Intranasal Insulin, Empagliflozin Have Promising Effects on Cognition

In continuation of my update Empagliflozan

Intranasal insulin (INI) and empagliflozin are safe and have promising effects on cognition, according to a study published online Oct. 7 in Alzheimer's & Dementia.

Jennifer M. Erichsen, from the Wake Forest University School of Medicine in Winston-Salem, North Carolina, and colleagues conducted a phase 2, 2x2 factorial double-blinded randomized trial involving 47 participants with mild cognitive impairment or early Alzheimer disease or who were amyloid-positive. Participants received INI, the sodium-glucose cotransporter-2 inhibitor empagliflozin, both, or placebo for four weeks. Treatment-related adverse events were examined as the primary outcome.

The researchers found that for all groups, treatment-related adverse events were mild and similar. They also found an increase in modified Preclinical Alzheimer's Cognitive Composite-5, modulated fractional anisotropy and cerebral blood flow, and reduced plasma glial fibrillary acidic protein with INI. Lower cerebrospinal fluid tau and modulated cerebral blood flow were seen with empagliflozin. Immune/inflammatory/neurovascular markers were moderated by both agents.

"For the first time, we found that empagliflozin, an established diabetes and heart medication, reduced markers of brain injury while restoring blood flow in critical brain regions. We also confirmed that delivering insulin directly to the brain with a newly validated device enhances cognition, neurovascular health and immune function. Together, these findings highlight metabolism as a powerful new frontier in Alzheimer's treatment," coauthor Suzanne Craft, Ph.D., also from the Wake Forest University School of Medicine, said in a statement.

Aptar Pharma provided the intranasal delivery devices.

Abstract/Full Text (subscription or payment may be required)

Intranasal Insulin, Empagliflozin Have Promising Effects on Cognition 

GLP-1 diabetes drugs likely trump metformin for curbing dementia risk in type 2 diabetes, study finds

In continuation of my update  "Metformin"

GLP-1 receptor agonists, a class of drug used to treat type 2 diabetes, likely trump the widely prescribed metformin for curbing dementia risk in people with the condition, finds the largest study of its kind, published in the open access journal BMJ Open Diabetes Research & Care.

The findings suggest that future clinical guidelines for the treatment of type 2 diabetes would do well to consider prioritizing drugs with both blood glucose and neuroprotective effects, say the researchers.

Published research suggests that both GLP-1 receptor agonists and metformin, which are widely used to treat type 2 diabetes, protect the brains of people with the disease. But as yet there have been no direct real-world comparisons of the potential impact of these drugs on dementia risk—a risk that is around 70% higher in people with type 2 diabetes.

To explore this further, the researchers drew on anonymized electronic health records from a global health research network (Trinetx) spanning the period 2004 to 2024 to track the development of dementia in patients with type 2 diabetes, treated with either GLP-1 receptor agonists or metformin (87,229 patients in each group; average age 58) for at least six consecutive months.

There was no significant difference in vascular dementia risk between the two types of drug when used as first line therapy.

But GLP-1 receptor agonist use was associated with a significantly lower cumulative (10%) risk of developing dementia, overall, with an incidence of almost 2.5% (2,130 people) compared with an incidence of nearly 5% (4,215 people) for metformin.

And specifically, taking this type of drug was associated with a 12% lower risk of developing Alzheimer's disease, and a 25% lower risk of developing non-vascular dementias than metformin use.

Further in-depth analyses showed that these positive effects were evident across all age groups, but with the strongest effect among the over 60s, women, and those of white ethnicity.

Risk of death from any cause was also lower: nearly 5% of those treated with GLP-1 receptor agonists died compared with nearly 9% of those treated with metformin.

"Both medications demonstrate neuroprotective properties, such as reducing neuroinflammation and oxidative stress, improving insulin sensitivity, and enhancing cerebrovascular health, which likely contribute to their benefits in overall dementia," explain the researchers.

But unlike metformin, whose benefits primarily derive from systemic metabolic effects, GLP-1 receptor agonists exert direct central nervous system effects by crossing the blood-brain barrier, they add.

"However, the multifactorial nature of [vascular dementia], driven by cerebrovascular damage, such as small vessel disease and white matter lesions, poses significant challenges for pharmacological interventions targeting metabolic or neurodegenerative pathways," they continue.

This is an observational study, and as such, no firm conclusions can be drawn about cause and effect. And the researchers point out that the tracking period, while sufficient for observing dementia outcomes, may not fully capture long-term cognitive effects, especially given the progressive nature of Alzheimer's disease.

But they nevertheless conclude, "Given the severe societal, familial, and economic burden of diabetes-related dementia, these findings raise important considerations about the role of GLP-1 [receptor agonists] as first-line therapies in [type 2 diabetes] management.

