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

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

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

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

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

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

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

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

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

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

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

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.

Thank you Simon Kerr MSc, CEO, Cypralis simon.kerr@cypralis.com Mob: +44 7802 875 819 Michael Peel Ph.D, CSO, Cypralis michael.peel@cypralis.com Mob: + 44 7540 810 595 Cypralis Limited, Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS. UK Tel: + 44 1277 367 020 Fax:+ 44 1277 367 099 www.cypralis.com