Adalta Ltd. · ASX:1AD
Adalta — Anti-Fibrotic Drug Development Summit, Boston, 2017
40 slides from Adalta's conference presentation, Nov 13, 2017
Slide 1: AdAlta to present at Anti-Fibrotic Drug Development Summit in Boston
ASX Announcement AdAlta to present at Anti-Fibrotic Drug Development Summit in Boston For personal use only MELBOURNE Australia, 13 November, 2017: AdAlta Limited (ASX:1AD), the biotechnology Company advancing its lead i-body candidate towards clinical development, announces Chief Scientific Officer
Slide 2: Notes to Editors: About AdAlta
Notes to Editors: About AdAlta AdAlta Limited is an Australian-based drug development company headquartered in Melbourne. The Company is focused on using its proprietary technology platform to generate i-bodies, a new class of protein therapeutics, with applications as therapeutic drugs to treat dis
Slide 3: i-bodies: a novel therapeutic approach for the treatment of fibrosis
For personal use only i-bodies: a novel therapeutic approach for the treatment of fibrosis Anti-Fibrotic Drug Development, Boston November 2017 Mick Foley, CSO [email protected]
Slide 4: Disclaimer
Disclaimer For personal use only Investment in AdAlta is subject to investment risk, including possible loss of income and capital invested. AdAlta does not guarantee any particular rate of return or performance, nor do they guarantee the repayment of capital. This presentation is not an offer or in
Slide 5: i-body technology
i-body technology For personal use only AdAlta is developing a new technology platform that produces unique proteins known as i-bodies. An i-body is a human protein that combines the advantages of small molecules (stability) and antibodies (high affinity and specificity) in one powerful treatment. 3
Slide 6: i-bodies: human single domains
i-bodies: human single domains For personal use only Shark Human Human VNAR Ribbon Overlay NCAM Domain 1 i-body library 4
Slide 7: i-body technology advantages
i-body technology advantages For personal use only Challenging targets Because of the long binding loop of the i-body, that is lacking in traditional antibodies, i-bodies recognise and bind to a diverse range of therapeutically-relevant targets including those that are difficult/intractable to acces
Slide 8: Fibrosis is a complex interplay of inflammation and wound healing
Fibrosis is a complex interplay of For personal use only inflammation and wound healing Inflammation Fibrocyte migration Deposition of collagen/ECM 6
Slide 9: CXCR4 is involved in fibrosis and other disease states
CXCR4 is involved in fibrosis and other For personal use only disease states CXCR4 is important in maintaining stem cells in bone marrow with Mozobil (AMD3100) approved for single use. HIV-1 uses CXCR4 as a co-receptor for viral entry into host cells and CXCR4 has been associated with more than 23 t
Slide 10: Evidence supporting CXCR4 as a fibrosis target
Evidence supporting CXCR4 as a fibrosis target For personal use only Receptors & Clinical Investigation 2015; 2: e791. doi: 10.14800/rci.791; © 2015 by Leah Campeau, et al. http://www.smartscitech.com/index.php/rci Significant literature to support hypothesis of the involvement of CXCR4 in fibrosis
Slide 11: CXCR4 increased in disease
CXCR4 increased in disease CXCR4 For personal use only Normal human Diseased IPF lung tissue lung tissue IPF diseased lung tissue (B) has increased A B CXCR4 expression as compared with normal lung tissue (A) CXCR4 present in hyperplastic epithelium (EP) of honeycomb cysts (HC) and also within a Dis
Slide 12: CXCR4 as a biomarker in IPF
590 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 179 2009 included. Diagnosis of IPF was based on guidelines of the American monary artery, carina, and 1 cm above the right diaphragm. Fibrotic changes Thoracic Society and European Respiratory Society (3). Surgical lung were quantif
Slide 13: CXCR4 increased in fast progressing IPF patients
CXCR4 increased in fast progressing IPF For personal use only patients Patients that rapidly progress express more CXCR4 compared to slow IPF progressors 11
