Hemi Malkki

Trial Watch: Glioblastoma vaccine therapy disappointment in Phase III trial

factor receptor (EGFR) does not seem to improve overall survival in patients with newly diagnosed EGFR variant III (EGFRvIII)-positive glioblastoma, according to a press release from Celldex Therapeutics. The company reports that it has discontinued the ACT IV Phase III trial of rindopepimut in newly diagnosed glioblastoma after interim analysis by the independent Data Safety and Monitoring Board showed no significant benefit of the vaccine on overall survival, the primary outcome of the trial. The results are disappointing news after promising findings in the Phase II trial of rindopepimut, which suggested that the peptide vaccine improves overall survival. “While this is certainly not the desired outcome, we remain steadfast believers in the power of immunotherapy to transform the future of cancer treatment,” comments Anthony Marucci, Chief Executive Officer of Celldex Therapeutics. In patients with glioblastoma, post-resection therapy with concurrent temozolamide and radiation prolongs survival, but virtually all patients eventually relapse, and no standard treatment exists for recurrent disease. The lack of treatment options that provide a long-term survival benefit has prompted investigation into immunotherapies. EGFR mutations that lead to its overexpression are the most common genetic alteration in glioblastoma, present in about 40% of patients. EGFRvIII is the most common type of EGFR mutation — seen in approximately 25% of patients — and confers a poor prognosis. Rindopepimut consists of an EGFRvIII peptide sequence conjugated to keyhole limpet hemocyanin. Injected rindopepimut can trigger an immune response that targets EGFRvIII-mutated cells and does not destroy other cells. In the ACT IV trial, patients with newly diagnosed glioblastoma were randomly assigned to receive either intradermal rindopepimut injections and temozolomide, or temozolomide and placebo. According to ClinicalTrials.gov, about 700 patients were enrolled in the study. Overall survival in the rindopepimut arm, as reported in the press release, was 20.4 months, which is comparable to that seen in the Phase II trial of rindopepimut (21.8 months; 65 enrolled participants). However, median overall survival in the control arm was greater (21.1 months). One possible reason for the failure of the trial to show a survival benefit of rindopepimut is that overall survival in the control arm was longer than that in the Phase II trial, in which 74 matched control participants were selected from the RTOG cohort and their median overall survival was only 16.0 months. Despite the negative results in the ACT IV trial, the ReACT trial of rindopepimut in recurrent glioblastoma continues. In ReACT, patients with relapsed glioblastoma are given either rindopepimut in combination with the angiogenesis inhibitor bevacizumab, or bevacizumab alone. Celldex Therapeutics is also continuing Phase I and II cancer immunotherapy combination trials for other types of cancer. Hemi Malkki Trial Watch

Alzheimer disease: Sleep alleviates AD-related neuropathological processes.

