Adalta Ltd. · ASX:1AD
Adalta — 2024 ASCEPT, APFP & APSA Joint Congress
27 slides from Adalta's conference presentation, Dec 2, 2024
Slide 1: AdAlta to present at ASCEPT, APFP & APSA Joint Congress
ASX Announcement/Press Release | 2 December 2024 AdAlta Limited (ASX:1AD) AdAlta to present at ASCEPT, APFP & APSA Joint Congress Key highlights • AdAlta’s Senior Scientist II Jason Lynch will make an invited presentation at the 2024 ASCEPT, For personal use only APFP & APSA Joint Congress, in Melbo
Slide 2: About AdAlta Limited
For further information, please contact: AdAlta Limited (ASX:1AD) Media & Investor Enquiries Tim Oldham The Capital Network CEO & Managing Director Julia Maguire P: +61 3 9479 5159 P: +61 2 7257 7338 E: t.oldham@adalta.com.au E: julia@thecapitalnetwork.com.au About AdAlta Limited AdAlta Limited is a
Slide 3: Clinical dose estimation for anti CXCR4 i-body-Fc fusion AD-214 for the treatment of fibrotic diseases
For personal use only Clinical dose estimation for anti CXCR4 i-body-Fc fusion AD-214 for the treatment of fibrotic diseases Jason P. Lynch, PhD AdAlta Limited (ASX:1AD) ASCEPT December 3rd 2024
Slide 4: Disclosures
Disclosures I am a paid employee for AdAlta Ltd. For personal use only 3
Slide 5: i-bodies: humanized single domain Ab inspired by shark VNAR Ab
i-bodies: humanized single domain Ab inspired by shark single domain VNAR Ab CDR3 CDR3 Long loop CDR1 For personal use only CDR1 “Humanizing” Shark Human Human Ribbon overlay* Domain 1 of hNCAM (aka CD56) i-body library Shark VNAR Ab … introduction of • Small size (~15 kDa) … observed that shark … l
Slide 6: CXCR4: Role in IPF
CXCR4: Role in IPF CXCR4 and its role in fibrotic diseases including IPF CXCR4: CXCR4 CXCR4 is upregulated in IPF Very limited expression in High BAL cell CXCR4 expression • SDF-1 receptor – chemotaxis lung tissue normal or non-diseased tissues correlates with worse of immune cells outcomes in IPF p
Slide 7: The need: Better outcomes for IPF and other fibrotic diseases
The need: Better outcomes for IPF and other fibrotic diseases IPF prevalence >490,000 worldwide 72,000 78,000 For personal use only Europe USA 14,000 Japan 159,000 China 6,000 Slow, but do not halt progression. Serious side effects limit compliance, tolerability Au stralia 3-5 $5.1b $4.3b >100,000 p
Slide 8: CXCR4 i-body library selection and enrichment
CXCR4 lipoparticles For personal use only (Integral Molecular) Affinity maturation i-body library (phage display) Enrichment for CXCR4 binders 0.600 CXCR4 lipo 0.500 Null lipo A-450nm AMA-1 0.400 EGFR 0.300 0.200 0.100 0.000 6 et al 2016 Griffiths
Slide 9: Characterised library of CXCR4 binding i-bodies
Characterised library of CXCR4 binding i-bodies • Affinity matured anti-CXCR4 i-bodies differ in only a few residues and modeling suggests they engage different epitopes. For personal use only 7 et al 2016 Griffiths
Slide 10: Distinct pharmacological outcomes of anti-CXCR4 i-bodies: biased signaling?
Distinct pharmacological outcomes of anti-CXCR4 i-bodies: biased signaling? AD-114 AD-272 AD-523 Scaffold For personal use only (Domain 1 of CXCR4 human NCAM-1) binding i-body Long CXCR4 specific binding loops CDR1 CDR3 Affinity to CXCR4 4.2 1.8 9.2 (KD/nM)1 Inhibition of β-arrestin (IC50/M)1 1.18
Slide 11: AD-114 has been developed into therapeutic candidate AD-214
AD-114 has been developed into therapeutic candidate AD-214 AD-214, an Fc (human)-fusion Fc = “silent” (point mutated to remove effector function) For personal use only Avidity Half life Efficacy 9 Lynch et al [under review]. Preprint on Research Square.
