Alterity Therapeutics Ltd. · ASX:ATH
Alterity Therapeutics — AAIC 2014
31 slides from Alterity Therapeutics's conference presentation, July 2014
Slide 1: How to change and monitor the rates of Aβ amyloid accumulation
How to change and monitor the rates of Aβ amyloid accumulation and cognitive decline in Alzheimer’s disease AAIC, Copenhagen, July 2014
Slide 2: The Amyloid Plaque
The Amyloid Plaque From W Spielmeyer, Histopathologie des Nervensystems. 1922 Disclosures Consultant to Eli Lilly and ad hoc consultant to Prana Biotechnology
Slide 3: How to monitor Aβ accumulation?
How to monitor Aβ accumulation? • What does PET-Aβ and CSF-Aβ actually report? • Why are we having such difficulty in achieving a link between cognitive variables and these two markers?
Slide 4: The metabolic pools of Aβ
The metabolic pools of Aβ ISF/CSF Aβmonomer low nanoM Aβo low picoM Urea / detergent Formate TBS Carbonate extractable pool extractable pool extractable pool extractable pool 32% 64% 0.1% 4% low microM low microM low nanoM 200 nanoM Total Brain Aβ Control 2.7mg [Aβ]fibril, extracellular AD 9.6mg “PL
Slide 5: P3 oligomer model based on crystal structure: the toxic Aβ-oligomer target?
P3 oligomer model based on crystal structure: the toxic Aβ-oligomer target? Streltsov, Nuttall 2011
Slide 6: The Australian Imaging, Biomarkers and Lifestyle Study of Aging
The Australian Imaging, Biomarkers and Lifestyle Study of Aging (Australian ADNI)
Slide 7: 11C-PIB for Ab imaging
11C-PIB for Ab imaging HC AD SUVR 3.0 1.5 0.0 Villemagne / Rowe
Slide 8: Longitudinal PiB PET follow-up
Longitudinal PiB PET follow-up HC Progression to aMCI Progression to naMCI 3.5 (n=104) Progression to AD 3.3 3.0 2.8 Neocortical SUVR 2.5 2.3 2.0 1.8 1.5 1.3 1.0 55 60 65 70 75 80 85 90 95 Age (years) * PiB+/PiB- SUVR cut-off = 1.5 Villemagne / Rowe
Slide 9: Longitudinal PiB PET follow-up
Longitudinal PiB PET follow-up MCI Progression to FTD Progression to VaD 3.5 (n=48) Progression to AD 3.3 3.0 2.8 Neocortical SUVR 2.5 2.3 2.0 1.8 1.5 1.3 1.0 55 60 65 70 75 80 85 90 95 Age (years) * PiB+/PiB- SUVR cut-off = 1.5 Villemagne / Rowe
Slide 10: Longitudinal PiB PET follow-up
Longitudinal PiB PET follow-up AD 3.5 (n=33) 3.3 3.0 2.8 Neocortical SUVR 2.5 2.3 2.0 1.8 1.5 1.3 1.0 55 60 65 70 75 80 85 90 95 Age (years) * PiB+/PiB- SUVR cut-off = 1.5 Villemagne / Rowe
Slide 11: AIBL: Aβ deposition over time
AIBL: Aβ deposition over time MCI+ 3.0 AD Neocortical SUVRcb HC+ 2.5 Mean SUVR AD+ (2.33) 2.0 2.9%/yr (95%CI 2.5-3.3%/yr) 1.5 19.2 yr (95%CI 17-23 yrs) Mean SUVR HC- 12.0 yr (1.17) (95%CI 10-15 yrs) 1.0 HC- MCI- 0 10 20 30 40 Time (years)
Slide 12: AIBL: Relationship between abnormality and CDR of 1.0
AIBL: Relationship between “abnormality” and CDR of 1.0
Slide 13: Trajectories of cognitive decline in preclinical AD: ApoE and BDNF