Sleep alleviates AD-related neuropathological processes Sleep disturbances have previously been associated with Alzheimer disease (AD) and age-related cognitive decline. Now, three studies have addressed the link between sleep and pathological processes that underlie neurodegeneration and cognitive impairment. Adam Spira and colleagues found that poor sleep quality in older adults was associated with increased brain levels of amyloid-β (Aβ), a well-known AD biomarker. Andrew Lim and co-workers showed that unfragmented sleep could decrease AD incidence and attenuate AD pathology in individuals with the ε4 allele of apolipoprotein E (APOE), which is the bestestablished genetic risk factor for sporadic AD. Connecting with the findings in humans, Maiken Nedergaard and her team discovered that sleep enhanced clearance of Aβ peptide from the brain interstitial fluid in mice. Sleep deprivation has been shown to increase Aβ plaque deposition in a mouse model of AD. In humans, Aβ levels in the cerebrospinal fluid (CSF) vary with the sleep–wake cycle. In a study of 70 community-dwelling older adults from the Baltimore Longitudinal Study of Aging (mean age 76 years), Spira et al. combined data on Aβ burden, as measured by PET scanning, with the participants’ selfreports of sleep duration and quality. The investigators found that individuals who reported shorter sleep duration and poorer sleep quality had higher Aβ burden than participants who reported sleeping well. The researchers note that their study cannot resolve the causality of the relationship between sleep quality and Aβ accumulation. “We need to conduct prospective studies to examine whether poor sleep comes before or after the increase in amyloid deposition,” Spira explains. Furthermore, self-reported sleep quality should be validated against objective measures of sleep. To investigate whether the increased risk of AD associated with APOE ε4 might be influenced by sleep, Lim and colleagues collected APOE genotype data, cognitive testing results and actigraphic recordings from 698 community-dwelling older adults (mean age 82 years) for a follow-up period of up to 6 years. In addition, autopsy data that enabled quantification of Aβ and another hallmark of AD—neurofibrillary tangles—were available from 201 members of the cohort. Lim et al. found that unfragmented sleep could reduce the risk of AD and attenuate age-related cognitive decline and development of neurofibrillary tangles in individuals with the APOE ε4 genotype. “Even among APOE ε4 carriers, there is a subset of individuals with excellent sleep consolidation who may be at a reduced risk of AD, and there is also a subset of individuals with very poor sleep who may be at a particularly high risk of AD,” says Lim. The study in mice by Nedergaard and colleagues represents an important step towards unveiling the neuropathological mechanisms by which sleep disturbances are linked to cognitive impairment. In both wild-type and AD model mice, levels of Aβ peptide in the brain interstitial fluid correlate with time spent awake and decreases during sleep. Nedergaard’s research group had previously described the function of the brain glymphatic system, which clears interstitial proteins through recirculation of CSF, which interchanges with interstitial fluid. The team hypothesized that the energy-consuming transport of fluids and soluble molecules might be affected by the sleep–wake cycle. Nedergaard’s team used fluorescent markers and two-photon imaging in awake, sleeping and anaesthetized mice to follow the transport of brain interstitial fluid and Aβ peptides. To their surprise, they found that the interstitial space in the brain was about 60% larger in sleeping and anaesthetized mice than in awake mice, which increased exchange between CSF and interstitial fluid, thereby enabling moreefficient clearance of neurotoxins from the brain during sleep. Together, these studies shed light on the mechanisms that link sleep disturbance with AD pathophysiology, and suggest that the importance of sleep might relate to its ability to enhance clearance of metabolic waste products from the brain. According to Nedergaard, the findings support the idea that neurologists should take sleep disorders seriously and perhaps treat them more aggressively. Both Lim and Spira suggest that future directions should include intervention trials. “If we find evidence that poor sleep precedes or increases the rate of amyloid deposition in humans, we will need prevention trials to investigate whether we can prevent or slow AD by improving sleep or preventing insomnia,” Spira concludes.

Neurodevelopmental disorders: Human gut microbiota alleviate behavioural symptoms in a mouse model of autism spectrum disorder

Neurodevelopmental disorders: Human gut microbiota alleviate behavioural symptoms in a mouse model of autism spectrum disorder

Alzheimer disease: Chaperone protein clusterin is involved in amyloid-[beta]-associated entorhinal atrophy in early AD

Alzheimer disease: Chaperone protein clusterin is involved in amyloid-β-associated entorhinal atrophy in early AD

