Bapineuzumab Phase 3 trials in mild to moderate Alzheimer’s disease dementia in apolipoprotein E e 4 carriers (Study 302) and non-carriers (Study 301) CSF and Volumetric MRI Biomarkers Nick C Fox, MD, FRCP Professor of Neurology, MRC Senior Clinical Fellow Institute of Neurology, University College London, UK On Behalf of the Bapineuzumab Study Investigators Clinical Trials in Alzheimer’s Disease October 29, 2012 1
Disclosures • Prof. Fox served on the scientific advisory boards of Alzheimer’s Research Form, GE Healthcare, Janssen AI, and Wyeth. He is a paid consultant for Eli Lilly, Abbott Laboratories, Eisai, Elan, Wyeth, Janssen AI, GE Healthcare, Sanofi-Aventis, and Lundbeck, and received research support from GlaxoSmithKline, Elan, Wyeth, Janssen AI, Lundbeck, Sanofi-Aventis, IXICO and Pfizer Inc for contracted image analysis. • Dr. Salloway is the Chair of 301/302 Steering Committee, is a bapineuzumab IV P3 study investigator, serves on the scientific advisory boards of Janssen AI and Pfizer, and receives honoraria from Janssen AI and Pfizer. • Dr. Sperling serves on the 301/302 Steering Committee, is a consultant to Janssen AI (unpaid), and was a site investigator in Janssen AI and Pfizer trials for bapineuzumab IV. She is also a consultant for Roche, Merck, Bristol-Myers-Squibb, Eli-Lilly, Satori, Eisai, and Biogen. • Dr. Raskind serves on and is a paid member of the 301/302 Steering Committee, and is a bapineuzumab IV P3 study investigator for Janssen AI and Eli Lilly. • Dr. Ferris serves on the 301/302 Steering Committee,and is a consultant to Pfizer, Eisai, Bristol Myers- Squibb, Eli Lilly, Merck and Baxter. • Dr. Honig serves on and is a paid member of the Study 301/302 Steering Committee, and is a bapineuzumab IV P3 study investigator. • Dr. Porsteinsson serves on the Study 301/302 Steering Committee, is a bapineuzumab IV P3 study investigator, and receives honoraria from Janssen AI. • Dr. Sabbagh serves on the Study 301/302 Steering Committee, is a bapineuzumab IV P3 study investigator, and previously served on speaker’s bureau for Pfizer. • E Liu, E Yuen, Y Lu, D Wang, B Nejadnik, V Guenzler, J Lull, M Miloslavsky, C Tudor, M Reichert, N Ketter, and B Brashear are employees of Janssen Alzheimer Immunotherapy R&D, LLC. • R Black was an employee of Pfizer Inc. • M Grundman is a consultant to Janssen Alzheimer Immunotherapy R&D, LLC. Study funding: Janssen Alzheimer Immunotherapy and Pfizer Inc 42 2
Key Biomarker Secondary Endpoints: CSF p-tau, BBSI 43 3
Change in CSF Phospho-tau by Treatment Group at Week 71 APOE ε4 Carriers (CSF analysis population) APOE ε 4 Carriers 8 Placebo (n=85) 6 Reduction Bap 0.5 mg/kg (n=127) 4 2 CSF P-tau 0 181P -2 -4 Mean (+/-SE) -6 Change From -8 Baseline (pg/mL) -10 Bap 0.5 mg/kg p=0.005 -12 0 71 Weeks 44 4
Change in CSF phospho-tau by Treatment Group at Week 71 APOE ε4 Non -Carriers (CSF analysis population) APOE ε4 Non -Carriers 8 Placebo (n=77) 6 Reduction Bap 0.5 mg/kg (n=47) 4 Bap 1.0 mg/kg (n=54) 2 CSF p-tau 0 181P -2 -4 Mean (+/-SE) -6 Change From -8 Baseline (pg/mL) Bap 0.5 mg/kg p=0.984 -10 Bap 1.0 mg/kg p=0.009 -12 0 71 Weeks *Pre-specified primary analyses of pooled bapineuzumab doses was not significant, p=0.106 45 5
Pooled 302/301: Change in CSF phospho-tau by Treatment Group at Week 71 (CSF analysis population) All Subjects Mild Subjects 12 12 Placebo (n=97) Placebo (n=162) Bap 0.5 mg/kg (n=174) Bap 0.5 mg/kg (n=110) Reduction 8 8 Bap 1.0 mg/kg (n=35) Bap 1.0 mg/kg (n=54) 4 4 0 0 CSF p-tau 181P -4 -4 Mean (+/-SE) Change From -8 -8 Baseline (pg/mL) -12 - 12 -16 -16 -20 -20 0 71 0 71 Weeks Weeks Placebo vs Bap 0.5 mg/kg p=0.185 Placebo vs Bap 0.5 mg/kg p=0.014 Placebo vs Bap 1.0 mg/kg p=0.041 Placebo vs Bap 1.0 mg/kg p=0.002 Significant effect at both doses in moderate group 46 6
Change in CSF Total-tau and A b at Week 71 • Total-tau • Treatment related reductions consistent with changes in p-tau only observed in non-carriers only at 1.0 mg/kg dose (p<0.05) • No treatment related differences seen in carriers or pooled studies • A b • No treatment differences observed in levels of A b x-40 or A b x-42 in either study 47 7
Volumetric MRI Analyses all based upon registered T1-weighted scans 8
Baseline 48 9
BBSI = 9.0ml Week 19 VBSI = 2.6ml LHBSI = 0.021ml RHBSI = 0.058ml 49
BBSI = 15.7ml Week 45 VBSI = 4.9ml LHBSI = 0.048ml RHBSI = 0.120ml 50
BBSI = 23.9ml Week 71 VBSI = 7.3ml LHBSI = 0.113ml RHBSI = 0.177ml 51
Baseline 48 13
BBSI = 23.9ml Week 71 VBSI = 7.3ml LHBSI = 0.113ml RHBSI = 0.177ml 51
