Study funding: Janssen Alzheimer Immunotherapy and Pfizer Inc 19 2 - - PowerPoint PPT Presentation

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Study funding: Janssen Alzheimer Immunotherapy and Pfizer Inc 19 2 - - PowerPoint PPT Presentation

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Bapineuzumab Phase 3 trials in mild to moderate Alzheimers disease dementia in apolipoprotein E e 4 carriers (Study 302) and non-carriers (Study 301) Safety and PiB PET Amyloid Imaging Sperling R, Salloway S, Raskind M, Ferris S, Honig L,

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Bapineuzumab Phase 3 trials in mild to moderate Alzheimer’s disease dementia in apolipoprotein E e4 carriers (Study 302) and non-carriers (Study 301)

Safety and PiB PET Amyloid Imaging

Sperling R, Salloway S, Raskind M, Ferris S, Honig L, Porsteinsson A, Sabbagh M, Fox N, Yuen E, Liu E, Lu Y, Lull J, Miloslavsky M, Wang D, Tudor C, Banerjee K, Nejadnik B, Guenzler V, Reichert M, Ketter N, Grundman M, Black R, Brashear R

Reisa Sperling, MD

Center for Alzheimer Research and Treatment Brigham and Women's Hospital, Massachusetts General Hospital Professor of Neurology, Harvard Medical School On Behalf of the Bapineuzumab Study Investigators

Clinical Trials in Alzheimer’s Disease October 29, 2012

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Disclosures

  • 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. 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. 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.

  • 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.

  • 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

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Results: Safety

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Amyloid Related Imaging Abnormalities

Multi-focal gray and white matter edema (ARIA-E) Subtle lepto- meningeal involvement (ARIA-E) Sulcal effusion (ARIA-E) Micro- hemorrhages (ARIA-H) Sperling et al. Alz & Dementia 2011

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Treatment Emergent Adverse Events of Special Circumstance

AEs of Special Circumstance Placebo N=448 (%) Bapineuzumab 0.5 mg/kg N=673 (%) ARIA-E (vasogenic edema) 1 (0.2) 103 (15.3) Symptomatic ARIA-E* 0 (0.0) 16 (2.4) Intracranial hemorrhage** 7 (1.6) 7 (1.0) Seizure/Convulsion 1 (0.2) 7 (1.0) DVT/PE 4 (0.9) 5 (0.7)

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*Symptoms in ARIA-E subjects included: headache, confusional state, cognitive disorder, agitation, dizziness, memory impairment, hemiparesis, abnormal behavior, fatigue, and gait disturbance. **Excludes hemosiderin deposits, such as microhemorrhage

APOE ε4 Carriers

AEs of Special Circumstance Placebo N=524 (%) Bapineuzumab 0.5 mg/kg N=337 (%) Bapineuzumab 1.0 mg/kg N=329 (%) ARIA-E (vasogenic edema) 1 (0.2) 14 (4.2) 31 (9.4) Symptomatic ARIA-E* 0 (0.0) 5 (1.5) 5 (1.5) Intracranial hemorrhage** 7 (1.3) 1 (0.3) 6 (1.8) Seizure/Convulsion 5 (1.0) 1 (0.3) 7 (2.1) DVT/PE 6 (1.1) 2 (0.6) 3 (0.9)

Non-Carriers

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Treatment Emergent Serious Adverse Events Occurring in ≥1% of Subjects in Any Treatment Group

Serious AEs (determined by investigator) Placebo N=448 (%) Bapineuzumab 0.5 mg/kg N=673 (%) ARIA-E (Vasogenic edema) 0 (0.0) 14 (2.1) Syncope 10 (2.2) 11 (1.6) Dehydration 2 (0.4) 8 (1.2)

