Intravenous immunoglobulin for Alzheimer's disease
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Comment 218 www.thelancet.com/neurology Vol 12 March 2013 Intravenous immunoglobulin for Alzheimer’s disease Intravenous immunoglobulin contains naturally occurring antibodies against amyloid β and, like solanezumab, has been postulated to remove cerebral amyloid β through a peripheral sink mechanism, by shifting amyloid β from the CSF to the blood. 1,2 Two small open-label studies 3,4 support this hypothesis; they suggest that intravenous immunoglobulin can stabilise Alzheimer’s disease and increase the plasma concentration of amyloid β. In this issue of The Lancet Neurology, Richard Dodel and colleagues 5 report the first published randomised, placebo-controlled trial of intravenous immunoglobulin, in 58 patients with Alzheimer’s disease. Their findings, against the backdrop of recent failures of immunotherapeutic strategies in phase 3 trials, are sobering. The main anticipated outcome, based on the sink hypothesis, was that the plasma concentration of amyloid β 1–40 would increase with treatment. However, plasma amyloid β 1–40 concentration did not differ significantly between five of the intravenous immunoglobulin dose groups and the placebo groups. Furthermore, in the one group (0·4 g/kg every 2 weeks) that had a significantly different amyloid β 1–40 plasma concentration compared with placebo (area under the curve [AUC] 47·0 vs 159·5; difference 134·5, 95% CI 4·5–500·5; p=0·0216), plasma amyloid β 1–40 concentration decreased compared with placebo— opposite to the direction that was predicted. For amyloid β 1–42 the AUC was significantly higher in the placebo group than in the groups that took 0·25 g/kg and 0·4 g/kg every 2 weeks. Many of the other secondary outcomes—concentrations of CSF amyloid β 1–40 , amyloid β 1–42 , total tau, and p-tau, and MRI assessments of hippocampus and whole brain atrophy—did not differ significantly between treatment and placebo groups. The only significant difference that was in the anticipated direction was that glucose metabolism in the hippocampal and temporomesial regions fell significantly less in the combined treated groups than in the placebo group. However, the biological relevance of this finding is unclear, since the areas of the brain typically affected by Alzheimer’s disease did not improve. Unexpected biological outcomes—eg, increased brain atrophy—do occur after active amyloid β Published Online January 31, 2013 http://dx.doi.org/10.1016/ S1474-4422(13)70015-2 See Articles page 233 immunisation. 6 However, the treatment being studied might still have potential as treatment if clinical results are favourable. If these findings had also been accompanied by adverse clinical outcomes it seems unlikely that there would have been much appetite for further development of these compounds. The additional finding 5 of a significant difference in favour of placebo for one of the four clinical outcomes (clinical dementia rating scale—sum of boxes score) when the pooled intravenous immunoglobulin group was compared with the pooled placebo group is, therefore, not encouraging. Faced with these findings the investigators have understandably emphasised the safety of their approach. Intravenous immunoglobulin was not associated with any major differences in the overall proportions of adverse events or serious adverse events and the researchers report it as having an acceptable safety profile. However, one patient who received intravenous immunoglobulin had an ischaemic stroke (a known side effect of intravenous immunoglobulin) and in the 6 month treatment period six of 42 patients (14%) who received intravenous immunoglobulin had incident microbleeds compared with none in the placebo group. This is a small study. It is clearly underpowered to show significant clinical differences and the varying dose regimens make interpretation of the grouped analysis difficult. As Dodel and colleagues rightly state, “we cannot rule out that intravenous immunoglobulin treatment might not be effective in patients with Alzheimer’s disease” and we should await the findings of the larger ongoing randomised placebo-controlled trial (NCT00818662). However, these findings are not what the Alzheimer’s disease research community were hoping for and echo the largely negative results of the other recent immunotherapy studies (unpublished) of bapineuzumab and solanezumab for Alzheimer’s disease. Clive Holmes University of Southampton, Memory Assessment and Research Centre, Moorgreen Hospital, Southampton, S030 3JB, UK [email protected] I declare that I have no conflicts of interest. 1 Solomon B. Intravenous immunoglobulin and Alzheimer’s disease immunotherapy. Curr Opin Mol Ther 2007; 9: 79–85.
