Blindness, Liver Fibrosis, & Cancer. October 2018

Transcription

1 Blindness, Liver Fibrosis, & Cancer October

2 First-in-Class Treatment for Unmet Medical Need Lin Bioscience is a drug development company focused on sourcing/advancing first-inclass 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

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

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

5 RBP4 PLATFORM 5

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

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

8 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 Treatments RPD ODD for Stargardt (US & EU) 10M Blind victims suffer from macular degeneration in the US 170M 1 in 10,000 Stargardt Disease Juvenile onset macular degeneration (rare pediatric disease & orphan disease) $20B Most Advanced Candidate Cases of AMD worldwide with a global direct healthcare cost of USD 255B Estimated global market Reference: Globaldata, Lancet, Orphanet, STEM CELLS Translational Medicine 8

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

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

11 Down-Regulated Enzymes MOA Overview: Visual Cycle Retinal Isomers Pigments PRODUCT DISEASE PROFILE Rhodopsin PHOTORECEPTORS 11c-Ral A2E at-ral at-rdh RPE restores once A2E level reduces 11c-RDH Retinal isomers are required by normal visual function. They are also precursors to the cytotoxic A2E causing dry AMD and Stargardt. RETINAL PIGMENT EPITHELIUM (RPE) 11c-Rol RPE65 at-re LRAT at-rol BLOODSTREAM LBS-008 Inhibits RBP4 from delivering retinal into RPE, reducing A2E accumulation by 50% RBP4 Primary transporter of retinal into RPE 11

12 Stargardt Disease: Juvenile Macular Degeneration COMPOUND TESTING IN THE ABCA4-/-RDH8-/- MICE Rhodopsin PHOTORECEPTORS Loss of photoreceptors, ERG abnormalities 11c-Ral A2E (bisretinoid) at-ral ABCA4 11c-RDH at-rdh RETINAL PIGMENT EPITHELIUM (RPE) 11c-Rol RPE65 at-re LRAT at-rol BLOODSTREAM LBS-008 Inhibits RBP4 from delivering retinal into RPE, reducing A2E accumulation by 50% RBP4 Primary transporter of retinal into RPE 12

13 Reduces Bisretinoid Accumulation by 80% IN ABCA4-/-RDH8-/- MICE, COMPARED TO LBS-008-TREATED A2E Concentration (pmol per eye) 26 Serum RBP4 (ug/ml) p=0.003; unpaired t-test Wild Type untreated control DKO vehicle-treated control DKO LBS-008-treated 13

14 ONL thickness (μm) Degeneration in Abca4-/-Rdh8-/- Mice ANIMAL STUDY DATA Dry AMD or Stargardt s is associated with thinning of the outer nuclear layer (ONL) and the loss of photoreceptor cells, indicating macular degeneration inferior Distance from ONH LBS- superior 008- C57BL/6J DKO, untreated DKO, BPN14967-treated We quantified the ONL thickness and found ONL thickness was significantly decreased in the diseased group (abcd4/rdh8 knockout mice), as compared to the diseased group treated with LBS-008, ONL were preserved, which implies the treatment group has not loss photoreceptor cells. 14

15 RBP4 Reduction Stops AMD Progression PRODUCT DISEASE PROFILE In the 300 mg fenretinide dose cohort showed a trend for slowing of lesion growth, particularly among patients who had RBP and retinol levels reduced by more than 50%. Pharmacotherapy of AMD Charpter 67, Mark S. Bluemenkranz (2015) Patients in the 300mg treatment group who completed the 2-year study achieved reductions of RBP4 <2mg/dL correlated with further reductions of lesion growth rate (a mean reduction of 0.33mm 2 in yearly lesion growth). 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) 15

16 Robust Serum RBP4 Reduction MONKEY STUDY DATA Serum RBP4 (% reduction) % Reduction 48h after single dose Since LBS-008 reduces RBP4 in the circulation and cleared from the kidney, it can be easily measured in blood and urine samples, and thus the amount of retinol that gets into the visual cycle can be predicted and easily controlled and managed. 3X Better Than Target for Clinical Efficacy in Humans Time (hours) 16

17 NIH Endorsement 17

18 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 Treatments for Non-Alcoholic Steatohepatitis (NASH) 100M Individuals with NAFLD in the US alone 30% of general population 1.4B Cases of NAFLD worldwide 9M $20B NASH cases in the US alone 3% of general population Addressable total global market by Global market for type 2 diabetes estimated to reach $64B by 2026 Reference: NIH, Clinical Dilemmas in Non-Alcoholic Fatty Liver Disease, Marketwatch, Globadata 18

