RBP4 Technology for Anti-Aging Blindness & Liver Fibrosis Feb - - PowerPoint PPT Presentation
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
BELITE BIO / 1
Blindness & Liver Fibrosis
Feb 2019
BELITE BIO / 2
PLATFORM FORM OVE VERVIEW VIEW
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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Anti-RBP4 Platform for Aging Metabolic Diseases
HOPE TO INCURABLE BLINDNESS THE PATH TO METABOLIC DISEASE
Dry Age-Related Macular Degeneration & Stargardt Disease Non-Alcoholic Fatty Liver Disease & Type 2 Diabetes
LBS
PRE-CLINICAL PHASE I
LBS
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For r Dr Dry Age-Re Rela late ted d Macu cular ar De Degenera rati tion
& Star arga gard rdt Di Dise sease ase
HOP OPE E TO IN O INCU CURABLE RABLE BLIN INDESS DESS 10M $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 size
Stargardt Disease Juvenile
(rare pediatric disease &
MARKET KEY OPPORTUNITY
DISCOVERY PRE-CLINICAL
PHASE I
PHASE II / III MARKET
LBS
RPD ODD
for Stargardt (US & EU) Most Advanced Candidate
Reference: Globaldata, Lancet, Orphanet, STEM CELLS Translational Medicine
NIH Blueprint
L B S
008
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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
L B S
008
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PRODUCT DISEASE PROFILE: 90% AMD ARE “DRY” AMD
Normal al Retina RPE Changes Rods Die, Cones Spared Cones Die
Vision Loss
L B S
008
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RBP4 Transports Retinol (Precursor to Ccytotoxic A2E) into Retina by Way of Visual Cycle
PHOTORECEPTORS (PR) RETINAL PIGMENT EPITHELIUM (RPE) BLOODSTREAM
LBS-008 RBP4
Inhibits RBP4 from delivering retinol into RPE, reducing A2E accumulation by 50% Primary transporter
Loss of RPE
A2E
RPE65 LRAT 11c-RDH at-RDH
at-Ral at-RE at-Rol 11c-Rol
Retinal isomers are required by normal visual
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 STARGARDT
11c-Ral
Gene mutation causes loss of ABCA4 transporter function STARGARDT
L B S
008
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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)
L B S
008
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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. 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 study achieved 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) Lesion Increase (%, from baseline)
L B S
008
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MONKEY 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% Reduction
12h after single dose
70% Reduction
36h after single dose
BELITE BIO / 12 DISCOVERY
PRE-CLINICAL
PHASE I PHASE II / III MARKET
LBS
For r Non-Al Alco coholic
tty Liver ver Di Disea sease se & & Type pe 2 Di Diabet etes es
THE PATH H TO O METABOLI BOLIC C DIS ISEASES EASES 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 size by 2026. Global market size for type 2 diabetes estimated to reach $59B by 2026
Cases of NAFLD worldwide 20% of global population
MARKET KEY OPPORTUNITY
for Non-Alcoholic Steatohepatitis (NASH)
Reference: NIH, Clinical Dilemmas in Non-Alcoholic Fatty Liver Disease, Marketwatch, Globadata
L B S
009
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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
“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
L B S
009
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PRODUCT DISEASE PROFILE “We found that full-length RBP4 levels were associated with a 3-fold increased risk
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
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 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.”
cardiometabolic profiles at follow-up.
ability to predict the onset and persistence of Metabolic Syndrome after 10-year follow-up
predicted:
L B S
009
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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
L B S
009
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RBP4 Causes Liver Inflammation & Insulin Resistance, Resulting in NASH & Diabetes
LBS-009 Induced Down-Regulation
APC activation + inflammation insulin resistance + hypersecretion
LBS-009
FREE FATTY ACIDS TRIGLYERCIDES
NASH
Non-Alcoholic Steatohepatitis
LIVER
T2D
Type 2 Diabetes
PANCREAS
Enlarged Adipocytes
FAT TISSUE INSULIN INFLAMMATORY CYTOKINE SECRETION CD4 T CELL MACROPHAGE
RBP4
L B S
009
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ANIMAL STUDY DATA: -single 5 mg/kg PO dose in rats
85% Reduction
10h after single dose
60% Reduction
36h after single dose
L B S
009
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Liver Histology Score
Regular Diet +
Vehicle
HFD +
Vehicle
HFD +
LBS-009
t d 1 2 3 4
**** **** ***
Regular Diet HFD HFD + LBS-009
Liver Histology Score RBP4 TRANSGENIC MICE ON HFD
2.9 1.6
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Blindness & Liver Fibrosis
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