BELITE BIO / 1
Blindness & Liver Fibrosis
Feb 2019
RBP4 Technologyfor Anti-Aging
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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 Expressedin the liver and adipose tissue
Easily Measuredvia blood samples (ELISA)
Linked to Aging Metabolic DiseasesEvidence linking elevated RBP4 to diabetes, liver disease and macular degeneration
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Anti-RBP4 Platform for Aging Metabolic Diseases
MEET THE UNMET NEED
HOPE TO INCURABLE BLINDNESS
THE PATH TO METABOLIC DISEASE
Dry Age-Related Macular Degeneration & Stargardt Disease
Non-Alcoholic Fatty Liver Disease & Type 2 Diabetes
009LBS
PRE-CL IN ICAL
PHASE I
008LBS
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For Dry Age-Related Macular Degeneration & Stargardt DiseaseHOPE TO INCURABLE BLINDESS
10M
$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 size
1 in 10,000Stargardt Disease Juvenile onset macular degeneration (rare pediatric disease & orphan disease)
MARKETKEY OPPORTUNITY
Zero ApprovedTreatments
DISCOVERY
PRE-CLINICAL
PHASE I
PHASE II / III
MARKET
LBS
008
RPD ODDfor Stargardt (US & EU)
Most Advanced Candidate
Reference: Globaldata, Lancet, Orphanet, STEM CELLS Translational Medicine
NIH Blueprint
L B S
008
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Symptoms of AMDPRODUCT DISEASE PROFILE
NormalCentral Vision
Blurry &DistortedCentral Vision
LostCentral Vision
Normal Macula
Early Dry AMDLipofuscin accumulation
Drusen formationand inflammation
Late Stage Geographic Atrophy
L B S
008
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Pathogenesis of AMD & Stargardt DiseasePRODUCT DISEASE PROFILE: 90% AMD ARE “DRY” AMD
Normal Retina RPE Changes Rods Die, Cones Spared Cones Die
Vision Loss
L B S
008
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MOA: Dry AMD & StargardtRBP4 Transports Retinol (Precursor to Ccytotoxic A2E) into Retina by Way of Visual Cycle
PHOTORECEPTORS(PR)
RETINAL PIGMENT EPITHELIUM (RPE)
BLOODSTREAMLBS-008 RBP4Inhibits RBP4 from delivering retinol into RPE, reducing A2E accumulation by 50%
Primary transporter of retinol into RPE
Loss of RPE
A2E
RPE65 LRAT
11c-RDHat-RDH
at-Ral
at-RE at-Rol11c-Rol
Retinal isomers are required by normal visual function. They are also precursors to the cytotoxic
A2E, which causes dry AMD and Stargardt.
Rhodopsin
LBS-008 Induced Down-Regulation
Retinal Isomers
Enzymes
Pigments
ABCA4
DRY AMD
Loss of PR, ERG abnormalities
STARGARDT11c-Ral
Gene mutation causes loss of
ABCA4 transporter
function
STARGARDT
L B S
008
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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)
L B S
008
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Degeneration in Abca4-/-Rdh8-/- Mice
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.
IN ABCA4-/-RDH8-/- MICE, COMPARED TO LBS-008-TREATED
LBS-008-
L B S
008
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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 Chapter 67, Mark S. Bluemenkranz (2015)
“Patients in the 300mg treatment group who completed the 2-year studyachieved reductions of RBP4 <2mg/DL (1 uM) 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)
Le
sio
n I
ncr
ea
se(%
, fro
m b
ase
line
)
RBP4 Reduction Stops AMD Progression
L B S
008
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Robust Serum RBP4 ReductionMONKEY STUDY DATA: -5 mg/kg PO dose in non-human primates
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
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DISCOVERY
PRE-CLINICAL
PHASE I
PHASE II / III
MARKET
LBS
009 For Non-Alcoholic Fatty Liver Disease & Type 2 DiabetesTHE PATH TO METABOLIC DISEASES
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 size by 2026. Global market size for type 2 diabetes estimated to reach $59B by 2026
1.46BCases of NAFLD worldwide
20% of global population
MARKETKEY OPPORTUNITY
Zero ApprovedTreatmentsfor Non-Alcoholic Steatohepatitis (NASH)
Reference: NIH, Clinical Dilemmas in Non-Alcoholic Fatty Liver Disease, Marketwatch, Globadata
L B S
009
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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
(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 adipokinemight be related to pathogenesis of NAFLD.”
J A Seo et al. 2008Clin Endocrinol. 68(4) 555-560
“Iinsulin resistance is the strongest determinant of elvated serum RBP4 levels in IGT and T2D.”
Qin Yang et al. 2012Endocrinology. 153(3): 1519-1527
“These findings suggest that RBP4 might be related to pathogenesis of NAFLD.”
N A Ibrahim et al. 2016Int J Adv Res Biol Sci 3(4): 71-79
L B S
009
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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
L B S
009
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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 levelsmeasured 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)
L B S
009
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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
L B S
009
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MOA Overview: RBP4 in Liver Disease & DiabetesRBP4 Causes Liver Inflammation & Insulin Resistance, Resulting in NASH & Diabetes
LBS-009 Induced Down-Regulation
APC activation+ inflammation
insulin resistance+ hypersecretion
LBS-009FREE FATTY ACIDS
TRIGLYERCIDES
NASHNon-Alcoholic SteatohepatitisLIVER
T2DType 2 DiabetesPANCREAS
Enlarged AdipocytesFAT
TISSUE
INSULIN INFLAMMATORY CYTOKINE SECRETION CD4 T CELL MACROPHAGE
RBP4
L B S
009
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Robust Serum RBP4 Reduction ANIMAL STUDY DATA: -single 5 mg/kg PO dose in rats
85% Reduction10h after single dose
60% Reduction36h after single dose
L B S
009
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Decreased Liver Lipid Deposition in HFD Animals
Liver Histology Score Regular Diet +
VehicleHFD +
VehicleHFD +
LBS-009
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
core
RBP4 TRANSGENIC MICE ON HFD
0 2.9 1.6
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