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

Blindness, Liver Fibrosis, & Cancer

March 2019

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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

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First-in-Class Treatment for Unmet Medical Need

All Indications are potential Blockbusters

Potential Multiple Solid Tumors Treatment

Obtained ODD (US) on ALL Estimated global market $6B Most advanced candidate $10M+ funding to date

NIH Blueprint Sponsored Expected Drug Approval in 4 years

Seek Fast Track + Accelerated Approval based on RBP4 biomarker predicting clinical efficacy Rare Pediatric Disease Designation (US) & Orphan Drug Designation (US & EU)

Obtained RPD + ODD

Eligible for Priority Review Voucher upon NDA Worth $150-350M upon transfer

Eligible for PRV

Estimated global market for Stargardt + AMD + NASH + Leukemia / Multiple Solid Tumor

$1B + 20B + 20B + 6B Market

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Pipeline

RBP4 Platform Oncology Programs

Dry AMD Stargardt Disease (FDA RPD, FDA ODD, EMA ODD) Non Alcoholic Fatty Liver Disease (NASH) / Type 2 Diabetes Acute Leukemia (FDA ODD) Multiple Solid Tumors Glioblastoma / Brain Metastasis

DISCOVERY PRE-CLINICAL PHASE I PHASE II / III MARKET

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RBP4 PLATFORM

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PLATFORM OVERVIEW

Anti-RBP4 Platform

Therapies for Aging Metabolic Diseases

RBP4 protein transports retinol (vitamin A) from the liver to peripheral tissues. It is:

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

DISCOVERY

PHASE I

PHASE II/III MARKET PRE-CLINICAL

✓

Bring HOPE TO INCURABLE BLINDESS

For Dry Age-Related Macular Degeneration & Stargardt Disease

Anti-RBP4 Platform for Aging Metabolic Diseases

DISCOVERY PHASE I PHASE II/III MARKET

PRE-CLINICAL

✓

Block THE PATH TO METABOLIC DISEASES

For Non-Alcoholic Fatty Liver Disease & Type 2 Diabetes 7

MEET THE UNMET NEED

DISCOVERY

PHASE I

PHASE II/III MARKET PRE-CLINICAL

✓

Bring Hope To Incurable Blindness

For Dry Age-Related Macular Degeneration & Stargardt Disease

11M $20B 170M

Blind victims suffer from macular degeneration in the US Cases of AMD worldwide with a global direct healthcare cost of USD 255B Estimated global market

1 in 10,000

Stargardt Disease Juvenile onset macular degeneration (rare pediatric disease & orphan disease)

MARKET KEY OPPORTUNITY

Zero Approved Treatments

RPD ODD

for Stargardt (US & EU) Most Advanced Candidate

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Reference: Globaldata, Lancet, Orphanet, STEM CELLS Translational Medicine

NIH Blueprint

Symptoms of AMD

PRODUCT DISEASE PROFILE

Normal

Central Vision

Blurry & Distorted

Central Vision

Lost

Central Vision

Normal Macula Early Dry AMD

Lipofuscin accumulation Drusen formation

and inflammation

Late Stage Geographic Atrophy

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Pathogenesis of AMD & Stargardt Disease

PRODUCT DISEASE PROFILE

Normal Retina RPE Changes Rods Die, Cones Spared Cones Die

Vision Loss

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MOA: Dry AMD & Stargardt

RBP4 Transports Retinol (Precursor to Cytotoxic A2E) into Retina by Way of Visual Cycle

PHOTORECEPTORS (PR) RETINAL PIGMENT EPITHELIUM (RPE) BLOODSTREAM Loss of PR, ERG abnormalities

STARGARDT

Loss of RPE

DRY AMD RPE65 LRAT

at-Ral at-RE at-Rol 11c-Rol

ABCA4 11c-RDH

Retinal isomers are required by normal visual function. They are also precursors to the cytotoxic A2E causing dry AMD and Stargardt.

