Alterity Therapeutics Ltd. · ASX:ATH
Alterity Therapeutics — Prana Biotechnology — AAIC 2014, Copenhagen
31 slides from Alterity Therapeutics's conference presentation, Jul 18, 2014
Slide 1: How to change and monitor the rates of Aβ amyloid accumulation and cognitive decline
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 / Disclosures
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 A β accumulation? • What does PET - A β and CSF - A β 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 A β TBS extractable pool 0.1% low nanoM Carbonate extractable pool 4% 200 nanoM Urea / detergent extractable pool 32% low microM Formate extractable pool 64% low microM ISF/CSF A β monomer low nanoM A β o low picoM [A β ] fibril, extracellular “PLAQUES” PET - A β Blaine Robert
Slide 5: P3 oligomer model based on crystal structure: the toxic Aβ-oligomer target?
P3 oligomer model based on crystal structure: the toxic A β - oligomer target? Streltsov, Nuttall 2011
Slide 6: The Australian Imaging, Biomarkers and Lifestyle Study of Aging (Australian ADNI)
The Australian Imaging, Biomarkers and Lifestyle Study of Aging (Australian ADNI)
Slide 7: PIB for Aβ imaging
Villemagne / Rowe 11 C - PIB for A b imaging SUVR 3.0 1.5 0.0 AD HC
Slide 8: Longitudinal PiB PET follow-up: healthy controls
Neocortical SUVR Age (years) * PiB+/PiB - SUVR cut - off = 1.5 1.0 1.3 1.5 1.8 2.0 2.3 2.5 2.8 3.0 3.3 3.5 55 60 65 70 75 80 85 90 95 HC ( n=104 ) Progression to aMCI Progression to naMCI Progression to AD Longitudinal PiB PET follow - up Villemagne / Rowe
Slide 9: Longitudinal PiB PET follow-up: MCI
Neocortical SUVR Age (years) * PiB+/PiB - SUVR cut - off = 1.5 1.0 1.3 1.5 1.8 2.0 2.3 2.5 2.8 3.0 3.3 3.5 55 60 65 70 75 80 85 90 95 MCI ( n=48 ) Progression to FTD Progression to VaD Progression to AD Longitudinal PiB PET follow - up Villemagne / Rowe
Slide 10: Longitudinal PiB PET follow-up: AD
* PiB+/PiB - SUVR cut - off = 1.5 Neocortical SUVR Age (years) 1.0 1.3 1.5 1.8 2.0 2.3 2.5 2.8 3.0 3.3 3.5 55 60 65 70 75 80 85 90 95 AD ( n=33 ) Longitudinal PiB PET follow - up Villemagne / Rowe
Slide 11: AIBL: Aβ deposition over time
1.0 1.5 2.0 2.5 3.0 Neocortical SUVR cb Time (years) Mean SUVR AD+ (2.33) 19.2 yr (95%CI 17 - 23 yrs) Mean SUVR HC - (1.17) 12.0 yr (95%CI 10 - 15 yrs) 2.9%/yr (95%CI 2.5 - 3.3%/yr) HC - MCI+ AD MCI - HC+ 0 10 20 30 40 AIBL: Aβ deposition over time DA2
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: effect of 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
Xilinas, Barnham, Bush, Curtain Case Study: M etal - chaperones with moderate affinity (nanomolar 10 - 9 ) (low picomolar 10 - 11 )
Slide 15: PBT2 scaffold and screening
N O H R R R R R R Substituent “ R ” groups influence: • solubility • Hydrophobicity • BBB permeability • metal chaperone “ ionophore ” property • metal binding affinity fused ring scaffold with transition metal binding motif (dissociation constant Cu/Zn/Fe low picomolar 10 - 11 ) in vitro screening:
Slide 16: PBT2 inhibits formation of high order Aβ oligomers and promotes Aβ clearance
PBT2 inhibits the formation of high order Aß oligomers in vitro and promotes Aß clearance in vivo Tim Ryan, Blaine Roberts, unpublished Adlard et al., Neuron 2008 ISF Aß in tg mice ( in vivo microdialysis) %basal ISF A β Time post administration (hr) Aß 1 - 40 (analtyical ultacentrifugation) Sedimen
Slide 17: PBT2 reduces soluble Aβ in human CSF (Euro Phase IIa)
PBT2 reduces soluble A β 42 in human CSF (“Euro” Phase IIa , 12 Weeks) Lannfelt et al., Lancet Neurology (2008) (A) CSF A β 42 , (B) CSFA β 40 , 13% fall in CSF A β 42 from baseline Dose dependent improvement in executive function
Slide 18: PBT2 reduced CSF Aβ in Phase IIa; reflected in plaque burden?
