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• W2989578503 abstract "As the year 2020 approaches, Alzheimer’s disease research is more generously funded and richly infused with biomarker studies and clinical trials addressing a diversity of therapeutic targets and approaches that move beyond anti-amyloid therapies — to tau, for instance, and to neuroinflammation and neurodegeneration — than it was a decade ago. Although amyloid remains a common target of phase 2 and phase 3 disease-modification clinical trials for Alzheimer’s disease — which may still prove fruitful, according to several leaders in the field — the tide has turned toward earlier intervention. “Almost all of the clinical trials using amyloid drugs have been in people who already have some level of cognitive decline,” in whom, it is now appreciated, the pathological process of Alzheimer’s disease has long been underway, said Keith N. Fargo, PhD, director of scientific programs and outreach for the Alzheimer’s Association. “Now, a major outstanding question is whether or not treatment with an anti-amyloid drug would be beneficial in people who don’t already have symptoms.” Eyes are on the ongoing Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study — the first “secondary prevention” trial in clinically normal older individuals who have been identified as at-risk for Alzheimer’s dementia based on positron-emission tomography (PET) images showing elevated levels of brain amyloid. (Other secondary prevention trials are being conducted in genetically at-risk cohorts, such as the Dominantly Inherited Alzheimer Network, or DIAN, study.) The placebo-controlled, 60-site A4 study is testing the impact of solanezumab (a humanized monoclonal antibody that targets the build-up of amyloid in the brain) on a composite of well-validated neuropsychological tests that are sensitive for tracking a decline from “normal” to subtly impaired cognitive performance. In addition to this primary outcome, measured every six months, the more than 1,100 patients enrolled in the multicenter trial take cognitive tests on an iPad on intervening three months (at nine months, 15 months, etc). Investigators decided about two years ago to quadruple the dose of the drug based on new study results from Eli Lilly, and to extend the trial (which had launched in 2014) out to four-and-a-half years. Additional funding from the National Institute of Aging (NIA) has also allowed an open-label extension period starting early this year. “This was thrilling, because it wasn’t clear at the beginning that we’d be able to do that,” said Reisa A. Sperling, MD, coprincipal investigator of the A4 trial and director of the Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital in Boston. “Everyone is now able to get the drug once they’ve finished the double-blind phase of the trial.” Dr. Sperling said the results are expected in 2022. Dr. Sperling and her coprincipal investigator, Paul Aisen, MD, of the University of Southern California’s Alzheimer’s Therapeutic Research Institute, envision the A4 trial design serving as a platform for additional secondary prevention trials with other anti-amyloid agents — and eventually for combinations of drugs. Up next — starting in 2020, they hope — is a trial of the investigational BAN2401 antibody (Eisai Co.), which targets small pieces of amyloid called protofibrils. The drug is currently being evaluated in a phase 3 clinical trial in patients with early symptomatic Alzheimer’s disease.Aducanumab Trial RevivedSeveral trials of experimental anti-amyloid drugs were halted this year, most notably aducanumab for a projected lack of efficacy in slowing cognitive impairment in a futility analysis. Aducanumab, a humanized monoclonal antibody, had been shown in earlier trials to clear amyloid plaques from the brain. It was being tested in large phase 3 trials of patients in the early symptomatic phase of disease. Biogen, the manufacturer of aducanumab, announced in October that further analyses had suggested some efficacy at higher doses and that it would file for regulatory approval in early 2020. Several trials of experimental anti-amyloid drugs were halted this year, most notably aducanumab for a projected lack of efficacy in slowing cognitive impairment in a futility analysis. Aducanumab, a humanized monoclonal antibody, had been shown in earlier trials to clear amyloid plaques from the brain. It was being tested in large phase 3 trials of patients in the early symptomatic phase of disease. Biogen, the manufacturer of aducanumab, announced in October that further analyses had suggested some efficacy at higher doses and that it would file for regulatory approval in early 2020. “My hope [for this new trial] is that we can get the [minimum] age down to 55 years instead of 65 [as in the A4 trial],” Dr. Sperling said. The results of an almost 15-year-old “big push” at the NIA to diversify the therapeutic pipeline are increasingly evident in the institute’s Alzheimer’s disease clinical trials research portfolio, said Laurie