Trajectories of cognitive decline over 54 months in preclinical AD: effect of ApoE and BDNF polymorphisms Lim, Maruff et al. unpublished
Slide 14: Case Study: Metal-chaperones with moderate affinity
Case Study: Metal-chaperones with moderate affinity (nanomolar 10-9) (low picomolar 10-11) Xilinas, Barnham, Bush, Curtain
Slide 15: PBT2
R R R R Substituent “R” groups influence: • solubility PBT2 • Hydrophobicity R N R • BBB permeability OH • metal chaperone “ionophore” property fused ring scaffold with • metal binding affinity transition metal binding motif (dissociation constant Cu/Zn/Fe low picomolar 10-11) in vitro screening: •
Slide 16: PBT2 inhibits high order Aß oligomers in vitro and promotes clearance in vivo
PBT2 inhibits the formation of high order Aß oligomers in vitro and promotes Aß clearance in vivo Aß 1-40 ISF Aß in tg mice (analtyical ultacentrifugation) (in vivo microdialysis) %basal ISF Aβ Sedimentation coefficient (S) Time post administration (hr) Tim Ryan, Blaine Roberts, unpublished Adlard e
Slide 17: PBT2 reduces soluble Aβ in human CSF
PBT2 reduces soluble Aβ 42 in human CSF (“Euro” Phase IIa, 12 Weeks) Dose dependent improvement (A) CSF Aβ42, (B) CSFAβ40, in executive function 13% fall in CSF Aβ42 from baseline Lannfelt et al., Lancet Neurology (2008)
Slide 18: PBT2 reduced CSF Aβ in Phase IIa study; is that reflected in plaque burden?
PBT2 reduced CSF Aβ in Phase IIa study; is that relected in plaque burden? PBT2-204 (Imagine) RCT, Phase IIa, prodromal or mild AD, Inclusion criteria PiB-PET > 1.7, MMSE >20, 12 months, n=40 (placebo 15, drug 25), Sponsor: Prana Biotechnology with support from ADDF. • Primary objective: effect of P
Slide 19: PiB PET
PiB PET SUVR cb 2.55 2.50 2.45 2.40 p= 0.82 2.35 2.30 2.25 -2 0 2 4 6 8 10 12 Time PLACEBO (n=15) PBT2 (n=25) (months)
Slide 20: Relationship between baseline Ab burden and change
Relationship between baseline Ab burden and change at 12 months PLACEBO PBT2 r= -0.14 (p=0.63) r= -0.42 (p=0.035) D SUVRcb SUVRcb Slope Placebo= -0.048 (sem 0.097) PLACEBO (n=15) e4 non-e4 Slope PBT2 = -0.240 (sem 0.107) PBT2 (n=25) e4 non-e4 (p=0.2)
Slide 21: PiB PET (adjusted for baseline SUVR)
PiB PET (adjusted for baseline SUVR) adj SUVRcb 2.70 2.65 2.60 2.55 p=0.06 2.50 2.45 p=0.71 2.40 2.35 p=0.048 2.30 2.25 -2 0 2 4 6 8 10 12 14 16 18 20 PLACEBO (n=15) Time (months) PBT2 (n=25) AIBL [shaded area 95% CI] (MCI or AD, SUVR>1.7; MMSE>20; matched for baseline SUVR (n=46))
Slide 22: Changes in Ab burden
Changes in Ab burden SUVR <2.5 SUVR >2.5 2.40 2.90 2.30 2.80 p=0.67 p=0.35 SUVRcb 2.20 2.70 p=0.46 p=0.36 2.10 2.60 p=0.08 p=0.0017 2.00 2.50 -2 0 2 4 6 8 10 12 -2 0 2 4 6 8 10 12 Time (months) Time (months) PLACEBO (n=8) PLACEBO (n=7) PBT2 (n=14) PBT2 (n=11)
Slide 23: Changes in Ab burden (e4 & non-e4)
