EXPEDITION3: A Phase 3 Trial of Solanezumab in Mild Dementia due to Alzheimer s Disease

Transcription

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

2 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.

3 EXPEDITION3: Initiated in Mild AD Dementia Patient Disposition Patients Randomized N=2129 Discontinued N=164 (15.3%) Adverse Event 39 (3.6%) N=172 N=157 Discontinued N=143 (13.5%) Adverse Event 48 (4.5%) Death 16 (1.5%) Death 9 (.9%) Subject Decision 45 (4.2%) Subject Decision 33 (3.1%) Caregiver Decision 41 (3.8%) Caregiver Decision 33 (3.1%) Physician Decision 7 (.7%) Physician Decision 11 (1.%) Protocol Violation 7 (.7%) Protocol Violation 1 (.1%) Lost to Follow Up (.%) Entry Criteria Not Met 9 (.8%) Completed N=98 (84.7%) Completed N=914 (86.5%) Lost to Follow Up 3 (.3%) Entry Criteria Not Met 5 (.5%) Abbreviations: AD=Alzheimer s disease; ECG=electrocardiogram; N=number.

4 EXPEDITION3: Initiated in Mild AD Dementia Study Design for EXPEDITION3 Study LZAX (NCT19665): double-blind, Phase 3, randomized to solanezumab (4 mg per dose) or placebo every 4 weeks for 8 weeks; optional open-label extension Age 55 to 9 years Probable AD by NINCDS/ADRDA criteria 1 Amyloid positive by F18 florbetapir PET or CSF Aβ 1-42 MMSE score 2-26 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 21 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. 1. McKhann et al. Neurology, 1984; 34(7):

5 EXPEDITION3: Initiated in Mild AD Dementia Baseline Demographics Demographic N=172 N=157 p-value Age, years, mean (SD) 73.3 (8.) 72.7 (7.8).73 Female, n (%) 631 (58.9%) 6 (56.8%).335 Race, n (%).758 White 894 (9.7%) 878 (9.5%) 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).96 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 Based on number of patients with available APOE status (placebo N=133; solanezumab N=127). Abbreviations: AD=Alzheimer s disease; n=number; SD=standard deviation; APOE=apolipoprotein E.

6 EXPEDITION3: Initiated in Mild AD Dementia Change in Cognition - ADAS-Cog 14 (Primary) n=167 n= p.5; p.1 p=.95 n=893 n=98 11% Less Decline Abbreviations: AD=Alzheimer s disease; ADAS-Cog 14 =AD Assessment Scale-Cognitive 14-item Subscale; LS=least squares; n=number; SE=standard error.

7 EXPEDITION3: Initiated in Mild AD Dementia Change in Cognition - MMSE p=.14 13% Less D ecline n=167 n=154 p.5 n=876 n=893 Abbreviations: AD=Alzheimer s disease; LS=least squares; MMSE=Mini Mental State Examination; n=number; SE=standard error.

8 EXPEDITION3: Initiated in Mild AD Dementia Change in Complex ADLs - ADCS-iADL n=163 n= p.5 n=896 n=98 p=.19 14% Less D ecline 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.

9 EXPEDITION3: Initiated in Mild AD Dementia Change in Complex ADLs - FAQ n=166 n= p=.14 n=892 n=97 7% Less Decline Abbreviations: AD=Alzheimer s disease; ADL=Activities of Daily Living; FAQ=Functional Activities Questionnaire; LS=least squares; n=number; SE=standard error.

10 EXPEDITION3: Initiated in Mild AD Dementia Change in Composite Scale - CDR-SB n=166 p.1 n=895 n=152 n=93 p=.4 15% Less D ecline Abbreviations: AD=Alzheimer s disease; CDR-SB=Clinical Dementia Rating Sum of Boxes; LS=least squares; n=number; SE=standard error.

11 EXPEDITION3: Initiated in Mild AD Dementia Change in Cognition and ADLs at 8 LS Mean Change (SE) at 8 Less Decline p-value ADAS-Cog (.36) 6.65 (.36) 11%.95 MMSE (.16) (.15) 13%.14 ADCS-iADL (.32) (.32) 14%.19 ADCS-ADL (.39) (.39) 15%.9 FAQ 5.57 (.21) 5.17 (.21) 7%.14 CDR-SB 2.21 (.11) 1.87 (.1) 15%.4 Abbreviations: AD=Alzheimer s disease; ADL=Activities of Daily Living; ADAS-Cog 14 =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 8-Week scale data; N/A=not applicable; MMSE=Mini Mental State Examination; SE=standard error.