at-RDH

11c-Ral

LBS-008 RBP4

Inhibits RBP4 from delivering retinol into RPE, reducing A2E accumulation by 50% Primary transporter of retinol into RPE

Gene mutation causes loss of ABCA4 transporter function STARGARDT

LBS-008 Induced Down-Regulation Retinal Isomers Enzymes Pigments

A2E

Rhodopsin

Reduces Bisretinoid Accumulation by 80%

IN ABCA4-/-RDH8-/- MICE, COMPARED TO LBS-008-TREATED

1.75 26 6 56 48 3

p=0.003; unpaired t-test

Wild Type

untreated control

DKO

vehicle-treated control

DKO

LBS-008-treated

Serum RBP4

(ug/mL)

A2E Concentration

(pmol per eye)

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Degeneration in Abca4-/-Rdh8-/- Mice

ANIMAL STUDY DATA

10 20 30 40 50 60 70 ONL thickness (μm) inferior Distance from ONH superior C57BL/6J DKO, untreated DKO, BPN14967-treated

Dry AMD or Stargardt’s is associated with thinning of the outer nuclear layer (ONL) and the loss of photoreceptor cells, indicating macular degeneration.

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.

LBS- 008-

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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 0.33mm2 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)

placebo 300 mg

Medium Lesion Growth (50%)

RBP Reduction (%, from baseline) Lesion Increase (%, from baseline)

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Robust Serum RBP4 Reduction

MONKEY STUDY DATA 15

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.

90% Reduction

12h after single dose

70% Reduction

36h after single dose

NIH Endorsement

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DISCOVERY PHASE I PHASE II/III MARKET

✓

PRE-CLINICAL

✓

Block The Path To Metabolic Diseases

For Non-Alcoholic Fatty Liver Disease & Type 2 Diabetes

100M $20B 9M

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 by

• 2025. Global market for type 2

diabetes estimated to reach $64B by 2026

1.4B

Cases of NAFLD worldwide

MARKET KEY OPPORTUNITY

Zero Approved Treatments

for Non-Alcoholic Steatohepatitis (NASH)

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Reference: NIH, Clinical Dilemmas in Non-Alcoholic Fatty Liver Disease, Marketwatch, Globadata

RBP4 Contributes to Diabetes & Liver Disease

PRODUCT DISEASE PROFILE

51.7 62.8

Normal

(n=86)

NAFLD

(n=73)

23.5 61 70.6

NGT

(n=19)

IGT

(n=20)

T2D

(n=20)

35.1 46.9 53

Control

(n=30)

T2D

(n=30)

T2D + NAFLD

(n=30)

* * * *

***

RBP4 (ug/mL)

P vs Normal P vs NGT P vs Control

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.”

J A Seo et al. 2008 Clin Endocrinol. 68(4) 555-560

“Iinsulin resistance is the strongest determinant of elvated serum RBP4 levels in IGT and T2D.”

Qin Yang et al. 2012

• Endocrinology. 153(3): 1519-1527

“These findings suggest that RBP4 might be related to pathogenesis of NAFLD.”

N A Ibrahim et al. 2016 Int J Adv Res Biol Sci 3(4): 71-79

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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. 2013 May 14; 127(19): 1938–1947

Odds Ratio (95% CI) of CHD at 8 Years Since Baseline Quartiles of Plasma RBP4 Levels (full length, μg/mL)

1 0.7 1.58 3.56 Q1 Q2 Q3 Q4

“… Visceral fat … secretes hormones and a host

• f 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 11

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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:
• Blood Pressures elevation (P = 0.015)
• Triglyceride elevation (P < 0.001)
• Hyperglycemia (P = 0.009)
• Insulin Resistance (P = 0.015)
• Metabolic Syndrome (P = 0.002)

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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). 1073-1081

RETINOL FATTY ACID RBP4 side chains bound to RBP4 side chains bound to

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MOA Overview: RBP4 in Liver Disease & Diabetes

RBP4 Causes Liver Inflammation & Insulin Resistance, Resulting in NASH & Diabetes

