Study funding: Janssen Alzheimer Immunotherapy and Pfizer Inc 42 2 - - PowerPoint PPT Presentation

1

Bapineuzumab Phase 3 trials in mild to moderate Alzheimer’s disease dementia in apolipoprotein E e4 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

2

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

3

Key Biomarker Secondary Endpoints: CSF p-tau, BBSI

43

4

Change in CSF Phospho-tau by Treatment Group at Week 71 APOE ε4 Carriers (CSF analysis population)

CSF P-tau 181P

44

Weeks Baseline (pg/mL)

71

• 12
• 10
• 8
• 6
• 4
• 2

2 4 6 8

Mean (+/-SE) Change From

Reduction

Placebo (n=85) Bap 0.5 mg/kg (n=127) Bap 0.5 mg/kg p=0.005

APOE ε4 Carriers

5

Change in CSF phospho-tau by Treatment Group at Week 71 APOE ε4 Non-Carriers (CSF analysis population)

CSF p-tau 181P

71

Weeks

• 12
• 10
• 8
• 6
• 4
• 2

2 4 6 8

Mean (+/-SE) Change From Baseline (pg/mL)

Reduction

Placebo (n=77) Bap 0.5 mg/kg (n=47) Bap 1.0 mg/kg (n=54)

45

Bap 0.5 mg/kg p=0.984 Bap 1.0 mg/kg p=0.009

*Pre-specified primary analyses of pooled bapineuzumab doses was not significant, p=0.106

APOE ε4 Non-Carriers

6

Pooled 302/301: Change in CSF phospho-tau by Treatment Group at Week 71 (CSF analysis population)

CSF p-tau 181P 71

Weeks

Change From

Placebo vs Bap 0.5 mg/kg p=0.014 Placebo vs Bap 1.0 mg/kg p=0.002

• 20
• 16
• 12
• 8
• 4

4 8 12

Mean (+/-SE) Baseline (pg/mL)

Reduction

Bap 0.5 mg/kg (n=174) Bap 1.0 mg/kg (n=54)

All Subjects Mild Subjects

71

Weeks

• 20
• 16
• 12
• 8
• 4

4 8 12

Placebo (n=97) Bap 0.5 mg/kg (n=110) Bap 1.0 mg/kg (n=35)

Placebo vs Bap 0.5 mg/kg p=0.185 Placebo vs Bap 1.0 mg/kg p=0.041

46

Significant effect at both doses in moderate group

Placebo (n=162)

7

Change in CSF Total-tau and Ab at Week 71

• Total-tau
• Treatment related reductions consistent with changes in p-tau
• nly observed in non-carriers only at 1.0 mg/kg dose (p<0.05)
• No treatment related differences seen in carriers or pooled

studies

• Ab
• No treatment differences observed in levels of Abx-40 or Abx-42

in either study

47

8

Volumetric MRI

Analyses all based upon registered T1-weighted scans

9

Baseline

48

Week 19 BBSI = 9.0ml VBSI = 2.6ml LHBSI = 0.021ml RHBSI = 0.058ml

49

Week 45 BBSI = 15.7ml VBSI = 4.9ml LHBSI = 0.048ml RHBSI = 0.120ml

50

Week 71 BBSI = 23.9ml VBSI = 7.3ml LHBSI = 0.113ml RHBSI = 0.177ml

51

13

Baseline

48

Week 71 BBSI = 23.9ml VBSI = 7.3ml LHBSI = 0.113ml RHBSI = 0.177ml

51

15

Rate of Change in MRI Brain Volume (BBSI) by Treatment Group at Week 71 (vMRI analysis population)

52 BBSI: Brain Boundary Shift Integral

4 8 12 16 20 24

Mean (+/-SE) Annualized Rate of Change from Baseline to Week 71 (mL/year)

Decreasing Rate of Change

Placebo (n=238) Bap 0.5 mg/kg (n=352)

p=0.128

APOE e4 Carriers

4 8 12 16 20 24

Placebo (n=244) Bap 0.5 mg/kg (n=169) Bap 1.0 mg/kg (n=146)

p=0.725 p=0.132

Non-Carriers

16

Pooled 302/301: Rate of Change in MRI Brain Volume (BBSI) by Treatment Group at Week 71 (vMRI analysis population)

p=0.323 p=0.034

BBSI: Brain Boundary Shift Integral

4 8 12 16 20 24 28

Mean (+/-SE) Annualized Rate of Change From Baseline (mL/year) to Week 71

Decreasing Rate of Change

Placebo (n=482) Bap 0.5 mg/kg (n=521) Bap 1.0 mg/kg (n=146)

All Subjects

4 8 12 16 20 24 28

Placebo (n=275) Bap 0.5 mg/kg (n=278) Bap 1.0 mg/kg (n=87)

Mild Subjects

p=0.018 p=0.030

53

No significant effect in moderate group

17

Rate of Change in Hippocampal Volume at Week 71

• Left Hippocampal Volume
• Increased rate of hippocampal volume loss compared to placebo
• bserved 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

18

Rate of Change in MRI Ventricular Volume (VBSI) by Treatment Group at Week 71 (vMRI analysis population)

55

VBSI: Ventricular Boundary Shift Integral Mean (+/-SE) Annualized Rate of Change from Baseline to Week 71 (mL/year)

p<.001

APOE ε4 Carriers

2 4 6 8

Decreasing Rate

• f Change

Placebo (n=238) Bap 0.5 mg/kg (n=352)

19

Rate of Change in MRI Ventricular Volume (VBSI) by Treatment Group at Week 71 (vMRI analysis population)

56

VBSI: Ventricular Boundary Shift Integral Mean (+/-SE) Annualized Rate of Change from Baseline to Week 71 (mL/year)

2 4 6 8

Decreasing Rate

• f Change

Placebo (n=244) Bap 0.5 mg/kg (n=169) Bap 1.0 mg/kg (n=146)

p=0.362 p=0.001

APOE ε4 Non-Carriers

20

Pooled 302/301: Rate of Change in MRI Ventricular Volume (VBSI) by Treatment Group at Week 71 (vMRI analysis population)

57

p=0.0005 p=0.0002

VBSI: Ventricular Boundary Shift Integral Mean (+/-SE) Annualized Rate of Change from Baseline to Week 71 (mL/year) 0

2 4 6 8 10

Decreasing Rate

• f Change

Placebo (n=482) Bap 0.5 mg/kg (n=521) Bap 1.0 mg/kg (n=146)

All Subjects Mild Subjects

2 4 6 8 10

Placebo (n=275) Bap 0.5 mg/kg (n=278) Bap 1.0 mg/kg (n=87)

p<0.0001 p=0.0013

No significant effect in moderate group

21

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
• bserved 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
• bserved in carrier, non-carrier studies and pooled analyses

58

22

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

23

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

24

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

25

Future Directions

• Analyses to fully elucidate the findings
• Amyloid-positive patients only (PET and CSF substudies)
• Secondary clinical endpoints in mild subgroup
• Time course of volumetric MRI changes
• Drug concentrations (AUC) relationship with clinical and

biomarker outcomes

• Relationship of ARIA to clinical and biomarker outcomes
• Very disappointing for patients and families
• These data may inform future anti-amyloid

therapeutic trials at earlier stages of AD

62

26

Acknowledgments

Thanks to:

• Principal Investigators & Clinical Site Study Staff
• Phase 3 Steering Committee
• Data Safety Monitoring Committee
• Janssen Alzheimer Immunotherapy and Pfizer Study

Teams

• Most of all, grateful acknowledgement of the

contribution of the participating AD patients and their caregivers

63