ARVO Annual Meeting, May 1, 2018, Honolulu, Hawaii

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ARVO Annual Meeting, May 1, 2018, Honolulu, Hawaii A novel oral plasma kallikrein (PKal) inhibitor KV123833 blocks VEGF-mediated retinal vascular hyperpermeability in a murine

1 ARVO Annual Meeting, May 1, 2018, Honolulu, Hawaii A novel oral plasma kallikrein (PKal) inhibitor KV blocks VEGF-mediated retinal vascular hyperpermeability in a murine model of retinal edema (#3464) Nivetha Murugesan, Allen C. Clermont, Louise J. Rushbrooke, Peter A. Robson, Robrecht Thoonen, Stephen J. Pethen, Sally L. Hampton & Edward P. Feener

2 Diabetic Macular Edema (DME) Approximately 900,000 patients in the United States have active DME and are at serious risk of vision loss 1 DME is caused by breakdown of the blood-retinal barrier resulting in the leakage of fluid and circulating proteins into the neural retina 2 Normal Retina Severe NPDR Centralinvolved DME 2 Source: (1) Zhang X et al. JAMA. 2010;304(6): ; (2) Duh et al, JCI Insight 2017, July 20, 2(14)

40% of Eyes with DME have Minimal Visual Improvement in Response to Ranibizumab at 12 weeks Post hoc analysis of Protocol I: Early and Long-term responses Mean BCVA response among stratified

3 40% of Eyes with DME have Minimal Visual Improvement in Response to Ranibizumab at 12 weeks Post hoc analysis of Protocol I: Early and Long-term responses Mean BCVA response among stratified ranibizumab treated eyes * Mean Change: 12 weeks 15.2 letters 6.9 letters -0.3 letters Eyes 37% (126 of 340) 23% (79 of 340) 40% (135 of 340) 3 Source: * Gonzalez VH et al. Am J Ophthalmol 2016;172:72 79.

Plasma Kallikrein and VEGF do not Correlate in DME Vitreous Not all DME patients have increased VEGF 1 Mainly PKal All patients show increased PKal 1 increased VEGF & PKal increased 4000 PREKAL VS

4 Plasma Kallikrein and VEGF do not Correlate in DME Vitreous Not all DME patients have increased VEGF 1 Mainly PKal All patients show increased PKal 1 increased VEGF & PKal increased 4000 PREKAL VS VEGF VEGF (PG/ML) r=0.168, p = PLASMA PREKALLIKREIN (nm) DME Patients with high PPK and low VEGF 4 Source: (1) Kita T et al. Diabetes 2015;64:

5 The Kallikrein Kinin System 1 ~50µg/ml in plasma Contact Activation System Inflammation & Edema 5 Source: (1) Phipps JA & Feener EP Kidney International. 73(10):1114-9, 2008 May

6 Plasma Kallikrein Mediates Retinal Vascular Permeability and Edema Induced by Multiple Triggers Factors implicated in triggering macular edema: % Reduction in retinal vascular permeability/edema with: Plasma Kallikrein Inhibitor Plasma PreKallikrein Gene Knockout Diabetes/Hyperglycemia -83% 1-78% 2 Inflammation (TNFα) -52% 3 Hypertension -70% 4 Hemorrhage (carbonic anhydrase) -81% 5 VEGF -57% 3-47% 3 6 Source: (1) Clermont et al, Diabetes 2011; (2) Kita et al, Diabetes 2015; (3) Clermont et al, IOVS 2016; (4) Phipps et al, Hypertension 2009; (5) Gao et al, Nature Medicine 2007

7 VEGF increases Plasma Kallikrein levels in the Retina 1 VEGF Kallikrein Activation Saline VEGF IVT Injection 7 Source: (1) Clermont et al. Invest Ophthalmol Vis Sci. 2016;57: Green endothelial cells (CD31) Red plasma prekallikrein (PPK)

Plasma Prekallikrein contributes to VEGF-induced Retinal Edema in Mice 1 Knock-out of plasma prekallikrein reduced retinal edema triggered by intravitreal injection of VEGF Plasma kallikrein

8 Plasma Prekallikrein contributes to VEGF-induced Retinal Edema in Mice 1 Knock-out of plasma prekallikrein reduced retinal edema triggered by intravitreal injection of VEGF Plasma kallikrein activity mediates, in part, the edematous effects of VEGF on the retina Plasma Prekallikrein (Klkb1) knockout in mice p < Source: (1) Clermont et al Invest Ophthalmol Vis Sci. 2016;57:

