GPCR targeted drug discovery...hit discovery in vitro + in vivo pharmacodynamics target discovery GPCR biosensors, revolutionizes drug development by enabling hit discovery and ...

GPCR targeted drug discovery

Grace O. Mizuno, PhD Co-Founder & CEO

Domain expert who established company’s platform

Lin Tian, PhD Co-Founder & Scientific advisorInventor of company technology

Seven Bioscience’s leadership team is made up of key scientific leaders and business experts

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Mark von Zastrow, MD, PhDScientific advisor

Kit Lam, MD, PhDScientific advisor

Friedhelm Blobel, PhDStrategic advisor

G Protein-Coupled Receptors (GPCRs) are implicated in diseases across every therapeutic area but a majority of druggable GPCRs have not been targeted

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Not targeted (224) In clinical trials (67) Established (107)0%

10%

20%

30%

40%

50%

60%

224 druggable GPCRs have not been successfully targeted

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USABLE IN PRE-CLINICAL ANIMAL MODELS IN REAL-

TIME

REPORTS DIRECT RECEPTOR-LIGAND

DYNAMICS (TEMPORAL KINETICS)

USED TO IDENTIFY BIASED LIGANDS

USED TO INTERROGATE ALLOSTERIC

MODULATION

USED FOR ORPHAN RECEPTORS

SUITABLE FOR ALL GPCRS

Our technology ✔ ✔ ✔ ✔ ✔ ✔

Radioligand binding ✔ ✔ ✔ ✔

CRE/ SRE reporter ✔ ✔

Fluo-4 Ca2+ assays ✔ ✔

IP3 assays

cAMP assays

BRET/ FRET B-Arrestinrecruitment ✔ ✔ ✔

BRET/ FRET Dimerization ✔ ✔ ✔

Despite decades of effort, existing GPCR technologies produce compounds that often lack clinical efficacy due to their inability to readout the functional physiology of the target

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Does not require

• Structural information• Known endogenous ligand• Known g-protein coupling

pathway

Seven’s technology, GPCR biosensors, overcomes the challenges other technologies face

• Kd• Emax• Ligand binding kinetics• Receptor conformation• Constitutive activity • Allostery/ dimerization• Off-target effects

Real-time output

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hit discoveryin vitro + in vivo

pharmacodynamics target discovery

GPCR biosensors, revolutionizes drug development by enabling hit discovery and candidate development in vivo and in vitro

HIT DISCOVERY

• affinity• potency• conformation defined functional

states dimerization modulation• residence time• subtype specificity + off target effects

PRE-CLINICAL PHARMACODYNAMICS

• real-time cellular + anatomical specificity

• msec temporal resolution

POWERFUL PRE-CLINICAL MODELS

TARGET DISCOVERY

• deorphanization• in vivo target validation compatible

with genetic animal models and behavior paradigms

NEW VALIDATED TARGETS

NEW CHEMISTRY

Tian et al., 2009Huber et al., 2012

Objec&on discrimina&on task

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The compounds that we identify have a higher probability of success in the clinic because our technology achieves answers to difficult to address pre-clinical questions

Illustration

Questions we can answer in pre-clinical animal models:• Is the pathophysiology changing in response to drug X?• What is the real-time efficacy of drug X?• What is the real-time safety profile of drug X?• Are there any off-target effects?• How does drug X perform in vivo compared to drug Y?

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*3-5 months to generate new sensor

cpGFP

cpmApple

We can explore a broad range of GPCRs since GPCR biosensors can be engineered for any GPCR including orphans

• MOR, KOR, DOR opioid • GRP (BB2) gastrin releasing

peptide • CRF corticotrophin releasing factor • DRD1, DRD2, DRD4 dopamine• 𝛽1 and 𝛽2 adrenergic • 5HT2a serotonin • A2a adenosine • MT2 melatonin • NPY neuropeptide Y• NTR neurotensin

Sensors generated to date

• Single fluorescent protein preserves optical bandwidth for imaging with multiple sensors, even closely related receptor subtypes: target selectivity/ off-target effects

• High signal to noise ratio: easy to obtain EC50/ IC50, activation/ deactivation kinetic information in HTS format (Z-prime = 0.7 using FLIPR Tetra)

• Easy to optimize and implement for all GPCRs (class A, B, etc.) including orphans, without structural information

• Directly reflects ligand induced conformation changes which enables the identification of biased ligands

• Allows both discovery and characterization of the effect of: PAMs, NAMs, agonists, antagonists, inverse agonists

• High spatial and temporal (real-time) resolution for pre-clinical animal imaging

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Seven’s technology is unmatched, powerful and revolutionary

Our business model integrates an in house and partnered pipeline

v Partnered drug development§ Partnered drug discovery § Partnered pre-clinical developmentà Licensing of development assets

v In house drug development*§ In house assay development§ In house drug discovery§ In house pre-clinical development à Licensing of development assets

*Possible separate target-based LLC subsidiaries

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Grace O. Mizuno, PhD

[email protected]