Ryan, PhD, chief of the Dementias of Aging Branch of the NIA. “Even if anti-amyloid treatments prove to be successful in early stages, it won’t be the only thing we need. Ultimately, Alzheimer’s-related dementia is like other complex diseases — more of a syndrome, with multiple pathways,” Dr. Ryan said. “Researchers are still looking at amyloid as a target, but using different approaches. They’re also looking at tau, oxidative stress, alpha-synuclein, and neuro-inflammation, for example … and cell therapies like neural stem cell transplantation” as well as agents aimed at promoting synaptic plasticity and protecting against neurodegeneration, she said. The ongoing clinical trials in such areas are largely phase 1 and early phase 2 trials, she said. As an example, Dr. Ryan referenced an ongoing phase 2a trial of a small molecule compound called LM11A-31 (PharmatrophiX), which targets the p75 neurotrophin receptor. Earlier research in late-stage Alzheimer’s mice showed reversals in the loss of synaptic connections and declines in neural degeneration. The grant awards portfolio of the Alzheimer’s Association similarly includes numerous grants targeting neurodegeneration, such as funding for a phase 2a study looking at the hormone allopregnanolone as a regenerative therapeutic, and a phase 2a trial of the experimental neurotrophic activator NDX-1017, which has been shown in preliminary research to stimulate brain cell growth and survival. Neuroinflammation is also “a “huge new area of research for us,” said the association’s Dr. Fargo. “We’re learning more about its role in Alzheimer’s practically by the day, and we think there’s enormous potential there.”“If we had a blood test that we could do before we’d do the PET scan, we could save a lot of money and exposure in figuring out who’s at greater risk and who isn’t.”— Reisa Sperling, MD Other innovative targets and methods currently being investigated in clinical trials include inhaled insulin and a drug that targets proteins released in the brain by Porphyromonas gingivalis. Recently presented 18-month data from a phase 2/3 trial of inhaled insulin in people with mild cognitive impairment or mild Alzheimer’s (12 months, followed by a 6-month open-label extension) showed statistically significant improvements in cognitive test scores — as well as improvement in the amyloid beta 42/40 ratio and the amyloid beta 42/tau ratio in the cerebrospinal fluid (CSF), both of which are regarded as important biomarkers of Alzheimer’s-related pathology in the brain. The study used two different inhalers, one of which led to these positive outcomes after originally malfunctioning. Co-lead investigator Suzanne Craft, PhD, of the Wake Forest School of Medicine in Winston-Salem, NC, who presented the results at this year’s Alzheimer’s Association International Conference (AAIC 2019), said the benefits of insulin — in enhancing communication between neurons, for instance, as well as increasing the brain’s blood flow and protecting against abnormal beta-amyloid and tau — are clear. Now, she said, the delivery techniques must be fine-tuned. “We now need to validate our study results in a phase 3 study with a device that has demonstrated efficacy in reaching the central nervous system,” she said in an email communication. The drug targeting toxic virulence factors secreted by P. gingivalis (bacteria that can cause chronic progressive degenerative gum disease) is being evaluated in people with mild to moderate Alzheimer’s in a recently initiated phase 2/3 trial. Patients enrolled in the GingipAIN Inhibitor for Treatment of Alzheimer’s Disease (GAIN) trial will be randomized to one of two doses of the investigational agent COR388 (Cortexyme) or placebo for 48 weeks. As reported at AAIC 2019, people taking the drug in a phase 1b trial had approximately 30% lower levels of inflammation, as measured by the inflammatory biomarker RANTES, over 28 days of treatment, and 30% lower levels of fragmented proteins in the CSF. P. gingivalis has been identified in the brains of over 90% of people across multiple studies (Sci Adv 2019:5:eaau3333). Regarding tau as a target, there are a number of ongoing trials of anti-tau therapies, mostly in the phase 2 stage. A 2019 Alzheimer’s disease drug pipeline review led by Jeffrey Cummings, MD, of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, NV, shows that of 96 agents in disease modification trials, 40% have amyloid as the primary target or part of a combination target, and 18% have tau as a primary or combination target. Of the tau agents under investigation, seven are small molecules, and 10 are biologics (Alzheimers Dement 2019;5:272–293). “Right now,” Dr. Sperling noted, “all of the trials of anti-tau agents are in symptomatic Alzheimer’s disease. Our work in the Harvard Aging Brain Study has shown that tau builds up earlier than we’ve thought … it appears to shoot up right at the point that people start to get symptoms. So I think the anti-tau agents should also be tried very early.” Repurposing drugs that