Malcolm Weir –EVP, Chief R&D Officer · 2019-09-19 · 2015 EVP, CHIEF R&D OFFICER, 4 YEARS...

Malcolm Weir – EVP, Chief R&D Officer

NON‐CONFIDENTIAL

12 September 2019 | R&D Investor Day

Good morning everyone, my name is Malcolm Weir, the Chief R&D Officer of Sosei Heptares.

It is my great pleasure this morning to take you through an update of our R&D pipeline.

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Malcolm Weir – EVP, Chief R&D OfficerAbout Me

BRITISH HERITAGE;UK‐BASED

IMPERIAL COLLEGE

BSc.,PhD.VISITING PROF

MALCOLM CAMPBELL MEMORIAL PRIZE

2015

EVP, CHIEF R&D OFFICER, 4 YEARS

CO‐FOUNDER AND CEO,8 YEARS

CEO & CSO,6 YEARS

Good morning everyone, my name is Malcolm Weir, the Chief R&D Officer of Sosei Heptares.

It is my great pleasure this morning to take you through an update of our R&D pipeline.

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Introduction

Chief R&D Officer

Platform Technology Drug Discovery

Protein Engineering

Biomolecular Structure

Biophysics

Comp.Chemistry

Medicinal Chemistry

Molecular Pharmacology

Translational Sciences

Clinical Drug Development

Clinical Development

Preclinical Development

Please turn to Slide 3.

Many of you may already be familiar with my role at Sosei Heptares, however for anyone new in the room please let me give you some context.

This morning you have met three of our fantastic scientists (and a harmonica player), Rie Suzuki from our Early Development team, Stacey Southall from Platform Technology team, and Chris De Graaf from our Drug Discovery team.

As the Chief R&D Officer, it is my job to oversee all of the exciting progress across these teams, and to lead and drive our Group R&D strategy to ensure we continue to maintain our position as the world’s leading GPCR‐targeted discovery and development company.

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We are the world leader in GPCR drug discovery and development

WE ARE RECOGNIZED GLOBALLY FOR WORLD‐CLASS, PIONEERING SCIENCE

Solved

260+Molecular structures

From

25+Different GPCRs

Solved

>30%Structures of GPCR targets

OUR TECHNOLOGY HAS ATTRACTED WORLD LEADING PHARMA AND

BIOTECHS AS KEY PARTNERS

COLLABORATIONS WITH LEADING ACADEMIC GROUPS KEEP US AT THE

CUTTING EDGE OF SCIENTIFIC RESEARCHOUR CO‐FOUNDER

RICHARD HENDERSON WAS AWARDED THE

NOBEL PRIZE IN CHEMISTRY

FORMED 2 SPIN‐OUT COMPANIES

PRODUCTS ON MARKET

GLOBALLY

R&D PROGRAMSDISCLOSED WITH

BROAD AND DEEP PIPELINE BEHIND

Slide 4, please.

We have come a long way in the nearly three decades of innovation at Sosei Heptares.

Our R&D team continue to challenge the frontiers of science – we have solved over 25 molecular structures which represents over 30% of all structures of GPCR targets that are known. We are indeed the world leader in GPCR drug discovery and development.

We continue to invest in innovative GPCR structure and drug design technology we expect to maintain our world leadership status for many years to come.

We are also exploiting this technology very effectively as we are 2‐3 times more productive than the industry standard in discovering and developing new drugs.

Our technology, and the assets we generate using it, will continue to form the basis of many high‐quality partnerships for the future.

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In 2015, our pipeline was early stage and predominantly unpartneredDiscovery Preclinical Phase 1 Phase 2 Phase 3 Marketed

M1M4

M1M4

A2A

CGRP

GLP‐1 ant

OX‐1 ant

Ultibro®

Seebri®

Oravi®Ph 1a

Undisclosed

APP13007*

APP13002*

* Originally designed and developed at Activus Pharma (former wholly owned subsidiary of Sosei Group Corporation). Activus was divested to Formosa Pharmaceuticals in August 2017. Sosei Heptares remains eligible to receive undisclosed milestone payments based on the progression of Activus’ pipeline at Formosa

Slide 5, please.

In 2015, Sosei Group executed a transformational acquisition of Heptares Therapeutics.

At the time of acquisition, the combined R&D pipeline was very early stage and largely unpartnered.

Targets were chosen based on their attractive markets, unmet medical needs and signals of pharma interest.

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Today, we have a broad and deep partnered and in‐house portfolioDiscovery Preclinical Phase 1 Phase 2 Phase 3 Marketed

M1M1M4

Undisc.

Undisc.

CXCR4

GLP‐1 ant

OX‐2 ag Ultibro®

Seebri®

Oravi®

QVM149A2APh 1b

M4

A2A

mGlu5

SSTR

M1DLB1

CGRP

GLP‐2

OX‐2 ag

Undisc.