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APOE ε4 Carriers

Serious AEs (determined by investigator) Placebo N=524 (%) Bapineuzumab 0.5 mg/kg N=337 (%) Bapineuzumab 1.0 mg/kg N=329 (%) Pneumonia 8 (1.5) 3 (0.9) 8 (2.4) Convulsion 4 (0.8) 1 (0.3) 6 (1.8) ARIA-E (Vasogenic edema) 0 (0.0) 5 (1.5) 5 (1.5) Syncope 5 (1.0) 4 (1.2) 4 (1.2) Diverticulitis 1 (0.2) 0 (0.0) 4 (1.2) Hip Fracture 2 (0.4) 4 (1.2) 4 (1.2) Subdural Hematoma 6 (1.1) 0 (0.0) 2 (0.6) Urinary Tract Infection 6 (1.1) 0 (0.0) 2 (0.6) Atrial Fibrillation 6 (1.1) 2 (0.6) 2 (0.6)

Non-Carriers

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Initiation of Final MRI Read Project

  • Phase 2 Final Read revealed 40% of ARIA-E cases not detected during the

study (Sperling et al, Lancet Neurology, 2012)

  • Main Objective:
  • Determine incidence of ARIA uniformly with standardized methods
  • Methods:
  • Review of all MRI scans in studies 301 and 302 (>15,000 MRI scans)
  • Neuroradiologist pairs performed sequential, locked readings for the full series of

images for each subject after completing the study

  • Final result adjudicated between readers by consensus

Subject MRI Scan Final Adjudicated Reads Neurorad 1 Neurorad 2 Initial Read Locked Initial Read Locked Final Individual Reads

24 view prior scans

Final Individual Reads

view prior scans

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Treatment Emergent ARIA-E on MRI by Safety Read and Final Read

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Analysis Group Placebo N=448 (%) Bapineuzumab 0.5 mg/kg N=673 (%) Safety Read 1 (0.2) 103 (15.3) Final Read 5 (1.1) 143 (21.2) Analysis Group Placebo N=524 (%) Bapineuzumab 0.5 mg/kg N=337 (%) Bapineuzumab 1.0 mg/kg N=329 (%) Bapineuzumab 2.0 mg/kg N=141 (%) Safety Read 1 (0.2) 14 (4.2) 31 (9.4) 20 (14.2) Final Read 3 (0.6) 19 (5.6) 44 (13.4) 28 (19.9)

APOE ε4 Carriers Non-Carriers

Reasons for additional cases of ARIA-E in Final Read:

  • 1. Not detected by local radiologist (central reads implemented during study)
  • 2. Not detected by central neuroradiologist
  • 3. Site PI did not acknowledge ARIA-E finding at safety read
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Timing of ARIA-E

  • Majority of cases associated with the first three infusions
  • A small percentage of cases occurred late (after infusions 4, 5, or 6):
  • 15.4% in carriers; 9.9% in non-carriers
  • Proportion of cases associated with first infusion:
  • 27.2% in carriers; 49.5% in non-carriers
  • Proportion of cases in non-carriers associated with first infusion

increased with bapineuzumab dose level:

  • 0.5 mg/kg: 26.3%; 1.0 mg/kg: 52.3%; 2.0 mg/kg: 60.7%

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Placebo Bapineuzumab 0.5 mg/kg Bapineuzumab 1.0 mg/kg Bapineuzumab 2.0 mg/kg Carriers 92 (72, 286) 129 (32, 457)

  • Non-carriers

97 (44, 189) 141 (88, 234) 108 (49, 390) 91 (11, 274)

Median Duration of ARIA-E (days, range)

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Pooled 302/301: ARIA-E by APOE ε4 Copy Number (Final Read)

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Placebo Bap 0.5 mg/kg

5 10 15 20 25 30 35 40 45

Incidence Proportion (%)

3/524 4/337 1/111 19/337 86/508 57/165

Non-carrier ε4 heterozygote ε4 homozygote

ε4 heterozygote: RR=3.0 (95% CI: 1.9 – 4.8; p<0.0001) ε4 homozygote: RR=6.1 (95% CI: 3.8 – 9.9; p<0.0001)

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ARIA-E Effect on Cognition: First to Last Measure