Changes in Ab burden (e4 & non-e4) Bapi trial PBT2 trial (Salloway et al., NEJM, 2014) 2.60 2.60 Bapi 0.5mg/kg (n=87) Placebo (n=55) 2.50 2.50 2.40 2.40 SUVR 2.30 2.30 2.20 2.20 2.10 2.10 Placebo (n=15) PBT2 (n=25) 2.00 2.00 -20 0 20 40 60 80 -20 0 20 40 60 80 Time (weeks)
Slide 24: Changes in Ab burden (DLMM – e4)
Changes in Ab burden (DLMM – e4) Bapi trial PBT2 trial (Salloway et al., NEJM, 2014) 0.12 0.12 0.10 0.10 0.08 0.08 0.06 0.06 0.04 0.04 0.02 0.02 SUVR 0.00 0.00 -0.02 -0.02 -0.04 -0.04 -0.06 -0.06 -0.08 Placebo (n=40) -0.08 Placebo (n=10) Bapi 0.5mg/kg (n=75) PBT2 (n=19) -0.10 -0.10 -20 0 20 40 60 80
Slide 25: Rates of hippocampal atrophy
Rates of hippocampal atrophy 0.10 Rate of hippocampal atrophy 0.05 0.00 (cc/yr) -0.05 -0.10 -0.15 -0.20 PLACEBO PBT2 PBT2 declined at almost half the rate of the placebos (-0.055 vs -0.028 cc/yr for placebo and PBT2, PLACEBO (n=15) e4 non-e4 respectively. ns). *Neuroquant software PBT2 (n=25) e4 non
Slide 26: The metabolic pools of Aβ
The metabolic pools of Aβ ISF/CSF PBT2 Aβmonomer low nanoM Aβo low picoM ? Urea / detergent Formate TBS Carbonate extractable pool extractable pool extractable pool extractable pool 32% 64% 0.1% 4% low microM low microM low nanoM 200 nanoM peripheral Integral Fibrllar membrane membrane Total Brain A
Slide 27: Preliminary conclusions from PBT2-204 Trial (Imagine)
Preliminary conclusions from PBT2-204 Trial (Imagine) • Significant correlation between baseline SUVR and change over 12 months in PBT2 group (decline in SUVR with higher baseline [>2.5], not seen in placebo), and significant decrease in PBT2 group after adjusting for baseline • BUT intake SUVR valu
Slide 28: General conclusions
General conclusions • Some Aß-directed therapies are shifting the PET/CSF signals, but the effect so far is weak: Mcabs to the N-terminus (Bapi) promote plaque clearance but may not affect toxic species (no cognitive effect); Mcabs to the mid-region (Sola) may neutralize soluble toxic species (with
Slide 29: The AIBL Study Team
The AIBL Study Team Osca Acosta Asawari Killedar Svetlana Pejoska David Ames Neil Killeen Kelly Pertile Jennifer Ames Tae Wan Kim Lorien Porter Manoj Agarwal Eleftheria Kotsopoulos Roger Price David Baxendale Gobhathai Kunarak Parnesh Raniga Carlita Bevage Rebecca Lachovitski Alan Rembach Pierrick B
Slide 30: Neurodegeneration Research Group
Neurodegeneration Research Group • Paul Adlard • David Finkelstein The University of • Scott Ayton • Kevin Barnham • Michelle Fodero-Tavoletti • Qiao-Xin Li Melbourne • Chris Fowler • Jeffrey Liddell • Shayne Bellingham • Laura Bica • Mark Greenough • Maree Mastwyk • Ashley Bush • Alexandra Grubman
Slide 31: Collaborators
Collaborators • Alfred Hospital: Catriona McLean • Austin Health: Chris Rowe, Victor Villemagne • Cogstate: Paul Maruff • CSIRO (Structural Biology): Jose Varghese, Victor Streltsov, Stewart Nuttall • Imperial College London: Craig Ritchie • Mass General Hospital / Harvard Med School: Rudy Tanzi • N