By Dr Antonella Macerollo
For August 2020, we have selected Turner R.S. et al. “Nilotinib Effects on Safety, Tolerability,and Biomarkers in Alzheimer’s Disease” Annals of Neurology 2020;88:183–194. doi: 10.1002/ana.25775. Epub 2020 May 28.
Nilotinib is a US Food and Drug Administration (FDA)-approved drug for leukemia.
Our paper of the month evaluated the safety, tolerability, and pharmacokinetics of nilotinib
in participants with mild to moderate dementia due to Alzheimer’s Disease (AD) through a phase two, randomised, double-blind, placebo-controlled study.
The secondary outcome of the study was to investigate whether this medication had any effect on amyloid biomarkers—CSF (Aβ42 and Aβ40), CNS amyloid burden (Florbetaben positrone mission tomography [PET]), markers of neurodegeneration—CSF [phospho-tau (ptau-181), total tau] and hippocampal volume.
The authors randomized participants into two groups receiving a daily oral dose of
150 mg nilotinib for six months followed by 300 mg nilotinib for six months (12 months total) versus placebo.
Inclusion criteria were: mild to moderate dementia and a biomarker-supported diagnosis of AD according to the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease (MMSE 14 to 24 and either CSF Aβ42 < 1,100 pg/ml or a positive amyloid PET (visual read), or both).
Participants of all races and nationalities aged 50 to 85 years were recruited with no restriction to geographic boundaries as long as they complied with study visits and procedures.
The following clinical scales were used during the study: Alzheimer Disease Assessment
Scale–cognitive subscale (ADAS-Cog), Alzheimer’s Disease Cooperative Study–Instrumental Activities of Daily Living Inventory (ADCS-ADL), Clinical Dementia Rating–Sum of Boxes (CDR-SOB), Neuropsychiatric Inventory (NPI) and Mini-Mental Status Examination (MMSE).
37 participants were enrolled in the study (27 female) with a mean age of 70.7 (±6.48) years.
In the group receiving nilotinib, CNS amyloid burden was significantly reduced in the frontal lobe compared to the placebo group. Cerebrospinal fluid Aβ40 was reduced at 6 months and Aβ42 was reduced at 12 months in the nilotinib group compared to the placebo. Hippocampal volume loss was attenuated (−27%) at 12 months and phospho-tau-181 was reduced at six months and 12 months in the nilotinib group.
Regarding the safety, some side effects and particularly mood swings [agitation (52.9%) and irritability (35.2%)] were reported by patients on the 300 mg. Therefore, a lower dose of 150 mg daily may be preferable in future studies to avoid behavioural adverse effects.
In conclusion, our paper of the month showed promising data to guide the design of a further larger multicentre phase three study to evaluate the safety and efficacy of nilotinib in subjects with mild to moderate AD.