RBP4 Technology for Anti-Aging Blindness & Liver Fibrosis Feb 2019 BELITE BIO / 1
FORM OVE VERVIEW VIEW PLATFORM RBP4 protein transports retinol (vitamin A) from the liver to peripheral tissues. It is: 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 BELITE BIO / 2
MEET THE UNMET NEED Anti-RBP4 Platform LBS 008 for Aging Metabolic Diseases HOPE TO INCURABLE BLINDNESS Dry Age-Related Macular Degeneration PHASE I & Stargardt Disease LBS 009 THE PATH TO METABOLIC DISEASE Non-Alcoholic Fatty Liver Disease & Type 2 PRE-CLINICAL Diabetes BELITE BIO / 3
NIH Blueprint (rare pediatric disease & macular degeneration in the US Cases of AMD worldwide with a global direct healthcare cost of USD 255B Estimated global market size Stargardt Disease Juvenile onset macular degeneration orphan disease) Most Advanced Candidate MARKET KEY OPPORTUNITY DISCOVERY PRE-CLINICAL PHASE I PHASE II / III MARKET RPD ODD Blind victims suffer from for Stargardt (US & EU) LBS HOP OPE E TO IN O INCU CURABLE RABLE BLIN INDESS DESS 008 For r Dr Dry Age-Re Rela late ted d Macu cular ar De Degenera rati tion on & & Star arga gard rdt Di Dise sease ase Zero Approved 1 in 10,000 10M Treatments 170M $20B Reference: Globaldata, Lancet, Orphanet, STEM CELLS Translational Medicine BELITE BIO / 4
Atrophy Central Vision Geographic Late Stage and inflammation Drusen formation Lipofuscin accumulation Early Dry AMD Normal Macula Central Vision Lost Distorted Blurry & Central Vision Normal PRODUCT DISEASE PROFILE L B S Symptoms Sy oms of of AMD 008 BELITE BIO / 5
Vision Loss PRODUCT DISEASE PROFILE: 90% AMD ARE “DRY” AMD Cones Die Rods Die, Cones Spared RPE Changes al Retina Normal L B S Pa Pathogen hogenesis esis of of AMD & D & St Star argardt gardt Di Disease ease 008 BELITE BIO / 6
RBP4 Transports Retinol (Precursor to Ccytotoxic A2E) into Retina by Way of Visual Cycle L B S MOA: Dry AMD & Stargardt 008 LBS-008 Induced Enzymes Down-Regulation Retinal Isomers Pigments Rhodopsin STARGARDT 11c-Ral at-Ral Loss of PR , ERG STARGARDT A2E abnormalities Gene mutation PHOTORECEPTORS causes loss of (PR) ABCA4 ABCA4 transporter function at-RDH Retinal isomers are required by normal visual DRY AMD 11c-RDH function. They are also precursors to the cytotoxic Loss of RPE A2E , which causes dry AMD and Stargardt. at-RE at-Rol 11c-Rol RETINAL PIGMENT RPE65 LRAT EPITHELIUM (RPE) LBS-008 RBP4 BLOODSTREAM Inhibits RBP4 from delivering retinol into Primary transporter RPE , reducing A2E accumulation by 50% of retinol into RPE BELITE BIO / 7
IN ABCA4-/-RDH8-/- MICE, COMPARED TO LBS-008-TREATED L B S Reduces Bisretinoid Accumulation by 80% 008 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 BELITE BIO / 8
IN ABCA4-/-RDH8-/- MICE, COMPARED TO LBS-008-TREATED Degeneration in Abca4 -/- Rdh8 -/- Mice L B S 008 70 Dry AMD or Stargardt’s is associated with 60 thinning of the outer nuclear layer (ONL) 50 and the loss of photoreceptor cells, ONL thickness ( μ m) indicating macular degeneration. 40 30 We quantified the ONL thickness and found ONL thickness was significantly decreased in the diseased 20 group (abcd4/rdh8 knockout mice), as compared to the diseased group treated with LBS-008, ONL were 10 preserved, which implies the treatment group has not loss photoreceptor cells. 0 inferior Distance from ONH superior LBS-008- C57BL/6J DKO, untreated DKO, BPN14967-treated BELITE BIO / 9
PRODUCT DISEASE PROFILE L B S RBP4 Reduction Stops AMD Progression 008 “ In the 300 mg fenretinide dose cohort…showed “Patients in the 300mg treatment group who completed the 2-year study a trend for slowing of lesion growth, particularly achieved reductions of RBP4 <2mg/DL (1 uM) correlated with further reductions of lesion growth rate (a mean reduction of 0.33mm 2 in yearly among patients who had RBP and retinol levels lesion growth). ” reduced by more than 50%. ” Pharmacotherapy of AMD Chapter 67, Mark S. Bluemenkranz (2015) “ Fenretinide treatment also reduced approx. 45% incidence of choroidal neovascularization (Wet AMD)” 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) BELITE BIO / 10