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Influence of ARIA-E on ADAS-Cog 11 Study 302 – Carriers

Baseline Last Observation

5 10 15 20 25 30 35 40 45 50

Placebo non-ARIA-E (n=443) Bap non-ARIA-E (n=530) Bap ARIA-E (n=143)

Improvement

Influence of ARIA-E on ADAS-Cog 11 Study 301 – Non-carriers

Baseline Last Observation

5 10 15 20 25 30 35 40 45 50

Placebo non-ARIA-E (n=521) Bap non-ARIA-E (n=716) Bap ARIA-E (n=91)

Improvement

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Influence of ARIA-E on DAD Study 302 – Carriers

Baseline Last Observation

10 20 30 40 50 60 70 80 90 100

Placebo non-ARIA-E (n=443) Bap non-ARIA-E (n=530) Bap ARIA-E (n=143)

Improvement

ARIA-E Effect on Function: First vs Last Measure

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Influence of ARIA-E on DAD Study 301 – Non-carriers

Baseline Last Observation

10 20 30 40 50 60 70 80 90 100

Placebo non-ARIA-E (n=521) Bap non-ARIA-E (n=716) Bap ARIA-E (n=91)

Improvement

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Number of Deaths per Study

Placebo (N=448) n (%) Bapineuzumab (N=673) n (%) Total Number of Deaths 5 (1.1) 15 (2.2)

APOE ε4 Carriers

Placebo N=524 (%) Bapineuzumab 0.5 mg/kg N=337 (%) Bapineuzumab 1.0 mg/kg N=329 (%) Total Number of Deaths 7 (1.3) 4 (1.2) 7 (2.1)

Non-Carriers

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Summary of Treatment Emergent Deaths From All Causes APOE ε4 Carriers

Reason for death Placebo (N=448) n (%) Bapineuzumab (N=673) n (%)

Total Number of Deaths

5 (1.1) 15 (2.2)

Cancer deaths

0 (0.0) 6 (0.9)

Metastases to abdominal cavity

  • 1 (0.1)

Oesophageal cancer metastatic

  • 1 (0.1)

Ovarian cancer

  • 1 (0.1)

Ovarian epithelial cancer

  • 1 (0.1)

Pancreatic carcinoma

  • 1 (0.1)

Renal cancer metastatic

  • 1 (0.1)

Other deaths

5 (1.1) 9 (1.3)

AD related deaths 3 (0.7) 3 (0.4) Asthenia

  • 1 (0.1)

Cardiac 1 (0.0) 2 (0.3) Diabetic ketoacidosis

  • 1 (0.1)

Multiple injuries (automobile accident)

  • 1 (0.1)

Pneumonia

  • 1 (0.1)

Respiratory arrest 1 (0.0)

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Summary of Treatment Emergent Deaths From All Causes Non-Carriers

Reason for death

Placebo N=524 (%) Bapineuzumab 0.5 mg/kg N=337 (%) Bapineuzumab 1.0 mg/kg N=329 (%)

Total Number of Deaths 7 (1.3) 4 (1.2) 7 (2.1) Cardiac

  • 3 (0.9)

Generalized Disorders 2 (0.4)

  • Infections
  • 2 (0.6)

Neoplasm 2 (0.4)

  • 1 (0.3)

Nervous System Disorders 2 (0.4) 3 (0.9)

  • Respiratory
  • 1 (0.3)
  • Renal
  • 1 (0.3)

Trauma 1 (0.2)

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Key Biomarker Secondary Endpoint: PiB PET Amyloid Imaging

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Study 302 Placebo Bapi: 0.5 mg/kg

Baseline (GCA: 2.54) Week 71 (GCA: 2.66) Baseline (GCA: 2.55) Week 71 (GCA: 2.36)

High PiB binding to amyloid Low PiB binding to amyloid

3.5

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Change in Amyloid Burden as assessed by [11C] PiB-PET at Week 71 APOE ε4 Carriers (PiB PET analysis population)