Alzheimer disease: NGF gene therapy activates neurons in the AD patient brain

Genetic delivery of nerve growth factor (NGF) could activate neuronal trophic responses in patients with Alzheimer disease (AD), according to results from a phase I clinical trial, published recently in JAMA Neurology. The findings suggest that genetic delivery of growth factors might help prevent or reduce loss of cholinergic neurons in AD. “This is the largest series of humans that have undergone postmortem analysis of the brain to evaluate the effects of growth factors,” says Mark Tuszynski, who led the study. Degeneration of cholinergic neurons is an early and prominent contributor to cell loss and cognitive decline in AD. Previous studies in animal models of AD have shown that NGF can stimulate cholinergic neurons and prevent their death. However, growth factors are a potent class of biologically active proteins, and can cause off-target adverse effects, necessitating a targeted delivery strategy to control their localization and spread in the brain. Tuszynski and colleagues from the University of California, San Diego, USA, used viral vectors for controlled amplification of NGF secretion in the basal forebrains of 10 patients with early AD. After the patients’ deaths—on average, 5.4 years later—their brains were harvested and the effects of NGF gene therapy on cholinergic neurons were evaluated via immunohistochemical analysis. “We found a neuronal growth response to the presence of NGF in every patient,” says Tuszynski. Axons—including those of neurons that exhibited tau pathology—sprouted toward the local source of NGF. The investigators did not observe any adverse pathological effects related to NGF. According to the authors, the degenerating neurons retained an ability to sense and respond to NGF up to 10 years after NGF gene transfer. The safety and consistent, long-lasting effects of NGF gene therapy support expansion of the investigations. A phase II multicentre, shamsurgery-controlled trial of NGF in AD will be completed later in 2015. This trial will also compare the cognitive outcomes of NGF gene therapy and sham surgery in patients with AD.

Neurodevelopmental disorders. Altered epigenetic regulation in early development associated with schizophrenia.

Neurodevelopmental disorders: Altered epigenetic regulation in early development associated with schizophrenia

Multiple sclerosis: Could simvastatin slow down secondary progressive MS?

Statins might provide a safe and inexpensive treatment option for secondary progressive multiple sclerosis (MS), which is currently intractable. According to the results from the MS-STAT phase II trial, published in The Lancet, a high dose of simvastatin—a common hypercholesterolaemia drug with a favourable safety profile—can slow down brain atrophy, which is frequently observed in late-stage MS. Many patients with relapsing–remitting MS will eventually develop a progressive form of the disease, which accounts for most of the disability burden in patients with MS. Although multiple immunomodulatory pharmacotherapies are available for relapsing–remitting MS, no drug has been previously shown to efficiently alleviate the progressive, neurodegenerative form of the disease. A team led by Jeremy Chataway from the National Hospital for Neurology and Neurosurgery (London, UK) randomly assigned 140 patients with late-stage, progressive MS to either placebo or simvastatin (80 mg per day). MRI scans were obtained at baseline, 12 months and 25 months. “Our main measure of success was to reduce the rate of brain atrophy,” explains Chataway. Brain atrophy is considered to be a biological marker for MS progression and disability. In the progressive stage of MS, the brain shrinks by about 0.6% a year. In contrast with placebo-treated patients, those who received a high dose of simvastatin showed a lower annualized atrophy rate of 0.3% a year, indicating a 43% reduction after adjustment for baseline factors such as sex and disability. Although the trial was not designed to test how simvastatin affects clinical outcomes, a small but significant effect on disability scores was observed at the 2-year follow-up: the increase in these scores was smaller in the simvastatin group than in the placebo group, suggesting that simvastatin could alleviate MS-associated disability. “The results present a very encouraging first step towards developing treatment for progressive MS,” comments Chataway. Despite the consistently slower brain atrophy rate in the simvastatin group throughout the study period, no difference was observed in immunological markers. According to Chataway, a non-immunological mechanism of action, possibly through vascular or endothelial functions, could explain the effects of simvastatin in patients with secondary progressive MS. At this stage, the results should be interpreted with caution. “The brain imaging findings might not necessarily translate into clinical benefit,” Chataway remarks. “However, our promising results warrant further investigation in larger, phase III disability-driven trials.”

Epilepsy-burning questions and emerging therapies.

