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

Abstract

Introduction To date there is no cure for Alzheimer's disease (AD). After amyloid beta immunotherapies have failed to meet primary endpoints of slowing cognitive decline in AD subjects, the inhibition of the beta-secretase BACE1 appears as a promising therapeutic approach. Pre-clinical data obtained in APP23 mice suggested that the anti-cancer drug thalidomide decreases brainBACE1 and Aβ levels. This prompted us to develop an NIH-supported Phase IIa clinical trial to test the potential of thalidomide for AD. We hypothesized that thalidomide can decrease or stabilize brain amyloid deposits, which would result in slower cognitive decline in drug- versus placebo-treated subjects. Methods This was a 24-week, randomized, double-blind, placebo-controlled, parallel group study with escalating dose regimen of thalidomide with a target dose of 400mg daily in patients with mild to moderate AD. The primary outcome measures were tolerability and cognitive performance assessed by a battery of tests. Results A total of 185 subjects have been pre-screened, out of which25 were randomized. Mean age of the sample at baseline was 73.64 (±7.20) years; mean education was 14.24 (±2.3) years; mean MMSE score was 21.00 (±5.32); and mean GDS score was 2.76 (±2.28).Among the 25 participants, 14 (56%) terminated early due to adverse events, dramatically decreasing the power of the study. In addition, those who completed the study (44%) never reached the estimated therapeutic dose of 400 mg/day thalidomide because of reported adverse events. The cognitive data showed no difference between the treated and placebo groups at the end of the trial. Conclusion This study demonstrates AD patients have poor tolerability for thalidomide, and are unable to reach a therapeutic dose felt to be sufficient to have effects on BACE1. Because of poor tolerability, this study failed to demonstrate a beneficial effect on cognition.

Neuroprotection by the Immunomodulatory Drug Pomalidomide in the Drosophila LRRK2WD40 Genetic Model of Parkinson’s Disease

“…Thalidomide is currently used mainly to treat multiple myeloma and erythema nodosum leprosum (Franks et al, 2004), but its long-term use at doses required to stop inflammation has been associated with peripheral neuropathy as well as teratogenic effects (Vargesson, 2009). Indeed, in a recent clinical trial of Thalidomide in Alzheimer's disease, poor tolerability precluded the agent being administered at the perceived efficacious dose (Decourt et al, 2017). Lenalidomide is a more potent anti-inflammatory drug as compared with Thalidomide, effectively inhibiting TNF-α at lower doses than the parent compound.…”

Effects of thalidomide on growth and VEGF-A expression in SW480 colon cancer cells

“…THD, a drug initially synthesized by Chemie Gruneenthal, was used to treat morning sickness during pregnancy but was later withdrawn from the market due to serious side effects of phocomelia (17). However, studies have also reported that THD has anti-inflammatory, immunomodulatory, and anti angiogenic effects (16).…”

“…However, the use of THD during pregnancy led to phocomelia and consequently the drug was withdrawn from the market (17). Subsequent studies have reported that THD has anti-inflammatory, immunomodulatory and anti-angiogenic effects (18)(19)(20)(21)(22).…”

<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>

“…9 Preliminary tests showed a significant decrease in brain TNF-α mRNA, BACE1 mRNA and protein levels, and Aβ plaque loads, as well as improved cognitive measures in APP23 mice administered lenalidomide (unpublished observations; work done under IACUC protocols at Banner Health #1102, at Arizona State University #16-1456R and 19-1669R, and at Cleveland Clinic #2019-2206). Therefore, capitalizing on our experience with a recent thalidomide clinical trial we conducted in house 10 and on our animal observations, in the current project, we aim to test the central hypothesis that lenalidomide reduces inflammatory and AD-associated pathological biomarkers and improves cognition. For this, we designed an 18-month, Phase II, proof-of-mechanism, clinical study where patients with mild cognitive impairment (MCI) due to AD will be administered 10 mg/day lenalidomide for 12 months followed by a 6 month washout.…”