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

20 RBP4 is Strongly Associated with CHD Risk PRODUCT DISEASE PROFILE We found that full-length RBP4 levels were associated with a 3-fold increased risk of incident CHD in women. Qi Sun et al. Circulation May 14; 127(19): Odds Ratio (95% CI) of CHD at 8 Years Since Baseline 3.56 Visceral fat secretes hormones and a host of other chemicals linked to diseases that commonly afflict older adults. One such substance is called RBP4 that was found in a 16- year study of nurses to increase the risk of developing coronary heart disease. New York Times, 2018 Jun Q1 Q2 Q3 Q4 Quartiles of Plasma RBP4 Levels (full length, μg/ml) 20

21 Childhood RBP4 levels are strong predictors of developing Insulin Resistance and Metabolic Syndrome in Adults PRODUCT DISEASE PROFILE high levels of childhood RBP4 at baseline were associated with an adverse cardiovascular risk profile at baseline and upon 10 year follow-up Li et al. Cardiovasc Diabetol (2018) 17:69 The most striking, novel finding of this study is that RBP4 levels measured in childhood were strong predictors of the subsequent development of Metabolic Syndrome and each of its components (including insulin resistant, hyperglycemia, hypertension and hyperlipidemia) 10 years later, and is independent of obesity. 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) 21

22 RBP4 Also Found to Bind to Fatty Acids PRODUCT DISEASE PROFILE 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) RBP4 side chains bound to RETINOL RBP4 side chains bound to FATTY ACID 22

23 MOA Overview: RBP4 in Liver Disease & Diabetes PRODUCT DISEASE PROFILE LBS-009 NASH Non-Alcoholic Steatohepatitis LIVER insulin resistance + hypersecretion TG FFA APC activation + inflammation RBP4 T2D Type 2 Diabetes PANCREAS Enlarged Adipocytes FAT TISSUE Up-Regulated Down-Regulated 23

24 MOA Detail: RBP4 in Diabetes PRODUCT DISEASE PROFILE β-cell Compensation Insulin Output T2D Glucose Uptake PANCREAS PEPCK Glucose Output LIVER Insulin Signal Glucose Uptake SKELETAL MUSCLE RBP4 Enlarged Adipocytes TLR4 FAT TISSUE Insulin Resistance Inflammatory Cytokine Secretion CD4 T Cell Macrophage Up-Regulated Down-Regulated 24

25 MOA Detail: RBP4 in NAFLD / NASH PRODUCT DISEASE PROFILE Glucose Uptake AMPK Activation Adiponectin NAFLD Liver Inflammation TG FFA RBP4 Insulin Resistance TLR4 Enlarged Adipocytes FAT TISSUE NASH LIVER Inflammatory Cytokine Secretion CD4 T Cell Macrophage Up-Regulated Down-Regulated 25

26 Robust Serum RBP4 Reduction ANIMAL STUDY DATA 0 Serum RBP4 (% reduction) % Reduction 12h after single dose 40% Reduction 48h after single dose Time (hours) 26

27 Decreased Liver Lipid Deposition in HFD Animals ANIMAL STUDY DATA Liver Histology Score Liver Histology Score L iv e r h is to lo g y s c o re **** **** *** Regular Diet r e g u la r d ie t HFD HFD + LBS-009 H F D + C o m p o u n d Regular Diet + Vehicle HFD + Vehicle HFD + LBS

28 ONCOLOGY PROGRAMS 28

29 Natural non-atp CDC7 Inhibitor for treatment of Broad Variety of Cancers DISCOVERY PRE-CLINICAL PHASE I KEY OPPORTUNITY MARKET PHASE II/III MARKET Novel Anti-Cancer Target Therapy $5B 1.7 in 100k Expected 2026 market size of AML & ALL Acute lymphoblastic leukemia (orphan disease) ODD for ALL (US) $55B $6B Expected 2023 market size of pancreatic, lung, ovarian cancers Estimated global market Reference: Globaldata, Marketwatch, NIH National Cancer Institute 29

30 Inhibits CDC7 in Cell Cycle Regulation LBS INHIBITS 3 TARGETS S Phase Progression CDC7 s role in DNA Replication PREVENTS Cell Division 30

31 Potently Inhibits Multiple Cancer Cell Lines & Primary Patient Samples of Blood Cancers EC 50 (nanom) Lymphoma Lung Cancer Breast Cancer Hematopoietic Cell Line Primary Patient Sample Solid Tumor Cell Line 31

32 LBS-007 Effective Against Blood Cancers Inhibits TKI-Resistant Acute Lymphoblastic Leukemia (ALL) growth in vivo using a continuous infusion regimen Reference: Unpublished data from Dr. Mark Frattini D O R S A L V E N T R A L DOSE-RESPONSIVE MANNER 32

33 LBS-007 Also Effective Against Solid Tumors in Animal Models Inhibits Ovarian Tumor growth in vivo Reference: Unpublished data from Dr. Mark Frattini Control mg/kg DOSE-RESPONSIVE MANNER 33

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35 Blindness, Liver Fibrosis, & Cancer Hao-Yuan Chuang, CFO 35