<p>MCLENA-1: A Phase II Clinical Trial for the Assessment of Safety, Tolerability, and Efficacy of Lenalidomide in Patients with Mild Cognitive Impairment Due to Alzheimer’s Disease</p>

Abstract

With the general population reaching higher ages, a surge in Alzheimer's disease (AD) incidence will happen in the coming decades, putting a heavy burden on families and healthcare systems Worldwide. This emphasizes the pressing need for AD therapeutic interventions. Accumulating evidence indicates that inflammation is prominent both in the blood and central nervous system of AD sufferers. These data suggest that systemic inflammation plays a crucial role in the cause and effects of AD neuropathology. Capitalizing on our experience from a previous clinical trial with thalidomide, we hypothesize that modulating inflammation via the pleiotropic immunomodulator lenalidomide may alter AD if administered during a proper time window in the course of the disease. Thus, in this Phase II, proof-of mechanism study, 30 amnestic mild cognitive impairment (aMCI) subjects will be treated with lenalidomide at 10 mg/day for 12 months on a 1:1 ratio, followed by a 6 months washout period. The primary objective of this study is to investigate the effect of lenalidomide on cognition, which is assessed at regular intervals. The secondary objective is to assess the safety and tolerability of lenalidomide in aMCI patients evaluated through adverse events, vital signs, clinical biochemistry, and physical and neurological examinations. Tertiary objectives are to analyze the effects of lenalidomide on brain amyloid loads (Florbetapir PET imaging) and neurodegeneration (volumetric MRI) by comparing pre-and post-dosing data. Finally, exploratory objectives will investigate whether blood inflammatory markers can serve as surrogate markers of therapeutic efficacy. Our study should determine whether lenalidomide is safe in AD subjects and whether it can alter the clinical progression of AD when administered before dementia onset. If effective, lenalidomide would become the first drug capable of delaying the trajectory of AD, which could lead the way to find additional, less toxic treatments in the near future.

Neuroinflammation in Alzheimer’s Disease

“…Compared with similar anti-inflammatory drugs, currently marketed IMiDs have improved BBB permeability and bioavailability, making them viable candidates for neurological disorders [ 360 ]. Chronic thalidomide administration significantly reduces both astrocytes and microglia activation, and Aβ generation in brains of APP23 transgenic mice through inhibition of β-secretase (BACE1) [ 361 , 362 ]. 3,6′-dithiothalidomide (3,6′-DT) effectively lowers TNF-α, nitrite, and secreted amyloid precursor protein (sAPP) levels in vitro in LPS-activated macrophage-like cells.…”

Repositioning of Immunomodulators: A Ray of Hope for Alzheimer’s Disease?

“…Lenalidomide, used for multiple myeloma and myelodysplastic syndromes, acts as immunomodulator, anti-cancer and antiangiogenic drug (Quach et al, 2010). The pleiotropic antiinflammatory activity of the drug, combined with evidence from previous clinical trials with thalidomide, led to the construction of the study MCLENA-1 (Decourt et al, 2020) a clinical trial for the assessment of Lenalidomide in patients with MCI. The investigators designed an 18-month, Phase II, double-blind, randomized, two-armed, parallel group, placebo controlled clinical trial aimed to test the hypothesis that lenalidomide reduces inflammatory and AD-associated pathological biomarkers, thus improving cognition.…”

Anticancer drugs repurposed for Alzheimer’s disease: a systematic review

“…Moreover, frequent serious AEs (i.e., elevated triglycerides) were observed [ 54 ]. Other anticancer drugs such as thalidomide, lenalidomide, and pexidartinib have been shown to exert neuroprotective effects and attenuate neuroinflammation in experimental models [ 37 – 40 , 46 , 59 ]. Masitinib, as well, showed promising anti-neuroinflammatory effects through the modulation of microglia and amyloidosis, or with a synaptoprotective action in relation with mast cell inhibition [ 30 – 34 ].…”