"While further long-term studies are warranted to validate these results, integrating GLP-1 [receptor agonists] as primary therapeutic agents may represent a paradigm shift in preventing the cognitive complications of diabetes."

Ref: https://en.wikipedia.org/wiki/Metformin

Daily Multivitamin May Protect Against Cognitive Decline in Older Adults

In continuation of my update on Vitamin and their importance 

A daily multivitamin may provide cognitive benefits for older adults, according to a study published online Sept. 14 in Alzheimer’s & Dementia.

Laura D. Baker, Ph.D., from the Wake Forest University School of Medicine in Winston-Salem, North Carolina, and colleagues assessed whether daily use of cocoa extract (containing 500 mg/day flavanols) versus placebo and a commercial multivitamin-mineral (MVM) versus placebo improved cognition in 2,262 older women and men (mean age, 73 years).

The researchers found that cocoa extract had no effect on global cognition. However, compared with placebo, daily MVM supplementation resulted in a statistically significant benefit on global cognition, with a more pronounced effect seen in participants with a history of cardiovascular disease. Benefits of MVM were also seen for memory and executive function. There were no significant interactions observed between cocoa extract and MVM for any of the cognitive composites.

"Our study showed that although cocoa extract did not affect cognition, daily multivitamin-mineral supplementation resulted in statistically significant cognitive improvement. This is the first evidence of cognitive benefit in a large longer-term study of multivitamin supplementation in older adults," Baker said in a statement. "It's too early to recommend daily multivitamin supplementation to prevent cognitive decline. While these preliminary findings are promising, additional research is needed in a larger and more diverse group of people."

Ref : Daily Multivitamin May Protect Against Cognitive Decline in Older Adults 

Alzheimer's disease drug may help fight against antibiotic resistance

In continuation of my update on PBT2

Researchers from The University of Queensland, The University of Melbourne and Griffith University have discovered that the drug called PBT2 is effective at disrupting and killing a class of bacteria -- known as Gram-negative bacteria -- that cause infections such as pneumonia, bloodstream infections and meningitis.

UQ's Professor Mark Walker said the metal transport drug may offer a last line of defence against some of the world's most difficult to treat superbugs.

"The emergence of antibiotic-resistant superbugs is an urgent threat to human health, undermining the capacity to treat patients with serious infection," Professor Walker said.

"Alternative strategies to treat such multi-drug resistant bacteria are urgently needed.

"Led by UQ's Dr David De Oliveira, our team hypothesised that, by using this experimental Alzheimer's treatment to disrupt the metals inside these bacteria, we would also disrupt their mechanisms of antibiotic resistance.

"This was shown to be the case, with the Alzheimer's drug -- combined with the antibiotic polymyxin -- successfully tackling antibiotic-resistant superbugs like Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Escherichia coli."

Griffith University's Professor Mark von Itzstein AO from the Institute for Glycomics said the new treatment was effective, and offered a range of other benefits.

"Based on its use as an experimental Alzheimer's treatment, there's been a significant amount of solid science done on this drug already," Professor von Itzstein said.

"We know, for example, that clinical studies of PBT2 show that it is safe for use in humans.

"And, given that we've been able to combine it with the antibiotic polymyxin to treat polymyxin-resistant bacteria, we may be able to make other now-ineffective antibiotics become effective again for treating infectious diseases.

"This could resharpen, so to speak, some of the weapons we thought we'd lost in our fight against antibiotic-resistant bacteria."

The University of Melbourne's Associate Professor Christopher McDevitt, from the Peter Doherty Institute for Infection and Immunity (Doherty Institute), said the drug had already proved effective beyond the petri dish.

"Animal studies show that the combination of polymyxin and PBT2 kills polymyxin-resistant bacteria, completely clearing any infection," Associate Professor McDevitt said.

"Hopefully in the not-too-distant future people will be able to access this type of treatment in the clinic.

"New techniques are critical in addressing this building threat to human health, and this treatment is an additional weapon in our arsenal to fight the accelerating threat of antibiotic resistance.

"If these new solutions aren't developed, it's estimated that by 2050, antimicrobial-resistant bacteria will account for more than 10 million deaths per year.

"This new treatment could help turn the tide on antibiotic resistance."

https://en.wikipedia.org/wiki/PBT2

Plant flavonols significantly reduce Alzheimer’s risk

A new study published in the journal Neurology in January 2020 concludes that increasing the intake of plant flavonols steeply reduces the risk of Alzheimer’s dementia (AD) by up to a half. In other words, AD could be prevented in many people simply by regularly eating and drinking more foods containing these compounds such as tea, oranges, and broccoli.

Alzheimer’s disease

AD is a progressive brain disorder in which the individual loses cognitive skills, including memory and thinking skills, and the ability to perform simple tasks. It is by far the leading cause of such disorders and affects over 5 million Americans.

