A randomized placebo‐controlled lovastatin trial for neurobehavioral function in neurofibromatosis I

Abstract

ObjectiveLovastatin has been shown to reverse learning deficits in a mouse model of Neurofibromatosis Type 1 (NF1), a common monogenic disorder caused by a mutation in the Ras‐MAPK pathway and associated with learning disabilities. We conducted a randomized double‐blind placebo‐controlled trial to assess lovastatin's effects on cognition and behavior in patients with NF1.MethodForty‐four NF1 patients (mean age 25.7+/−11.6 years; 64% female) were randomly assigned to 14 weeks of lovastatin (N = 23; maximum dose of 80 mg/day for adult participants and 40 mg/day for children) or placebo (N = 21). Based on findings in the mouse model, primary outcome measures were nonverbal learning and working memory. Secondary outcome measures included verbal memory, attention, and self/parent‐reported behavioral problems, as well as tolerability of medication. Participants also underwent neuroimaging assessments at baseline and 14 weeks, to determine whether neural biomarkers were associated with treatment response. Linear mixed models assessed for differential treatment effects on outcome measures.ResultsTwelve participants dropped from the study prior to completion (8 placebo, 4 lovastatin), resulting in 32 completers (15 placebo, 17 lovastatin). Lovastatin was well‐tolerated, with no serious adverse events. Differential improvement favoring lovastatin treatment was observed for one primary (working memory; effect size f 2 = 0.70, P < 0.01) and two secondary outcome measures (verbal memory, f 2 = 0.19, P = 0.02, and adult self‐reported internalizing problems, f 2 = 0.26, P = 0.03). Exploratory moderator analyses revealed that higher baseline neural activity in frontal regions was associated with larger treatment effects.InterpretationThese preliminary results suggest beneficial effects of lovastatin on some learning and memory functions, as well as internalizing symptoms in patients with NF1.

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“…Subsequent translational trials in human NF1 have shown mixed results. Improvements in verbal and non‐verbal memory were reported within a 12‐week phase 1 observational study of lovastatin in 23 children aged 10–17 years (Acosta et al., ) and in a 14‐week RCT of lovastatin in 44 10–50 years olds (Bearden et al., ); an n = 7 case series from the former cohort showed evidence of treatment normalising pseudoresting state functional connectivity in areas of the default mode network (Chabernaud et al., ). Four days of high‐dose (200 mg) lovastatin improved synaptic plasticity and phasic alertness, as measured with trans‐cranial magnetic stimulation, in a case‐controlled study of 11 adults with NF1 (Mainberger et al., ).…”

Randomized placebo-controlled study of lovastatin in children with neurofibromatosis type 1

“…8 More recently, results from a small randomized controlled trial in children and adults with NF1 reported beneficial effects of lovastatin on learning and memory. 9 In the current study, we tested the hypothesis that 16 weeks of lovastatin will result in cognitive, behavioral, and quality-of-life improvements for children with NF1. The safety profile of lovastatin was also evaluated.…”

“…4 In contrast to our findings, results from a recent study of adults (n 5 30; 80 mg/d) and children (n 5 14; 40 mg/d) with NF1 for 14 weeks suggested possible beneficial effects of lovastatin on working memory, verbal memory, and adult self-reported internalizing problems. 9 Unfortunately, a high dropout rate (27%) resulted in only 32 evaluable patients (15 placebo, 17 lovastatin), reducing statistical power. Failure to analyze the ITT population and to adjust for baseline performance may also have resulted in overestimation of the effect size and led to nonrandom attrition of participants.…”

Cell type-specific roles of RAS-MAPK signaling in learning and memory: Implications in neurodevelopmental disorders

“…Moreover, in clinical trials, FDA-approved statins, which showed beneficial effects in mouse models, were tested on neurobehavioral phenotypes in NF1 patients (Bearden, Hellemann, Rosser, Montojo, Jonas, Enrique et al, 2016;Krab, de GoedeBolder, Aarsen, Pluijm, Bouman, van der Geest et al, 2008a;Mainberger, Jung, Zenker, Wahllander, Freudenberg, Langer et al, 2013;van der Vaart, Plasschaert, Rietman, Renard, Oostenbrink, Vogels et al, 2013). Although small trials with lovastatin suggested beneficial effects of statins on cognitive function in NF1 patients (Bearden et al, 2016;Mainberger et al, 2013), large scale randomized placebo-controlled trials with simvastatin were not successful in showing efficacy against cognitive impairments (Krab et al, 2008a;van der Vaart et al, 2013), which suggests the necessity of developing next generation treatment strategies. As reviewed here, the RAS-MAPK pathway is controlled in specific ways by a distinctive set of regulators, depending on cell type.…”