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45 71

Weeks

  • 0.16
  • 0.12
  • 0.08
  • 0.04

0.04 0.08 0.12 0.16 0.2

Reduction

Placebo (n=40) Bap 0.5 mg/kg (n=75)

PiB PET Global Cortical Average SUVr Mean (+/-SE)

Bap 0.5 mg/kg p=0.004

APOE ε4 Carriers

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Change in Amyloid Burden as assessed by [11C] PiB-PET at Week 71 APOE ε4 Non-Carriers (PiB PET analysis population)

Pre-specified primary analyses of pooled bapineuzumab doses was not significant, p=0.724 Post hoc exploratory analysis showed a within cohort trend for reduction in PiB PET at 1.0 mg/kg dose (nominal p = 0.057)

PiB PET Global Cortical Average SUVr Mean (+/-SE)

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Weeks

  • 0.16
  • 0.12
  • 0.08
  • 0.04

0.04 0.08 0.12 0.16 0.2

Reduction

Placebo (n=15) Bap 0.5 mg/kg (n=12) Bap 1.0 mg/kg (n=12)

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Bap 0.5 mg/kg p=0.193 Bap 1.0 mg/kg p=0.466

APOE ε4 Non-Carriers

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Distribution of PIB PET Global Cortical Average SUVr

8/123 (6.5%) 22/61 (36.1%) Below threshold for inclusion

Baseline PiB PET GCA SUVr

1 1.35 1.5 2 2.5 3

APOE e4 carriers 302 Study N=123 Non-carriers 301 Study N=61

Heterozygotes Homozygotes Noncarrier

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Carrier GCA SUVr Non-Carrier GCA SUVr P-value All PiB PET population 2.07 1.72 p<0.0001 PiB PET analysis population 2.14 2.05 p=0.18

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45 71

Weeks

  • 0.2
  • 0.15
  • 0.1
  • 0.05

0.05 0.1 0.15 0.2 0.25

Reduction

Placebo (n=55)

Pooled 302/301: Change in Amyloid Burden as assessed by [11C] PiB-PET at Week 71 (PiB PET analysis population)

Placebo vs Bap 0.5 mg/kg p=0.027 Placebo vs Bap 1.0 mg/kg p=0.028

Bap 1.0 mg/kg (n=12) Bap 0.5 mg/kg (n=87)

All Subjects

45 71

Weeks

  • 0.2
  • 0.15
  • 0.1
  • 0.05

0.05 0.1 0.15 0.2 0.25

Placebo (n=25) Bap 0.5 mg/kg (n=46) Bap1.0 mg/kg (n=9)

Placebo vs Bap 0.5 mg/kg p=0.009 Placebo vs Bap 1.0 mg/kg p=0.020

No significant effect in moderate group

38 PiB PET Global Cortical Average SUVr Mean (+/-SE)

Mild Subjects (MMSE≥21)

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Data Summary – Safety

ARIA-E: .

  • ARIA-E associated with bapineuzumab, additional cases identified on final read
  • Increased risk in APOE e4 carriers
  • Increased risk with higher dose in non-carriers
  • Preliminary analyses did not show evidence of ARIA-E-associated decline in

cognition or function

Other Safety:

  • Slightly higher rate of seizures in bapineuzumab treated groups

Deaths:

  • More deaths in the bapineuzumab–treated carriers, primarily due to cancer
  • No imbalance in cancer deaths in non-carriers
  • Analyses of all bapineuzumab Phase 3 studies did not show an imbalance of

cancer or deaths due to cancer when reviewed by unblinded, independent SMC

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Data Summary PiB PET Imaging

  • Reduced accumulation in amyloid burden on

PiB PET relative to placebo observed in carrier and pooled studies

  • High proportion of “amyloid negatives” on PiB

among non-carriers

  • Perhaps not surprising given 15-20% of AD patients

(across genotypes) do not meet neuropathological criteria for AD at autopsy

  • Evaluate proportion of “amyloid negatives” using CSF
  • Should future anti-amyloid trials, especially in non-

carriers, implement amyloid cut-off?

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