1. Simon Kerr, CEO • BioTrinity Conference • 25-27th April 2016
Unlocking the Potential of Cyclophilin Inhibition for Degenerative Diseases
Simon Kerr, CEO • BioTrinity Conference • 25-27th April 2016

2. Overview of Cypralis
Selcia spin-out in 2013 Extensive drug discovery platform Potent, selective cyclophilin inhibitors Disease-modifying mechanisms Opening up new treatment pathways

3. Cypralis Cyclophilin Inhibitors
Cypralis Strategy
Selective targeting of cyclophilins to modulate mitochondrial mediated cell death (CypD) and/or inflammation (CypA) will lead to novel treatments for degenerative diseases
Tissue
Pancreatitis, SIRS, MCI
Acute disease
Cypralis Cyclophilin Inhibitors
CNS
Traumatic brain injury
Tissue
Muscular dystrophies, diabetes
Chronic disease
CNS
Alzheimer's, dementia, Parkinson’s
Cypralis development
Partnered

4. Cyclophilins as Drug Targets
Enzymes with well characterized active sites
Assayable via binding or functional methods
Existing inhibitors are non-selective and have poor drug properties
Amenable to X-ray structural analysis
Disease associated – stable KO and RNA silencing methods
Tractable targets for small molecule drug discovery

5. Cypralis Focus on Key Cyclophilins
Cyclophilin A
Cyclophilin B
Cyclophilin D
Widely distributed
Secreted
Cytokine and chemokine
Inflammation target
Endoplasmic reticulum
Secreted
Cytokine and chemokine
Inflammation/cancer target
Mitochondrial membrane
Modulates MPTP
Inhibition controls cell death
Target for degenerative conditions

6. Cyclophilin D and Degenerative Diseases
Opening of the MPTP is a key step in mitochondria mediated cell death
Deregulated cell death is a hallmark of acute and chronic degenerative diseases
Cyclophilin inhibition offers a novel approach to degenerative diseases
Ischaemic injury
Neurodegeneration
Acute/chronic
Inflammatory tissue injury
Muscular
dystrophies

7. Cyclophilin Inhibitors
The cyclophilin inhibitor field has an urgent need for novel, potent and selective compounds, with good drug-like properties, as treatments for acute and chronic degenerative diseases
Cyclosporin A
Immunosuppressive
Non-selective for cyclophilins
Non-immunosuppressive analogues (e.g. Alisporivir) also non-selective
Poor PK properties
Sanglifehrin A
Immunomodulator
Non-selective for cyclophilins
Difficult to scale
Poor drug properties

8. Cypralis Cyclophilin Inhibitor Platform
Assays
PPIases
Cyclophilins
FKBPs
Parvulins
(CYP A,B,C,D)
FKBP (12,38,51,52)
(Pin 1)
Inhibitor collection
Cypralis library (>1000)
Cyclic peptides
Macro-lactones
Macro-heterocycles
>5 sub families
>3 sub families
>8 sub families
Assets and Capabilities
Patent estate
(10 NME patents)
Academic KOL network:
Therapeutic experts • Structural biology

9. Cypralis Cyclophilin Inhibitors – Cell Protection
Inhibitor Design – Potent and selective inhibitors achieved
Cyclophilin A Ki, (nM)
Cyclophilin D Ki, (nM)
Cyclosporin A 5 15
CC-714
320 6
CC-763 29
597
Cell protection
Cellular protection of hepatocytes, myocytes, T-cells and pancreatic acinar cell by selective cyclophilin D inhibitors

10. Cypralis First Indication - Acute Pancreatitis
Acute pancreatitis is an unmet medical need with a rising incidence rate
Occurrence and Outcomes:
Incidence in UK 10-40/100,000/year and increasing
Higher in USA & Scandinavia (up to ~70/100,000)
500,000/year hospital admissions in US/EU for AP
Risk factors include: alcohol, hyperlipidaemia, diabetes, obesity
Incidence has doubled in 20 years
Overall mortality ~5%
Product Opportunity:
Intravenous delivered drug to treat signs and symptoms of mild/moderate acute pancreatitis
Short treatment period, 7-14 days
Favourable health economics by reducing mean stay in ICU (typically > 10 days for severe AP)
No disease-modifying drug exists

11. Cypralis Acute Pancreatitis Programme
…mitochondrial permeability transition pore induction and damage in the pancreas: inhibition [of cyclophilin D] prevents acute pancreatitis…
Professor Robert Sutton, Royal Liverpool University Hospital (Gut, 2015)
As marker of pancreatic damage
Cypralis’ lead compounds show:
Potent inhibition of CypD
Protection of pancreatic acinar cells from apoptotic/necrotic stress
Good distribution properties upon i.p. dosing
Cypralis has demonstrated that a cyclophilin D selective compound is efficacious in vivo (murine model of AP)
Cypralis cmpd

12. Strategy & Financing
Cypralis has an unmatched platform of cyclophilin inhibitors with the potential for first-in-class drugs to treat acute & chronic degenerative diseases
Series A fundraising (H1 2017) will focus on generating early clinical proof of principle:
formulation, development, CTA-enabling & early clinical studies in AP
explore additional indications
In parallel, pursuit of chronic degenerative diseases via existing & new partnerships:
Gilead Sciences Inc. (liver diseases)
Janssen Pharmaceuticals Inc. (chronic neurodegeneration)
If you are interested to know further details, we will be pleased to discuss our Series A funding plans with you.

13. Thank you Simon Kerr MSc, CEO, Cypralis
Mob:
Michael Peel Ph.D, CSO, Cypralis
Mob:
Cypralis Limited, Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS. UK
Tel: Fax: