MCLENA-1: A Phase I-B Clinical Trial for the Assessment of
Safety, Tolerability, and Efficacy of Lenalidomide in Patients
with Mild Cognitive Impairment Due to Alzheimer’s Disease:
Safety and Feasibility Demonstrated

Background: 

Accumulating evidence indicates that
inflammation mediated by tumor necrosis
factor alpha (TNF alpha), interleukins (e.g.
IL-1 beta, IL-2, and IL-6), and chemokines
(e.g. IL-8), are elevated in Alzheimer’s
disease (AD) patients, suggesting that
systemic inflammation plays a crucial role in
the cause and effects of AD neuropathology.

Objectives: 

To investigate immunomodulatory, anti-
cancer agent drug lenalidomide as possible treatment for AD.

• Primary Aim: to assess the effect of 12
months of treatment with lenalidomide on
cognition and imaging parameters.
• Secondary Aim: to assess the safety and
tolerability of lenalidomide in aMCI patients.

Methods:

• Design: Phase I-B, proof-of mechanism,
placebo-controlled clinical study on single and
multiple domain amnestic mild cognitive
impairment (aMCI) subjects.
• Treatment: 10 mg/day of lenalidomide (n=3) or
placebo (n=3) for 12 months on a 1:1 ratio
followed by a 6 months washout period.
Inclusion criteria:
• Outpatients 50–89, community-dwelling.
• Diagnosis of aMCI.
• MMSE score 22–28 at screening.
• Evidence of cerebral amyloid deposition on
Florbetapir PET imaging
• Stable dose of cholinesterase inhibitors for at
least 3 months prior to enrollment.
Exclusion criteria:
• Significant neurological or psychiatric
disorders within the past 3 years (e.g.,
Parkinson's disease, major depression, seizure
disorders).
• Living alone, pregnancy, MRI/PET ineligible,
cardiac pacemaker/defibrillator, HIV+.
• Active cancer, unstable cardiovascular
disease, severe pulmonary disease, or organ
failure.
• Recent Interventions: Investigational drugs
(<30 days) or devices (<2 weeks).

Results:

• The study did not meet its enrollment goals
before the conclusion of the funding period.
• 15 participants signed consent, 7 screen
failed, 2 withdrew consent and 6 completed
treatment after 12 months.

• Adverse events were consistent with the label
for lenalidomide. No SAEs occurred during
the study.
• Importantly, assuming a 1:1 randomization in
the blinded phase, participants have received
lenalidomide continuously for 12 months.
• Compared to the placebo group, the
treatment group exhibited a slower decline in
hippocampal volume, slower increase in
ventricular volume and faster decline in whole
brain volume.

• Overall, improved outcomes across cognitive,
global, and imaging domains were observed
in the treatment group, although these
differences did not reach statistical
significance.

Conclusion: 

• The null hypothesis was not demonstrated.
Our study demonstrates feasibility and safety
in administering lenalidomide to MCI
participants for at least 12 months
continuously.
• The TEAEs were expected and safety and
tolerability were manageable.

Limitations & future directions:

• The sample size is too small to determine a
robust efficacy signal but could be sufficient
to inform a phase II or III design.
• A second study, termed MCLENA 2, has
started with a focus on biomarker (CSF and
plasma) endpoints following treatment for 6
months.

Acknowledgements:

Supported by R01AG059008 and ADDF
GC-2013717