OX‐1 ant

Apelin

GPR35

H4

PAR2

Norlevo®

1 Phase 2 trial of HTL0018318 for DLB in Japan remains under voluntary suspension. 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 future


I am proud to say that four years later – today ‐ we have:

A broad and deep R&D pipeline, which is continuously being added to and advancingPartnerships with many world‐leading and innovative pharmaceutical companiesMultiple programs in clinical developmentA sustainable pipeline of early discovery and preclinical programs moving through to partnering value inflections

Emerging disease foci in neuroscience and GI/immunology areasHigher than average productivity rates – we can move from Hit to PCC stage in roughly 2 years which is much faster than our peers

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Our core strengths differentiate us from our peers

NEW GPCR TARGET STRUCTURE AND FUNCTION

HIGH QUALITY COMPOUNDS

GLOBAL DEVELOPMENT CAPABILITY

FLEXIBLE PARTNERING STRATEGY


To recap our core pillars of strength:

Firstly, our patent‐protected Platform StaR® Technology is our crown jewel – it continues to enable us to produce new and exciting GPCR structures by engineering stabilized GPCR targets which we call StaRs.

Our exceptional Structure‐based Drug Discovery (SBDD) efforts have led to the identification of 22 high quality preclinical candidates at rates well above industry average

Our Global Development teams have a good track record of clinical development

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Finally, our Business Development strategy is being executed to plan, with all our BD objectives for 2019 being met in the first 7 months of the year.

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Committed to remaining at the cutting edge of technology

Platform Technology (StaR® ‐ Structure)

Drug Discovery

(SBDD)Development

Business Development (New/Existing Partners)

Collaboration with the University of Cambridge to roll out artificial intelligence / machine learning across the platform

Investment in state‐of‐the‐art Cryo‐electron microscopy and DNA encoded libraries

New multi‐target research, development and commercialization partnership with Genentech

Two candidates nominated under the Pfizer multi‐target collaboration to advance into clinical development

Now turning to Slide 8.

We are 100% committed to being at the forefront of cutting edge technology.

In Platform:

Development and application of AI technology is an increasing focus for drug design and development

• We have in‐house and collaborative approaches to integrating and looking for patterns in biological and chemical information that leverages our proprietary GPCR structure and pharmacology data

• We are applying this to target selection, validation, drug discovery and patient selection – so in other words all aspects of drug discovery and early

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development

StaR proteins are not just useful for X‐Ray crystallography – new technology for structure elucidation by low temperature electron microscopy (cryoEM) and screening of vast libraries of compounds are just two new applications that we have added to our technology offering.

We are also increasingly applying the directed evolution approach incorporated following the G7 acquisition to improve the StaR generation process.

Our world leading position in GPCR structural biology is clearly shown by the three successive deals with Pfizer, Genentech and Takeda – all of them with highly expert in‐house structural biology groups – but needing to come to Sosei Heptares in order to successfully prosecute their GPCR projects.

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Generating new waves of high quality novel compounds


Drug Discovery

(SBDD)Development


15 programs ongoing in the discovery phase and 6 programs advancing in preclinical development

Shifting portfolio shape to align with translational capabilities in place for CNS and Immunology indications

Creation of two asset‐centric companies, Orexia and Inexia, to develop the treatment of neurological diseases

New strategic multi‐target research, development and commercialization partnership with Takeda

Turn to Slide 9, please.

Our Drug Discovery team continues to generate wave after wave of new, exciting, high quality molecules.

In Drug Discovery:

As mentioned, we have a sustainable pipeline of early discovery and preclinical programs moving towards partnering value inflections, with emerging disease foci in neuroscience and immunology.

This can be exemplified by the two major deals our Business Development team executed this year:

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• In February, we announced that we signed a highly innovative deal with Medicxi, to create two asset‐centric companies Orexia and Inexia to develop treatments for neurological diseases, particularly narcolepsy

• In August, we announced that we entered into a strategic multi‐target partnership with Takeda directed at multiple GPCR targets across a range of diseases, with an initial focus on high‐priority gastrointestinal targets

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Successfully advancing novel molecules into the clinic


Drug Discovery

(SBDD)Development


8 programs currently in clinical trials, both with partners and in‐house (pre‐partnered)

In‐house (pre‐partnered) programs mGlu5 and SSTR5 entered into Phase 1 development

Partnered programs A2a, M1 and M4 are all progressing with confidence, with A2a in particular advancing to Phase 2

development for multiple solid tumors

Valid Marketing Authorization Application submitted to the EMA for partnered program QVM149

Turning to Slide 10.

We continue to advance multiple novel molecules into, and through, human clinical development.

In Development:

All our 8 programs in clinical trials are progressing well.

Our in‐house programs mGlu5 and SSTR5 recently entered into Phase 1.

Our partnered programs with AstraZeneca and Allergan are progressing with

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confidence.

And our respiratory partnered portfolio with Novartis is healthily advancing, with QVM149 recently gaining EU Marketing Authorization Approval, and will launch next year.

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Executing strategic collaborations with new innovative partners


Drug Discovery

(SBDD)Development


$26m upfront and near‐term payments and $1bn+ in potential milestone payments from new Genentech collaboration

$26m upfront and near‐term payments, research funding, and $1.2bn+ in progress related milestones

from new Takeda partnership

Medicxi to invest up to €40m in new collaboration, creating two asset‐centric companies

$6m received from Pfizer, $15m received from AstraZeneca and $2.5m received from Novartis in progress related milestones

Turning to Slide 11

Executing strategic collaborations with new innovative partners is a cornerstone of our business model – and our technology and molecules continue to remain in high demand.

