Retinab for Diabetic Retinopathy

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1 Retinab for Diabetic Retinopathy Tarnhelm Therapeutics January 2014

2 Tarnhelm Therapeutics Company Background Virtual company based in Bryn Mawr, PA Developing biologics for diabetic retinopathy (DR) and idiopathic pulmonary fibrosis. Management Martin D. Phillips, M.D. (CEO) Almost 30 years of academic medical practice, grant funded research, pharmaceutical and biotech experience, angel investing, consulting and philanthropic board service Extensive collaborations with academic thought leaders, industry leadership and CROs David Clemmons, M.D. (Founder & Retinab CSO) Over 300 papers published in the field in IGF-1 signaling Chief, Division of Endocrinology & Metabolism, School of Medicine, UNC CH Biotech experience in founding a company and functioning as CSO though IND.

3 2013 Tarnhelm Therapeutics What is Diabetic Retinopathy?

3 Tarnhelm Therapeutics What is Diabetic Retinopathy? High blood sugar causes damage to capillaries over time Diabetic patients have changes in the capillaries of the retina Damaged capillaries lead to visual problems Leaky vessels ooze fluid into the retina where it accumulates, known as Diabetic Macular Edema (DME) It is like trying to read through a water balloon. Abnormal new vessels (Proliferative Diabetic Retinopathy; PDR) form in response to poor blood supply These poorly formed new vessels leak fluid and bleed into the retina, causing microaneurysms, cotton wool spots, hemorrhage and exudates

4 Tarnhelm Therapeutics Unmet Need in Diabetic Retinopathy Diabetes is increasing in prevalence with aging and obesity DR is the most common cause of blindness in working age adults in developed countries Two marketed therapies, Lucentis and Eylea target vascular endothelial growth factor (VEGF) These drugs treat the leakage problem in about 50% of patients* They do not prevent progression of new blood vessel formation (PDR) in most patients Lucentis is only approved for DME, not PDR; Eylea only for AMD Collectively bring in >$3 Billion/year in revenue *NICE Commission Review, January 2013, 10 letter improvement only in patients with diabetic macular edema

5 Tarnhelm Therapeutics How Does High Blood Sugar Damage the Retina? Poor circulation in retinal capillaries leads to hypoxia, which in turn results in production of Insulin-Like Growth Factor (IGF-1) locally in the eye IGF-1 binds to its receptor and triggers a harmful signal to the retinal endothelial cells that damage the cells function The signals are sent by a complex of three proteins: the IGF receptor, CD47 and SHPS-1 For IGF-1 to send damaging signals, CD47 needs to form a complex with SHPS-1 High blood sugar also causes deleterious changes to CD47 These changes function like a switch locked into the on position This creates a positive feedback loop leading to more damage

2013 Tarnhelm Therapeutics Normal cell 6 IGF-1 IGF-1

IGF-1 binds receptor Diabetic Retinopathy Plus Retinab

CD47 inactive; No damaging signals Tri-molecular complex

6 2013 Tarnhelm Therapeutics Normal cell 6 IGF-1 IGF-1 Receptor SHPS-1 CD47 Diabetic Retinopathy: Increased IGF-1 IGF-1 binds receptor Diabetic Retinopathy Plus Retinab CD47 cleaved CD47 not cleaved, switch locked on Retinab CD47 inactive; No damaging signals Tri-molecular complex causes damaging signals Retinab inactivates CD47 and prevents signaling

7 Tarnhelm Therapeutics Why is IGF-1 Important? Diabetics treated with somatostatin (IGF-1 release blocker) exhibit reduced severity of DR Dwarfs who lack IGF-1 may have diabetes, but do not get DR IGF-1 levels are high in the eyes of diabetics with DR Mice genetically altered to make IGF-1 in the eye get DR No increase in DR with systemic IGF-1 overproduction IGF-1 injected into pig eyes leads to DR Polymorphisms of the IGF-1 gene are associated with a predilection for DR

8 2013 Tarnhelm Therapeutics 8 Retinab Monoclonal antibody directed against CD47, specifically in a region that prevents the signaling from the IGF-1 receptor Disrupts the IGF-1 / CD47 / SHPS-1 complex and prevents transmission of the damaging signals Effectively prevents DR in rodents with diabetes Works upstream in the signaling pathway in comparison to VEGF inhibitors, current standard of care in diabetic retinopathy Numerous experiments show that Retinab: Prevents formation of signaling complex Decreases VEGF mrna (target of marketed products) Decreases edema; increases adhesive proteins at cell junctions Decreases inflammation Prevents damage to existing capillaries and prevents formation of abnormal new capillaries

9 2013 Tarnhelm Therapeutics 9 Preclinical Data

2013 Tarnhelm Therapeutics 10 Anti-CD47 Inhibits the Signal Cascade from IGF-1 In diabetes, when CD47 and SHPS-1 form a complex, the IGF-1 receptor transmits a signal into the cells that Increases

10 2013 Tarnhelm Therapeutics 10 Anti-CD47 Inhibits the Signal Cascade from IGF-1 In diabetes, when CD47 and SHPS-1 form a complex, the IGF-1 receptor transmits a signal into the cells that Increases VEGF Increases fluid leakage and Stimulates formation of incompetent capillaries that that bleed into the retina. In this figure, the height of the bars indicates the number of CD47-SHPS1 complexes that are formed. Diabetic rats have a high number of complexes, but rats treated with anti-cd47 have the same number as the control rats.