One study was carried out on over 900 people, who were part of a community-wide ongoing larger research project called the Rush Memory and Aging (MAP) Project. These participants were assessed yearly for their neurologic health and dietary patterns, for an average of 6 years, but some for as long as 12 years. The average age was 81 years, and 3 out of 4 were female.

The findings

In the first study, 220/921 participants developed AD during the study. The risk of AD fell with a greater intake of flavonols. This finding held good even after the researchers adjusted for other health-associated factors – because those with the highest total flavonol intake were also the best educated, most active and took part in more cognitive activities. They also accounted for genetic factors like the presence of the APOE4 gene, and for cardiovascular risk factors that could influence the risk of AD, such as diabetes mellitus, history of heart attack, or stroke, or hypertension.

When classified into five groups based on decreasing flavonol intake, the participants in the first group (highest intake) consumed over 15 mg of flavonols a day. Compared to those in the lowest fifth (about 5 mg a day), these individuals showed an approximately 50% reduction in AD risk.

In concrete terms, 28 of 186 patients in the highest-intake group developed AD, vs. 54 of 182 in the lowest-intake group.

With respect to individual flavonols, kaempferol intake was linked to a reduction of almost 50%, and both myricetin and isorhamnetin by 40% each. A fourth flavonol, called quercetin, had no noticeable effect on AD risk.

Participants with the highest flavonol intake drank about one cup of black tea a day. Kale, and about a glass of red wine each day, could also supply flavonols.

Sources of flavonols

Kaempferol is richly present in green leafy vegetables, including spinach, broccoli, beans, tea and kale – and also in tea. Isorhamnetin-rich foods include olive oil, red wine, pears and tomato sauce. Myricetin is found in tea, kale, oranges, tomatoes and red wine.

Researcher Thomas Holland says, “More research is needed to confirm these results, but these are promising findings. Eating more fruits and vegetables and drinking more tea could be a fairly inexpensive and easy way for people to help stave off Alzheimer's dementia.”

Implications

Many scientists disagree with the emphasis on flavonols. Though these were thought to have antioxidant activity in the body, this theory was discredited many decades earlier. Antioxidant activity ceases when they are ingested and subjected to the activity of enzymes in the digestive tract.

They point out that flavonols are found in many plants, fruits and vegetables, which have been associated with good health for centuries. Nutritionists say that the AD-delaying effects of such foods are likely due to other plant chemicals which are relatively more abundant. On the other hand, taking flavonol pills or tea extracts is unlikely to produce the same healthful effect, and overdoses could be counterproductive.

This is not to say that eating more flavonol-rich foods or drinking a cup of black tea in the morning would hurt, since any foods containing these chemicals would also contain many more healthful compounds including vitamins, minerals and plant fiber. Holland makes a valid point with his conclusion: “'With the elderly population increasing worldwide, any decrease in the number of people with this devastating disease, or even delaying it for a few years, could have an enormous benefit on public health.”

https://n.neurology.org/content/early/2020/01/29/WNL.0000000000008981

Plant flavonols significantly reduce Alzheimer’s risk

New compound prevents amyloid formation to fight Alzheimer’s disease

It is known that Alzheimer’s disease is caused by the formation of amyloid plaques and tau tangles in the brain. A novel compound shows promise in preventing amyloid formation, fighting Alzheimer’s disease development.

       

Alzheimer’s disease (AD) is the most common form of dementia, affecting about 50 million people worldwide. In the United States, 5.5 million people are living with neurodegenerative diseases, making it the 6th leading cause of death in the country.

AD is caused by the abnormal build-up of proteins, amyloid, and tau, in and around the brain. These proteins form plaques and tangles in brain cells, leading to memory loss and other symptoms. Abnormal proteins form toxic clumps, dubbed as fibrils, inside the brain, affecting brain regions that are vital for brain processes.

In the study published in the journal Chemical Communications by the Royal Society of Chemistry, reveals that the new compound, known as “C1”, can prevent the enzyme gamma-secretase from producing amyloids.

What is the role of C1?

Amyloid fibrils are made of peptide amyloid-beta, produced when certain enzymes make cuts to the amyloid precursor protein, which is found in the brain cell membrane. A type of covalent gamma-secretase inhibitor, the compound works by blocking the active site of the enzyme, hence, preventing the formation of amyloid.

The team of researchers at the Center for Biotechnology and Interdisciplinary Studies (CBIS) at Rensselaer Polytechnic Institute noted that there were samples of gamma-secretase inhibitors in the past, but these failed since they have severe side effects. What happened is, the inhibitors used stopped all the functions of gamma-secretase.

“Our compound binds to the cleavage site of the precursor protein instead of the enzyme itself, which may avoid many problems associated with traditional enzyme inhibitors,” Chunyu Wang, a professor of biological sciences and author of the study, said.