In Business Development:

2019 is turning out to be a very successful year, with all our BD goals already being met in the first 7 months of 2019.

We have executed two out‐licensing deals with Genentech and Takeda.

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We have entered into a highly innovative deal with Medicxi to create two asset‐centric companies.

We have also received multiple progress‐related milestones from our existing partnered programs with Pfizer, AstraZeneca and Novartis.

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We are developing new therapies for areas of high unmet medical need

Sources: World Health Organization, EvaluatePharma, Management Estimates. Notes: Market sizes represent global sales of products targeted at any aspect of the market. Sosei Heptares may choose to only target a segment of the specific market. 1 Represents market size for Cushing’s syndrome, rather than Cushing’s disease

~300Kaffected globally

$1.1bn20241

Cushing’s

~50Maffected globally

$7.4bn2024

Dementia

~1.6Maffected in US (mod‐sevuncontrolled)

$6.6bn2024

Atopic Dermatitis

~50Kaffected globally

$5.7bn2024

PAH

~450K affected globally

$1.2bn2024

ALS

~42Maffected globally

$220bn2024

Cancer

~3.1Maffected globally

$19.1bn2024

IBD

• SSTR agonist• M1 agonist• M4 agonist• M1/M4 agonist

• H4 antagonist• PAR2 mAb • Apelin agonist • mGlu5 NAM • A2a antagonist

• CXCR4 mAb • GPR35 agonist

~1.1Baffected globally

$8.3bn2024

Migraine

• CGRP antagonist

Slide 12.

Now, to bring this all together, I am so proud to show you just how many therapies we are developing across multiple areas of high unmet medical need.

One great quality of our StaR® technology is that it is not specific to a particular therapeutic area or disease. We can use it to target a broad range of diseases – ones which are prevalent and affect lots of people in the world such as Alzheimer’s Disease and Cancer, and ones which are rare or specialty, where they may not affect as many people, but these people are severely suffering without any good treatment options, and we could make a huge difference to their lives.

These are just some of the diseases we are developing new therapies for.

Moving forward we have chosen to focus more on neuroscience and GI/immunology, building disease biology and translational medicine expertise in these areas. Novel targets in these areas have significant potential for future partnerships

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with transformative value for the company.

In this next section, I would like to talk to you in more detail about some of the specific diseases and health problems that we at Sosei Heptares are fighting every day, to build a better life for patients in the future.

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Dementia affects 50 million people globally1

Sources: 1 Alzheimer’s Disease International; 2 Alzheimer’s Research UK, Dementia Statistics Hub; 3 Coherent Market Insights, Dementia Drugs Market – Global Forecast to 2026 (2018); 4 OECD (via Financial Times)

FIGHTING DEMENTIA FOR A BETTER FUTURE

Global cost of Dementia2

Dementia cases are Alzheimer’s

Disease3

People with Dementia per 1,000 population4


Dementia is a truly devastating disease, with more than 50 million people suffering worldwide. Japan accounts for over 5 million patients and leads in the number of dementia patients per capita.

Because of its scale and impact, dementia is a social and political priority globally, with an enormous global cost burden exceeding $817 billion.

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Giving Alzheimer’s patients hope with symptomatic treatment

Sources: Cummings, J. et al “Alzheimer’s disease drug development pipeline: 2018” Alzheimer’s & Dementia: Translational Research & Clinical Interventions (2018) 4: 195‐214 (based on Clinicaltrials.gov information as of 30‐Jan‐18); Cumming, J. et al “Drug development in Alzheimer’s disease: the path to 2025” Alzheimer’s Research & Therapy (2016) 8:39

Ph 3Ph 2Ph 1 2018Alzheimer’s

Drug Dev.Pipeline

HTL18318

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9 26 5

DISEASE‐MODIFYING THERAPIES (DMT) SYMPTOMATIC TREATMENTS

Disease‐modifying immunotherapy Disease‐modifying small molecule Symptom‐reducing small molecule # Number of candidate agents being tested in each phase of development

• Primary aim to modify the course of disease and slow progression or delay its onset

• Memantine and combination Memantine-donepezil – the last approved novel treatments for Alzheimer’s (Allergan)

• No approved candidate agents –all Ph 3 amyloid DMTs have failed

• Recent Ph 3 drug failures have targeted amyloid‐beta (Abeta)

• aducanumab (Biogen/Eisai)

• crenezumab (Roche/AC Immune)

• solanezumab (Eli Lilly)

• Primary aim to temporarily improve memory and attention symptoms

• 4 cholinesterase inhibitors and memantine have received marketing approval at a global level

• Allergan partnership puts us in the best position to offer significant hope to patients in near future

• Heavily weighted focus on DMTs has left patients without new treatments

• Additionally, 3 g‐secretase inhibitors and 4 BACE inhibitors have not arrested cognitive decline

• Sosei Heptares and Allergancommitted to selective M1 and/or M4 agonism to offer a FIC symptomatic treatment with a novel post‐synaptic MoA


With regards to Alzheimer’s Disease, in the longer term we would all love to see disease modifying treatments. However, all approaches tried to date have been failures.