Epilepsy imposes a major burden at both global and individual levels. Worldwide, about 1% of people have epilepsy, and nearly 4% will experience epilepsy at some point during their lifetime. In almost 30% of patients with epilepsy, antiseizure medications do not provide sufficient seizure control. Treatment-resistant epilepsy is a disabling disorder that can dramatically impair quality of life, and is linked with severe morbidities and increased mortality. Surgery is an option only for a minority of patients with refractory epilepsy, and even in disorders amenable to surgical intervention, such as temporal lobe epilepsy, there is a risk of cognitive impairment. Novel therapies for medication-resistant epilepsy are, thus, in high demand. 2013 saw major breakthroughs in epilepsy research: novel genes involved in epilepsy syndromes were discovered, the patterns underlying sudden unexpected death in epilepsy (SUDEP) were elucidated, and translational research paved the way to gene therapy for epilepsy. Nature Reviews Neurology is excited to publish this special Focus on Epilepsy issue, which brings together an ensemble of cutting-edge investigators from leading research institutes around the world to highlight the important challenges and progress in epilepsy research and clinical practice. In the News & Views section, Michael Duchowny and Sanjiv Bhatia discuss the prospects of optimizing surgical intervention in temporal lobe epilepsy to minimize adverse effects on verbal memory, and Elinor Ben-Menachem and Gregory Krauss comment on a new follow-up study that assessed the safety and efficacy of an implantable, responsive neurostimulation device—a treatment approved by the FDA in 2013—in patients with medically intractable epilepsy. Efficient management of epilepsy is particularly important in paediatric patients because of the possible detrimental effects of the uncontrolled seizures on the developing brain. In the Reviews section of this issue, Jo Wilmshurst and colleagues outline the most important challenges in treating infants and children with epilepsy. The scarcity of Class I evidence in paediatric epilepsies remains a problem, and many standard practices are not based on clinical evidence. In 2013, the American Academy of Neurology published an evidence-based guideline update for chronic vagus nerve stimulation. Although vagus nerve stimulation can reduce seizure frequency in many patients with medically retractable epilepsy, electrical brain stimulation has the potential to provide targeted and more-robust seizure control without adverse effects on the vocal apparatus. Robert Fisher and Ana Luisa Velasco review the use of deep brain stimulation in epilepsy, highlighting the most important knowledge gaps. SUDEP remains the leading cause of mortality in patients with refractory epilepsy, with an estimated lifetime risk of 35%, but the awareness of the increased risk of sudden death remains poor among both patients and physicians. Cory Massey and coauthors review the current knowledge of the mechanisms of SUDEP, along with potential interventions and preventive treatments. Over the past few years, an increasing number of epilepsies have been found to have a genetic contribution. Rhys Thomas and Samuel Berkovic review the recent discoveries and urge clinicians to adopt a new paradigm: the proportion of idiopathic epilepsies is much smaller than previously thought, so the possibility of finding a genetic diagnosis should not be overlooked. The bounty of newly discovered epilepsy-related genes, along with decreasing cost of whole-exome sequencing, means that genetic testing and personalized medicine are entering clinical practice. In the Perspectives section, Annapurna Poduri and colleagues discuss the ethical dilemmas related to genetic testing in the epilepsies. Increasing our understanding of the genetic background of epilepsy is just a starting point in finding a cure for this condition. In their Perspectives article, Dimitri Kullmann and colleagues expand the horizon of epilepsy therapies by outlining a roadmap towards clinical trials. We thank UCB for their financial support for producing this Focus on Epilepsy issue. With the sponsor support, all of the Focus articles can be accessed for free until the end of October 2014 at www.nature.com/ nrneurol/focus/epilepsy. With the exception of the Sponsor Feature and Adverts, the content of this supplement has been developed indepen dently of UCB. Nature Publishing Group carries sole responsibility for the editorial content.

Alzheimer disease: increased orexin level correlates with sleep disruption and cognitive decline in Alzheimer disease.

Alzheimer disease: Increased orexin level correlates with sleep disruption and cognitive decline in Alzheimer disease

CNS infections: Mouse studies confirm the link between Zika virus infection and microcephaly

CNS infections: Mouse studies confirm the link between Zika virus infection and microcephaly