Lovastatin, a cholesterol-lowering medication, improves cognitive deficits in children with Neurofibromatosis type 1: Phase 1 study results

Maria T. Acosta, M.D.
Children’s National Medical Center, Washington, DC, USA

Background: Cognitive deficits are the most important long term co-morbidity in NF1 patients. In a mouse model of neurofibromatosis type 1(NF1), lovastatin improved cognitive deficits and executive functioning.

Methods:  Using a standard phase 1 study design, we examined the safety and biological impact of lovastatin as a treatment for the neurocognitive deficits in a group of 24 children 10-17 years old with diagnosis of NF1. A subset of patients underwent a 12-hour pharmacokinetics analyses.

Results: Lovastatin plasma concentration was varied between participants as area under the curve (AUC) profiles ranged from 2.61 ng*hr/mL to 14.05 ng*hr/mL.  Change in LDL cholesterol levels during the study ranged from +10.5% to -44.6%. Medication was safe in all patients with minimal side effects, and the relation of cholesterol subtypes and other metabolic measurements stayed in the normal limits.  Significant improvements (p=<.05) were found several cognitive variables that deal with processing speed, verbal memory, nonverbal memory, and visuospatial skills (on the TEA-Ch, CVLT, WRAML2, and JLO, respectively).  Additionally, change in LDL cholesterol was used in regression analyses to explain variance seen in the attention (on TEA-Ch) and memory (on CVLT) results.

Conclusions: Lovastatin was well tolerated and no safety concerns arose during the three-month period of our study.  Despite small number of patients and variability in pharmacokinetics in the individuals, metabolism of cholesterol correlated with neuropsychological assessment.  While the data is encouraging, further studies of drug efficacy on neuropsychological functioning are necessary. A phase 2 study is currently ongoing to further assess these observations.