Open-Label, Multicenter, Phase III Extension Study of Idalopirdine as Adjunctive to Donepezil for the Treatment of Mild-Moderate Alzheimer’s Disease

Article type: Research Article

Authors: Frölich, Lutz^{a; *} | Atri, Alireza^{b; c} | Ballard, Clive^d | Tariot, Pierre N.^e | Molinuevo, José Luis^{f; g} | Boneva, Neli^h | Geist, Marie A.^h | Raket, Lars L.^h | Cummings, Jeffrey L.ⁱ

Affiliations: [a] Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany | [b] Banner Sun Health Research Institute, Banner Health, Sun City, AZ, USA | [c] Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA | [d] University of Exeter Medical School, Exeter, UK | [e] Banner Alzheimer’s Institute, Phoenix, AZ, USA | [f] Alzheimer’s disease and other cognitive disorders unit, Hospital Clinic i Universitari, Barcelona, Spain | [g] BarcelonaBeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain | [h] H. Lundbeck A/S, Valby, Denmark | [i] Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA

Correspondence: [*] Correspondence to: Lutz Frölich, Prof. Dr., Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. Tel.: +49 621 17033301; Fax: +49 621 17033305; E-mail: [email protected].

Abstract: This open-label extension study evaluated the long-term safety and tolerability of idalopirdine 60 mg/day as adjunctive therapy in patients with mild-moderate Alzheimer’s disease (AD). This extension study was a continuation of Studies 1 and 2 of the Phase III development program for idalopirdine and comprised a 28-week open-label treatment period (“OLEX”) and a subsequent 24-week open-label treatment period with memantine (“MEMOLEX”) in selected patients. The previous studies had shown no evidence of efficacy with idalopirdine as adjunctive treatment to donepezil but with good tolerability (of 1,791 patients randomized, 1,609 [90%] completed the double-blind studies). Of those, 1,463 patients (91%) entered the open-label extension study. During the 28-week OLEX period, the percentage of patients having treatment-emergent adverse events (TEAEs) ranged between 51% and 59% across the treatment groups originating from the lead-in studies. During the subsequent 24-week MEMOLEX period, 51% of the patients had TEAEs. Increases in liver enzymes (occurring in 1–3% of trial participants) were transient and no new safety signals were observed with longer term exposure. No consistent effects demonstrating benefits with idalopirdine were observed on efficacy parameters when patients transitioned to 60 mg in the extension study. Overall, idalopirdine was safe and well tolerated when added to donepezil, and when memantine was added to a prior combination of idalopirdine and donepezil. There were no new safety signals observed with up to 18 months of exposure at the described doses to idalopirdine.

Keywords: 5-HT₆ , Alzheimer’s disease, dementia, idalopirdine, treatment

DOI: 10.3233/JAD-180595

Journal: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 303-313, 2019