
standard; a proportion of SBDD
efforts are derived from thisscaffold with structural insights
allowing MPro activity to betuned

229E

80

MRC56040
2001000.1-20concentration (µM)

1

10100

concentration (µM)

Series 3 compound SH-594 shows much greater anti-viral activity than
Chloroquine against a range of human coronaviruses

SBDD underpins the project, driven inhouse at Sosei Heptares.
We exploited public domain structures
for early design and each chemical series
is structurally enabled with at least onehigh resolution in-house crystal structure.

Crystal structure of SARS-CoV-2 MPro (blue) bound to Boceprevir (Left, Pink; PDB ID: 6WNP) and in-house crystal
structure of SARS-CoV-2 MPro bound to an exemplar from the most advanced Series (Right, Orange) showcases thepower of SBDD to drive design and optimization of inhibitors towards better potency and drug-like properties.

SH-580 and related examples in the series have lower in vitro
clearance than Boceprevir, translating into superior in vivo clearanceand plasma exposure critically important to inhibit the virus.
SH-580 has comparable oral bioavailability to the marketed drug
Boceprevir with a clear and structurally enabled strategy in place toimprove bioavailability within the series.
Cl 52 mL/min/kg
t1/2 0.25 hr

STRUCTURE-BASEDDRUG DESIGNCl 11 mL/min/kg
t1/2 2.82 hr

Plasma conc (ng/mL)

PROMISING PK RESULTS FROM OUR MOST ADVANCED SERIES

Mean plasma concentration-time profiles
following 1 mg/kg IV administrationin SD rats()
(n=3)
10000
SH-580

1000*Boceprevir

100101012345Time (h)*Boceprevir plasma concentration
below LoQ (1 ng/mL) at 3 hSH-580 represents an excellent opportunity for further optimization togenerate an oral drug for the treatment of COVID-19 and related viral infections

678

ABOUT SOSEI HEPTARESWorld leader in
GPCR drug discoveryand early development
Proprietary GPCR-targetedStaR® technology and SBDD
platform capabilities
Japan-anchored biotech, withstate-of-the-art R&D center inCambridge, UK
Listed on Tokyo Stock
Exchange (4565-JP)

160+

75+

EMPLOYEESWORLDWIDEPHDS WITHINTHE COMPANY

200+SCIENTIFIC
PUBLICATIONS500+

GLOBALPATENTS300+

STRUCTURESSOLVED

IN BRIEF | Unparalleled ability to deliver novel, high quality drug candidates into development pipelines
EVOLVING WITH A SPECIALISTTHERAPEUTIC FOCUS
Sosei Heptares is advancing abroad and deep pipeline ofpartnered and in-house drugcandidates in multiple
therapeutic areas, including:Immunology
Gastroenterology
OtherPrograms in Preclinical / Early Dev.
30%

6%

Sosei Heptares has developed a unique and powerful platform
technology capability called StaR® (Stabilized Receptor) that, for thefirst time, enables powerful structure-based drug design (SBDD)
approaches to be applied to functional, stabilized GPCRs.

DRUG DISCOVERY

Neurology

34%

TECHNOLOGY & PLATFORM

Sosei Heptares’ StaR®/SBDD platform capabilities allow us to develop
better, differentiated drug candidates against established andemerging novel GPCR target mechanisms. Our highly productive
discovery engine has generated 24 high quality novel preclinicalcandidates and produced seven IND clinical candidates in the last 10years. This rate is well above industry averages.

30%EARLY DRUG DEVELOPMENT
Programs in Pre-Discovery / Discovery
29%

23%

39%

9%

Sosei Heptares has fully established early development teams in the
UK and Japan. Multiple clinical and non-clinical programs areunderway both in-house and through our partnerships with leading
global pharma companies.

PRODUCT PIPELINE
Product/Program

Modality1

Indication

Partner

Collaboration Type

SME
SME
SME
SME

COPD
COPD
As thma
Oropha ryngeal candidiasis

Roya l ty
Roya l ty
Roya l ty
Product Sa les

SME
SME

mCRPC
DLB (Japan)

Out-l i censed
In-House

SME
SME
SME
SME
SMESME
Pepti deSol id tumors
Al zheimer’s disease
Al zheimer’s disease
T2DM/Obesity
Inflammatory bowel disease
Subs tance Use Disorders
Endocri ne disorders

Out-l i censed
Out-l i censed
Out-l i censed
Out-l i censed
Out-l i censed
As s et centric company
In-House (Pre-partnered)

SME
mAb
SME
SME
SME
SME
SME
SME
mAb

Meta bolic a nd other
Immuno-oncology
Mi gra ine
Atopi c Dermatitis
Immuno-oncology
IBD
Intestinal failure
Neurology diseases
Atopi c dermatitis

Out-l i censed
Co-development
In-House (Pre-partnered)
In-House (Pre-partnered)
In-House (Pre-partnered)
In-House (Pre-partnered)
In-House (Pre-partnered)
In-House (Pre-partnered)
In-House (Pre-partnered)

SME/LME
SME/LME
SME
SME
Pepti deSME
SME

Mul ti ple i ndications
Mul ti ple i ndications
Mul ti ple i ndications
Inflammatory diseases
Inflammation
Na rcol epsy
Na rcol epsy

Out-l i censed
Out-l i censed
Out-l i censed
Out-l i censed
Co-development
As s et centric company
As s et centric company

Marketed ProductsSeebri® Breezhaler®
Ul ti bro® Breezhaler®
Enerzair® Breezhaler®
ORAVI®

Phase 2A2A a nta gonist combo
M1 agonist1Phase 1
A2A a nta gonist
M1 a gonist
M4 a gonist
GLP-1 a gonist
CCR6 a ntagonistmGl u 5 NAM
SSTR 5 a gonist

PreclinicalSi ngle targetCXCR4 mAb
CGRP a nta gonist
H4 a nta gonist
EP4 a ntagonist
GPR35 a gonist
GLP-2 a gonist
GPR52 a gonist
PAR2
Di s covery
Mul ti -target
Mul ti -target
Mul ti -target
Si ngle target
Si ngle target
Orexi n a gonists
Orexi n a gonists

BUSINESS DEVELOPMENT
Sosei Heptares is recognized globally for challenging the frontiers of science, having solved more than 300 structuresfrom more than 30 different GPCR targets. Large and untapped regions of the GPCR target universe, previously
regarded as undruggable, are now tractable for rational drug discovery using our StaR® technology and SBDD
platform. Our strategic focus is to leverage our world-leading technology platform and generate valuable, high quality
novel clinical drug candidates which are attractive to innovative pharmaceutical and biotechnology companies.

CONTACT US
Hea dquarters
PMO Hanzomon 11F, 2-1 Kojimachi, Chiyoda-ku, Tokyo 102-0083, Japan
Corporate Office North West House, 119 Marylebone Road, London NW1 5PU, United Kingdom
R&D Facility
Steinmetz Building, Granta Park, Cambridge CB21 6DG, United Kingdom
Investor Relations IR@SoseiHeptares.com
Pa rtnering
Covid19@SoseiHeptares.com

https://soseiheptares.com@soseiheptaresco

Note: SME = small molecule; LME = large molecule; mAb = monoclonal antibody. 2 Phase 2 trial of HTL0018318 for DLB in Japan has been withdrawn. The Group plans to resubmit a new clinical trial
notification for HTL0018318 (or another novel M1 agonist) to the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) in the future1