We and others are investigating alternative approaches to disease modification such as GPCRs in neuroinflammation, but such work is very early indeed.

Symptomatic approaches will always be needed – and they remain the best hope for providing patients with some relief in the next 10‐15 years.

This is why we created a series of many molecules targeting the muscarinic receptors, and all of these molecules were partnered with Allergan in 2015, the current world leader in symptomatic dementia treatments. Together, our goal is to create a first‐in‐class symptomatic treatment for Alzheimer’s Disease.

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Potential first‐in‐class therapy with a novel post‐synaptic MoA

1 Clinical Trial Posting: https://clinicaltrials.gov/ct2/show/NCT03244228

PARTNERED WITH

Muscarinic M1 Muscarinic M4

• Work continues on the portfolio of M1 agonists to advance certain compounds through development

• Multiple compounds with the potential to be new candidates have been discovered

• HTL18318 investigation progressing – update late 2019

• HTL16878 continues to progress towards IND patient studies

• Current Phase 1 studyprogressing well1

• Backup compounds advancing in parallel

Dual M1 / M4

First‐in‐class, selective small molecule muscarinic M1receptor agonist as a potential new symptomatic treatment of cognition in neurodegenerative disorders

Designed to be selective for M1 receptors and to avoid unwanted side effects and off‐target binding seen with other poor muscarinic agonists

Works through the cholinergic pathway, however bypasses presynaptic activity, stimulating the M1 receptor directly and does not rely on Ach levels in the brain

High selectivity offers the possibility for an improved safety profile over previous non‐selective muscarinic receptor agonists

First‐in‐class, selective and orally available small molecule muscarinic M4 receptor agonist designed to work through a different MoA than available antipsychotics

Please turn to slide 15.

We believe the muscarinic hypothesis represents the best and most validated approach to treating the cognitive deficits and psychosis effects experienced by patients with Alzheimer’s Disease.

It is a potential first‐in‐class therapy, with a novel, post‐synaptic mechanism of action.

The muscarinic hypothesis utilizes the well‐understood cholinergic pathway, the same pathway that the approved drug Aricept targets (generic name donepezil), but Aricept only partly reduces degradation of acetylcholine and is non‐selective.

We have clinical evidence from our M1 programme that we can overcome side effect issues of earlier non‐selective muscarinic agents such as Xanomeline by avoiding M2 and M3 receptors.

Our M4 program in Phase 1 clinical studies continues to progress well with Allergan.

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Cancer was responsible for 9.6 million deaths in 20181

Sources: 1 World Health Organization; 2 EvaluatePharma; 3 Prasad, V., Mailankody, S. Research and Development Spending to Bring a Single Cancer Drug to Market and Revenues After Approval. JAMA Intern Med. 177(11):1569–1575 (2017); 4 EvaluatePharma. I/O Checkpoint Inhibitors includes Keytruda, Opdivo, Tecentriq, Imfinzi and Bavencio

ATTACKING CANCER WITH NEXT‐GEN

THERAPIES

Global market in 20242

Cost to develop a cancer drug3

2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024

Global I/O Sales ($bn)4

$16.3bn

$35.6bn


Cancer is the second leading cause of death globally – responsible for 9.6 million deaths last year.

It is a large market globally, expected to reach $220bn by 2024.

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Targeting adenosinergic signaling in cancer immunotherapy

Source: Computational and Structural Biotechnology Journal 13 (2015) 265–272

Accumulation of extracellular adenosine within the microenvironment is a strategy exploited by tumors to

escape immune surveillance

Adenosine signalling through the high affinity A2aR on immune cells elicits a range of immunosuppressive effects

which can promote tumor growth and limit efficacy of immune checkpoint inhibitors

Blocking A2a receptor activation can reverse adenosine mediated immune suppression to markedly enhance anti‐tumor immunity. A2a antagonists are the next generation

checkpoint blockade for cancer immunotherapy

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Adenosine‐A2aR signaling: the emergence of a novel immune checkpoint pathway


Immuno‐oncology, pioneered in Japan, is a huge R&D focus by Pharma and academia for the development of new therapies.

Despite its promise, response rates are rarely above 30% and some tumor types do not respond at all to current approved therapies. New combinations are needed to boost immune responses and improve treatment outcomes.

Adenosine is a natural immunosuppressant – reversal of its effects in the tumormay lead to greater efficacy, especially when combined with anti‐PD1/PD‐L1 antibodies.

So, we created a molecule some time ago called HTL‐1071 which was designed to block activation of the Adenosine A2a receptor. This same molecule was partnered with AstraZeneca and is now called AZD4635.