The team started to screen drugs to determine a potential compound that can target the amyloid precursor protein substrate, blocking the gamma-secretase activity that is tied to amyloid production. Using a computer model, they tested millions of compounds in the hopes of finding the one that can show promise in battling Alzheimer’s disease.

Though there were several candidates found, C1 showed high accuracy and effectiveness in cell cultures and test tubes. The patent for the compound is still pending but the researchers hope that the new drug can be studied more to determine its efficacy in people at a high risk of developing Alzheimer’s disease.

Implications of the compound

The discovery of the novel compound can pave the way for the development of new drugs that can prevent and treat Alzheimer’s disease. The new approach targets the disease, based on tis principal pathology.

Currently, there is no cure for Alzheimer’s disease and the treatment revolves around providing a safe environment for patients. Therapy is also effective in providing support, but scientists are racing to finally find a medicine for the condition.

What is Alzheimer’s disease?

Alzheimer’s disease is a type of dementia, which is a neurodegenerative disease. The disease is irreversible and progressive, which means that it worsens over time. The condition affects brain sections responsible for memory, thinking skills, and cognitive ability. In time, the symptoms worsen, often causing the inability to carry out the simplest tasks or activities of daily living.

The disease first appears in people who are in their mid-60s but can emerge earlier in some cases. Scientists don’t fully understand the exact cause of Alzheimer’s disease, but it may be a combination of various factors. These include age, since older adults are mostly affected, and hereditary because it can run in families. There is also evidences that changes in the brain starting even years before the start of the symptoms may have occurred.

https://pubs.rsc.org/en/Content/ArticleLanding/2020/CC/C9CC09170J#!divAbstract

New compound prevents amyloid formation to fight Alzheimer’s disease

Study: Antioxidant flavonol linked to lower risk of Alzheimer's dementia

In continuation of my update on kaempferol, myricetin and  quercetin

 

                                                                 kaempferol

                                                                       

                                                                      myricetin

                                                 

                                                                          Quercetin

        

People who eat or drink more foods with the antioxidant flavonol, which is found in nearly all fruits and vegetables as well as tea, may be less likely to develop Alzheimer's dementia years later, according to a study published in the January 29, 2020, online issue of Neurology, the medical journal of the American Academy of Neurology.

"More research is needed to confirm these results, but these are promising findings," said study author Thomas M. Holland, MD, of Rush University in Chicago. "Eating more fruits and vegetables and drinking more tea could be a fairly inexpensive and easy way for people to help stave off Alzheimer's dementia. With the elderly population increasing worldwide, any decrease in the number of people with this devastating disease, or even delaying it for a few years, could have an enormous benefit on public health."

Flavonols are a type of flavonoid, a group of phytochemicals found in plant pigments known for its beneficial effects on health.

The study involved 921 people with an average age of 81 who did not have Alzheimer's dementia. The people filled out a questionnaire each year on how often they ate certain foods. They were also asked about other factors, such as their level of education, how much time they spent doing physical activities and how much time they spent doing mentally engaging activities such as reading and playing games.

The people were tested yearly to see if they had developed Alzheimer's dementia. They were followed for an average of six years. The researchers used various tests to determine that 220 people developed Alzheimer's dementia during the study.

The people were divided into five groups based on how much flavonol they had in their diet. The average amount of flavonol intake in US adults is about 16 to 20 milligrams per day. In the study, the lowest group had intake of about 5.3 mg per day and the highest group consumed an average of 15.3 mg per day.

The study found that people in the highest group were 48 percent less likely to later develop Alzheimer's dementia than the people in the lowest group after adjusting for genetic predisposition and demographic and lifestyle factors. Of the 186 people in the highest group, 28 people, or 15 percent, developed Alzheimer's dementia, compared to 54 people, or 30 percent, of the 182 people in the lowest group.

The results were the same after researchers adjusted for other factors that could affect the risk of Alzheimer's dementia, such as, diabetes, previous heart attack, stroke and high blood pressure.

The study also broke the flavonols down into four types: isorhamnetin, kaempferol, myricetin and quercetin. The top food contributors for each category were: pears, olive oil, wine and tomato sauce for isorhamnetin; kale, beans, tea, spinach and broccoli for kaempferol; tea, wine, kale, oranges and tomatoes for myricetin; and tomatoes, kale, apples and tea for quercetin.

People who had high intake of isorhamnetin were 38 percent less likely to develop Alzheimer's. Those with high intake of kaempferol were 51 percent less likely to develop dementia. And those with high intake of myricetin were also 38 percent less likely to develop dementia. Quercetin was not tied to a lower risk of Alzheimer's dementia.

Holland noted that the study shows an association between dietary flavonols and Alzheimer's risk but does not prove that flavonols directly cause a reduction in disease risk.

Other limitations of the study are that the food frequency questionnaire, although valid, was self-reported, so people may not accurately remember what they eat, and the majority of participants were white people, so the results may not reflect the general population.

https://en.wikipedia.org/wiki/Myricetin

https://en.wikipedia.org/wiki/Quercetin

https://medicalxpress.com/news/2019-07-high-hemoglobin-linked-dementia.html

Suvorexant May Improve Insomnia With Alzheimer Disease

In continuation of my update on Suvorexant

Suvorexant improves total sleep time (TST) in patients with probable Alzheimer disease (AD) dementia and insomnia, according to a study published online Jan. 15 in Alzheimer's & Dementia.

W. Joseph Herring, M.D., Ph.D., from Merck & Co., in Kenilworth, New Jersey, and colleagues randomly assigned patients with both probable AD dementia and insomnia to four weeks of suvorexant 10 mg (136 patients; could be increased to 20 mg based on clinical response) or placebo (141 patients). Overnight polysomnography in a sleep laboratory was used to assess TST.

The researchers found that at week 4, the mean improvement from baseline in TST was 73 minutes for the suvorexant group and 45 minutes for the placebo group. Patients taking suvorexant were twice as likely to show an improvement of ≥60 minutes in TST compared with those taking placebo. In suvorexant-treated patients, somnolence was reported by 4.2 percent of participants versus 1.4 percent of placebo-treated patients.

"Suvorexant did not appear to impair next-day cognitive or psychomotor performance as assessed by objective tests, although these assessments do not constitute a comprehensive assessment of cognition," the authors write.

Several authors disclosed financial ties to pharmaceutical companies, including Merck, which manufactures suvorexant and funded the study.

https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/alz.12035

https://en.wikipedia.org/wiki/Suvorexant

Study first to show pharmacological chaperone therapy prevents Alzheimer's in mice

Like pieces of tape that crumple, stick together, and can be turned into a ball, proteins that begin to lose their shape become sticky and tend to clump together. When this happens, rather than being transported to recycling sites within cells, old or dysfunctional proteins instead become trapped within cellular compartments. Eventually, they accumulate to the point that they gum up cellular machinery, causing major problems.

Fortunately, cells are equipped with molecular machinery that detects defective proteins, sorts them out, and then either removes or stabilizes them, preventing them from accumulating and causing harm. In recent years, scientists have developed small drug molecules, known as pharmacological chaperones, that can help in this process.

Now, scientists at the Lewis Katz School of Medicine at Temple University show that pharmacological chaperones could fill a critical role in Alzheimer's disease therapy. In a new study published online January 21 in the journal Molecular Neurodegeneration, they describe a novel pharmacological chaperone capable of preventing Alzheimer's disease in animals prone to developing the condition.

The study is the first to show that a pharmacological chaperone drug can effectively disrupt the abnormal processes that damage neurons in the brain, fuel memory loss, and ultimately give rise to Alzheimer's disease.

"Our chaperone drug specifically restored levels of a sorting molecule known as VPS35, which helps move proteins out of endosomes, compartments inside cells where proteins are sorted for degradation," explained Domenico Praticò, MD, the Scott Richards North Star Charitable Foundation Chair for Alzheimer's Research, Professor in the Departments of Pharmacology and Microbiology, and Director of the Alzheimer's Center at Temple in the Lewis Katz School of Medicine. Dr. Praticò was a senior investigator on the new study.

The trafficking of proteins from endosomes to the cell membrane or to another cellular compartment known as the Golgi apparatus is fundamental for normal cell function. VPS35 is of particular importance to this trafficking system since it separates out dysfunctional and old proteins and sends them off for recycling.

In previous work, Dr. Praticò and colleagues found that VPS35 actively clears the brain of potentially harmful proteins such as amyloid-beta and tau. However, in Alzheimer's disease, VPS35 levels are reduced. This reduction is associated with the formation of tau tangles inside neurons, as well as the accumulation of amyloid-beta outside neurons. Eventually, these deposits of abnormal proteins interrupt neuron activity and contribute to neurodegenerative disorders, including Alzheimer's disease.

In the new study, the researchers investigated the effects of a pharmacological chaperone on protein sorting in mice engineered to develop Alzheimer's disease as they age. Mice were treated from a young age, before they began to show signs of disease. As the animals grew older, they were tested for effects on memory and learning.

Dr. Praticò's team found that, compared to untreated mice destined for Alzheimer's disease, the treated animals had much better memory and behaved just like normal, or wild-type, mice. When the researchers examined neurons from treated mice, they observed significant decreases in tau tangles, as well as decreases in amyloid-beta plaques—another type of protein aggregate that contributes to Alzheimer's disease. The researchers further noticed that VPS35 levels were restored and the junctions where neurons come together to exchange information, known as synapses, were fully functional following the pharmacological chaperone therapy.

"Relative to other therapies under development for Alzheimer's disease, pharmacological chaperones are inexpensive, and some of these drugs have already been approved for the treatment of other diseases," Dr. Praticò said. "Additionally, these drugs do not block an enzyme or a receptor but target a cellular mechanism, which means that there is much lower potential for side effects. All these factors add to the appeal of pursuing pharmacological chaperone drugs as novel Alzheimer's treatments."

Before moving to trials in human patients, however, Dr. Praticò plans to next investigate the effects of pharmacological chaperone therapy in older mice. "Because our most recent investigation was a preventative study, we want to know now whether this therapy could also work as a treatment for patients already diagnosed with Alzheimer's disease," he added.

https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-019-0350-4

https://en.wikipedia.org/wiki/Pharmacological_chaperone

https://en.wikipedia.org/wiki/VPS35

Study first to show pharmacological chaperone therapy prevents Alzheimer's in mice

Eisai and Imbrium Therapeutics Announce U.S. FDA Filing Acceptance of New Drug Application for Lemborexant for the Treatment of Insomnia

In continuation of my update on lemborexant

Eisai Co., Ltd. (CEO: Haruo Naito, “Eisai”) and Imbrium Therapeutics L.P. (Imbrium Therapeutics), a clinical-stage biopharmaceutical company and operating subsidiary of Purdue Pharma, L.P. (President and CEO: Craig Landau, MD),  announced that the U.S. Food and Drug Administration (FDA) has accepted for review the New Drug Application (NDA) for lemborexant, an investigational agent being studied for the treatment of insomnia, a sleep-wake disorder. A Prescription Drug User Fee Act (PDUFA) date is set for December 27, 2019.

The NDA submission was based on data from the clinical development program including two pivotal Phase 3 studies of lemborexant – SUNRISE 1 (Study 304) and SUNRISE 2 (Study 303).

• SUNRISE 1: a one-month Phase 3 clinical study to evaluate the efficacy and safety of lemborexant versus placebo and versus an active comparator (zolpidem tartrate extended release, “zolpidem ER”) in 1,006 patients 55 years and older (45 percent of all patients were aged 65 years and older) with insomnia disorder. This study assessed sleep latency (using latency to persistent sleep; primary objective); sleep efficiency and wake after sleep onset (effect on maintaining sleep; key secondary objectives) objectively using polysomnography, and achieved its primary and key secondary objectives. The most common adverse events (AEs) reported in the lemborexant arms were headache and somnolence.1
• SUNRISE 2: a 12-month placebo-controlled (first six months) Phase 3 clinical study to evaluate the long-term efficacy and safety of lemborexant in 949 adult patients (18 to 88 years of age) with insomnia disorder. This study evaluated subjective (patient-reported) sleep onset latency (primary objective), sleep efficiency, and wake after sleep onset (key secondary objectives) using sleep diaries, and achieved its pre-specified primary and key secondary efficacy objectives. The most common AEs reported in the lemborexant arms were somnolence, nasopharyngitis, headache, and influenza.2

“Our ultimate goal for the development of a sleep-wake treatment is to bring to patients living with insomnia a new option that has the potential to improve their ability to fall asleep, stay asleep and wake the next morning without impairment,” said Lynn Kramer, MD, Chief Clinical Officer and Chief Medical Officer, Neurology Business Group, Eisai. “This milestone for lemborexant brings us one step closer to addressing unmet needs for millions of patients who experience insomnia.”

“Insomnia, a disorder of sleep quality and quantity, causes significant impairment in daily functioning and has long-term consequences for health and well-being,”3 said John Renger, PhD, Vice President, Head of Research & Development and Regulatory Affairs, Imbrium Therapeutics. “We are committed to working with our partner Eisai to make this investigational treatment available to patients, pending regulatory approval.”

Lemborexant is being jointly developed by Eisai and Imbrium Therapeutics for the treatment of multiple sleep-wake disorders, including insomnia disorder. Information about ongoing clinical studies is available at clinicaltrials.gov.

Eisai and Imbrium Therapeutics are striving to address new unmet medical needs and to improve the lives of patients and their families.

This release discusses investigational uses of an agent in development and is not intended to convey conclusions about efficacy or safety. There is no guarantee that such an investigational agent will successfully complete clinical development or gain health authority approval.

About Lemborexant

Lemborexant is a novel investigational small molecule compound, discovered and developed by Eisai in-house scientists, that inhibits orexin signaling by binding competitively to both orexin receptor subtypes (orexin receptor 1 and 2). In individuals with normal daily sleep-wake rhythms, orexin signaling is believed to promote periods of wakefulness. In individuals with sleep-wake disorders, it is possible that orexin signaling that regulates wakefulness is not functioning normally, suggesting that inhibiting inappropriate orexin signaling may enable initiation and maintenance of sleep. Eisai and Imbrium Therapeutics are investigating lemborexant as a potential treatment option for multiple sleep-wake disorders, such as insomnia. Additionally, a Phase 2 clinical study of lemborexant in patients with irregular sleep-wake rhythm disorder (ISWRD) and mild to moderate Alzheimer's dementia is underway.