9 KV123833: Pharmacological Profile MW: < 500 daltons Human Pkal Ki: 3nM > 500 fold selectivity vs. serine proteases Solubility: >500 µg/ml (aqueous and gastric fluid) Species PKal KV IC 50 Human 11.0nM ± 6.2 Mouse 14.8nM ± 5.7 Rat 17.5nM ± 8.4 Oral bioavailability: 36% (rats) 9

10 Ex-Vivo Assay to Measure Plasma Kallikrein Activity in Whole Plasma HK (full length) Dextran sulfate-stimulated kininogen (HK) cleavage in undiluted human plasma FXII Pkal PPK Cleaved HK % full-length HK FXIIa KV is protective against HK cleavage in undiluted human plasma 10

Plasma and Retina exposure of KV123833 following systemic administration in mice using Alzet 1003D osmotic pumps VEGF increases retinal exposure of circulating

11 Plasma and Retina exposure of KV following systemic administration in mice using Alzet 1003D osmotic pumps VEGF increases retinal exposure of circulating KV DAY1 DAY2 DAY3 Osmotic Pumps (s.c) VEH/KV Plasma Exposure VEGF/PBS IVT Collect Plasma Perfuse & Harvest Retina Retinal Exposure KV VEHICLE 137 ng/ml 11

12 Systemically administered PKal inhibitor KV reduces VEGF-induced RVP in mice DAY1 DAY2 DAY3 DAY4 Retinal Vascular Permeability VEGF IVT (24hrs) Osmotic Pumps (s.c) VEH/KV VEGF/PBS IVT EB infusion (2h) Retinal isolation Retinal EB assay KV123833: 1.92 mg/kg/day (2mg/ml in 10% PEG400/90% PBS (v/v)) 1003D Alzet pumps inserted s.c. in mice % 12

13 Oral Pharmacokinetics of KV in mice Oral gavage of 45 mg/kg KV in mice maintains plasma exposure over 137 ng/ml for about 9 hours Mean Plasma Exposure of KV (ng/ml) ~ 137 ng/ml 13

14 Orally administered PKal inhibitor KV is protective against VEGFinduced retinal leakage in mice DAY1 DAY2 DAY3 Retinal Vascular Permeability VEGF IVT (24hrs) -GAVAGE 1 (VEH/833) -IVT VEGF/PBS -GAVAGE 2 (VEH/833) -GAVAGE 3(VEH/833) -EVANS BLUE (EB) circulation -Retina & Plasma collection -Retinal EB assay % Nominally 50mg/kg bid (in 10% DMSO/10% Cremophor/80% H2O)

15 Conclusions Orally administered PKal inhibitor KV is highly protective against VEGF-induced retinal edema in mice Intravitreal injection of VEGF increases retinal exposure of circulating KV suggesting that retinal vascular hyper-permeability increases drug distribution to the retina Previous work has implicated plasma kallikrein in mediating VEGF-independent DME. This current study suggests that oral PKal inhibitors may also provide an opportunity to reduce the edematous effects of VEGF in DME. 15

16 Diabetic Retinopathy Retina ischemia Breakdown of the BRB, leaky microaneurysms, retinal hemorrhages Anti-VEGF therapies VEGF Plasma Kallikrein system Anti-PKal Therapies IVT injection KVD001 Oral PKal Inhibitor Diabetic Macular Edema 16

17 Study of the Intravitreal Plasma Kallikrein Inhibitor, KVD001, in Subjects With Center-Involving Diabetic Macular Edema (cidme) Approximately 123 patients who have discontinued treatment with anti-vegf therapy and who still have significant edema and reduced visual acuity Sham-controlled, double-masked clinical trial will evaluate two doses Efficacy endpoints include best corrected visual acuity (BCVA), central subfield thickness (CST), and the diabetic retinopathy severity scale (DRSS) ClinicalTrials.gov Identifier: NCT Enrollment 2-month washout 3 months of treatment (4 injections) 3-month follow up Readout H

Corporate Presentation. July 2018

Corporate Presentation. July 2018 Corporate Presentation July 2018 Forward-Looking Statements This presentation and the accompanying oral presentation contain forward-looking statements within the meaning of the safe harbor provisions