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AZD4635 is a highly potent and selective A2a antagonist

1 Clinical Trial Posting: https://clinicaltrials.gov/ct2/show/NCT027409852 Clinical Trial Posting: https://clinicaltrials.gov/ct2/show/NCT03381274

PARTNERED WITH

AZD4635A2aR antagonist

MONOTHERAPY

AZD4635

Anti‐PD‐L1

A2aR antagonist

durvalumab

AZD4635

oleclumabAnti‐CD73

A2aR antagonist

AZD4635 enhances immune activation and increases CD8+ infiltration in combination with anti‐PD‐L1

Treatment with AZD4635 alone and in combination with an anti‐PD‐L1 Ab led to a reduction in tumor growth in both adenosine high and low syngeneic tumor models

AZD4635 enhances expression of genes associated with T‐cell and antigen presenting cell functions

AZD4635 is currently in Ph1b/2 clinical trials as a single agent and in combination with durvalumab (anti‐PD‐L1 Ab)1 in patients with solid malignancies, and in combination with oleclumab (anti‐CD73 Ab)2

Blockbuster potential as both a monotherapy and combination therapy, across multiple tumor types

CHECK


AZD4635 is a highly potent and selective A2a antagonist.

It is currently in Phase 1b/2 clinical trials as a single agent and in combination with IMFINZI durvalumab (AstraZeneca’s approved anti‐PDL1 drug) and oleclumab (AstraZeneca’s investigational anti‐CD73 drug).

Our partner, AstraZeneca, recently presented positive preclinical and Phase 1a data on AZD4635, where it was shown to:

• Restore antitumor activity by preventing adenosine‐mediated suppression of immune cells

• Exhibit clinical activity as a monotherapy or in combination with IMFINZI (durvalumab) in patients with advanced solid tumors

We are very pleased with the progress of our partnered next generation immuno‐oncology program – it certainly has blockbuster potential as both a

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monotherapy and combination therapy, across multiple tumor types.

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The average life expectancy for ALS patients is 2 to 5 years1

Source: 1 ALS Association

STRIVING TO IMPROVE SURVIVAL DURATION

AND QUALITY OF LIFE

Every

Someone is diagnosed and

someone perishes1

Cost to develop a drug to slow/stop ALS progression1

Amyotrophic lateral sclerosis (ALS) is aPROGRESSIVE NEURODEGENERATIVE DISEASE that is 100% FATAL. There is NO CURE for ALS.

Progressive loss of muscle control

ALS gradually prohibits the ability to:• Speak• Swallow• Walk• Grasp objects• Move• Breathe

Slide 19, please.

ALS is a progressive neurodegenerative disease that is 100% fatal.

There is no cure for ALS. Patients will gradually not be able to speak, eat, walk, move and breathe.

The average life expectancy for ALS patients is a mere 2 to 5 years from diagnosis.

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mGlu5 NAM HTL14242 is a novel therapeutic target for ALS


CURRENTLY WHOLLY‐OWNED

HTL14242mGlu5 NAM

PHASE 1

Regulatory toxicology package complete

Investigators Brochure and IMPD complete

Ongoing preclinical work including further ALS related studies

Phase 1 clinical program initiated 1

• Double blind placebo controlled single ascending dose in healthy volunteers

• Encouraging initial PK

mGlu GPCRs are expressed throughout CNS where they modulate neurotransmission and have been shown to have potential in a variety of neurological indications

HTL14242 maintains motor function for longer and shows trend to increase survival dosed in model from disease onset

Strong preclinical evidence that mGlu5 NAM can benefit functional and survival as demonstrated in SOD1G93A

mouse model of ALS

Attractive landscape for an effective mGlu5 NAM therapeutic agent in ALS – current standard of care, Riluzole, prolongs life by ~3 months

ALS, Dystonia and Levodopa‐induced Dyskinesia (PD‐LID) represent promising therapeutic and competitive opportunities for this mechanism


Metabotropic glutamate receptors (commonly called mGlu receptors) are expressed throughout the central nervous system where they modulate neurotransmission.

Exciting animal model data generated by our collaborators suggests there is potential for an mGlu5 inhibitory drug to have an impact in ALS. The modulation of the glutamate pathway could preserve neurones and motor function for patients providing significant improvement in their quality of life.

This is why we created a series of molecules targeting mGlu5, and we currently have Phase 1 studies underway to establish safety and tolerability of HTL14242 at likely therapeutic doses.

There is also potential for combination therapy with riluzole which is a glutamate inhibitor.

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Significant potential in GPCR peptide therapeutics

Peptides

Teduglutide(GLP2)

Exenatide(GLP1)

Tesamorelin(GHRH)

Pramlintide(Amylin)

Icatibant(BK2)

HTS

Maraviroc(CCR5)

Suvorexant(OX 1/2)

Vorapaxar(PAR1)

Chemocentric

Rasmelteon(MT1)

Mirabegron(β3)

First‐in‐Class (FIC) GPCR Drugs 2005‐2015

Almost half of the FIC GPCR drugs in this 10 year period are injectable peptides

Phenotypicscreening

Fingolimod(S1P1)

Vismodegib(SMO)

Chemical ModificationsBridges and

staples

D‐Amino Acids

Fatty Acid and PEG

group additions

N‐ and alpha methylation

Applying Structure‐based Drug Discovery (SBDD) to Peptides

Opportunity to broaden our use of SBDD to peptides

Developing modified peptide hormones which may be more tractable / faster to clinic than

small molecules

Peptide FIC by subcutaneous / long‐acting injectable, with

potential to follow up with oral small molecules

Oral, topical peptides to target gastrointestinal disorders


We have also identified that there is significant potential for peptide‐based therapeutics that target GPCRs.

