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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 PlatformTherapies 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
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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
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MEET THE UNMET NEED
DISCOVERY
PHASE I
PHASE II/III
MARKET
PRE-CLINICAL
✓
Bring Hope To Incurable BlindnessFor Dry Age-Related Macular Degeneration & Stargardt Disease
11M
$20B170M
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 10,000Stargardt Disease Juvenile onset
macular degeneration (rare
pediatric disease & orphan
disease)
MARKETKEY OPPORTUNITY
Zero ApprovedTreatments
RPD ODDfor Stargardt (US & EU)
Most Advanced Candidate
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Reference: Globaldata, Lancet, Orphanet, STEM CELLS Translational Medicine
NIH Blueprint
Symptoms of AMDPRODUCT DISEASE PROFILE
NormalCentral Vision
Blurry &Distorted
Central Vision
LostCentral Vision
Normal Macula
Early Dry AMDLipofuscin accumulation
Drusen formationand inflammation
Late Stage Geographic Atrophy
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Pathogenesis of AMD & Stargardt DiseasePRODUCT DISEASE PROFILE
Normal Retina RPE Changes Rods Die, Cones Spared Cones Die
Vision Loss
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MOA: Dry AMD & StargardtRBP4 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-Rol11c-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 RBP4Inhibits 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
DKOvehicle-treated control
DKOLBS-008-treated
Serum RBP4(ug/mL)
A2E Concentration(pmol per eye)
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Degeneration in Abca4-/-Rdh8-/- MiceANIMAL STUDY DATA
0
10
20
30
40
50
60
70
ON
L th
ickn
ess
(μ
m)
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 ProgressionPRODUCT 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)
Lesio
n In
cre
ase
(%, fr
om
baselin
e)
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Robust Serum RBP4 ReductionMONKEY STUDY DATA
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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% Reduction12h after single dose
70% Reduction36h after single dose
NIH Endorsement
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DISCOVERY
PHASE I
PHASE II/III
MARKET
✓
PRE-CLINICAL✓
Block The Path To Metabolic DiseasesFor Non-Alcoholic Fatty Liver Disease & Type 2 Diabetes
100M
$20B9M
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
1.4BCases of NAFLD worldwide
MARKETKEY OPPORTUNITY
Zero ApprovedTreatmentsfor 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 DiseasePRODUCT 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)
**
**
***
RB
P4
(u
g/m
L)
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 RiskPRODUCT 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
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 11
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Childhood RBP4 levels are strong predictors of developing
Insulin Resistance and Metabolic Syndrome in AdultsPRODUCT 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)
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RBP4 Also Found to Bind to Fatty AcidsPRODUCT 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 & DiabetesRBP4 Causes Liver Inflammation & Insulin Resistance, Resulting in NASH & Diabetes
APC activation+ inflammation
insulin resistance+ hypersecretion
NASHNon-Alcoholic Steatohepatitis
T2DType 2 Diabetes
LBS-009
FREE FATTY ACIDS
LIVER
PANCREAS
Enlarged Adipocytes
FAT TISSUE
RBP4
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LBS-009 Induced
Down-Regulation
TRIGLYERCIDES
MACROPHAGECD4 T CELLINFLAMMATORY
CYTOKINE
SECRETION
INSULIN
Robust Serum RBP4 Reduction ANIMAL STUDY DATA: -single 5 mg/kg PO dose in rats
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85% Reduction10h after single dose
60% Reduction36h after single dose
Decreased Liver Lipid Deposition in HFD AnimalsRBP4 TRANSGENIC MICE ON HFD
regula
r die
t
HFD
HFD
+ C
om
pound
0
1
2
3
4
Liv
er h
isto
log
y s
co
re
****
****
***
Regular
Diet
HFD HFD +
LBS-009
Liv
er
His
tolo
gy S
co
re
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Liver Histology Score Regular Diet +
VehicleHFD +
VehicleHFD +
LBS-009
0 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
of pancreatic, lung, ovarian
cancers
Estimated global market
1.7 in 100kAcute lymphoblastic leukemia
(orphan disease)
MARKET
Reference: Globaldata, Marketwatch, NIH National Cancer Institute
ODDfor ALL (US)
Inhibits CDC7 in Cell Cycle Regulation
TARGETSS Phase Progression
1 2 3INHIBITSCDC7’s role in
DNA Replication
PREVENTSCell Division
LBS-007
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HematopoieticCell Line
Primary PatientSample
Solid Tumor Cell Line
5 1000
EC50 (nanoM)
Lymphoma Breast CancerLung 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
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