1. ADI Disease International 7-10 March, 2012
ELND005 (Scyllo‐inositol) Effects on Emergence of Neuropsychiatric Symptoms (NPS) in Mild/Moderate Alzheimer’s disease
Roy Jones MB FRCP1, Constantine Lyketsos MD, MPH2,
Gerald CransPhD3, Chito Hernandez PhD 3, Susan Abushakra3MD
1The RICE Centre, Royal United Hospital, Bath UK, 2Johns Hopkins Medical Institutions, Baltimore, MD,
3Elan Pharmaceuticals, South San Francisco, CA

2. Disclosures
Dr. Jones
RICE (The Research Institute for the Care of Older People), Royal United Hospital, Bath UK Serves on scientific advisory boards of major Pharmaceutical companies including Elan Pharmaceuticals. He has also received lecture fees and his Institute has received research support grants from various Pharmaceutical/Biotech companies and foundations including Elan.
Dr. Lyketsos
Johns Hopkins University
Serves on scientific advisory boards of major Pharmaceutical companies including Elan Pharmaceuticals. He also receives research support grants from various Pharmaceutical/Biotech companies and foundations including Elan.
Dr. Abushakra, Dr. Hernandez, and Dr. Crans
Elan Pharmaceuticals Inc.
Employees of Elan Pharmaceuticals and hold stock and stock options in Elan Pharmaceuticals.

3. Legal Disclaimer
The referenced activities and their execution are intended to be non-promotional and scientific in nature. Any promotional activities conducted by Elan are within product label and are for FDA approved uses only.

4. Objectives and Background
Neuropsychiatric symptoms (NPS) in AD are common, and increase in prevalence with disease progression1
Some types of NPS are thought to reflect regional mono-aminergic neuronal dysfunction
Unlike cognition/function, NPS have a fluctuating course especially at earlier stages of AD2
Assessment of NPS burden at study endpoint may therefore not capture the effect of treatment on emergence of new NPS
This post-hoc analysis evaluated the effects of ELND005 on emergence of new NPS over the 78 weeks of Phase 2 Study3
1Lyketsos et al. JAMA Sep 25;288(12): ; 2Tschanz et al, Am J Geriatr Psychiatry Sep;19(9):814-24; 3Salloway et al. Neurology Sep 27;77(13):

5. ELND005 Background
ELND005 (Scyllo-inositol) is in development as a potential disease-modifying agent:
In vitro, it has amyloid anti-aggregation and synaptic protective effects1,2
In vivo, it reduced amyloid burden and improved learning deficits in Tg CRND8 mice3
Main Phase 2 results4:
The 2 highest dose arms (1000mg bid and 2000mg bid) were discontinued due to safety findings, efficacy analyses compared placebo and 250mg bid arms
In Mild/Moderate (M/M) AD: ELND005 effects on co-primary NTB, ADCS-ADL did not achieve significance (NS), but CSF Aβ42 levels were significantly reduced at 78 weeks
In the pre-specified Mild AD group, ELND005 effect on NTB was significant in study completers (per protocol population, p= 0.007)
The effects of ELND005 on the 12-item NPI (Neuropsychiatric Inventory) scores were NS in M/M or Mild patients
1McLaurin et al., J Biol Chem 2000; 2Townsend et al., Ann Neurol 2006; 3McLaurin et al., Nature Med 2006, 4AD201 Safety and efficacy results have been published (Salloway et al. Neurology Sep 27;77(13): )

6. Methods Data were from a 78 week Study AD201 in M/M AD
A total of 353 patients randomized to placebo or 1 of 3 doses (all bid)
m-ITT : N= 341; Placebo=83, 250mg=88, 1000mg=89, 2000mg = 91
Randomization stratified by AD drug use, ApoE4 status, and AD severity (Mild 22-26, Moderate 16-21)
Analyses of 12-Item NPI, a secondary endpoint
Scale range: 0-144; sum of sub-item scores, each is frequency x severity
Protocol-specified analysis: change from baseline (CBL) of total score
Post-hoc analysis of “Emergence of ≥ 2 NPS”:
Emergence : NPI item with 0 baseline score, becomes > 0 at a subsequent visit
No p-value adjustments for multiplicity testing

7. Proportion of Patients with Individual NPS at Baseline
Nighttime Behavior
Depression
Depression
Depression
Irritability
Agitation
Appetite
Irritability
Agitation
Agitation
Appetite
Apathy
Anxiety
Apathy
Anxiety
Appetite
Apathy
Anxiety
Data above consistent with: F. DiLulio et al. 2010, Occurrence of Neuropsychiatric Symptoms and Psychiatric Disorders in Mild Alzheimer’s Disease and Mild Cognitive Impairment subtypes. Int’l Psychogeriatrics 22 (4):
Elan data on file

8. Total NPI Score Change from Baseline Mild AD (m-ITT)
Weeks
Improvement
Decline
Protocol-specified; p-values not adjusted for multiplicity
Elan data on file

9. Proportion of Patients with at Least 2 New NPS at Any Follow-up Visit (m-ITT)
Percent
N= 79, 82
N= 35, 39
N= 44, 43
p-values not adjusted for multiplicity
Elan data on file

10. Kaplan-Meier (KM)-Plot for Time to Emergence of 2 New NPS Mild AD (22-26) m-ITT
p-values not adjusted for multiplicity
Elan data on file

11. Frequency of Individual Emergent NPS at Any Follow-up Visit
Mild AD (m-ITT)
Elan data on file
N = 44
N = 43

12. Emergence of Symptom Clusters: p-values of Log-Rank Test (KM Analysis)
MMSE 20-26
MMSE 22-26
Cluster
Cluster KM (m-ITT)
Cluster KM
(PPS)
(m-ITT)
Affective: Depression and Anxiety
0.003
0.017
0.015
Psychotic: Delusions and Hallucinations
0.733
0.381
0.555
0.244
Apathy: Apathy
0.406
0.316
0.266
0.446
Frontal: Elation and Disinhibition
0.512
0.736
0.787
0.977
Behavioral: Aberrant Motor and Nighttime Behaviors
0.641
0.573
0.390
0.913
KM Analysis: Kaplan Meyer Survival Analysis; Log-rank Test p-values
p-values not adjusted for multiplicity
Elan data on file 12 12

13. p-values not adjusted for multiplicity
Elan data on file

14. p-values not adjusted for multiplicity
Elan data on file

15. Baseline Depression and Anxiety Scores: All Mild AD (22-26) Subjects in (m-ITT)
Percent
Elan data on file

16. Baseline and Week 78 Depression and Anxiety Scores: Placebo Mild AD (22-26) Subjects in (m-ITT)
Placebo (Mild AD): Baseline
N = 32
Percent
Placebo (Mild AD): Week 78
N = 32
Percent
Elan data on file

17. Conclusions
In mild AD, ELND mg decreased emergence of new NPS was driven by depression and anxiety; to a lesser extent apathy and appetite change.
These effects are clinically relevant since NPS are frequently associated with increased morbidity.
Study limitation: Some of the analyses presented were based on post hoc analysis with small sample sizes; therefore, it is difficult to draw conclusions based solely on statistical significance.
The potential beneficial effect of ELND005 on emergence of NPS in Mild AD requires further study.
Analyses of emergence may be more appropriate in Mild AD than CBL in total scores.

18. Acknowledgements
We acknowledge and thank the 58 investigators, their coordinators/staff, the patients and their caregivers/families for participation in Study AD201