In our analysis, almost 50% of all the first‐in‐class GPRC‐targeted drugs approved in the 10‐year period to 2015 were injectable peptides.

Some GPCR targets more readily drugged with peptides, meaning they can reach the clinic faster than small molecules.

Therefore, Sosei Heptares has developed a set of novel peptide candidates using our SBDD approach, which have the potential to be first‐in‐class with subcutaneous and topical oral drugs.

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Current standard of care for Cushing’s Disease is inadequate

Sources: 1 EvaluatePharma; 2 Castinetti, F. et al. Cushing’s Disease. Orphanet J Rare Dis. 2012; 7:41.; 3 Melmed, S. et al. A Consensus Statement on acromegaly therapeutic outcomes. Nature Reviews Endocrinology 14, 552‐561 (2018)

2018 2019 2020 2021 2022 2023 2024

Mifepristone Pasireotide Levoketoconazole Relacorilant

$418m

$1,064mEndogenous Cushing’s Syndrome

cases are Cushing’s Disease2

Patients suffer hyperglycaemia after pasireotide

treatment3

EFFECTIVE TREATMENT IN THE ABSENCE OF

HYPERGLYCAEMIA

Global market for Cushing’s Syndrome1

Slide 22, please.

Cushing’s Disease is another disease where there is a huge unmet medical need.

Current treatments are not effective and are poorly tolerated. The majority of patients who take pasireotide suffer from hypoglycaemic‐ related side effects.

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HTL30310 is the first SSTR5 selective somatostatin agonist



HTL30310SSTR5 somatostatin agonist

PHASE 1

Package of non‐clinical GLP safety studies completed

Confirmed good safety margin vs. predicted clinical efficacious dose

Investigators Brochure and IMPD complete

Phase 1 clinical program initiated 1

• Double blind placebo controlled single ascending dose in healthy volunteers

• Two cohorts completed with no safety findings

Novel profile clearly differentiated from 1st Gen SSTR2 selective agonists Octreotide and Lanreotide and 2nd Gen non‐selective Pasireotide (not effective and poorly tolerated)

Good observed PK in non‐clinical species and good subcutaneous bioavailability across species

In vivo non‐human primate data confirms HTL30310potential to avoid SSTR2 mediated hyperglycaemia

HTL30310 offers novel therapy with equivalent efficacy to pasireotide, with significantly improved safety and tolerability profile surrounding hyperglycaemia and GI side effects

Exploring potential of HTL30310 for use in Neuroendocrine Tumors (NETs) and treatment‐resistant acromegaly

Slide 23.

Cushing’s Disease is an indication where we have identified the significant potential for a peptide‐based therapeutic.

Somatostatin agonists have the potential to be used across a variety of diseases –Cushing’s Disease, neuroendocrine tumours, and acromegaly.

We are developing a unique SSTR5 selective peptide agent aimed at overcoming side effect issues with non‐selective or SSTR2 selective agents. HTL30310 is currently in Phase 1 clinical studies.

Cushing’s Disease is our initial focus but alternative diseases such as neuroendocrine tumors and treatment‐resistant acromegaly are both equally interesting commercially and medically.

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Large global migraine market covering a wide indication spectrum

Source: 1 EvaluatePharma; 2 The Migraine Trust

Global market in 20241

thMost disabling disease among

all diseases2

DELIVERING A RAPID ONSET AND EXTENDED PERIOD OF PAIN RELIEF

Company Modality Name Indication Progress

Amgen S/C mAb Erenumab (Aimovig) Prophylaxis FDA ApprovedTeva S/C mAb Fremanezumab (AJOVY) Prophylaxis FDA ApprovedAlder IV mAb Eptinezumab Prophylaxis Phase 3 +ve

Lilly S/C mAb Galcanezumab (Emgality) Prophylaxis FDA Approved

Allergan Oral SME Ubrogepant Acute Phase 3 +ve; Filed

Biohaven Oral SME Rimegepant Acute Phase 3 +ve

Allergan Oral SME Atogepant Prophylaxis Phase 2b +ve

Biohaven IN SME BMS‐742413/BHV‐3500 Acute Phase I IN initiated

Anti‐CGRP agents currently in clinical development

Outstanding value proposition for Acute Migraine• Clinically well validated mechanism

• High value market with high unmet medical need, with room for multiple players and modalities

• Additional potential for other severe/episodic cluster headaches and pain disorders


Migraine is a neurological disease with extremely incapacitating neurological symptoms. It is ranked globally as the 7th most disabling disease among all diseases.

The global migraine market is very large, with room for multiple players and modalities.

Our initial focus is on the acute migraine part of the spectrum, with additional potential to target severe/episodic cluster headaches and pain disorders.

We have created a unique molecule with broad therapeutic potential.

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Targeting intranasal delivery for a differentiated product profile

Note: SC = subcutaneous; IN = intranasal; PUL = pulmonary; SL = sublingual

Efficacy

Highest

Lowest

Safety BetterWorse

OralRimegepant/Ubrogepant

OralLasmiditan

HTL22562SC/IN/PUL/SL

• Efficacy similar to SC suma.• Superior safety profile

• Faster onset of action vs. orals• Superior efficacy vs. orals• Substantial sub‐population of

migraineurs refractory to orals

SCSumatriptan

OralSumatriptan

Slide 25.

