Adalta Ltd. · ASX:1AD
Adalta — Discovery on Target 2023
32 slides from Adalta's conference presentation, Sep 26, 2023
Slide 1: Invited Presentation at International Discovery on Target Conference, Boston
26 September 2023 ASX Announcement INVITED PRESENTATION AT INTERNATIONAL DISCOVERY ON TARGET CONFERENCE, BOSTON MELBOURNE Australia, 26 September 2023: AdAlta Limited (ASX:1AD), the clinical stage drug discovery company developing novel protein and cell therapeutic products from its i-body platform,
Slide 2: Shareholders: please update your communication preferences
Shareholders: please update your communication preferences We encourage shareholders to update their share registry preferences to receive all communications electronically. Doing so helps us communicate with you in a time-efficient manner on important matters, while minimising our mail costs and en
Slide 3: Further information and contacts
Further information can be found at: https://adalta.com.au For more information, please contact: Investors Media Tim Oldham, CEO & Managing Director IR Department Tel: +61 403 446 665 Tel: +61 411 117 774 E: t.oldham@adalta.com.au E: jane.lowe@irdepartment.com.au
Slide 4: Single domain i-bodies from sharks to Clinical Trials
Single domain i-bodies from sharks to Clinical Trials Discovery on Target September 26-28, 2023
Slide 5: i-bodies: human single domains
i-bodies: human single domains i-body inspired by the shark VNAR structure Long CDR3 loop enables penetration of active sites/ligand binding sites and hydrophobic pockets in target proteins 2
Slide 6: CXCR4: Role in Idiopathic Pulmonary Fibrosis
CXCR4 plays a roleCXCR4: Role in Idiopathic in IPFFibrosis Pulmonary CXCR4 CXCR4 is upregulated in Very limited expression in CXCR4 is a critical player in many IPF lung tissue normal or non-diseased tissues fibrotic indications including: • Lung • Kidney • Heart • Eye • Skin Normal lung histology C
Slide 7: Selecting i-bodies against CXCR4
Selecting i-bodies against CXCR4 CXCR4 lipoparticles (Integral Molecular) Affinity maturation i-body library Enrichment for CXCR4 0.600 CXCR4 lipo 0.500 Null lipo AMA-1 A-450nm 0.400 EGFR 0.300 0.200 0.100 0.000 … 2… A… A… A… A… A… A… N 4
Slide 8: CXCR4 i-bodies: novel pharmacology
CXCR4 i-bodies: novel pharmacology Protein Affinity to IC50 (nM) in b- CXCR4 Arrestin BRET (nM) assay ADCX-99 700 No activity AD-320 21.8 1419 AD-245 14.88 ~uM AD-126 14.75 610 AD-466 13.83 6322 AD-661 9.53 1544 AD-523 8.55 12713 AD-613 7.83 1826 AD-1121 7.21 796 AD-920 7.18 ~uM AD-746 5 741 AD-114
Slide 9: CXCR4 i-bodies: novel physiological outcomes
CXCR4 i-bodies: novel physiological outcomes AD-114 inhibits SDF-1 induced platelet aggregation (AD-272 & AD-523 Inhibit to a Lesser Degree) AD-114 Reduces fibrosis in a mouse model of macular degeneration AD- 523 does not Light transmission 6
Slide 10: Biased signaling?
Biased signaling? Modelling suggests the panel of affinity matured have different fine specificities which may drive diverse signaling events resulting in distinct pharmacologies 7
Slide 11: AD-214 retains specificity for CXCR4
AD-214 retains specificity for CXCR4 AD-214 consists of the CXCR4 binding i-body (AD-114) fused to human Fc AD-214 binds specifically to CXCR4 8
Slide 12: AD-214 binds with high affinity to CXCR4
AD-214 binds with high affinity to CXCR4 AD-214 binds to human A C CXCR4 lipoparticles with affinity of ~4pM (A) AD-214 binding to CXCR4 expressing CHO cells but not to parental cells (B) B Flow cytometry shows that AD-214 can bind to CXCR4 expressed on human CD3+ T cells (C). 9
Slide 13: AD-214 Phenotypic profile lung fibrosis panel
AD-214 Phenotypic profile lung fibrosis panel SAEMyoF and MyoF consisting of a co-culture of Small Airway epithelial cells & fibroblasts Fibroblasts lung fibroblasts and small airway epithelial cells. Key activities of AD-214: – AD-214 is not cytotoxic at the concentrations tested in this study. – F
Slide 14: AD-214 attenuates collagen deposition in human PCLS
AD-214 attenuates collagen deposition in human PCLS AD-214 in vitro at 1 µM attenuated collagen deposition in Precision Cut Lung Slices treated with a fibrotic cocktail ✱✱ ✱✱ ✱✱ ✱ 8 % collagen/field average 6 4 2 0 ia pa C -2 uM TD M M F ed 1u 1u 1 M 14 da N D 5- A Representative images of Masson tr
Slide 15: AD-214 efficacy validated in IPF murine model
AD-214 efficacy validated in IPF murine model AD-214 inhibited the development of fibrosis in a bleomycin mouse model of lung fibrosis at concentrations as low as 1 mg/kg every two days and 10 mg/kg every four days Statistical Significance1 to 21 d Bleomycin Normal mouse lung tissue ns ns ns ns Ashc
Slide 16: AD-114 is antifibrotic in a mouse model of kidney fibrosis
AD-114 is antifibrotic in a mouse model of kidney fibrosis CXCR4 is upregulated in several models of kidney fibrosis AD-114 administration attenuated tissue damage when given at the time of injury or after fibrosis was established AD-114 blocked TGF-β–induced production of extracellular matrix and a
