EXPEDITION3: A Phase 3 Trial of Solanezumab in Mild ... · PDF fileEXPEDITION3: A Phase 3...

EXPEDITION3: A Phase 3 Trial of Solanezumab in Mild Dementia due to Alzheimer’s Disease Lawrence S. Honig, MD, PhD On behalf of the EXPEDITION3 Study Team

Disclosure Statement

♦ I will discuss investigational use only.

♦ Dr. Honig has received support as a consultant/steering committee member from Forum, Fujirebio, Lundbeck, and Eli Lilly.

♦ Dr. Honig has received research funding as an investigator for AstraZeneca, Bristol-Myer Squibb, Forum, Genentech, Janssen, Eli Lilly, Lundbeck, Pfizer, Roche, TauRx, vTv.

♦ EXPEDITION3 is funded by Eli Lilly and Company.

© 2016 Eli Lilly and Company

Patients Randomized N=2129

Placebo

N=1072 Solanezumab

N=1057

Completed N=908 (84.7%)

Completed N=914 (86.5%)

Discontinued N=143 (13.5%)

Adverse Event 48 (4.5%)

Death 9 (0.9%)

Subject Decision 33 (3.1%)

Caregiver Decision 33 (3.1%)

Physician Decision 11 (1.0%)

Protocol Violation 1 (0.1%)

Lost to Follow Up 3 (0.3%)

Entry Criteria Not Met 5 (0.5%)

Discontinued N=164 (15.3%)

Adverse Event 39 (3.6%)

Death 16 (1.5%)

Subject Decision 45 (4.2%)

Caregiver Decision 41 (3.8%)

Physician Decision 7 (0.7%)

Protocol Violation 7 (0.7%)

Lost to Follow Up 0 (0.0%)

Entry Criteria Not Met 9 (0.8%)

Abbreviations: AD=Alzheimer’s disease; ECG=electrocardiogram; N=number.

EXPEDITION3: Solanezumab Initiated in Mild AD Dementia

Patient Disposition


♦ Study LZAX (NCT01900665): double-blind, Phase 3, randomized to solanezumab (400 mg per dose) or placebo every 4 weeks for 80 weeks; optional open-label extension

♦ Age 55 to 90 years ♦ Probable AD by NINCDS/ADRDA criteria1 ♦ Amyloid positive by F18 florbetapir PET or CSF Aβ1-42 ♦ MMSE score 20-26 inclusive ♦ On stable standard of care therapy (drug and non-drug)

• Acetylcholinesterase inhibitors and/or memantine • Continued concomitant medication use allowed throughout study

♦ Conducted in 11 countries at 210 sites Abbreviations: NINCDS/ADRDA=National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and

Related Disorders Association; PET=positron emission tomography; CSF=cerebrospinal fluid; MMSE=Mini Mental State Exam.


Study Design for EXPEDITION3

1. McKhann et al. Neurology, 1984; 34(7):939-944



Baseline Demographics

Demographic Placebo N=1072

Solanezumab N=1057 p-value

Age, years, mean (SD) 73.3 (8.0) 72.7 (7.8) .073 Female, n (%) 631 (58.9%) 600 (56.8%) .335 Race, n (%) .758 White 894 (90.7%) 878 (90.5%) Black or African American 19 (1.9%) 14 (1.4%) Asian 71 (7.2%) 75 (7.7%) APOE ε4 carriers, n (%)* 685 (66.3%) 712 (69.3%) .144 Education, years, mean (SD) 13.7 (3.8) 13.7 (3.7) .906 Symptom onset, years, mean (SD) 4.3 (2.6) 4.2 (2.5) .413 Diagnosis, years, mean (SD) 1.6 (1.7) 1.5 (1.6) .132 AChEI and/or memantine use, n (%) 856 (79.9%) 822 (77.8%) .244

Abbreviations: AD=Alzheimer’s disease; n=number; SD=standard deviation; APOE=apolipoprotein E. *Based on number of patients with available APOE status (placebo N=1033; solanezumab N=1027).


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Change in Cognition - ADAS-Cog14 (Primary)

Abbreviations: AD=Alzheimer’s disease; ADAS-Cog14=AD Assessment Scale-Cognitive 14-item Subscale; LS=least squares; n=number; SE=standard error.


p=.095


Change in Cognition - MMSE

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*


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Abbreviations: AD=Alzheimer’s disease; LS=least squares; MMSE=Mini–Mental State Examination; n=number; SE=standard error.


p=.014


Change in Complex ADLs - ADCS-iADL

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Abbreviations: AD=Alzheimer’s disease; ADL=Activities of Daily Living; ADCS-iADL=AD Cooperative Study-Instrumental Activities of Daily Living; LS=least squares; n=number; SE=standard error.


p=.019

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n = 8 9 2n = 9 0 7

7 % L e s sD e c lin e

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P la c e b o

Abbreviations: AD=Alzheimer’s disease; ADL=Activities of Daily Living; FAQ=Functional Activities Questionnaire; LS=least squares; n=number; SE=standard error.


Change in Complex ADLs - FAQ


p=.140

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Abbreviations: AD=Alzheimer’s disease; CDR-SB=Clinical Dementia Rating Sum of Boxes; LS=least squares; n=number; SE=standard error.