APC activation + inflammation

insulin resistance + hypersecretion

NASH

Non-Alcoholic Steatohepatitis

T2D

Type 2 Diabetes

LBS-009

FREE FATTY ACIDS LIVER PANCREAS

Enlarged Adipocytes

FAT TISSUE

RBP4

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LBS-009 Induced Down-Regulation

TRIGLYERCIDES

MACROPHAGE CD4 T CELL INFLAMMATORY CYTOKINE SECRETION INSULIN

Robust Serum RBP4 Reduction

ANIMAL STUDY DATA: -single 5 mg/kg PO dose in rats 23

85% Reduction

10h after single dose

60% Reduction

36h after single dose

Decreased Liver Lipid Deposition in HFD Animals

RBP4 TRANSGENIC MICE ON HFD

t d 1 2 3 4

**** **** ***

Regular Diet HFD HFD + LBS-009

Liver Histology Score 24

Liver Histology Score

Regular Diet +

Vehicle

HFD +

Vehicle

HFD +

LBS-009

2.9 1.6

ONCOLOGY PROGRAMS

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DISCOVERY PHASE I PHASE II/III MARKET PRE-CLINICAL

✓

Natural non-ATP CDC7 Inhibitor

for treatment of Broad Variety of Cancers KEY OPPORTUNITY

Novel Anti-Cancer

Target Therapy

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$5B $6B $55B

Expected 2026 market size of AML & ALL Expected 2023 market size

• f pancreatic, lung, ovarian

cancers Estimated global market

1.7 in 100k

Acute lymphoblastic leukemia (orphan disease)

MARKET

Reference: Globaldata, Marketwatch, NIH National Cancer Institute

ODD

for ALL (US)

Inhibits CDC7 in Cell Cycle Regulation

TARGETS

S Phase Progression

1 2 3 INHIBITS

CDC7’s role in DNA Replication

PREVENTS

Cell Division

LBS-007

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Hematopoietic Cell Line Primary Patient Sample Solid Tumor Cell Line

5 1000

EC50 (nanoM)

Lymphoma Breast Cancer Lung Cancer

Potently Inhibits Multiple Cancer Cell Lines & Primary Patient Samples of Blood Cancers

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LBS-007 – Effective Against Blood Cancers

DOSE-RESPONSIVE MANNER

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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

LBS-007 – Also Effective Against Solid Tumors in Animal Models

Control 0.3 1 3 mg/kg DOSE-RESPONSIVE MANNER

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Inhibits Ovarian Tumor growth in vivo

Reference: Unpublished data from

• Dr. Mark Frattini

This presentation is provided by Lin Bioscience, Inc. (“LBS”). The information contained within is not reviewed or reviewed by any accountant or any independent third party. Users should read this material in conjunction with all other public financial and operational information filed to the competent authorities by LBS. While we endeavor to provide accurate, complete and consistent information herein, LBS makes no guarantee or warranties as to the accuracy or correctness of all the material contained. After this presentation is released to the public, we undertake no obligation to update any relevant data to reflect any change hereafter. Users should also notice that this presentation may contain forward-looking statements. Statements that are not historical facts, including statements relating to the implementation of strategic initiatives, future business development and economic performance are forward-looking statements. By their nature, forward-looking statements involve uncertainties, risks, assumptions and other factors that could cause actual developments and results to differ materially from our statement in this presentation. These factors include, but not limited to, regulatory developments, competitive conditions, technological developments, general economic conditions and management changes. The information, statements or opinions in this presentation do not constitute a public offer under any applicable legislation or an offer to sell or solicitation of an

• ffer to buy any securities or financial instruments or any advice or recommendation respect to such securities or other financial instruments. LBS and all its

affiliates representatives, no matter for their negligence or any other reasons, should not be liable for any loss or damages arising from the use of or interpretation by others of information contained within this presentation or any matter related to this document.

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Blindness, Liver Fibrosis, & Cancer

Hao-Yuan Chuang, CFO hychuang@linbioscience.com

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