About SUNRISE 1 (Study 304)

SUNRISE 1 was a multicenter, randomized, double-blind, placebo-controlled, active comparator, parallel-group study evaluating the efficacy and safety of lemborexant in 1,006 male or female adult patients 55 years and older (45 percent of patients were 65 years and older) with insomnia disorder conducted in North America and Europe. SUNRISE 1 included a pre-randomization phase of up to 35 days (including a two-week placebo run-in period) and a randomization phase comprised of a 30-day treatment period and a minimum two-week period without treatment prior to the end-of-study visit. In this study, patients were randomized to receive placebo or one of three treatment regimens (lemborexant 5 mg, lemborexant 10 mg, zolpidem ER 6.25 mg).

The primary objective for SUNRISE 1 was to demonstrate using polysomnography that lemborexant at either the 5 mg or 10 mg dose is superior to placebo on objective sleep onset, as measured by latency to persistent sleep after the last two nights of one month of treatment. Key secondary objectives included change from baseline in sleep efficiency and wake after sleep onset (WASO) for both lemborexant doses compared to placebo, and WASO in the second half of the night (WASO2H) for both lemborexant doses compared to zolpidem ER, each after the last two nights of one month of treatment.

About SUNRISE 2 (Study 303)

SUNRISE 2 was a 12-month multicenter, global, randomized, controlled, double-blind, parallel-group study of the efficacy and safety of lemborexant in 949 male or female adult participants 18 to 88 years of age with insomnia disorder. SUNRISE 2 included a pre-randomization phase of up to 35 days (including a two-week placebo run-in period) and a randomization phase comprised of a six-month placebo-controlled treatment period, a six-month period of active-only treatment and a two-week period without treatment prior to the end-of-study visit. In this study, during the placebo-controlled treatment period, patients were randomized to receive placebo or one of two treatment regimens (lemborexant 5 mg or 10 mg). During the active-only treatment period, patients who received placebo during the first period were re-randomized to receive lemborexant 5 mg or 10 mg. Patients who received active treatment during the first period continued on the treatment to which they were originally randomized.

The primary objective was change from baseline in subjective sleep onset latency after six months of placebo-controlled treatment using patient reported (subjective) sleep diaries. Key secondary endpoints were change from baseline in subjective sleep efficiency and subjective wake after sleep onset (sWASO) by using patient reported (subjective) sleep diaries for both lemborexant doses after six months of placebo-controlled treatment.

https://en.wikipedia.org/wiki/Lemborexant

Eisai and Imbrium Therapeutics Announce U.S. FDA Filing Acceptance of New Drug Application for Lemborexant for the Treatment of Insomnia

Researchers find clues that depression may speed brain aging

In continuation of my updates on depression and its causes

Memory and thinking skills naturally slow with age but now scientists are peeking inside living brains to tell if depression might worsen that decline—and finding some worrisome clues. Depression has long been linked to certain cognitive problems, and depression late in life even may be a risk factor for the development of Alzheimer's. Yet how depression might harm cognition isn't clear.

One possibility: Brain cells communicate by firing messages across connections called synapses. Generally, good cognition is linked to more and stronger synapses. With cognitive impairment, those junctions gradually shrink and die off. But until recently, scientists could count synapses only in brain tissue collected after death.

Yale University scientists used a new technique to scan the brains of living people—and discovered that patients with depression had a lower density of synapses than healthy people the same age.

The lower the density, the more severe the depression symptoms, particularly problems with attention and loss of interest in previously pleasurable activities, Yale neuroscientist Irina Esterlis said Thursday at a meeting of the American Association for the Advancement of Science. She wasn't studying just seniors but a range of ages including people too young for any cognitive changes to be obvious outside of a brain scan—on the theory that early damage can build up.

"We think depression might be accelerating the normal aging," she said.

Her studies so far are small. To prove if depression really worsens that decline would require tracking synaptic density in larger numbers of people as they get older, to see if and how it fluctuates over time in those with and without depression, cautioned Jovier Evans, a staff scientist at the National Institute on Mental Health.

Esterlis is planning a larger study to do that. It's delicate research. Volunteers are injected with a radioactive substance that binds to a protein in the vesicles, or storage bins, used by synapses. Then during a PET scan, areas with synapses light up, allowing researchers to see how many are in different regions of the brain.

Esterlis said there are no medications that specifically target the underlying synapse damage.

But other brain experts said the preliminary findings are a reminder of how important it is to treat depression promptly, so people don't spend years suffering.

"If your mood isn't enough to make you go and get treated, then hopefully your cognition is," said Dr. Mary Sano, who directs the Mount Sinai Alzheimer's Disease Research Center in New York and wasn't involved in the new research.