Slide 12: AD-214: Fc-fusion increases affinity and potency; specificity retained
AD-214: Fc-fusion increases affinity and potency; specificity retained Specificity1 Affinity and Potency2 For personal use only 5,300 human membrane protein array, including 94% of all single-pass, multi- SPR pass and glycosylphosphatidylinositol SPR -Arrestin cAMP Internalisation (GPI)-anchored pr
Slide 13: AD-214 binds to CXCR4 on cells with high affinity
AD-214 binds to CXCR4 on cells with high affinity High hCXCR4 expressing cell line1 Primary CXCR4+ CD3+ T cells1 For personal use only 2000 1500 MFI 1000 500 0 100 10 1 0.1 0.01 0.001 AD-214 [nM] KD = 45 pM (donor 1, above) KD = 100-300 pM 495 pM (donor 2) 556 pM (donor 3) 1. Lynch et al [under revi
Slide 14: AD-214 and AD-114: preclinical efficacy, MOA in IPF and GLP-toxicology
AD-214 and AD-114: preclinical efficacy, MOA in IPF and GLP-toxicology in vitro / ex vivo • Potently inhibits SDF-1-induced CXCR4+ cell migration (AD-2141 and AD-1142) • Dose dependent reduction in pro-fibrotic, pro-inflammatory and pro-remodeling processes in For personal use only co-cultures of lu
Slide 15: Summary of Phase I clinical trials in healthy subjects administered AD-214 via IV infusion
Summary of Phase 1 clinical trials in healthy subjects administered AD-214 via IV infusion AD-214 was evaluated in single IV doses to 20 mg/kg (42 participants) and multiple doses at 5-10 mg/kg (16 For personal use only participants) in two placebo-controlled Phase I clinical study in healthy volunt
Slide 16: PK profile was consistent between dose and independent of ADA response
PK profile was consistent between dose 1 and dose 4 and independent of ADA response for all extension study participants For personal use only Cmax AUC 300000 50000 Dose 1 Dose 1 Dose 4 40000 Dose 4 AUC (ng/mL*day) Cmax (ng/mL) 200000 30000 20000 100000 10000 0 0 S002 S007 S008 S011 S013 S015 S002 S
Slide 17: White blood cell counts were consistent across all participants and doses
White blood cell counts (a PD marker) were consistent across all participants and all doses in extension study Participant WBC_unblinded 1st and 4th dose Dose 1 Dose 4 S002 For personal use only 25 S007 S008 20 S011 WBC (x109/L) 15 S013 S015 10 S001 (P) S010 (P) 5 0 0 1 2 3 4 5 112 113 114 115 116 S
Slide 18: Summary of Phase I clinical trials in healthy subjects administered AD-214 via IV infusion
Summary of Phase 1 clinical trials in healthy subjects administered AD-214 via IV infusion AD-214 was evaluated in single IV doses to 20 mg/kg (42 participants) and multiple doses at 5-10 mg/kg (16 For personal use only participants) in two placebo-controlled Phase I clinical study in healthy volunt
Slide 19: Sustained high levels of CXCR4 receptor occupancy on T-cells
Sustained high levels of CXCR4 receptor occupancy on T- cells: a key PD readout Understanding duration of receptor occupancy (RO) is critical For personal use only to inform dosing 1 week Blood T cells express CXCR4 in healthy individuals, providing an accessible surrogate for AD-214 target engageme
Slide 20: Are these RO levels sufficient for efficacy?
For personal use only Are these RO levels sufficient for efficacy? 4
Slide 21: Model system to link RO with inhibition of a model fibrotic process
Model system to link RO with inhibition of a model fibrotic process (T cell migration) For personal use only Primary human T cells 2. SDF-1 migration assay AD-214 AD-214 1% FCS (conc. gradient) (occupied) + CXCR4 CXCR4 5 µm transwell SDF-1/1% FCS Free CXCR4 Count migrated cells 1. Receptor occupancy
Slide 22: Linking inhibition of T cell migration and CXCR4 receptor occupancy
Linking inhibition of T cell migration, a model fibrotic process, and CXCR4 receptor occupancy Maximal inhibition of primary human T cell migration can be achieved with just 60-85% CXCR4 receptor Modellingoccupancy and suggests different finelow serumdespite specificities concentrations of AD-214 si
Slide 23: Phase I trial data informs dosing schedule
Phase 1 trial data informs dosing schedule Potentially efficacious receptor occupancy can be maintained for at least two weeks after an IV infusion in humans, a clinically viable dosing regimen For personal use only 21 Enabled us to set target RO needed to inhibit fibrotic process (i.e. migration):
Slide 24: Further exploring clinically viable AD-214 dosing using PK/PD modeling
Further exploring clinically viable AD-214 dosing using PK/PD modeling • A model of IV AD-214 administration was For personal use only developed and validated using SPR derived binding data and Phase I human PK, RO and total CXCR4 receptor data. • Preclinical PK results and reasonable assumptions al
Slide 25: q2w ≥10 mg/kg and q1w ≥1 mg/kg IV or SC predicted to achieve target RO
q2w ≥10 mg/kg and q1w ≥1 mg/kg IV or SC predicted to achieve target RO Intravenous (IV) • q2w 10 mg/kg IV maintains >30% RO (potential to For personal use only materially inhibit fibrosis) throughout the two-week interval between doses and greater than 60% receptor occupancy (potential to maximally
Slide 26: Bill van Nierop: IPF survivor speaks to challenge of living with IPF
Bill van Nierop: IPF survivor speaks to challenge of living with IPF For personal use only “…[diagnosis: 2015] 6 yrs with IPF before a “I talked with a 60 something grandmother, who really enjoyed days looking after double lung transplant…” grandkids, but as disease progressed she found sometimes sh
Slide 27: For more information please contact
For personal use only For more information please contact: Jason Lynch Senior Scientist j.lynch@adalta.com.au www.adalta.com.au