PBT2 reduced CSF A β 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: effe
Slide 19: PiB PET: placebo vs PBT2
PiB PET PLACEBO (n=15) PBT2 (n=25) 2.25 2.30 2.35 2.40 2.45 2.50 2.55 -2 0 2 4 6 8 10 12 SUVR cb Time (months) p= 0.82
Slide 20: Baseline Aβ burden and change at 12 months
SUVR cb Relationship between baseline A b burden and change at 12 months Slope Placebo= - 0.048 (sem 0.097) Slope PBT2 = - 0.240 ( sem 0.107) ( p =0.2 ) PLACEBO ( n =15) e 4 non - e 4 PBT2 ( n =25) e 4 non - e 4 r = - 0.14 ( p =0.63 ) r = - 0.42 ( p =0.035 ) D SUVR cb PLACEBO PBT2
Slide 21: PiB PET adjusted for baseline SUVR
PiB PET (adjusted for baseline SUVR) 2.25 2.30 2.35 2.40 2.45 2.50 2.55 2.60 2.65 2.70 -2 0 2 4 6 8 10 12 14 16 18 20 adj SUVR cb Time (months) p =0.71 p =0.048 p =0.06 PLACEBO ( n =15) 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 Aβ burden by baseline SUVR
SUVR cb 2.00 2.10 2.20 2.30 2.40 -2 0 2 4 6 8 10 12 2.50 2.60 2.70 2.80 2.90 -2 0 2 4 6 8 10 12 SUVR <2.5 SUVR >2.5 Time (months) Time (months) p =0.36 p =0.0017 p =0.35 p =0.46 p =0.67 p =0.08 PLACEBO ( n =8) PBT2 ( n =14) PLACEBO ( n =7) PBT2 ( n =11) Changes in A b burden
Slide 23: Changes in Aβ burden: Bapi trial vs PBT2 trial
2.00 2.10 2.20 2.30 2.40 2.50 2.60 -20 0 20 40 60 80 Bapi 0.5mg/kg (n=87) Placebo (n=55) 2.00 2.10 2.20 2.30 2.40 2.50 2.60 -20 0 20 40 60 80 Placebo (n=15) PBT2 (n=25) Time (weeks) SUVR Changes in A b burden ( e 4 & non - e 4) Bapi trial ( Salloway et al., NEJM, 2014) PBT2 trial
Slide 24: Changes in Aβ burden (ΔLMM – ε4)
-0.10 -0.08 -0.06 -0.04 -0.02 0.00 0.02 0.04 0.06 0.08 0.10 0.12 -20 0 20 40 60 80 Placebo (n=40) Bapi 0.5mg/kg (n=75) -0.10 -0.08 -0.06 -0.04 -0.02 0.00 0.02 0.04 0.06 0.08 0.10 0.12 -20 0 20 40 60 Placebo (n=10) PBT2 (n=19) Time (weeks) SUVR Changes in A b burden ( D LMM – e 4) Bapi trial ( Sallow
Slide 25: Rates of hippocampal atrophy
Rates of hippocampal atrophy Rate of hippocampal atrophy (cc/yr) PLACEBO PBT2 PBT 2 declined at almost half the rate of the placebos ( - 0 . 055 vs - 0 . 028 cc/yr for placebo and PBT 2 , respectively . ns) . * Neuroquant software 0.10 0.05 0.00 - 0.05 - 0.10 - 0.15 - 0.20 PLACEBO (n=15) e 4 non - e
Slide 26: The metabolic pools of Aβ and PBT2
The metabolic pools of A β TBS extractable pool 0.1% low nanoM Carbonate extractable pool 4% 200 nanoM Urea / detergent extractable pool 32% low microM Formate extractable pool 64% low microM ISF/CSF A β monomer low nanoM A β o low picoM [A β ] fibril, extracellular “PLAQUES” PET - A β Blaine Robert
Slide 27: Preliminary conclusions from PBT2 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 va
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
Slide 29: The AIBL Study Team
The AIBL Study Team Osca Acosta David Ames Jennifer Ames Manoj Agarwal David Baxendale Carlita Bevage Pierrick Bourgeat Belinda Brown Ashley Bush Andrew Currie David Darby Denise El - Sheikh Kathryn Ellis Kerryn Dickinson Jurgen Fripp Christopher Fowler Veer Gupta Gareth Jones Adrian Kamer Hannah Ko
Slide 30: Neurodegeneration Research Group
Neurodegeneration Research Group • Paul Adlard • Scott Ayton • Kevin Barnham • Shayne Bellingham • Laura Bica • Ashley Bush • Roberto Cappai • Michael Cater • Lesley Cheng • Robert Cherny • Joe Ciccotosto • Steven Collins • Peter Crouch • Cyril Curtain • Theresa Dang • David Darby • Simon Drew • Jam
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