Transcript of Intravenous immunoglobulin for Alzheimer's disease
Comment
218 www.thelancet.com/neurology Vol 12 March 2013
Intravenous immunoglobulin for Alzheimer’s diseaseIntravenous immunoglobulin contains naturally occurring antibodies against amyloid β and, like solanezumab, has been postulated to remove cerebral amyloid β through a peripheral sink mechanism, by shifting amyloid β from the CSF to the blood.1,2 Two small open-label studies3,4 support this hypothesis; they suggest that intravenous immunoglobulin can stabilise Alzheimer’s disease and increase the plasma concentration of amyloid β. In this issue of The Lancet Neurology, Richard Dodel and colleagues5 report the fi rst published randomised, placebo-controlled trial of intravenous immunoglobulin, in 58 patients with Alzheimer’s disease. Their fi ndings, against the backdrop of recent failures of immunotherapeutic strategies in phase 3 trials, are sobering.
The main anticipated outcome, based on the sink hypothesis, was that the plasma concentration of amyloid β1–40 would increase with treatment. However, plasma amyloid β1–40 concentration did not diff er signifi cantly between fi ve of the intravenous immunoglobulin dose groups and the placebo groups. Furthermore, in the one group (0·4 g/kg every 2 weeks) that had a signifi cantly diff erent amyloid β1–40 plasma concentration compared with placebo (area under the curve [AUC] 47·0 vs 159·5; diff erence 134·5, 95% CI 4·5–500·5; p=0·0216), plasma amyloid β1–40 concentration decreased compared with placebo—opposite to the direction that was predicted. For amyloid β1–42 the AUC was signifi cantly higher in the placebo group than in the groups that took 0·25 g/kg and 0·4 g/kg every 2 weeks. Many of the other secondary outcomes—concentrations of CSF amyloid β1–40, amyloid β1–42, total tau, and p-tau, and MRI assessments of hippocampus and whole brain atrophy—did not diff er signifi cantly between treatment and placebo groups. The only signifi cant diff erence that was in the anticipated direction was that glucose metabolism in the hippocampal and temporomesial regions fell signifi cantly less in the combined treated groups than in the placebo group. However, the biological relevance of this fi nding is unclear, since the areas of the brain typically aff ected by Alzheimer’s disease did not improve.
Unexpected biological outcomes—eg, increased brain atrophy—do occur after active amyloid β
Published OnlineJanuary 31, 2013
http://dx.doi.org/10.1016/S1474-4422(13)70015-2
See Articles page 233
immunisation.6 However, the treatment being studied might still have potential as treatment if clinical results are favourable. If these fi ndings had also been accompanied by adverse clinical outcomes it seems unlikely that there would have been much appetite for further development of these compounds. The additional fi nding5 of a signifi cant diff erence in favour of placebo for one of the four clinical outcomes (clinical dementia rating scale—sum of boxes score) when the pooled intravenous immunoglobulin group was compared with the pooled placebo group is, therefore, not encouraging.
Faced with these fi ndings the investigators have understandably emphasised the safety of their approach. Intravenous immunoglobulin was not associated with any major diff erences in the overall proportions of adverse events or serious adverse events and the researchers report it as having an acceptable safety profi le. However, one patient who received intravenous immunoglobulin had an ischaemic stroke (a known side eff ect of intravenous immunoglobulin) and in the 6 month treatment period six of 42 patients (14%) who received intravenous immunoglobulin had incident microbleeds compared with none in the placebo group.
This is a small study. It is clearly underpowered to show signifi cant clinical diff erences and the varying dose regimens make interpretation of the grouped analysis diffi cult. As Dodel and colleagues rightly state, “we cannot rule out that intravenous immunoglobulin treatment might not be eff ective in patients with Alzheimer’s disease” and we should await the fi ndings of the larger ongoing randomised placebo-controlled trial (NCT00818662). However, these fi ndings are not what the Alzheimer’s disease research community were hoping for and echo the largely negative results of the other recent immunotherapy studies (unpublished) of bapineuzumab and solanezumab for Alzheimer’s disease.
Clive HolmesUniversity of Southampton, Memory Assessment and Research Centre, Moorgreen Hospital, Southampton, S030 3JB, [email protected]
I declare that I have no confl icts of interest.