Still, she cautioned that normal cognitive aging is a complicated process that involves other health problems, such as heart disease that slows blood flow in the brain. It might be that depression, rather than worsening synaptic decline, just makes it more obvious, Sano noted.

With depression "at any age, there's a hit on the brain. At an older age the hit may be more visible because there may already be some loss," she explained.

Indeed, another way the brain ages: The blood-brain barrier, which normally protects against infiltration of damaging substances, gradually breaks down, Daniela Kaufer of the University of California, Berkeley, told the AAAS meeting. That triggers inflammation, setting off a cascade that can cause cognitive impairment. Her lab found a specific molecular culprit and is developing, in studies with mice, a way to block the inflammatory damage.

The University of Toronto's Etienne Sibille is developing a compound to target yet another piece of the puzzle, brain receptors that are impaired with both aging and depression. Mouse studies showed it could reverse stress-induced memory loss, he said. Any human testing is at least several years away.

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Researchers find clues that depression may speed brain aging

New Drug Application for Insomnia Disorder Treatment Lemborexant Submitted in the United States

Eisai Co., Ltd. (CEO: Haruo Naito, “Eisai”) and Purdue Pharma L.P. (President and CEO: Craig Landau, MD, “Purdue Pharma”) today announced that a new drug application has been submitted to the U.S. Food and Drug Administration (FDA) for lemborexant, an investigational agent for sleep-wake regulation, seeking approval for the treatment of insomnia, a sleep-wake disorder.

This application was based on the results of two pivotal Phase 3 clinical studies in patients with insomnia, SUNRISE 1 (Study 304) and SUNRISE 2 (Study 303), enrolling approximately 2,000 patients, as well as important safety studies, including assessment of postural stability after middle-of-the-night awakening and a next-morning driving study. SUNRISE 1, a one-month, double-blind, placebo-controlled study, included the first ever Phase 3 head-to-head comparison versus zolpidem ER and objectively assessed sleep parameters (time to sleep onset, sleep efficiency, and wake after sleep onset) resulting in the largest (objective) polysomnography dataset collected to date in patients with insomnia. SUNRISE 2 was a 12-month study and subjectively assessed for ability to fall asleep and stay asleep based on patient self reports (sleep diaries).

Lemborexant, which acts on the orexin neurotransmitter system and is believed to regulate sleep and wake by dampening wakefulness without impeding the ability to awaken to external stimuli, is being jointly developed by Eisai and Purdue Pharma for the treatment of multiple sleep-wake disorders, including insomnia disorder. In addition to the treatment of insomnia disorder, a Phase 2 clinical study of lemborexant in patients with irregular sleep-wake rhythm disorder and mild to moderate Alzheimer's dementia is underway. Information about ongoing clinical studies is available at clinicaltrials.gov.

Eisai and Purdue Pharma are striving to address new unmet medical needs and to improve the lives of patients and their families.

This release discusses investigational uses of an agent in development and is not intended to convey conclusions about efficacy or safety. There is no guarantee that such an investigational agent will successfully complete clinical development or gain health authority approval.

https://en.wikipedia.org/wiki/Lemborexant







New Drug Application for Insomnia Disorder Treatment Lemborexant Submitted in the United States

Cancer fighting effects of aspirin revealed in bowel tumor study

Researchers have shed light on how taking aspirin can help to stave off bowel cancer.

Experts found that the painkiller blocks a key process linked to tumour formation.

Regular use of aspirin is known to reduce a person's risk of developing colon cancer but the drug's tumour fighting properties have not been well understood.

Researchers at the University of Edinburgh focused on a structure found inside cells called the nucleolus.

Activation of the nucleolus is known to drive tumour formation and dysfunction has also been linked to Alzheimer's and Parkinson's.

The team at the University's Cancer Research UK Edinburgh Centre tested the effects of aspirin on cells grown in the lab and on tumour biopsies removed from colon cancer patients.

They found that aspirin blocks a key molecule called TIF-IA, which is essential for the nucleolus to function.

Not all colon cancer patients respond to aspirin but the researchers say their findings could help pinpoint those most likely to benefit.

Aspirin has side effects that include internal bleeding and it can cause certain types of stroke. Long term use is not recommended. The researchers say the study paves the way for the development of new, safer therapies that mimic aspirin's effects.

The research, published in Nucleic Acids Research, was funded by the Medical Research Council and the Biotechnology and Biological Sciences Research Council. Worldwide Cancer Research, Bowel and Cancer Research and The Rosetrees Trust also supported the work.

Dr. Lesley Stark, of the Cancer Research UK Edinburgh Centre at the University of Edinburgh, said: "We are really excited by these findings as they suggest a mechanism by which aspirin may act to prevent multiple diseases. A better understanding of howaspirin blocks TIF-IA and nucleolar activity provides great promise for the development of new treatments and targeted therapy."