A Randomized, Double-Blind, Placebo-Controlled, Phase II Study of Oral ELND005 (scyllo-Inositol) in Young Adults with Down Syndrome without Dementia

Article type: Research Article

Authors: Rafii, Michael S.^{a; b; *} | Skotko, Brian G.^{c; d} | McDonough, Mary Ellen^c | Pulsifer, Margaret^{d; e} | Evans, Casey^e | Doran, Eric^f | Muranevici, Gabriela^b | Kesslak, Patrick^g | Abushakra, Susan^h | Lott, Ira T.^f | for the ELND005-DS Study Group

Affiliations: [a] Alzheimer’s Therapeutic Research Institute (ATRI) at University of Southern California, San Diego, CA, USA | [b] Department of Neurosciences, University of California, San Diego, CA, USA | [c] Department of Pediatrics, Down Syndrome Program, Division of Medical Genetics, Massachusetts General Hospital, Boston, MA, USA | [d] Harvard Medical School, Boston, MA, USA | [e] Department of Psychiatry, Psychology Assessment Center, Massachusetts General Hospital, Boston, MA, USA | [f] Department of Pediatrics, University of California, Irvine, CA, USA | [g] ACADIA Pharmaceuticals, San Diego, CA, USA | [h] Alzheon, Inc., Framingham, MA, USA

Correspondence: [*] Correspondence to: Michael S. Rafii, MD, PhD, Alzheimer’s Therapeutic Research Institute (ATRI) at University of Southern California, Department of Neurosciences, University of California, San Diego, 9860 Mesa Rim Road, San Diego, CA 92121, USA. Tel.: +1 858 964 0638; E-mail: [email protected].

Abstract: Background: ELND005 (scyllo-Inositol; cyclohexane-1,2,3,4,5,6-hexol) has been evaluated as a potential disease-modifying treatment for Alzheimer’s disease (AD). Individuals with Down syndrome (DS) have an increased risk for developing AD dementia. Objective: To evaluate the safety and tolerability of ELND005 and to determine its pharmacokinetics (PK) and relationship between PK parameters, safety outcome measures, and exploratory efficacy outcome measures in young adults with DS without dementia. Methods: This was a prospective, randomized, double-blind, placebo-controlled, parallel-group, three-arm, multicenter Phase II study of the safety and pharmacokinetics of ELND005 administered orally for 4 weeks (ClinicalTrials.gov NCT01791725). Participants who met study eligibility criteria were randomly assigned in a 2 : 1:1 ratio to receive ELND005 at either 250 mg twice daily (BID) or 250 mg once daily (QD) or matching placebo for 4 weeks. Results: There were no apparent treatment group-related trends on cognitive or behavioral measures and there were no SAEs and no deaths in the study. Overall, mean changes from baseline in clinical laboratory parameters, vital sign measurements, electrocardiogram results, and other physical findings were unremarkable. ELND005 accumulation averaged approximately 2-fold with QD dosing, and 3- to 4-fold with BID dosing. Conclusion: Overall, treatment of adults with DS with ELND005 at both doses was well tolerated, achieved measurable blood levels and demonstrated no safety findings. Further studies will be needed to test efficacy.

Keywords: Alzheimer’s disease, amyloid, dementia, Down syndrome, Myo-inositol

DOI: 10.3233/JAD-160965

Journal: Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 401-411, 2017