1 Solomon B. Intravenous immunoglobulin and Alzheimer’s disease immunotherapy. Curr Opin Mol Ther 2007; 9: 79–85.
Comment
www.thelancet.com/neurology Vol 12 March 2013 219
Antiepileptic drugs during pregnancy and cognitive outcomes
Published OnlineJanuary 23, 2013http://dx.doi.org/10.1016/S1474-4422(13)70012-7
See Articles page 244
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Women with epilepsy are routinely advised to continue antiepileptic-drug treatment throughout pregnancy, based on the assumption that the maternal and fetal benefi ts of treatment in terms of maternal seizure control outweigh the teratogenic risks. In many studies, major congenital malformations, growth abnormalities, dysmorphic syndromes, and overt mental retardation have been attributed to specifi c antiepileptic drugs or specifi c combinations of drugs. However, cognitive development in off spring of mothers on antiepileptic drugs is less well understood; teratogenic assessment is especially needed for drugs that—by design—act on the CNS, cross the placental barrier, and might aff ect embryonic neurodevelopment.
In The Lancet Neurology, Kimford Meador and colleagues1 report a prospective observational study of cognitive development to the age of 6 years in children exposed in utero to valproate, lamotrigine, carbamazepine, or phenytoin. The investigators accounted for a large number of potentially confounding factors such as maternal intelligence quotient (IQ), maternal disease characteristics, coexposure to other drugs, and periconceptional folate use, and assessed possible dose-eff ect relations. They did not include a control group, which is a reasonable strategy in view of the fact that, for most women with epilepsy, stopping drug treatment during pregnancy is not an alternative (leaving only a choice between diff erent antiepileptic drug regimens). The number of women with active epilepsy who are not on drug treatment in the UK and USA is very small and not representative of those on drug treatment; these women presumably have diff erent kinds of epilepsy with other genetic loads and less seizure activity during pregnancy.
Meador and colleagues had to deal with known problems of long-term follow-up studies of pregnancy outcome, the most diffi cult of which was loss to
follow-up, but they handled this problem in a detailed manner. The investigators’ most prominent results were the identifi cation of a signifi cantly lower mean IQ at 6 years in children exposed to valproate compared with lamotrigine, carbamazepine, or phenytoin; a clear dose-response relation between valproate and child IQ; the virtual absence of a relation between mother and child IQ after valproate exposure compared with a clearly positive relation between mother and child IQ with the other drugs; and the reduced proportion of right handedness in children exposed to valproate and lamotrigine.
Meador and colleagues’ fi ndings confi rm results from previous studies that neurodevelopment is compromised by valproate use. Figure 2 in the linked paper1 is especially notable, in which child IQ is plotted against maternal IQ showing the absence of a relation with valproate use, but also an increased scatter of child IQ values towards the lower range. This pattern might be attributable to diff erences in individual susceptibility not related to maternal IQ and deserves further attention. After valproate exposure, verbal ability was more compromised than was non-verbal ability. Indeed, the simultaneous fi nding of decreased incidence of right handedness raises questions about the eff ect of valproate (and lamotrigine) on lateralisation of brain functions and its role in cognitive development in these children.
One surprising result of Meador and colleagues’ study1 was the signifi cant association between child IQ and use of periconceptional folate in all drug groups, which was least strong with valproate and had a positive dose-eff ect after its exclusion from the analysis. The eff ect of use of periconceptional folate had not been the primary target of the study and information about its use and dose were collected retrospectively at the time of enrolment. Although these fi ndings are in line with those from other studies in children of mothers without
2 Farlow M, Arnold SE, van Dyck CH, et al. Safety and biomarker eff ects of solanezumab in patients with Alzheimer’s disease. Alzheimers Dement 2012; 8: 261–71.
3 Dodel RC, Du Y, Depboylu C, et al. Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2004; 75: 1472–74.
4 Relkin NR, Szabo P, Adamiak B, et al. 18-month study of intravenous immunoglobulin for treatment of mild Alzheimer disease. Neurobiol Aging 2009; 30: 1728–36.
5 Dodel R, Rominger A, Bartenstein P, et al. Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer’s Disease: a phase 2, randomised, double-blind, placebo-controlled dose-fi nding trial. Lancet Neurol 2013; published online Jan 31. http://dx.doi.org/10.1016/S1474-4422(13)70014-0.
6 Vellas B, Black R, Thal LJ, et al. Long-term follow-up of patients immunized with AN1792: reduced functional decline in antibody responders. Curr Alzheimer Res 2009; 6: 144–51.