Slide 14: CXCR4 as a biomarker in IPF
Objectives: In this study, pulmonary CXCR4 expression was evaluated using quantitative positron emission tomography (PET), in order to test its role as a Figure 2: CXCR4 PET/CT scan of a patient with IPF/UIP. CT potential biomarker for IPF. CXCR4 as a biomarker in IPF scan shows the definite UIP pat
Slide 15: AD-114 binds to lung tissue from patients with fibrosis
AD-114 binds to lung tissue from patients with For personal use only fibrosis AD-114 was used for Immunohistochemical (IHC) staining of normal and diseased lung tissues to verify expression of CXCR4 in situ AD-114 does not bind lung tissue from AD-114 binds to lung tissue from lungs normal lungs wit
Slide 16: AD-114 specifically reduced migration/invasion with IPF lung fibroblasts
AD-114 specifically reduced migration/invasion For personal use only with IPF lung fibroblasts No effect Inhibits Inhibits MIGRATION on normal slow IPF fast IPF AD-114 specifically inhibited migration of fibroblasts progressors progressors slow and rapid IPF fibroblast migration but did not have any
Slide 17: AD-114 reduced collagen secretion in IPF fibroblasts
AD-114 reduced collagen secretion in IPF For personal use only fibroblasts AD-114 reduced soluble collagen 1 expression in IPF patient fibroblasts The negative i-body had no effect on soluble collagen 1 production 15
Slide 18: AD-114 prevents fibrosis in Bleomycin mouse model
AD-114 prevents fibrosis in Bleomycin mouse For personal use only model Normal IPF lung tissue IPF lung tissue + AD-114 lung tissue (lung disease mouse model) dosed for 21 days (lung disease mouse model) AD-114 reduces collagen content and inflammatory cell infiltration in the Bleomycin mouse model
Slide 19: AD-114 prevents fibrosis in Bleomycin mouse model
AD-114 prevents fibrosis in Bleomycin mouse For personal use only model 22 Vehicle bleomycin-induced lung injury (g) Negative i-body (10 mg/kg) Mouse weight following 20 AD-114 (10mg/kg) 18 16 14 12 0 5 10 15 20 Day AD-114 significantly reduced the AD-114 significantly prevented the Ashcroft score c
Slide 20: AD-114 reduces fibrotic gene expression in Bleomycin mouse model
AD-114 reduces fibrotic gene expression in For personal use only Bleomycin mouse model RNA extracted and analyzed for collagen gene expression Both COL1A1 and COL3A1 reduced in mice treated with i-body AD-114 in the Bloemycin mouse model The negative control i-body had no effect on either COL1A1 or
Slide 21: AD-114 reduces pulmonary infiltration of fibrocytes in the Bleomycin mouse model
AD-114 reduces pulmonary infiltration of For personal use only fibrocytes in the Bleomycin mouse model Pulmonary infiltration of Cola1+, CD45+ and CXCR4+ cells were also evaluated in the bleomycin mouse model Mice treated with AD-114 had reduced levels of CXCR4+ cells in their lungs when compared to
Slide 22: AD-114 blocks infiltration of leukocytes
AD-114 blocks infiltration of leukocytes For personal use only AD-114 has also been evaluated for its anti-inflammatory activity In a mouse air-pouch model, the inflammatory stimulant CXCL12 is added to an air-pouch created on the back of a mouse, which results in a dramatic increase in the amount o
Slide 23: AD-114 does not mobilize stem cells in vivo
AD-114 does not mobilize stem cells in vivo For personal use only AD-114 does not mobilize stem cells in humanised mouse model unlike the small molecule AMD3100 (Mozobil) AD-114 does not mobilise stem cells in non-human primates with single dose IV and SC, nor via increasing doses This data demonstr
Slide 24: Fibrosis in the eye
Fibrosis in the eye For personal use only Subretinal fibrosis is the end stage of wet AMD 15 Initial study HORIZON SEVEN-UP * ETDRS Letters 10 5 * 0 -5 -10 -15 -20 1 2 3 4 7.3 Years Eylea Rosenfeld et al, N Engl J Med 2006; 355(14): 1419. Subretinal scarring Lucentis Brown et al, N Engl J Med 2006;
Slide 25: What genes are altered in laser induced CNV?
