Alterity Therapeutics Ltd. · ASX:ATH

Alterity Therapeutics — American Academy of Neurology 2019

13 slides from Alterity Therapeutics's conference presentation, May 6, 2019

  1. Slide 1: A First in Human Study of PBT434, a Novel Small Molecule Inhibitor of α-Synuclein Aggregation

    A First in Human Study of PBT434, a Novel Small Molecule Inhibitor of α - Synuclein Aggregation David Stamler 1 , Margaret Bradbury 1 , Cynthia Wong 1 , Elliot Offman 2 1 Alterity Therapuetics , 2 Certara Strategic Consulting American Academy of Neurology – S4.001 Sunday, May 5, 2019 1

  2. Slide 2: Disclosures

    Disclosures • Authors are employees or paid consultants of Alterity Therapeutics 2

  3. Slide 3: Therapeutic Strategy

    Therapeutic Strategy • Disrupting the underlying disease process of synucleinopathies • Parkinson’s disease • Atypical parkinsonism • Inhibit accumulation and aggregation of intracellular α - synuclein • Target “labile” iron which is increased in disease • Oral agent, crosses BBB • Initial disease t

  4. Slide 4: Increased Brain Iron in Areas of Pathology in Synucleinopathy

    Increased Brain Iron in Areas of Pathology in Synucleinopathy 4 Substantia nigra (T) Substantia nigra (pc) Cerebellum n = 24 n = 13 nmol iron/g of human brain n = 9 n = 7 * n = 3 n = 8 * 0 10000 20000 30000 Dexter et al . Brain.1991;114 Langkammer . PLoS ONE 11(9): e0162460. 2016 Quantitative Suscep

  5. Slide 5: Role of Iron in the pathogenesis of MSA

    Role of Iron in the pathogenesis of MSA 5 • Oligodendroglia – CNS cell population richest in iron • Compelling evidence that “labile iron” is central in the pathogenesis of MSA • Elevated iron in regions of α - synuclein aggregation and neurodegeneration • Labile iron drives continuous redox cycling

  6. Slide 6: PBT434 Inhibits α-Synuclein Aggregation and Accumulation and Reduces Oxidative Stress

    PBT434 Inhibits α - Synuclein Aggregation and Accumulation and Reduces Oxidative Stress by Restoring Intracellular Iron Balance 6 PBT434 blocks Aggregation of α - synuclein in vitro Strong homology in Iron Responsive Element of Ferritin and α - Synuclein Ligand Kd for Fe 3+ α - Synuclein 10 - 5 PBT4

  7. Slide 7: PBT434 Reduces Alpha-synuclein and Lowers Glial Cell Inclusions

    PBT434 Reduces Alpha - synuclein and Lowers Glial Cell Inclusions Transgenic Mouse Model (PLP) - α - SYN of MSA 7 ↓ α - Synuclein Treatment: 30 mg/kg/day or Vehicle for 4 months Data presented are for animals at 16 mo age Vehicle PBT434 0.0 0.1 0.2 0.3 0.4 R e l a t i v e t o T o t a l P r o t e i n

  8. Slide 8: Phase 1 Study Design

    Phase 1 Design • Randomized, double blind, placebo controlled • Population: Healthy adult and older adult (≥65) volunteers (older adult data pending) • Objective: Assess safety, tolerability and PK of PBT434 after single and multiple oral doses for 8 days • Pharmacokinetics: Plasma and CSF • Plasma

  9. Slide 9: Pharmacokinetic Results

    Pharmacokinetic Results 9 Regimen AUCtau ( ng *h/ mL ) Cmax (ng/mL) Tmax ( hr ) Arithmetic mean (CV%) Median (Min - Max) 100 mg BID 2,561 (50.7) 961.3 (49.6) 1.25 (0.75 - 2) 200 mg BID 12,330 (46.4) 3,199 (39.2) 1.25 (0.5 - 2) 250 mg BID 13,000 (15.8) 3,329 (37.3) 1.13 (0.5 - 2) PK parameters after

  10. Slide 10: CSF Pharmacokinetics

    CSF Pharmacokinetics • Plasma concentrations of PBT434 in plasma strongly correlate with CSF levels in both humans and mouse • PBT434 at 200 to 250 mg bid achieve CSF levels greater than in mice dosed at 30 mg/kg/day – a dose level associated with robust efficacy in an MSA mouse model 10 Human 200 m

  11. Slide 11: Adverse Event Summary

    Adverse Event Summary Single Ascending Doses Placebo (N=8) 50 mg (N=6) 100 mg (N=6) 300 mg (N=6) 600 mg (N=6) Patients with ≥ 1 AE 3 (38%) 0 0 1 1 Patients with AEs leading to Withdrawal 0 0 0 0 0 Patients with Serious AEs 0 0 0 0 0 PBT434 was well tolerated with similar rates of AEs compared to pla

  12. Slide 12: Safety

    Safety • All AEs with PBT434 were mild to moderate in severity • Most common AEs reported in PBT434 subjects was headache • No clinically significant findings observed in vital signs, clinical laboratory parameters or 12 - lead ECGs 12

  13. Slide 13: Summary

    Summary • PBT434 is an orally bioavailable, brain penetrant small molecule inhibitor of α - synuclein aggregation • Single and multiple dose administration of PBT434 was well tolerated with an AE profile comparable to placebo • PBT434 demonstrated dose dependent pharmacokinetics after single and mul

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