have already been deemed safe for use in other conditions is another priority in Alzheimer’s research, Dr. Fargo and Dr. Ryan both noted. A low-dose formulation of the antiepileptic drug levetiracetam, for instance, is being tested in a phase 3 trial in patients with mild cognitive impairment. “There’s a theory that hyperactivity or excitability in the brain, not seizure activity, contributes to driving amyloid and tau pathology,” Dr. Ryan said. “This particular anti-epileptic has some slightly different mechanisms of action that may [help with this].” Efforts to characterize and develop biomarkers “are a major thrust in the field right now,” said Ronald C. Petersen, MD, PhD, director of the Mayo Clinic’s Alzheimer’s Disease Research Center in Rochester, MN, and of the Mayo Clinic Study of Aging. He and others are homing in not only on amyloid and tau, but also on small vascular changes in the brain and on other proteins that are “misfolded” or misprocessed across degenerative brain diseases. These proteins include alpha-synuclein, a major constituent of Lewy bodies, and TDP-43, which contributes to hippocampal atrophy. Neuroimaging technologies and blood assays — and some CSF testing — are under investigation. “The biomarker work and therapeutic work go hand-in-glove,” Dr. Petersen said. Biomarkers help shape new clinical trials, “allow us to intervene earlier in the suspected pathologic cascades of events,” and ultimately will help shape personalized, combination approaches to cognitive impairment, he said. It seems increasingly likely that researchers will soon have a plasma biomarker to screen cognitively normal people for brain amyloidosis — a development that Dr. Ryan said “would be the next huge leap” since amyloid PET scanning became available. Randall J. Bateman, MD, of the Washington University School of Medicine in St. Louis, MO, and his coinvestigators reported this year that plasma beta-amyloid 42/40, detected via high-precision assay, correlated highly with amyloid PET status (receiver operating characteristic area under the curve [AUC], 0.88). The AUC went up to 0.94 when plasma beta-amyloid 42/40 was combined with age and apolipoprotein E4 status. Moreover, those who were negative for amyloid on PET imaging at baseline but had a positive plasma assay had a 15-fold greater risk of converting to amyloid PET-positivity than those who had negative plasma assays, the investigators reported. The 158 patients in the study were mostly cognitive normal (Neurology 2019;93:e1647–1659). “If we had a blood test that we could do before we’d do the PET scan, we could save a lot of money and exposure in figuring out who’s at greater risk and who isn’t,” Dr. Sperling said. Although cognition is the main outcome of her A4 trial, the study is at the forefront of Alzheimer’s research in that it’s also collecting biomarker and imaging outcomes that could be useful in the future (for instance, magnetic resonance imaging; CSF measures of amyloid, tau, and phosphor-tau in a subset; and tau-PET imaging in a subset using a new ligand). Moreover, the A4 study is attempting to shed more light on the role of amyloid and nonamyloid factors in cognitive decline. A natural history observational arm of the A4 study — the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) cohort — involves about 500 individuals who “screen-failed” the main A4 study because they didn’t show elevated amyloid on PET screening. They’re undergoing many of the same cognitive, imaging, and biomarkers assessments as the treatment arm.Alzheimer’s Association TrialMatch® allows users to generate a list of ongoing clinical trials of both pharmacological and nonpharmacological interventions. To learn more, visit https://www.alz.org/alzheimers-dementia/research_progress/clinical-trials/about-clinical-trials. The A4 study is also “the first study of the gate” to abide by new data-sharing requirements for studies that are funded through the NIA and conducted through its Alzheimer’s Clinical Trial Consortium, formed in 2017 to speed research, Dr. Ryan said. All clinical and imaging screening data are publicly available, and the full data set from the A4 treatment arms and the LEARN cohort will be shared after the primary analyses are completed at the end of the trial. An increasing focus on open science atop significant public–private partnerships and a more than fivefold increase in federal funding for Alzheimer’s research since 2012 (to approximately $2.3 billion in 2019) is enabling research in diverse directions, sources said. “We have to figure out how to learn as much as possible more quickly. I’m optimistic, but I’m feeling pressured that we must go faster,” Dr. Sperling said. Christine Kilgore is a freelance writer based in Falls Church, VA." @default.
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• W2989578503 title "From Inhaled Insulin to Oral Bacteria: Ongoing Clinical Trials of Alzheimer’s Disease Biomarkers, Therapeutic Targets Show Promise" @default.
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