Therapeutics

Lenalidomide

Tools

Back to the Top

Overview

Name: Lenalidomide
Synonyms: Revlimid
Chemical Name: 3-(4-Amino-1-3-dihydro-1-oxo-2H-isoindol-2yl)-2,6-piperidinedione
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline), Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Celgene Corporation
Approved for: Multiple myeloma, lymphoma, myelodysplastic syndromes

Background

Lenalidomide is an anti-cancer drug with pleiotropic anti-inflammatory, anti-angiogenic, and immune stimulatory activities. Sold under the brand name Revlimid, lenalidomide has been used since 2006 to treat multiple myeloma, lymphoma, and myelodysplastic syndromes. The capsules are taken by mouth. In cancer patients, the main side effects are abnormal blood counts and blood clots. Lenalidomide is structurally similar to thalidomide, and as such is considered a teratogen with the potential to cause birth defects and fetal death.

Lenalidomide is being pursued as an alternative to thalidomide, whose development for AD was stopped because of dose-limiting toxicity in elderly patients (Decourt et al., 2017). Both drugs have anti-inflammatory activity, lowering the expression of TNFα, IL-6 and IL-8, and increasing expression of anti-inflammatory cytokines, e.g., IL-10. Both are also claimed to reduce amyloidogenesis by inhibiting BACE1 expression. In cancer patients, both drugs have the potential to induce cognitive impairment, according to published case reports (Argente-Escrig et al., 2018; Morgan et al., 2003; Rollin-Sillaire et al., 2013).

No preclinical data has been published for lenalidomide in AD models. In other models, the drug reportedly blocked α-synuclein toxicity by reducing inflammation (Valera et al., 2017; Valera et al., 2015) and extended survival in ALS mice (Neymotin et al., 2009; Kiaei et al., 2006).

Findings

In July 2020, a Phase 2 trial at Cleveland Clinic Lou Ruvo Brain Health Center in Las Vegas began testing lenalidomide in 30 people with mild cognitive impairment. The MCLENA-1 study is enrolling participants with a clinical diagnosis of amnestic MCI plus low hippocampal volume, or a positive amyloid PET scan, or an ApoE4 allele. Enrollees will receive 10 mg lenalidomide or placebo daily for one year, followed by a six-month washout. The primary outcome is cognition, including ADAS-Cog, ADCS-ADL, CDR-SB, and MMSE scores. Other outcomes are safety, measures of brain amyloid, structural MRI, and blood levels of inflammatory markers. The protocol is published (Decourt et al., 2020). The treatment phase is expected to be completed in September 2023.

For details on this trial, see clinicaltrials.gov.

Last Updated: 23 Apr 2021

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Therapeutics Citations

  1. Thalidomide

Paper Citations

  1. Decourt B, Wilson J, Ritter A, Dardis C, DiFilippo FP, Zhuang X, Cordes D, Lee G, Fulkerson ND, St Rose T, Hartley K, Sabbagh MN. 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. Epub 2020 Jan 7 PubMed.
  2. Decourt B, Drumm-Gurnee D, Wilson J, Jacobson S, Belden C, Sirrel S, Ahmadi M, Shill H, Powell J, Walker A, Gonzales A, Macias M, Sabbagh MN. Poor Safety and Tolerability Hamper Reaching a Potentially Therapeutic Dose in the Use of Thalidomide for Alzheimer's Disease: Results from a Double-Blind, Placebo-Controlled Trial. Curr Alzheimer Res. 2017;14(4):403-411. PubMed.
  3. Argente-Escrig H, Martinez JC, Gómez E, Balaguer A, Sevilla T, Bataller L. Lenalidomide induced reversible parkinsonism, dystonia, and dementia in subclinical Creutzfeldt-Jakob disease. J Neurol Sci. 2018 Oct 15;393:140-141. Epub 2018 Aug 28 PubMed.
  4. Morgan AE, Smith WK, Levenson JL. Reversible dementia due to thalidomide therapy for multiple myeloma. N Engl J Med. 2003 May 1;348(18):1821-2. PubMed.
  5. Rollin-Sillaire A, Delbeuck X, Pollet M, Mackowiak MA, Lenfant P, Noel MP, Facon T, Leleu X, Pasquier F, Le Rhun E. Memory loss during lenalidomide treatment: a report on two cases. BMC Pharmacol Toxicol. 2013 Aug 12;14:41. PubMed.
  6. Valera E, Spencer B, Fields JA, Trinh I, Adame A, Mante M, Rockenstein E, Desplats P, Masliah E. Combination of alpha-synuclein immunotherapy with anti-inflammatory treatment in a transgenic mouse model of multiple system atrophy. Acta Neuropathol Commun. 2017 Jan 5;5(1):2. PubMed.
  7. Valera E, Mante M, Anderson S, Rockenstein E, Masliah E. Lenalidomide reduces microglial activation and behavioral deficits in a transgenic model of Parkinson's disease. J Neuroinflammation. 2015 May 14;12:93. PubMed.
  8. Neymotin A, Petri S, Calingasan NY, Wille E, Schafer P, Stewart C, Hensley K, Beal MF, Kiaei M. Lenalidomide (Revlimid) administration at symptom onset is neuroprotective in a mouse model of amyotrophic lateral sclerosis. Exp Neurol. 2009 Nov;220(1):191-7. PubMed.
  9. Kiaei M, Petri S, Kipiani K, Gardian G, Choi DK, Chen J, Calingasan NY, Schafer P, Muller GW, Stewart C, Hensley K, Beal MF. Thalidomide and lenalidomide extend survival in a transgenic mouse model of amyotrophic lateral sclerosis. J Neurosci. 2006 Mar 1;26(9):2467-73. PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

No Available Further Reading