Blindness, Liver Fibrosis, & Cancer March 2019 1 - PowerPoint PPT Presentation

Blindness, Liver Fibrosis, & Cancer March 2019 1

First-in-Class Treatment for Unmet Medical Need Lin Bioscience is a drug development company focused on sourcing/advancing first-in- class therapeutic candidates in areas with significant unmet need, and then out-license these assets for partnership. The Company’s pipeline consists 2 technology platforms (RBP4 platform & CDC7 platform) and 4 distinct small molecule drug candidates: • 008: Dry Age-Related Macular Degeneration & Stargardt Disease • 009: Non-Alcoholic Fatty Liver Disease & Type 2 Diabetes • 007: Acute leukemia & Solid tumors • 002: Glioblastoma & Brain metastasis 2

All Indications are potential Blockbusters Obtained RPD + ODD Eligible for PRV NIH Blueprint Sponsored Rare Pediatric Disease Designation (US) & Eligible for Priority Review Voucher upon Most advanced candidate Orphan Drug Designation (US & EU) NDA $10M+ funding to date Worth $150-350M upon transfer Expected Drug Approval in $1B + 20B + 20B + 6B Potential Multiple Solid 4 years Market Tumors Treatment Seek Fast Track + Accelerated Approval Estimated global market for Stargardt + Obtained ODD (US) on ALL based on RBP4 biomarker predicting AMD + NASH + Leukemia / Multiple Solid Estimated global market $6B clinical efficacy Tumor 3

Pipeline DISCOVERY PRE-CLINICAL PHASE I PHASE II / III MARKET Dry AMD Stargardt Disease (FDA RPD, FDA ODD, EMA ODD) RBP4 Platform Non Alcoholic Fatty Liver Disease (NASH) / Type 2 Diabetes Acute Leukemia (FDA ODD) Multiple Solid Tumors Oncology Programs Glioblastoma / Brain Metastasis 4

RBP4 PLATFORM 5

RBP4 protein transports retinol (vitamin A) from the liver to peripheral tissues. It is: PLATFORM OVERVIEW Highly Expressed Anti-RBP4 Platform in the liver and adipose tissue Therapies for Aging Easily Measured Metabolic Diseases via blood samples (ELISA) Linked to Aging Metabolic Diseases Evidence linking elevated RBP4 to diabetes, liver disease and macular degeneration 6

MEET THE UNMET NEED Anti-RBP4 Platform for Aging Metabolic Diseases DISCOVERY Bring HOPE TO PRE-CLINICAL INCURABLE BLINDESS ✓ PHASE I For Dry Age-Related Macular PHASE II/III Degeneration & Stargardt Disease DISCOVERY MARKET ✓ PRE-CLINICAL PHASE I PHASE II/III MARKET Block THE PATH TO METABOLIC DISEASES For Non-Alcoholic Fatty Liver Disease & Type 2 Diabetes 7

Bring Hope To Incurable Blindness For Dry Age-Related Macular Degeneration & Stargardt Disease DISCOVERY PRE-CLINICAL ✓ PHASE I KEY OPPORTUNITY MARKET PHASE II/III MARKET Zero Approved 1 in 10,000 11M Treatments Blind victims suffer Stargardt Disease Juvenile onset from macular macular degeneration (rare degeneration in the US pediatric disease & orphan disease) RPD ODD 170M $20B for Stargardt (US & EU) Cases of AMD worldwide Estimated global market with a global direct NIH Blueprint healthcare cost of USD 255B Most Advanced Candidate Reference: Globaldata, Lancet, Orphanet, STEM CELLS Translational Medicine 8

Symptoms of AMD PRODUCT DISEASE PROFILE Normal Macula Normal Central Vision Blurry & Early Dry AMD Distorted Lipofuscin accumulation Central Vision Late Stage Geographic Atrophy Lost Central Vision Drusen formation and inflammation 9

Pathogenesis of AMD & Stargardt Disease PRODUCT DISEASE PROFILE Normal Retina RPE Changes Rods Die, Cones Spared Cones Die Vision Loss 10

LBS-008 Induced Enzymes Down-Regulation MOA: Dry AMD & Stargardt Retinal Isomers Pigments RBP4 Transports Retinol (Precursor to Cytotoxic A2E) into Retina by Way of Visual Cycle Rhodopsin STARGARDT Loss of PR , ERG 11c-Ral at-Ral abnormalities STARGARDT Gene mutation A2E PHOTORECEPTORS causes loss of (PR) ABCA4 ABCA4 transporter function at-RDH DRY AMD Retinal isomers are required by normal visual function. 11c-RDH They are also precursors to the cytotoxic A2E Loss of RPE causing dry AMD and Stargardt. RETINAL PIGMENT 11c-Rol at-RE at-Rol RPE65 LRAT EPITHELIUM (RPE) LBS-008 RBP4 BLOODSTREAM Inhibits RBP4 from delivering Primary transporter of retinol into RPE , reducing A2E retinol into RPE accumulation by 50% 11