Rate of Change in MRI Brain Volume (BBSI) by Treatment Group at Week 71 (vMRI analysis population) APOE e 4 Carriers Non-Carriers 24 24 Decreasing p=0.128 p=0.132 Rate of Change 20 20 p=0.725 16 16 BBSI: Brain Boundary Shift Integral 12 12 Mean (+/-SE) 8 8 Annualized Rate of Change from Baseline 4 to Week 71 4 (mL/year) 0 0 Bap Bap Placebo Bap Placebo 0.5 mg/kg 1.0 mg/kg 0.5 mg/kg (n=244) (n=238) (n=169) (n=146) (n=352) 52 15
Pooled 302/301: Rate of Change in MRI Brain Volume (BBSI) by Treatment Group at Week 71 (vMRI analysis population) All Subjects Mild Subjects 28 28 Decreasing Rate of 24 24 Change p=0.034 p=0.323 20 20 p=0.030 p=0.018 BBSI: 16 16 Brain Boundary Shift Integral 12 12 Mean (+/-SE) 8 8 Annualized Rate of Change From Baseline 4 4 to Week 71 (mL/year) 0 0 Bap Placebo Bap Placebo Bap Bap 0.5 mg/kg 1.0 mg/kg 0.5 mg/kg 1.0 mg/kg (n=482) (n=275) (n=278) (n=87) (n=521) (n=146) No significant effect in moderate group 53 16
Rate of Change in Hippocampal Volume at Week 71 • Left Hippocampal Volume • Increased rate of hippocampal volume loss compared to placebo observed only in non-carrier study and only at 1.0 mg/kg dose – Rate: 0.111 mL/yr +/- 0.006 vs 0.092 mL/yr +/- 0.005; p<0.05 • Right Hippocampal Volume • No treatment differences observed in either study 54 17
Rate of Change in MRI Ventricular Volume (VBSI) by Treatment Group at Week 71 (vMRI analysis population) APOE ε4 Carriers 8 p<.001 Decreasing Rate of Change 6 VBSI: Ventricular Boundary Shift Integral 4 Mean (+/-SE) Annualized Rate of Change 2 from Baseline to Week 71 (mL/year) 0 Bap Placebo 0.5 mg/kg (n=238) (n=352) 55 18
Rate of Change in MRI Ventricular Volume (VBSI) by Treatment Group at Week 71 (vMRI analysis population) APOE ε4 Non -Carriers 8 p=0.001 Decreasing Rate of Change p=0.362 6 VBSI: Ventricular Boundary Shift Integral 4 Mean (+/-SE) Annualized Rate of Change 2 from Baseline to Week 71 (mL/year) 0 Bap Bap Placebo 0.5 mg/kg 1.0 mg/kg (n=244) (n=146) (n=169) 56 19
Pooled 302/301: Rate of Change in MRI Ventricular Volume (VBSI) by Treatment Group at Week 71 (vMRI analysis population) All Subjects Mild Subjects 10 10 Decreasing Rate of Change 8 8 p=0.0005 p=0.0002 p<0.0001 p=0.0013 6 6 VBSI: Ventricular Boundary Shift Integral 4 4 Mean (+/-SE) Annualized 2 2 Rate of Change from Baseline to Week 71 (mL/year) 0 0 Bap Bap Bap Placebo Bap Placebo 1.0 mg/kg 0.5 mg/kg (n=482) 0.5 mg/kg 1.0 mg/kg (n=275) (n=278) (n=87) (n=521) (n=146) No significant effect in moderate group 57 20
Biomarker Summary • Reduced accumulation in amyloid burden on PiB PET relative to placebo observed in carrier and pooled studies • Reduced CSF p-tau relative to placebo observed in carrier, non-carrier and pooled studies • Increased rate of brain volume loss relative to placebo observed only in pooled studies • Increased rate of left hippocampal volume loss relative to placebo observed only in non-carrier study • Increased rate of ventricular expansion relative to placebo observed in carrier, non-carrier studies and pooled analyses 58 21
Interpreting Volumetric MRI • Increased whole brain volumetric loss • Small effect – observed only in pooled studies • Increased ventricular enlargement and hippocampal loss • Concordant with whole brain loss • Previously reported in AN-1792 • Unknown mechanism • Increased neurodegeneration? • Amyloid removal? • Reduction in amyloid-associated inflammation? • Changes in CSF absorption or other fluid shifts? 59 22
Dissociation between biomarker activity and primary clinical outcomes • No significant evidence of clinical effects in mild or moderate AD dementia based on pre-specified MMSE cut points • Differences in amyloid burden on PET amyloid imaging indicative of target engagement • Reduction in CSF p-tau consistent with effects on downstream neurodegeneration • Ventricular volume increase and brain volume loss in treatment group suggests biological effects 60 23
Questions • Wrong target? • Compelling genetic data supporting role of amyloid • Unclear which part of the amyloid cascade to target • Evidence of anti-amyloid treatment effects on a downstream marker of neurodegeneration (CSF p-tau) • Too little? • Higher doses limited by ARIA-E • Though significant differences were seen on PiB-PET, was amyloid lowering insufficient to alter clinical course? • Too late? • AD stage may be too far advanced to demonstrate clinical benefit • Anti-amyloid therapies may be more efficacious at earlier stages 61 24
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