12 EXPEDITION3: Initiated in Mild AD Dementia Plasma Changes in Aβ 1-4 and Aβ 1-42 Plasma Aβ 1-4 Plasma Aβ , 2, 15, LS Mean Change, pg/ml 125, 1, 75, 5, LS Mean Change, pg/ml 15, 1, 5, 25, n=15 n=842 n=15 n=116 n=841 n=13 p<.1 p<.1 Abbreviations: AD=Alzheimer s disease; LS=least squares; n=number. 8 n=84 n=848

13 EXPEDITION3: Initiated in Mild AD Dementia Florbetapir PET Change in Amyloid Deposition LS Mean Absolute Change (SE Bars) Cortical-to-Cerebellar SUVr with SSWM Correction Factor p=.13 1 n=791 n=85 LS Mean Absolute Change (SE Bars) Cortical-to-Cerebellar SUVr p=.18 1 n=791 n=85 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 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.

14 EXPEDITION3: Initiated in Mild AD Dementia CSF Changes in Total Tau and p-tau LS Mean Change, pg/ml (SE Bars) CSF Total Tau p=.6 n=97 n=11 LS Mean Change, pg/ml (SE Bars) CSF p-tau p=.55 9 n=111 n=128 Abbreviations: AD=Alzheimer s disease; CSF=cerebrospinal fluid; LS=least squares; n=number, p-tau=phosphorylated tau; SE=standard error.

15 EXPEDITION3: Initiated in Mild AD Dementia Flortaucipir PET Changes in Tau Deposition p= n=97 n=17 n=7 n=81 Abbreviations: AD=Alzheimer s disease; LS=least squares; n=number; PET=positron emission tomography; SE=standard error.

16 EXPEDITION3: Initiated in Mild AD Dementia MRI Whole Brain Atrophy/Ventricular Enlargement LS Mean Change, mm 3 (SE Bars) Whole Brain Atrophy p=.9 5 n=769 n=786 LS Mean Change, mm 3 (SE Bars) Ventricular Enlargement p=.22 7 n=77 n=788 Abbreviations: AD=Alzheimer s disease; LS=least squares; n=number; SE=standard error.

17 EXPEDITION3: Initiated in Mild AD Dementia Adverse Events Overview Category, n (%) N=167 N=154 p-value SAE 22 (18.9%) 175 (16.6%).173 Death 16 (1.5%) 9 (.9%).227 TEAE 89 (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.

18 EXPEDITION3: Initiated in Mild AD Dementia Treatment Emergent AE Differences (p.5) Preferred Term, n (%) N=167 N=154 p-value TEAE ( 1) 89 (83.4%) 891 (84.5%).515 Events more frequent in solanezumab treatment group Vitamin D Deficiency 6 (.6%) 15 (1.4%).5 Nasal Congestion 4 (.4%) 13 (1.2%).29 Spinal Osteoarthritis 4 (.4%) 12 (1.1%).47 Dysuria 2 (.2%) 9 (.9%).37 Events more frequent in placebo treatment group Gait Disturbance 18 (1.7%) 4 (.4%).4 Somnolence 13 (1.2%) 2 (.2%).7 Abbreviations: AD=Alzheimer s disease; AE=adverse event; n=number; TEAE=treatment-emergent adverse event.

19 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

20 Acknowledgements 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

21 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

22 EXP, EXP2, Pooled, EXP3: Initiated in Mild AD Dementia Change in Cognition - ADAS-Cog 14 EXPEDITION E XP ED ITIO N n=336 n=262 n=333 p.1 n=25 44% Less Decline n=324 n=258 n=321 n=248 2% Less Decline EXPEDITION/EXPEDITION2 Pooled E XP ED ITIO N n=66 n=524 n=654 n=498 34% Less Decline n=167 n=893 n=153 p.5; p.1 n=98 11% Less Decline Abbreviations: AD=Alzheimer s disease; ADAS-Cog 14 =AD Assessment Scale-Cognitive 14-item Subscale; LS=least squares; n=number; SE=standard error.

23 EXP, EXP2, Pooled, EXP3: Initiated in Mild AD Dementia Change in Complex ADLs - ADCS-iADL EXPEDITION % Less D ecline -8 n=336 n=262 n=332 n=251 E XP ED ITIO N n=324 p.5; p.1 n=259 n=32 n=249 23% Less D ecline EXPEDITION and EXPEDITION2 Pooled % Less D ecline -8 n=66 p.5 n=521 n=652 n=5 E XP ED ITIO N n=163 n=896 n=153 p.5 n=98 14% Less D ecline 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.