Reduces Bisretinoid Accumulation by 80% IN ABCA4-/-RDH8-/- MICE, COMPARED TO LBS-008-TREATED 56 48 A2E Concentration (pmol per eye) 26 Serum RBP4 (ug/mL) 6 3 1.75 p=0.003; unpaired t-test Wild Type DKO DKO untreated control vehicle-treated control LBS-008-treated 12

Degeneration in Abca4-/-Rdh8-/- Mice ANIMAL STUDY DATA 70 Dry AMD or Stargardt’s is associated 60 with thinning of the outer nuclear layer (ONL) and the loss of photoreceptor 50 ONL thickness ( μ m) cells, indicating macular 40 degeneration. 30 20 We quantified the ONL thickness and found ONL thickness was significantly decreased in the diseased group 10 (abcd4/rdh8 knockout mice), as compared to the diseased group treated with LBS-008, ONL were preserved, which 0 implies the treatment group has not loss photoreceptor cells. LBS- inferior Distance from ONH superior 008- C57BL/6J DKO, untreated DKO, BPN14967-treated 13

RBP4 Reduction Stops AMD Progression PRODUCT DISEASE PROFILE “Patients in the 300mg treatment group who completed the 2-year study “ In the 300 mg fenretinide dose cohort…showed achieved reductions of RBP4 <2mg/dL correlated with further reductions of a trend for slowing of lesion growth, particularly lesion growth rate (a mean reduction of 0.33mm 2 in yearly lesion growth). ” among patients who had RBP and retinol levels reduced by more than 50%. ” “ Fenretinide treatment also reduced approx. 45% incidence of choroidal neovascularization (Wet AMD)” Pharmacotherapy of AMD Charpter 67, Mark S. Bluemenkranz (2015) Investigation Of Oral Fenretinide For Treatment Of Geographic Atrophy in Age-Related Macular Degeneration (Nathan L. Mata, PhD) Lesion Increase (%, from baseline) placebo 300 mg Medium Lesion Growth (50%) RBP Reduction (%, from baseline) 14

Robust Serum RBP4 Reduction MONKEY STUDY DATA Since LBS-008 reduces RBP4 in the circulation and cleared from the kidney, it can be easily measured 90% Reduction in blood and urine samples , and 12h after single dose thus the amount of retinol that gets into the visual cycle can be predicted and easily controlled and managed. 70% Reduction 36h after single dose 15

NIH Endorsement 16

✓ Block The Path To Metabolic Diseases For Non-Alcoholic Fatty Liver Disease & Type 2 Diabetes DISCOVERY ✓ PRE-CLINICAL PHASE I KEY OPPORTUNITY MARKET PHASE II/III MARKET Zero Approved 1.4B 100M Treatments Individuals with Cases of NAFLD worldwide NAFLD in the US alone for Non-Alcoholic Steatohepatitis (NASH) 30% of general population 9M $20B NASH cases in the US alone Addressable total global market by 3% of general population 2025. Global market for type 2 diabetes estimated to reach $64B by 2026 Reference: NIH, Clinical Dilemmas in Non-Alcoholic Fatty Liver Disease, Marketwatch, Globadata 17

RBP4 Contributes to Diabetes & Liver Disease PRODUCT DISEASE PROFILE “These findings suggest that “ Iinsulin resistance is the “These findings suggest this newly defined adipokine strongest determinant of that RBP4 might be related 145 publications on RBP4 & Metabolic Syndrome might be related to elvated serum RBP4 levels to pathogenesis of pathogenesis of NAFLD .” in IGT and T2D .” NAFLD .” 84 publications on RBP4 & Fatty Liver J A Seo et al. 2008 Qin Yang et al. 2012 N A Ibrahim et al. 2016 Clin Endocrinol. 68(4) 555-560 Endocrinology. 153(3): 1519-1527 Int J Adv Res Biol Sci 3(4): 71-79 * P vs Normal P vs NGT 70.6 *** * 62.8 61 * P vs Control RBP4 (ug/mL) * 53 51.7 46.9 35.1 23.5 T2D + Normal NAFLD NGT IGT T2D Control T2D NAFLD (n=86) (n=73) (n=19) (n=20) (n=20) (n=30) (n=30) 18 (n=30)

RBP4 is Strongly Associated with CHD Risk PRODUCT DISEASE PROFILE “… Visceral fat … secretes hormones and a host of other chemicals linked to diseases that commonly afflict older adults . One such “ We found that full-length RBP4 levels substance is called RBP4 that was found in a 16- Odds Ratio (95% CI) of CHD were associated with a 3-fold increased year study of nurses to increase the risk of at 8 Years Since Baseline risk of incident CHD in women . ” developing coronary heart disease. ” New York Times, 2018 Jun 11 3.56 Qi Sun et al. Circulation. 2013 May 14; 127(19): 1938 – 1947 1.58 1 0.7 Q1 Q2 Q3 Q4 Quartiles of Plasma RBP4 Levels (full length, μg /mL) 19