11 2013 Tarnhelm Therapeutics 11 Anti-CD47 Decreases Retinal Edema Diabetic rats (middle bar) leak more Evans Blue (a dye that indicates leaked plasma) than normal control rats (lefthand bar). Anti-CD47 (right-hand bar) decreases leakiness to control levels.

2013 Tarnhelm Therapeutics 12 Anti-CD47 Decreases Production of VEGF mrna Anti-CD47 antibody decreases the amount of VEGF mrna induced by IGF-1 back to

12 2013 Tarnhelm Therapeutics 12 Anti-CD47 Decreases Production of VEGF mrna Anti-CD47 antibody decreases the amount of VEGF mrna induced by IGF-1 back to control levels (VEGF is the target of Lucentis and Eylea). By working upstream from these drugs, anti-cd47 has multiple mechanisms to decrease the effects of DR.

13 2013 Tarnhelm Therapeutics 13 Anti-CD47 Decreases Inflammation Inflammation contributes to the progression of DR. Anti-CD47 decreases the number of inflammatory white blood cells around the vessels in rats with diabetes back to control levels.

14 2013 Tarnhelm Therapeutics 14 Anti-CD47 Contributes to Competent Capillaries Occludin is a protein that resides at junctions between cells and serves as a molecular glue. Anti-CD47 restores the amount of Occludin to normal levels in diabetic rats retinal capillaries.

15 Anti-CD47 Maintains Normal Retinal Capillaries in Diabetic Rats 15 Vessels/ Vessels/mm millimeter squared Control n=9 Diabetic n=14 Diabetic + Ab n=13 Acellular Degenerate Capillaries/mm 2 Capillaries/mm 2 Pericyte Pricyte Ghosts/mm 2 2 Fig 3 Changes in pericytes and capillaries Normal capillaries are made of endothelial cells surrounded by pericytes, and constructed in orderly networks. In DR, the endothelial cells die out (acellular capillaries) and the pericytes and endothelial cells die and leave a footprint (pericyte ghosts). Diabetic rats were treated for 6 months with anti-cd47 then capillary and pericyte changes were quantified. Acellular capillaries and pericyte ghosts were maintained at normal levels. The number of degenerate capillaries approached normal levels Tarnhelm Therapeutics

Anti-CD47 Prevents Abnormal New Vessel Formation Rodent diabetic models do not replicate the formation of new abnormal capillaries (as seen in human DR) unless they become hypoxic Abnormal new

16 Anti-CD47 Prevents Abnormal New Vessel Formation Rodent diabetic models do not replicate the formation of new abnormal capillaries (as seen in human DR) unless they become hypoxic Abnormal new capillaries bleed into the retina and cause loss of vision In a model of retinopathy of prematurity, a disease caused by lack of oxygen from the retinal blood supply, anti-cd47 antibodies prevented the formation of abnormal new capillaries 16 New Capillaries 2013 Tarnhelm Therapeutics

17 Tarnhelm Therapeutics Clinical Development Pathway for Rapid Proof of Efficacy Diabetic retinopathy has two components: edema and new vessel formation Edema is quickly responsive to treatment and measurable Qualitative: patients can read more lines on an eye chart Quantitative: OCT measures retinal thickness with micrometer precision Clear changes expected in 4 weeks or less Prevention of abnormal vessel formation can be quantified with longer observation, but investment is not necessary until justified by fast read-out of edema Demonstration of prevention of neovasculature in humans would be novel Already demonstrated in pre-clinical experiments

18 2013 Tarnhelm Therapeutics 18 Current Status Preclinical proof of concept complete Next steps: Humanization by top echelon CRO, optimized for affinity and expression level Confirm POC in primates with humanized antibody GMP manufacture GLP toxicology study IND filing Phase 1 study with phase 2a efficacy readout Intellectual Property US Patent 8,613,922 issued on December 24, 2013 Covers target and composition of matter Divisional applications pending on additional claims Worldwide patent applications (published) PCT date Feb. 2014

19 Tarnhelm Therapeutics Partnering Suited to Needs of Licensee Several options for structure of a partnership Acquirer can license worldwide rights for complete internal development Tarnhelm is a nimble biotech with deep experience in monoclonal and biologic development Able to undertake any or all aspects of clinical development in cooperative research agreement

20 2013 Tarnhelm Therapeutics 20 Contact: Martin Phillips Mobile:

EyeGene Inc. Contact Information Korea Health Industry Development Institute

EyeGene Inc. Contact Information Korea Health Industry Development Institute EG-Mirotin: First-in-Class recombinant polypeptide novel subcutaneous drug containing RGD-motif targeted to suppress edema and vascular leakage for Nonproliferative Diabetic Retinopathy (NPDR) EyeGene