We are targeting a highly differentiated product profile for our drug candidate HTL22562 as illustrated by this slide – a highly novel molecule for intranasal delivery that would provide rapid relief.

Our analyses indicate CGRP oral drugs to date may not achieve full efficacy and continue to carry theoretically elevated safety risk.

Low dose, non‐oral delivery has the potential to give higher blood levels, rapid onset and reduced safety risk.

This is evidenced by subcutaneous sumatriptan (in the top left) showing clearly differentiated efficacy versus its oral counterpart (below).

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HTL22562 is a highly differentiated molecule preclinically

Clinical Trial Posting: https://clinicaltrials.gov/ct2/show/NCT03847207


HTL22562CGRP antagonist

IDENTIFIED CLINICAL CANDIDATE

Progressing towards Phase 1 FTIH in [Q4 2019]

Highly promising follow‐up program optimizing further highly differentiated molecules

Fast speed of action and greater efficacy vs. oralsPredicted fast onset and high exposure leading to improved pain freedom Extended duration of actionPredicted EC99/EC90 receptor coverage for ~9hrs/~20hrsGood safety and tolerabilityNo triptan sensations, serotonin side effects; Low risk of DILI

Potential for a strong clinical profile at low human efficacious exposures leading to superior speed, efficacy and safety profile

Predicted superior efficacy through rapid onset and long duration of action for parenteral administration

High solubility and predicted low risk of drug induced liver injury (DILI) due to differentiated physiochemical properties

High potency, competitive antagonist of CGRP and highly selective against closely related targets

Current development strategy provides opportunities for multiple routes of administration (e.g. intranasal, subcutaneous, pulmonary, sublingual)


Preclinical studies suggest our molecule, HTL22562, is highly differentiated.

Preclinical data of HTL22562 has demonstrated high potency and solubility –which positively points toward meeting our target product profile.

HTL22562 has the potential for a strong clinical profile at low human efficacious exposures, leading to:

Superior speed of onset

Superior efficacy

Superior safety profile

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HTL22562 is currently progressing towards Phase 1 first time in human studies in 2020.

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Our approach to GPCRs in the Gastrointestinal (GI) Tract

SIGNIFICANT $50 BN MARKET

~31 MILLION GI PATIENT VISITS / YR

~40 MILLION PRESCRIPTIONS / YR

RICH SOURCE OF GPCR TARGETS

MULTIPLE CLINICALLY VALIDATED MECHANISMS

OF ACTION

HIGH UNMET NEED

Mouth

Gastric EmptyingA

Oesophagus

Stomach

SmallIntestines

Small Intestinal TransitB

Colinic TransitC

Colon

Significant understanding of GI physiology Strategic GI Platform Approach

Establish target/ligand link to pathophysiology

Confirm efficacy in translational models

Determine functional effect and MoA in human primary cells and tissue

Design and optimize gut‐restricted compounds and provide a higher margin of safety than

systemically absorbed compounds

High drug levels

Low drug levels

1

2

3


The gastrointestinal market is a significant $50bn market and an area of significant unmet needs with ~31 million GI patient visits per year and ~40 million prescriptions per year.

For example, there are major unmet needs for adjunct or alternative therapies to anti‐inflammatory biologics and steroids in Inflammatory Bowel Disease.

There is a significant need for improved integrity of gut epithelial barrier, reduction in visceral pain and alternative anti‐inflammatory mechanisms.

As a result of this huge need, we have identified a number of GPCR targets that are active in GI disorders. Indeed, the focus of our recently announced partnership with Takeda is on developing new drugs that target GI diseases.

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Novel, selective GPR35 agonist for the treatment of IBD

Sosei Heptares uniquely positioned to rapidly develop and progress orally dosed GPR35 selective agonists – proven track record in cracking difficult GPCR drug targets

Developed a candidate quality GPR35 agonist molecule with minimized systemic exposure, excellent potency, selectivity and physiochemical properties

Potential to address unmet IBD needs through novel mechanism of action: potent immunomodulatory action plus anti‐diarrhea and visceral pain control function

GPR35 is the target for a known anti‐inflammatory asthma drug (cromoglycate) which has genetic association to IBD

Focus on chemistry design and optimization of high quality GPR35 agonists with low absorption and minimal systemic exposure


UndisclosedGPR35 agonist

CANDIDATE SELECTION PHASE


Separate from our recent partnership with Takeda, we are working on an exciting new selective molecule to treat IBD.

GPR35 is a known anti‐inflammatory drug target ‐ used in asthma and allergic conjunctivitis – but has inadequate pharmacokinetics.

GPR35 is also known to have genetic association with IBD.

With our proprietary StaR technology and SBDD capabilities, we have discovered high quality selective GPR35 agonists with low systemic exposure and have preclinical data supporting all three desirable mechanisms:

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• Novel immunomodulatory action

• Repair of the intestinal lining

• Visceral pain control

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We are the world leader in GPCR drug discovery and developmentSolved

Molecularstructures

From

Different GPCRs

Solved

Structures of GPCR targets

of viable GPCR targets yet to be

drugged

Significant opportunity to create new or

improved GPCR drugs

Decades of years left of GPCR drug

discovery potential

Please turn to Slide 29, my final slide for this Presentation.

