Study of ELND005 in Agitation and Aggression of Alzheimer’s Disease (HARMONY-AD):
Diagnostic Criteria and Patient Characteristics
Susan Abushakra (1), Anton P. Porsteinsson (2), Jacobo Mintzer (3), Earvin Liang (1), Aleksandra
Pastrak (4), Constantine Lyketsos (5)
(1) Transition Therapeutics USA, San Mateo CA
(2) Department of Psychiatry, University of Rochester, Rochester NY
(3) Clinical Biotechnology Research Institute, Roper St. Francis, Charleston, SC
(4) Transition Therapeutics, Toronto, ON, Canada
(5) Department of Psychiatry, Johns Hopkins University, Baltimore MD
Methodological Question: Diagnostic criteria defining the entity of Agitation/Aggression of AD were
recently published. We herein describe the baseline characteristics of patients enrolled in the ongoing
ELND005 Study (AG201), and compare them to the published criteria (Cummings et al., 2014).
Introduction: Agitation and Aggression are among the most disruptive neuropsychiatric symptoms
(NPS) in AD, and are associated with increased morbidity, caregiver burden and healthcare cost. To date,
there are no FDA approved drugs for this indication. ELND005 (Scyllo-inositol) is being evaluated in an
ongoing clinical trial of Agitation and Aggression in AD (HARMONY-AD Study AG201) based on its
effects on myo-inositol reduction in a previous 78-week AD trial (Salloway et al, 2011). Lowering brain
myo-inositol is thought to regulate phospho-inositol signaling in limbic frontal networks, leading to mood
stabilizing effects. Study AG201 design was similar to the “citalopram for Agit in AD study” or CiTAD
(Drye et al, 2011 for methodology), including the inclusion criteria and the miminum baseline severity of
Agit/Aggr.
Methods: Baseline data from the first 189 patients was analyzed. Study AG201 (NCT01735630) is a 12week, 2 arm study (ELND005 and placebo groups) in AD patients ages 50-95 with dementia (MMSE
range 5-24). The 12-item Neuropsychiatric Inventory (NPI, Cummings et al, 1999) is used for screening.
Subjects are eligible if screening and baseline NPI- Agit/Aggr score is ≥ 4 (at least moderate severity and
frequency). The primary outcome measure is the summed Agitation and Aggression scores from the NPIC, which separates Agitation and Aggression into distinct domains (expanded and clinician rated NPI, De
Medeiros et al, 2010). This summed NPI-C Agit and Aggr score provides a wider range (0-63) than the
NPI-Agit/Aggr subscore (0-12). Similar to the CitAD study, the Clinician global impression of change
(ADCS-CGIC) for Agit/Aggr is a key secondary measure to support clinical meaningfulness of NPI-C
treatment effects.
Results: For the 189 enrolled patients, mean age was 74 years (55% female; 84% Caucasian). Among
randomized subjects, baseline mean MMSE was 15.2 (range=2-28); NPI-total score was 48.0 (4-144), and
NPI Agit/Aggr score was 7.3 (4-12). The NPI-C combined Agit + Aggr score was 18.3 (Agitation 12.7,
SD 6.5; Aggression 5.6, SD 4.7). At baseline > 90% of patients had either anxiety or depression, and
70% had aberrant motor behavior. Baseline mean scores of depression, anxiety, apathy, and aberrant
motor behavior were all above 4 (moderate severity and frequency). The distribution of NPI-C scores
amongst mild, moderate and severe AD was similar.
Conclusions: The operational diagnostic criteria in this study, as applied by clinical investigators,
identify AD patients with at least moderate levels of Agitation and Aggression requiring pharmacologic
intervention. These patients also have high prevalence of anxiety, depression, apathy, and aberrant motor
behaviors of moderate severity. Patient characteristics of Study AG201 are consistent with the recently
proposed IPA criteria for Agitation and Aggression in AD (Cummings et al., 2014).
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Disclosures: Drs Abushakra, Liang, and Pastrak are full time employees and own stock of Transition
Therapeutics. Drs Porsteinsson and Mintzer are investigators in Study ELND005-AG201. Drs
Porsteinsson and Lyketsos are advisors to Transition Therapeutics.
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