What genes are altered in laser induced CNV? For personal use only 1 4 2 3 Fibrosis thickness 23
Slide 26: Effect of AD-114 in Laser induced CNV and fibrosis in preventative mode
Effect of AD-114 in Laser induced CNV and For personal use only fibrosis in preventative mode 24
Slide 27: AD-114 reduces fibrosis in Laser induced CNV
For personal use only 25 Eylea AD-114 AD-21H5 Lesion leakage size (µm2) 0 2 4 6 8 N eg at Sa iv lin e e i-b od y (5 02 µM * A ) D -1 14 *** 20 1µ M Ey le Lesion Size a (5 22 µM ) Fibrosis vs Choroid Thickness Ratio 0 2 4 6 N eg Ve at hi iv e cl e i-b od y (5 02 µM A ) D *** **** -1 14 Fibrosis (2 0
Slide 28: Affect of AD-114 in Laser induced CNV and fibrosis in therapeutic mode
Affect of AD-114 in Laser induced CNV and For personal use only fibrosis in therapeutic mode IVT injection AD-114 (Day 3) 26
Slide 29: AD-114 reduces fibrosis in Laser induced CNV
For personal use only 27 Lesion size (µm2) 0 1 2 3 N eg Ve at hi iv e cl e i-b od y ** **** (5 02 µM A ) D -1 14 (2 01 µM Ey ) Lesion Size le a (5 22 µM ) Fibrosis vs Choroid Thickness Ratio 0 2 4 6 N eg Ve at hi iv e cl e i-b od y (5 02 **** µM A ) D -1 14 (2 **** 01 Fibrosis µM Ey ) le a (5 22 µM
Slide 30: Model: Laser induced sub retinal haemorrhage
Model: Laser induced sub retinal haemorrhage For personal use only Mouse CNV model; laser burn to retina: – Induces subretinal haemorrhage – Contraction of retinal tissue – Upregulation of fibrotic genes IVT injection of single dose of AD-114 – Reduces lesion size i-body AD114 – Dramatically reduces
Slide 31: Liver Fibrosis
Liver Fibrosis For personal use only Stellic Institute- STAM NASH mouse model: Study plan for assessing the anti-NASH/fibrosis effects of i-body in STAMTM model of NASH 4 wks 6 wks 7 wks 8 wks 9 wks ND feeding Normal (n= 8) G-1 HFD feeding IP, QD for 3 weeks STAMTM + Vehicle (n= 8) G-2 IP, QD for 3
Slide 32: AD-114 prevents fibrosis in a mouse model of liver fibrosis
ID: 101 ID: 207 Normal Vehicle AD-114 prevents fibrosis in a mouse model of liver For personal use only fibrosis rographs of HE-stained liver sections x50 x50 x200 x200 Therapeutic setting ID: 207 ID: 308 Vehicle i-body x200 x50 x200 x50 x200 Normal NASH liver tissue NASH liver tissue + AD-114 ID: 3
Slide 33: AD-114 prevents fibrosis in a mouse model of liver fibrosis
Figure 3. Biochemistry Figure 3.1. Serum ALT Figure 3.2. L AD-114 prevents fibrosis in a mouse model of For personal use only liver fibrosis AD-114 decreased serum ALT levels compared with the vehicle or disease model group suggesting that i-body Figure 4.5. Ballooning score ameliorated hepatocellul
Slide 34: AD-114 is anti-fibrotic in the liver
AD-114 is anti-fibrotic in the liver For personal use only AD-114 also reduced the expression of inflammatory genes TNF-a, MCP1 and fibrosis gene TIMP-1 in a mouse model of liver fibrosis in therapeutic model AD-114 also decreased non-alcoholic fatty liver disease (NAFLD) score compared with the veh
Slide 35: Kidney Fibrosis
Kidney Fibrosis For personal use only CXCR4 is upregulated in fibrotic kidneys of animal and human patients Con DN patient Con STZ eNos-/- Con UUO Con Folic Acid 33
Slide 36: AD-114 inhibits key features of the fibrogenic pathway with novel MOA
AD-114 inhibits key features of the For personal use only fibrogenic pathway with novel MOA Modulate aspects Block fibrocyte recruitment Reduce ECM deposition of inflammation into the damaged tissue during tissue remodeling 34
Slide 37: AD-114 efficacy and safety
AD-114 efficacy and safety For personal use only Efficacy Safety – Lung: IPF – NHP studies demonstrate AD- • Animal models 114 well tolerated and no adverse effect: • Human IPF tissue • PK: IV and SC • Biomarker assessments (Alfred Health & others) • Dose range finder • Multi dosing studies – Broad
Slide 38: AD-114 development: key milestones
AD-114 development: key milestones For personal use only 2017 2018 2019 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Manufacturing Toxicology studies Phase I 36
Slide 39: AdAlta summary
AdAlta summary For personal use only Powerful proprietary technology platform to develop a pipeline of i-bodies for the treatment of a wide range of human diseases – Extreme stability of i-body similar to single domain shark antibody – Long loop of i-body binds deep in GPCR pocket and has functional
Slide 40: Mick Foley, CSO
For personal use only Mick Foley, CSO [email protected] www.adalta.com.au
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