A Polymorphism Cluster at the 2q12 locus May Predict Response to Piromelatine in Patients with Mild Alzheimer’s Disease - 21/11/24
, M. Laudon 2, T. Nir 2, J. Caceres 3, G. Ianniciello 3, M. Capulli 3, N. Zisapel 2, 4
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Abstract |
Background |
Piromelatine is a novel melatonin MT1/2/3 and serotonin 5-HT-1A/1D receptors agonist developed for mild Alzheimer’s disease (AD). In a randomized, placebo-controlled, dose-ranging study (ReCognition) of piromelatine (5, 20, and 50 mg daily for 6 months) in participants with mild dementia due to AD (n=371, age 60–85 years), no statistically significant differences were found between the piromelatine and placebo-treated groups on the primary (i.e., computerized neuropsychological test battery (cNTB)) and secondary outcomes (ADCS-CGIC, ADCS-MCI-ADL, ADAS-cog14, NPI, and Pittsburgh Sleep Quality Index (PSQI)) nor were there safety concerns (NCT02615002).
Objectives |
This study was aimed at identifying genetic markers predicting piromelatine treatment response using a genome-wide association approach (GWAS).
Design |
Variant genotyping of a combined whole genome and whole exome sequencing was performed using DNA extracted from lymphocytes from consenting participants. The general case-control allelic test was performed on piromelatine-treated participants, taking “responders” (i.e., >0.125 change from baseline in the cNTB) as cases and “non responders” as controls, using a Cochran-Armitage trend test.
Setting |
58 outpatient clinics in the US.
Participants |
371 participants were randomized in the trial; 107 provided informed consent for genotyping.
Results |
The GWAS sample did not differ from the full study cohort in demographics, baseline characteristics, or response to piromelatine. Six single-nucleotide polymorphisms (SNPs) in chromosome 2q12 (2:107,510,000-107,540,000) were associated with response (p-value < 1×10 −4 each). Post hoc analyses suggested that the carriers of the 2q12 polymorphism cluster (27% of the GWAS sample) improved significantly on the cNTB on piromelatine as compared to placebo but significantly worsened on the ADAS-Cog14 and PSQI. By contrast, “non-carriers” improved significantly with piromelatine compared to placebo on the ADAS-Cog14 (2.91 (N=23) with piromelatine 20 mg vs 1.65 (N=19) with placebo (p=0.03)) and PSQI.
Conclusions |
The 2q12 (2:107,510,000-107,540,000) 5–6 SNPs cluster may predict efficacy of piromelatine for mild AD. These findings warrant further investigation in a larger, prospective early-stage AD clinical trial for patients who are non-carriers of the 2q12 polymorphism cluster.
Le texte complet de cet article est disponible en PDF.Key words : Piromelatine, Alzheimer’s disease, GWAS, SNP, clinical trials, ADAS-cog, sleep, cognition
Plan
Vol 9 - N° 2
P. 247-254 - avril 2022 Retour au numéro
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