Repurposed Cancer Drug Lenalidomide Shows Feasibility and Safety in Phase 2 Study of MCI Due to Alzheimer Disease

A phase 2 proof-of-mechanism trial evaluating the anti-cancer drug lenalidomide (Revlimid; BMS) as an immunomodulatory therapy for mild cognitive impairment (MCI) due to Alzheimer disease (AD) demonstrated feasibility and a manageable safety profile over 12 months of treatment, according to data presented at the 2026 Alzheimer's Association International Conference (AAIC) in London.¹ Though the study fell short of its enrollment target and was underpowered to draw efficacy conclusions, the results are being used to support the design of MCLENA-2, a companion phase 2 study now underway focused on biomarker endpoints.

Led by Marwan N. Sabbagh, MD, a professor of neurology at the Barrow Neurological Institute in Phoenix, Arizona, the MCLENA-1 trial (NCT04032626) was built on a straightforward hypothesis: that the chronic neuroinflammation characterizing AD, including elevated TNF-alpha, IL-1 beta, IL-2, IL-6, and IL-8, represents a tractable therapeutic target. Lenalidomide is a pleiotropic immunomodulator that suppresses TNF-alpha and modulates both innate and adaptive immune responses, and carries existing FDA approval for multiple myeloma and certain hematologic malignancies.

The drug is structurally related to thalidomide, and prior work from the Sabbagh group in a thalidomide trial and in animal models showing reduced BACE1 expression, amyloid plaque load, and TNF-alpha mRNA in lenalidomide-treated APP23 mice provided the preclinical rationale.

MCLENA-1 was a randomized, double-blind, placebo-controlled trial targeting 30 patients with single or multiple domain amnestic MCI confirmed by amyloid PET. Participants were randomized 1:1 to lenalidomide 10 mg/day or placebo for 12 months, followed by a 6-month washout. All subjects underwent Florbetapir amyloid PET imaging. The primary objective was the effect of 12 months of lenalidomide on cognition, with secondary objectives assessing safety and tolerability, and exploratory objectives evaluating blood inflammatory markers as potential surrogate biomarkers of efficacy.

Overall, the study did not meet its enrollment targets before the conclusion of the funding period. Of 15 participants who signed consent, 7 screen-failed and 2 withdrew consent, leaving 6 who completed 12 months of treatment. No serious adverse events (AEs) occurred during the study, and AEs were consistent with the known lenalidomide label.¹ Nonsignificant trends favoring treatment over placebo were observed on cognition and global outcome measures, a directional signal that the investigators noted warrants cautious interpretation given the very small sample size.

The limitations of the study were significant: with only 6 completers, the trial was not powered to detect any efficacy signal, and the blinded randomization meant the allocation of those 6 completers across treatment and placebo arms was not fully characterized in the abstract. The results support feasibility and safety but cannot speak to whether lenalidomide meaningfully modulates neuroinflammation in this population.

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The findings set the stage for MCLENA-2 (NCT06177028), a companion phase 2 trial now enrolling at Barrow Neurological Institute and funded by the Alzheimer's Drug Discovery Foundation. MCLENA-2 is a 6-month study using 5 mg lenalidomide with a heavy focus on biomarkers, employing a 2:1 randomization of 30 patients on drug and 15 on placebo, with the primary endpoints centered on CSF biomarkers.³

The study aims to evaluate the effect of lenalidomide on cognition, neurodegeneration, and inflammatory biomarkers in both blood and CSF, with participants followed for up to 45 weeks including a 26-week treatment period.³ Where MCLENA-1 asked whether lenalidomide was safe and could move the needle on cognition over a year, MCLENA-2 asks whether 6 months of the drug at a lower dose can produce measurable changes in the molecular markers of AD pathology, providing the mechanistic evidence of target engagement needed to justify a larger efficacy trial.

The neuroinflammation angle in AD drug development has attracted renewed interest following the understanding that microglia and peripheral immune dysregulation contribute to amyloid and tau pathology rather than simply reacting to it. Lenalidomide's ability to cross the blood-brain barrier, modulate microglia, and suppress TNF-alpha production makes it a mechanistically plausible candidate, though no CNS anti-inflammatory approach has yet demonstrated disease modification in a phase 3 trial.²

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REFERENCES
1. Sabbagh MN, Wilson J, Beyene K, Dumitrescu L, DeCourt B. MCLENA-1: A phase II clinical trial for the assessment of safety, tolerability, and efficacy of lenalidomide in patients with MCI due to AD. Abstract presented at: Alzheimer's Association International Conference (AAIC); 2026; London, United Kingdom.
2. Decourt B, Wilson JR, Ritter A, et al. 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. Open Access J Clin Trials. 2020;12:1-13. doi:10.2147/OAJCT.S221914. https://pmc.ncbi.nlm.nih.gov/articles/PMC7051033/
3. MCLENA-2: A phase II clinical trial for the assessment of biomarker trajectory in patients with mild cognitive impairment due to Alzheimer's disease treated with lenalidomide. ClinicalTrials.gov. NCT06177028. Accessed July 13, 2026. https://clinicaltrials.gov/study/NCT06177028