I trust that today’s presentation has helped to explain how far we have come with our technology, and how we are applying and expanding this technology to create much needed treatments for patients.

We are the world leader in GPCR drug discovery and development.

We intend to stay at the forefront of technological advancements in our field of GPCRs – there is no sign of our position being eroded.

There is a vast opportunity for partnering with Pharma right across the disease spectrum as shown by our evolutionary tree picture of GPCRs with StaR

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structures generated to date labelled with our logo.

Progression through in‐house drug discovery and development of selected high‐value assets such as EP4, A2a, M1, M4 led to successive step‐changes in BD and enterprise value.

And there are many more platform and asset partnerships that we can create going forward.

There are decades left of GPCR drug discovery potential, and we at Sosei Heptares plan to be right at the forefront of this activity.

Thank you very much everyone for listening and I hope you all have a wonderful day.

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The material that follows is a presentation of general background information about Sosei Group Corporation and its subsidiaries (collectively, the “Company”) as of the date of this presentation. This material has beenprepared solely for informational purposes and is not to be construed as a solicitation or an offer to buy or sell any securities and should not be treated as giving investment advice to recipients. It is not targeted to the specificinvestment objectives, financial situation or particular needs of any recipient. It is not intended to provide the basis for any third party evaluation of any securities or any offering of them and should not be considered as arecommendation that any recipient should subscribe for or purchase any securities.The information contained herein is in summary form and does not purport to be complete. Certain information has been obtained from public sources. No representation or warranty, either express or implied, by theCompany is made as to the accuracy, fairness, or completeness of the information presented herein and no reliance should be placed on the accuracy, fairness, or completeness of such information. The Company takes noresponsibility or liability to update the contents of this presentation in the light of new information and/or future events. In addition, the Company may alter, modify or otherwise change in any manner the contents of thispresentation, in its own discretion without the obligation to notify any person of such revision or changes.This presentation contains “forward‐looking statements,” as that term is defined in Section 27A of the U.S. Securities Act of 1933, as amended, and Section 21E of the U.S. Securities Exchange Act of 1934, as amended. Thewords “believe”, “expect”, “anticipate”, “intend”, “plan”, “seeks”, “estimates”, “will” and “may” and similar expressions identify forward looking statements. All statements other than statements of historical facts included inthis presentation, including, without limitation, those regarding our financial position, business strategy, plans and objectives of management for future operations (including development plans and objectives relating to ourproducts), are forward looking statements. Such forward looking statements involve known and unknown risks, uncertainties and other factors which may cause our actual results, performance or achievements to bematerially different from any future results, performance or achievements expressed or implied by such forward looking statements. Such forward looking statements are based on numerous assumptions regarding ourpresent and future business strategies and the environment in which we will operate in the future. The important factors that could cause our actual results, performance or achievements to differ materially from those in theforward looking statements include, among others, risks associated with product discovery and development, uncertainties related to the outcome of clinical trials, slower than expected rates of patient recruitment,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 oninformation 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.This presentation does not constitute an offer, or invitation, or solicitation of an offer, to subscribe for or purchase any securities. Neither this presentation nor anything contained herein shall form the basis of any contract orcommitment whatsoever. Recipients of this presentation are not to construe the contents of this summary as legal, tax or investment advice and recipients should consult their own advisors in this regard.This presentation and its contents are proprietary confidential information and may not be reproduced, published or otherwise disseminated in whole or in part without the Company’s prior written consent. These materialsare not intended for distribution to, or use by, any person or entity in any jurisdiction or country where such distribution or use would be contrary to local law or regulation.This presentation contains non‐GAAP financial measures. The non‐GAAP financial measures contained in this presentation are not measures of financial performance calculated in accordance with IFRS and should not beconsidered as replacements or alternatives profit, or operating profit, as an indicator of operating performance or as replacements or alternatives to cash flow provided by operating activities or as a measure of liquidity (ineach case, as determined in accordance with IFRS). Non‐GAAP financial measures should be viewed in addition to, and not as a substitute for, analysis of the Company's results reported in accordance with IFRS.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 monthperiod 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 Heptares is a trading name. Sosei and the logo are Trade Marks of Sosei Group Corporation, Heptares is a Trade Mark of Heptares Therapeutics Limited. StaR is a Trade Mark of Heptares Therapeutics Limited

Disclaimer

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Locations

SOSEI HEPTARES

PMO Hanzomon 11F

2‐1 Kojimachi, Chiyoda‐ku

Tokyo 102‐0083

Japan

Steinmetz Building

Granta Park, Cambridge

CB21 6DG

United Kingdom

North West House

119 Marylebone Road

London NW1 5PU

United Kingdom

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Malcolm Weir –EVP, Chief R&D Officer · 2019-09-19 · 2015 EVP, CHIEF R&D OFFICER, 4 YEARS...

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Transcript of Malcolm Weir –EVP, Chief R&D Officer · 2019-09-19 · 2015 EVP, CHIEF R&D OFFICER, 4 YEARS...