Slide 17: AD-214 is antifibrotic in a mouse model of kidney fibrosis
AD-214 is antifibrotic in a mouse model of kidney fibrosis The effect of AD-214 on fibrosis induced A by Unilateral Ureteral Obstruction (UUO) was examined Mice were dosed with negative i-body or AD-214 i.p. the day following UUO and were then administered every second day until day 14. Representati
Slide 18: Non-human primate GLP toxicology: Phase I dose justification
Non-human primate GLP toxicology: Phase I dose justification Pharmacokinetics Pharmacodynamics Safety • Elimination half-life 22-29h • >60% receptor occupancy* for 72h at >30mg/kg • 3 non-human primate studies • Human equivalent: ~71h (estimate) • Human equivalent: ~10mg/kg (estimate) completed. • A
Slide 19: AD-214 IV administration Phase I healthy volunteer results
AD-214 IV administration Phase I healthy volunteer results AD-214 molecule has an excellent safety profile in single doses to 20 mg/kg and multiple doses to 5 mg/kg • No dose limiting toxicities or adverse events of clinical concern in single doses to 20 mg/kg • Moderate infusion related reactions (
Slide 20: Biomarkers of CXCR4 receptor engagement (5mg/kg)
Biomarkers of CXCR4 receptor engagement (5mg/kg) Transient increases in blood biomarkers demonstrate consistent engagement of the target receptor, CXCR4 across multiple AD-214 doses 17
Slide 21: Sustained high levels of CXCR4 receptor occupancy on T-cells
Sustained high levels of CXCR4 receptor occupancy on T- cells White blood cells naturally express CXCR4 in healthy individuals, providing an accessible surrogate for AD-214 target engagement or receptor occupancy (RO) Understanding duration of RO is critical to inform dosing Primary • >70% CXCR4 RO
Slide 22: Feasibility of direct lung delivery via inhalation demonstrated; SC under evaluation
Feasibility of direct lung delivery via inhalation demonstrated; SC under evaluation The ICRP661 model predicts that 17 - 46% of AD-214 delivered from commercial nebulisers will be delivered to the smallest (alveolar/interstitial) airways of the lungs where most IPF is found. PET imaging confirms AD
Slide 23: AD-214 is safe but is there a viable clinical product?
AD-214 is safe but is there a viable clinical product? 20
Slide 24: Linking inhibition of T cell migration and CXCR4 receptor occupancy
Linking inhibition of T cell migration and CXCR4 receptor occupancy Maximal inhibition of T cell migration can be achieved with just 60-85% CXCR4 receptor Modelling suggests different fine specificities despite similar sequences occupancywith Collaborating and low serum Colleagues concentrations to
Slide 25: Phase 1 information to inform dosing schedule
Phase 1 information to inform dosing schedule 22
Slide 26: Does modelling support the dosing schedule?
Does modelling support the dosing schedule? 23
Slide 27: IV and SC doses: predicted AD-214 plasma concentrations and CXCR4 RO
IV and SC doses: predicted AD-214 plasma concentrations and CXCR4 RO Simulated CXCR4 receptor occupancy following IV (red) and SC (blue) administration of AD-214 doses. Panel A simulates 10 mg/kg AD-214 administered every two weeks. Panel B simulates 1 mg/kg (left) and 3 mg/kg (right) AD-214 adminis
Slide 28: Phase I extension study delivers new data in 2023
Phase I extension study delivers new data in 2023 to support partnering and Phase II AD-214 multidose Phase I extension clinical study Establishes safety of AD-214 at likely maximum dose to be • Evaluating safety, PK and PD of multiple used in Phase II studies 10 mg/kg doses ü Shorter dose escalatio
Slide 29: Diverse applications of i-bodies
Diverse applications of i-bodies Therapeutic: Flexible modular format i-bodies with variable C- termini allow direct therapeutics (AD-214) PET Imaging: untagged i-body against important diagnostic targets eg i-body to GZMB (GE Healthcare) CAR-T: therapy is a fast-emerging form of cancer therapy. i-b
Slide 30: i-bodies enable optimized CAR constructs (i-CARs)
i-bodies enable optimized CAR constructs (i-CARs) SUPERIOR i-CAR PRODUCTS FEATURE BENEFIT § CARs against novel tumor antigens Increased CAR gene cassette/vector Small Size capacity, efficient multi-functional CAR cell § Dual and bi-specific CARs for enhanced creation specificity, reduced tumor escap
Slide 31: i-body enabled CAR-T (i-CAR-T) cells demonstrate in vitro cell killing
i-body enabled CAR-T (i-CAR-T) cells demonstrate in vitro cell killing1 UT CNA4002 CNA4003 LOVO LIM-1215 U87 CNA4004 100 100 100 80 80 80 % Lysis % Lysis % Lysis 60 60 60 40 40 40 20 20 20 0 0 0 10:1 3:1 1:1 10:1 3:1 1:1 10:1 3:1 1:1 E:T E:T E:T § Cell lines: colorectal cancer (LOVO and LIM1215); gl
Slide 32: Contact us: Mick Foley, Founding Chief Scientist
Contact us: Mick Foley, Founding Chief Scientist m.foley@adalta.com.au www.adalta.com.au