MONKEY STUDY DATA: -5 mg/kg PO dose in non-human primates L B S Robust Serum RBP4 Reduction 008 Since LBS-008 reduces RBP4 in the circulation and cleared from the kidney, it can be easily measured in blood and 90% Reduction urine samples , and thus the amount of 12h after single dose retinol that gets into the visual cycle can be predicted and easily controlled and managed. 70% Reduction 36h after single dose BELITE BIO / 11
DISCOVERY reach $59B by 2026 Individuals with NAFLD in the US alone 30% of general population NASH cases in the US alone 3% of general population Addressable total global market size by 2026. Global market size for type 2 diabetes estimated to Cases of NAFLD worldwide 20% of global population MARKET KEY OPPORTUNITY MARKET PHASE II / III PHASE I PRE-CLINICAL LBS THE PATH H TO O METABOLI BOLIC C DIS ISEASES EASES 009 For r Non-Al Alco coholic olic Fatty tty Liver ver Di Disea sease se & & Type pe 2 Di Diabet etes es Zero Approved 1.46B 100M Treatments for Non-Alcoholic Steatohepatitis (NASH) 9M $20B Reference: NIH, Clinical Dilemmas in Non-Alcoholic Fatty Liver Disease, Marketwatch, Globadata BELITE BIO / 12
PRODUCT DISEASE PROFILE L B S RBP4 Contributes to Diabetes & Liver Disease 009 “These findings suggest that “ Iinsulin resistance is the “These findings suggest 145 publications on RBP4 & Metabolic Syndrome this newly defined adipokine strongest determinant of that RBP4 might be related 84 publications on RBP4 & Fatty Liver might be related to elvated serum RBP4 levels to pathogenesis of NAFLD .” pathogenesis of NAFLD .” in IGT and T2D .” 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 * 53 RBP4 (ug/mL) 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) (n=30) BELITE BIO / 13
PRODUCT DISEASE PROFILE L B S RBP4 is Strongly Associated with CHD Risk 009 “… Visceral fat … secretes hormones and a host of other chemicals linked to diseases that commonly afflict “ We found that full-length RBP4 levels older adults . One such substance is called RBP4 that were associated with a 3-fold increased risk was found in a 16-year study of nurses to increase the Odds Ratio (95% CI) of CHD of incident CHD in women . ” risk of developing coronary heart disease. ” at 8 Years Since Baseline Qi Sun et al. Circulation. 2013 May 14; 127(19): 1938 – 1947 New York Times, 2018 Jun 11 3.56 1.58 1 0.7 Q1 Q2 Q3 Q4 Quartiles of Plasma RBP4 Levels (full length, μg /mL) BELITE BIO / 14
PRODUCT DISEASE PROFILE L B S Childhood RBP4 levels are strong predictors of developing 009 Insulin Resistance and Metabolic Syndrome in Adults “The most striking, novel finding of this study is that RBP4 levels “ high levels of childhood RBP4 at baseline measured in childhood were strong predictors of the subsequent were associated with an adverse development of Metabolic Syndrome and each of its components cardiovascular risk profile at baseline and (including insulin resistant, hyperglycemia, hypertension and upon 10 year follow- up” hyperlipidemia) 10 years later, and is independent of obesity.” Li et al. Cardiovasc Diabetol (2018) 17:69 • 10-year prospective study in 3445 children • Participants with higher childhood RBP4 levels had adverse cardiometabolic profiles at follow-up. • RBP4 is a reliable indicator of innate Insulin Resistance and its ability to predict the onset and persistence of Metabolic Syndrome after 10-year follow-up • After 10-year follow-up, baseline RBP4 (independent of BMI) predicted: o Blood Pressures elevation (P = 0.015) o Triglyceride elevation (P < 0.001) o Hyperglycemia (P = 0.009) o Insulin Resistance (P = 0.015) o Metabolic Syndrome (P = 0.002) BELITE BIO / 15
PRODUCT DISEASE PROFILE L B S RBP4 Also Found to Bind to Fatty Acids 009 “ We have shown that RBP4 is not specific for retinol but it is also found in plasma, urine and amniotic fluid bound to fatty acids . ” Massimiliano Perduca et al. Elsevier Data in Brief 18(2018). 1073-1081 RBP4 side chains bound to RBP4 side chains bound to RETINOL FATTY ACID BELITE BIO / 16
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