Change in Composite Scale - CDR-SB


p=.004

LS Mean Change (SE) at 80 Weeks Less

Decline p-value Placebo Solanezumab

ADAS-Cog14 7.44 ( 0.36) 6.65 (0.36) 11% .095

MMSE -3.66 (0.16) -3.17 (0.15) 13% .014

ADCS-iADL -7.17 (0.32) -6.17 (0.32) 14% .019

ADCS-ADL -8.77 (0.39) -7.42 (0.39) 15% .009

FAQ 5.57 (0.21) 5.17 (0.21) 7% .140

CDR-SB 2.21 (0.11) 1.87 (0.10) 15% .004

Abbreviations: AD=Alzheimer’s disease; ADL=Activities of Daily Living; ADAS-Cog14=AD Assessment Scale-Cognitive 14-item Subscale; ADCS-ADL=AD Cooperative Study-Activities of Daily Living; CDR-SB=Clinical Dementia Rating Sum of Boxes; FAQ=Function Activities Questionnaire; iADRS=Integrated AD Rating Scale; LS=least squares; n=number of patients with evaluable 80-Week scale data; N/A=not applicable; MMSE=Mini–Mental State Examination; SE=standard error.


Change in Cognition and ADLs at 80 Weeks



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Abbreviations: AD=Alzheimer’s disease; LS=least squares; n=number.


Plasma Changes in Aβ1-40 and Aβ1-42

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Abbreviations: AD=Alzheimer’s disease; PET=positron emission tomography; LS=least squares; n=number; SUVr=Standard Uptake Value ratio; SE=standard error; SSWM=subject-specific white matter.


Florbetapir PET Change in Amyloid Deposition


The cortical SUV is a composite summary that consists of the following 6 regions: medial orbital frontal, anterior cingulate, parietal, temporal, posterior cingulate, and precuneus

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Abbreviations: AD=Alzheimer’s disease; CSF=cerebrospinal fluid; LS=least squares; n=number, p-tau=phosphorylated tau; SE=standard error.


CSF Changes in Total Tau and p-Tau


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Abbreviations: AD=Alzheimer’s disease; LS=least squares; n=number; PET=positron emission tomography; SE=standard error.


Flortaucipir PET Changes in Tau Deposition


p=.685

Abbreviations: AD=Alzheimer’s disease; LS=least squares; n=number; SE=standard error.


MRI Whole Brain Atrophy/Ventricular Enlargement

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Category, n (%) Placebo N=1067


SAE 202 (18.9%) 175 (16.6%) .173

Death 16 (1.5%) 9 (0.9%) .227

TEAE 890 (83.4%) 891 (84.5%) .515

Discontinuation due to AE 39 (3.6%) 48 (4.5%) .325

Abbreviations: AD=Alzheimer’s disease; AE=adverse event; n=number; SAE=serious adverse event; TEAE=treatment-emergent adverse event.


Adverse Events Overview


Preferred Term, n (%) Placebo N=1067


TEAE (≥1) 890 (83.4%) 891 (84.5%) .515 Events more frequent in solanezumab treatment group

Vitamin D Deficiency 6 (0.6%) 15 (1.4%) .050 Nasal Congestion 4 (0.4%) 13 (1.2%) .029 Spinal Osteoarthritis 4 (0.4%) 12 (1.1%) .047 Dysuria 2 (0.2%) 9 (0.9%) .037

Events more frequent in placebo treatment group Gait Disturbance 18 (1.7%) 4 (0.4%) .004 Somnolence 13 (1.2%) 2 (0.2%) .007 Abbreviations: AD=Alzheimer’s disease; AE=adverse event; n=number; TEAE=treatment-emergent adverse event.


Treatment Emergent AE Differences (p≤.05)


EXPEDITION3 Conclusions

♦ Did not meet primary endpoint of decreasing cognitive decline

♦ Several secondary clinical endpoints directionally favored solanezumab, but the magnitudes of treatment differences were small

♦ Amyloid PET and CSF tau did not show significant treatment differences

♦ Factors possibly relevant to interpretation of study results include drug target, disease stage studied, and dosage of drug delivered


Many thanks to the patients and their families, and the

investigators and clinical trial staff, for their time and commitment to the

EXPEDITION3 study

Thank you to the EXPEDITION3 Steering Committee and Study Team

Acknowledgements


Panel Discussion

Lawrence S. Honig, MD, PhD, Columbia University Medical Center, New York, NY Paul Aisen, MD, University of Southern California, San Diego, CA Maria Carrillo, PhD, Alzheimer’s Association, Chicago, IL Bruno Vellas, MD, PhD, University Hospital of Toulouse, France Eric Siemers, MD, Eli Lilly and Company, Indianapolis, IN

EXP, EXP2, Pooled, EXP3: Solanezumab Initiated in Mild AD Dementia

Change in Cognition - ADAS-Cog14

Abbreviations: AD=Alzheimer’s disease; ADAS-Cog14=AD Assessment Scale-Cognitive 14-item Subscale; LS=least squares; n=number; SE=standard error.

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E X P E D IT IO N

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E X P E D IT IO N /E X P E D IT IO N 2 P o o le d

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E X P E D IT IO N 3


EXP, EXP2, Pooled, EXP3: Solanezumab Initiated in Mild AD Dementia

Change in Complex ADLs - ADCS-iADL

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E X P E D IT IO N a n d E X P E D IT IO N 2 P o o le d

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E X P E D IT IO N 3

Abbreviations: AD=Alzheimer’s disease; ADL=Activities of Daily Living; ADCS-iADL=AD Cooperative Study-Instrumental Activities of Daily Living; LS=least squares; n=number; SE=standard error.


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